Amylin Peptide: Dissertation
Amylin Peptide: An Association with Feed Intolerance in Preterm Neonates and Infants of Diabetic Mothers----------------------------------------------------------------------------------------------------------Dr Venkatesh Ramulu Kairamkonda----------------------------------------------------------------------------------------------------------A Dissertation Submitted to the Faculty of Medicine in Partial Fulfilment of the Requirements for the Degree of Doctor of Medicine at the University of Sheffield----------------------------------------------------------------------------------------------------------This Research is conducted at Departments of Neonatal Intensive Care Unit and Academic Unit of Reproductive and Developmental Medicine, Jessop Wing, Royal Hallamshire Hospital and Neonatal Intensive Care Unit, Doncaster General Hospital----------------------------------------------------------------------------------------------------------November 2012----------DeclarationI hereby declare that my dissertation entitled “Amylin peptide: An association with feed intolerance in preterm neonates and infants of diabetic mothers” is the result of my own work and includes nothing which is the outcome of work done in collaboration except as declared in the Preface and specified in the text. It is not substantially the same as any that I have submitted, or, is being concurrently submitted for a degree or diploma or other qualification at the University of Sheffield or any other University or similar institution except as declared in the Preface and specified in the text. I further state that no substantial part of my dissertation has already been submitted, or, is being concurrently submitted for any such degree, diploma or other qualification at the University of Sheffield or any other University of similar institution except as declared in the Preface and specified in the text. Where other sources of information have been used, they have been referenced and/or acknowledged.Dr Anton Mayer explored the role of amylin in critically ill paediatric patients with feed intolerance that provided the basis to investigate the role of amylin in neonatal population. He also contributed significantly towards this project as a study collaborator. Myself and Drs Robert Coombs and Robert Fraser helped formulate hypotheses and overall study methodology in the neonatal setting. As a principle investigator I was responsible for ethics application and coordination of the three studies at Jessop Wing, Royal Hallamshire Hospital. I was also responsible for arranging funding, consenting, blood collection, data collection and completion of case report forms, analyses, presentation and report writing. Dr Anjum Deorukhkar was the principle investigator responsible for ethics application and coordination of study C at the neonatal unit, Doncaster General Hospital. Neonatal nurses at Jessop Wing and Doncaster General Hospital routinely performed and documented prefeed gastric residual volumes. Blood samples were also collected by junior doctors and colleague registrars. Analytical expertise including sample size calculations for the individual study was provided by the statisticians at this University. All blood samples were assayed by Mrs Christine Bruce, technician at the academic unit of reproductive and developmental medicine, Jessop Wing, Royal Hallamshire Hospital. Name: Dr Venkatesh Ramulu Kairamkonda Date:November 2012Signature: AcknowledgementsI would like to thank my supervisor, Mr Robert Fraser, Reader at the University of Sheffield and Consultant Obstetrician, section of Reproductive & Developmental Medicine at Jessop Wing, Royal Hallamshire Hospital. His constant enthusiasm, assistance, guidance, patience and advice helped me to complete the project successfully.I am indebted to Dr Anton Mayer, Consultant Paediatric Intensivist, Royal Hallamshire Hospital, Sheffield and Dr Robert Coombs, Consultant Neonatologist, Jessop Baby Unit, Sheffield for their advice, encouragement, assistance and support towards the initiation and publication of this research.I thank Mrs Christine Bruce for her invaluable contribution in the analyses of the blood samples, but most of all for her continual encouragement and kindness. I would like to thank the infants and their parents whose trust and co-operation enabled this work to be completed. I would also like to thank the Clinical staff and Nursing staff of the Neonatal Intensive care unit at Jessop Baby Unit and Doncaster General Hospital for their patience and assistance.I would like to thank the Baby Fund at the Jessop Wing, Royal Hallamshire Hospital for providing the financial support for this project.Finally, I would like to thank my wife Manjula and daughter Coral for their encouragement, understanding and support. AbstractTitle: Amylin peptide: An association with feed intolerance in preterm neonates and infants of diabetic mothersIntroduction: Delayed enteral nutrition due to feed intolerance is common in preterm infants and infants of mothers whose pregnancy was complicated by diabetes mellitus (IMDM). Amylin, a 37 amino-acid polypeptide hormone, is a potent inhibitor of gastric emptying that may play a role in the patho-physiology of feed intolerance in these infants. Aims and Objectives: To determine serum amylin levels (i) at birth (umbilical cord) and postnatal day 5 (Guthrie) in healthy preterm and term infants-Study A, (ii) at birth (umbilical cord) and postnatal day 5 (Guthrie) in preterm and term IMDM-Study B, and (iii) in preterm infants experiencing feed-intolerance (nTOL) and feed-tolerance (TOL)-Study C.Hypothesis: Serum amylin levels are raised in (i) IMDM and (ii) preterm infants with increased gastric residual volumes (GRV); which may explain their feed intolerance.Methods and Material: Blood samples were analysed for total amylin immunoreactivity using monoclonal antibody based sandwich immunoassay. Results: Serum amylin concentrations (median (interquartile range)) in healthy term infants at birth (n=138) and postnatal day 5 (n=14) were 6.10 (3.30-9.70) pmol/L and 5.65 (3.10-8.20) pmol/L respectively. Similarly, the amylin concentrations in healthy preterm infants at birth (n=43) and postnatal day 5 (n=25) were 4.60 (1.90–8.30) pmol/L and 6.9 (2.75–9.50) pmol/L respectively. The amylin concentrations were significantly raised in both term IMDM at birth [n=17, 34.30 (28.35-50.00) pmol/L, p<0.0001] and postnatal day 5 [n=4, 25.20 (22.20-48.75) pmol/L, p<0.0001] and preterm IMDM at birth [n=14, 32.0 (18.65-44.27) pmol/L, p<0.0001] and postnatal day 5 [n=9, 23.4 (15.37-46.57) pmol/L, p<0.0001]. The amylin concentration was significantly elevated in nTOL group [n=30, 47.9 (21.4-79.8) pmol/L, p<0.0001)] compared to TOL group [n=30, 8.7 (5.7-16) pmol/L]. Conclusions: Amylin by virtue of its inhibitory effect on gastric emptying may be responsible in delaying establishment of enteral nutrition in preterm infants and infants of mothers whose pregnancy was complicated by diabetes mellitus.Outline of DissertationThe structure of this dissertation is based on the suggested MD dissertation by the University of Sheffield. Chapter 1 introduces to the research project, study rationale, hypotheses, aims and objectives. Chapters 2 to 6 present literature review relevant to the dissertation. Chapters 7 and 8 to 10 outline the project plan and describe in detail methodology, results, discussion and conclusions of individual study. Chapters 11 and 12 conclude the dissertation with emphasis on suggested future studies and work. Chapters 13 and 14 provide publications arising out of this project and appendices respectively. Finally, chapter 15 outlines bibliography relevant to the dissertation.Table of Contents TOC \o "1-3" \h \z \u Chapter 1-Overview & Background PAGEREF _Toc323552152 \h 221.1Foreword PAGEREF _Toc323552153 \h 221.2Study Rationale PAGEREF _Toc323552154 \h 231.3Study Hypotheses PAGEREF _Toc323552155 \h 231.4Study Aims PAGEREF _Toc323552156 \h 241.5Study Objectives PAGEREF _Toc323552157 \h 241.5.1Primary Objectives PAGEREF _Toc323552158 \h 241.5.2Secondary Objectives PAGEREF _Toc323552159 \h 24Chapter 2-Literature Review: Amylin Peptide PAGEREF _Toc323552160 \h 262.1Introduction & Background PAGEREF _Toc323552161 \h 262.2Amylin Synthesis, Sources, Release & Metabolism PAGEREF _Toc323552162 \h 262.3Amylin Structure, Gene & Relation to CGRP Superfamily PAGEREF _Toc323552163 \h 302.4Feto-Maternal Passage of Amylin PAGEREF _Toc323552164 \h 322.5Synthetic Analogue ‘Pramlintide’ PAGEREF _Toc323552165 \h 322.6Amylin Receptors & Signal Transduction Mechanisms PAGEREF _Toc323552166 \h 342.7Amylin Receptor Antagonist PAGEREF _Toc323552167 \h 352.8Biological Functions of Amylin PAGEREF _Toc323552168 \h 352.9Mechanisms of Amylin Action at Molecular level PAGEREF _Toc323552169 \h 392.10History of Discovery of Amylin PAGEREF _Toc323552170 \h 422.11Association of Amylin with Islet Amyloid Deposits in Diabetes PAGEREF _Toc323552171 \h 432.12Amyloidosis and Composition of Amyloid Deposits PAGEREF _Toc323552172 \h 432.13Laboratory Assays PAGEREF _Toc323552173 \h 48Chapter 3-Literature Review: Gastric Emptying PAGEREF _Toc323552174 \h 503.1Anatomy and Physiology of Gastric Motor Function PAGEREF _Toc323552175 \h 503.2Regulation of Gastric Emptying PAGEREF _Toc323552176 \h 513.3Role of Other Gastrointestinal Peptides on Gastric Emptying PAGEREF _Toc323552177 \h 523.4Diabetes and its Effects on Gastric Emptying PAGEREF _Toc323552178 \h 533.5Methods of Measurement of Gastric Emptying in Humans PAGEREF _Toc323552179 \h 553.6Methods and Factors Influencing Gastric Emptying in Neonates PAGEREF _Toc323552180 \h 58Chapter 4-Literature Review: Feed Intolerance in Preterm Infants PAGEREF _Toc323552181 \h 604.1Scale of the Problem PAGEREF _Toc323552182 \h 604.2Physiology of Gastric and Gastrointestinal Motility in Preterm Infants PAGEREF _Toc323552183 \h 604.3Definition of Feed Intolerance PAGEREF _Toc323552184 \h 614.4Patho-Physiology of Feed Intolerance PAGEREF _Toc323552185 \h 634.5Management of Feed Intolerance PAGEREF _Toc323552186 \h 65Chapter 5-Literature Review: Gestational Diabetes Mellitus PAGEREF _Toc323552187 \h 695.1Definition of Gestational Diabetes Mellitus PAGEREF _Toc323552188 \h 695.2Scale of the Problem PAGEREF _Toc323552189 \h 695.3Physiology of Insulin Secretion PAGEREF _Toc323552190 \h 695.4Physiology of Gestational Diabetes Mellitus PAGEREF _Toc323552191 \h 705.5Strategies to Prevent Fetal and Neonatal Hyperinsulinaemia PAGEREF _Toc323552192 \h 70Chapter 6-Literature Review: IMDM PAGEREF _Toc323552193 \h 726.1Scale of the Problem PAGEREF _Toc323552194 \h 726.2Physiology of Fetal Hyperinsulaemia PAGEREF _Toc323552195 \h 726.3Feed Intolerance in IMDM PAGEREF _Toc323552196 \h 736.4Proposed Patho-Physiology of Feed intolerance in IMDM PAGEREF _Toc323552197 \h 74Chapter 7-Overview of Project Plan PAGEREF _Toc323552198 \h 757.1General Design PAGEREF _Toc323552199 \h 757.2General Study Configuration and Methodology PAGEREF _Toc323552200 \h 787.3Ethics Consideration PAGEREF _Toc323552201 \h 817.4Data Handling and Record Keeping PAGEREF _Toc323552202 \h 837.5Benefits and Risks PAGEREF _Toc323552203 \h 847.6Funding PAGEREF _Toc323552204 \h 84Chapter 8-Clinical Study A: Umbilical & Guthrie Amylin in Preterm and Term Infants PAGEREF _Toc323552205 \h 858.1Introduction PAGEREF _Toc323552206 \h 858.2Methodology PAGEREF _Toc323552207 \h 858.2.1Study Design & Setting PAGEREF _Toc323552208 \h 858.2.2Consent PAGEREF _Toc323552209 \h 858.2.3Inclusion Criteria PAGEREF _Toc323552210 \h 858.2.4Exclusion Criteria PAGEREF _Toc323552211 \h 868.2.5Study Procedure PAGEREF _Toc323552212 \h 868.2.6Study End Point PAGEREF _Toc323552213 \h 878.2.7Sample Collection & Storage PAGEREF _Toc323552214 \h 888.2.8Sample Analysis PAGEREF _Toc323552215 \h 888.2.9Sample Size PAGEREF _Toc323552216 \h 898.2.10Statistical Analysis PAGEREF _Toc323552217 \h 898.2.11Data Collection & Case Report Form PAGEREF _Toc323552218 \h 908.2.12Study Summary PAGEREF _Toc323552219 \h 908.3Results PAGEREF _Toc323552220 \h 928.4Discussion PAGEREF _Toc323552221 \h 1168.5Conclusions PAGEREF _Toc323552222 \h 119Chapter 9-Clinical Study B: Umbilical and Guthrie Amylin in Preterm and Term IMDM PAGEREF _Toc323552223 \h 1209.1Introduction PAGEREF _Toc323552224 \h 1209.2Methodology PAGEREF _Toc323552225 \h 1209.2.1Study Design & Setting PAGEREF _Toc323552226 \h 1209.2.2Consent PAGEREF _Toc323552227 \h 1209.2.3Inclusion Criteria PAGEREF _Toc323552228 \h 1209.2.4Exclusion Criteria PAGEREF _Toc323552229 \h 1209.2.5Study Procedure PAGEREF _Toc323552230 \h 1219.2.6Study End Point PAGEREF _Toc323552231 \h 1219.2.7Sample Collection & Storage PAGEREF _Toc323552232 \h 1219.2.8Sample Analysis PAGEREF _Toc323552233 \h 1219.2.9Sample Size PAGEREF _Toc323552234 \h 1219.2.10Statistical Analysis PAGEREF _Toc323552235 \h 1229.2.11Data Collection & Case Report Form PAGEREF _Toc323552236 \h 1229.2.12Study Summary PAGEREF _Toc323552237 \h 1229.3Result PAGEREF _Toc323552238 \h 1259.4Discussion PAGEREF _Toc323552239 \h 1449.5Conclusions PAGEREF _Toc323552240 \h 147Chapter 10-Clinical Study C: Amylin Levels in Preterm infants with Feed Intolerance PAGEREF _Toc323552241 \h 14810.1Introduction PAGEREF _Toc323552242 \h 14810.2Methodology PAGEREF _Toc323552243 \h 14810.2.1Study Design & Setting PAGEREF _Toc323552244 \h 14810.2.2Consent PAGEREF _Toc323552245 \h 14810.2.3Inclusion Criteria PAGEREF _Toc323552246 \h 14810.2.4Exclusion Criteria PAGEREF _Toc323552247 \h 14910.2.5Study Procedure PAGEREF _Toc323552248 \h 14910.2.6Definition of feed intolerance PAGEREF _Toc323552249 \h 15010.2.7Definition of feed tolerance PAGEREF _Toc323552250 \h 15110.2.8Study End Point PAGEREF _Toc323552251 \h 15110.2.9Sample Collection & Storage PAGEREF _Toc323552252 \h 15110.2.10Sample Analysis PAGEREF _Toc323552253 \h 15110.2.11Sample Size PAGEREF _Toc323552254 \h 15110.2.12Statistical Analysis PAGEREF _Toc323552255 \h 15110.2.13Data Collection & Case Report Form PAGEREF _Toc323552256 \h 15210.2.14Study Summary PAGEREF _Toc323552257 \h 15210.3Results PAGEREF _Toc323552258 \h 15510.4Discussion PAGEREF _Toc323552259 \h 16610.5Conclusions PAGEREF _Toc323552260 \h 173Chapter 11-Conclusions of the Dissertation PAGEREF _Toc323552261 \h 174Chapter 12-Implications for Future Research PAGEREF _Toc323552262 \h 176Chapter 13-Publications arising from this Project PAGEREF _Toc323552263 \h 17913.1Amylin peptide levels are raised in infants of diabetic mothers. Arch Dis Child. 2005 Dec; 90(12):1279-82 PAGEREF _Toc323552264 \h 17913.2Amylin peptide is increased in preterm neonates with feed intolerance. Arch Dis Child Fetal Neonatal Ed. 2008 Jul; 93(4):F265-70 PAGEREF _Toc323552265 \h 184Chapter 14-Appendices PAGEREF _Toc323552266 \h 190Chapter 15-Bibliography PAGEREF _Toc323552267 \h 228Key to Figures TOC \h \z \c "Figure" Figure 1. Amylin is the second beta cell hormone PAGEREF _Toc323552326 \h 26Figure 2. Twenty four hour plasma profile of amylin and insulin in healthy adults PAGEREF _Toc323552327 \h 28Figure 3. Amylin response after a liquid sustacal meal in patients with type 1 & type 2 diabetes mellitus PAGEREF _Toc323552328 \h 29Figure 4. Representative concentration profiles of amylin (A), total amylin immunoreactivity (TAI) (B) and insulin (C) PAGEREF _Toc323552329 \h 30Figure 5. Alpha helix structure of human amylin PAGEREF _Toc323552330 \h 31Figure 6. Comparison of aminoacid sequence of amylin and pramlintide PAGEREF _Toc323552331 \h 33Figure 7. Role of amylin in regulation of postprandial glycemia PAGEREF _Toc323552332 \h 36Figure 8. Amylin binding sites in rat brain PAGEREF _Toc323552333 \h 39Figure 9. Location of amylin action within circumventricular organs in rat brain PAGEREF _Toc323552334 \h 41Figure 10. Amyloid deposit in pancreatic islet PAGEREF _Toc323552335 \h 44Figure 11. Amyloid deposit in lymph node showing birefringence PAGEREF _Toc323552336 \h 45Figure 12. Extended cross-beta structure of amyloid PAGEREF _Toc323552337 \h 46Figure 13. Superpleated beta structure of amyloid fibrils PAGEREF _Toc323552338 \h 47Figure 14. Region responsible for amyloid formation PAGEREF _Toc323552339 \h 48Figure 15. Site of synthesis of main gut hormones influencing appetite and gastric emptying PAGEREF _Toc323552340 \h 53Figure 16. Project plan Gantt chart PAGEREF _Toc323552341 \h 75Figure 17. Study plan Gantt chart PAGEREF _Toc323552342 \h 79Figure 18. General study methodology PAGEREF _Toc323552343 \h 80Figure 19. Study A Gantt chart PAGEREF _Toc323552344 \h 92Figure 20. Study A flow diagram of participants and blood samples PAGEREF _Toc323552345 \h 93Figure 21. Box-and-whisker plot of umbilical cord amylin levels in healthy term infants PAGEREF _Toc323552346 \h 96Figure 22. Box-and-whisker plot of Guthrie amylin levels in healthy term infants PAGEREF _Toc323552347 \h 98Figure 23. Notched box-and-whisker plot of amylin levels at birth and postnatal day 5 in healthy term infants PAGEREF _Toc323552348 \h 100Figure 24. Box-and-whisker plot of umbilical cord amylin levels at birth in healthy preterm infants PAGEREF _Toc323552349 \h 102Figure 25. Box-and-whisker plot of amylin levels at postnatal day 5 in healthy preterm infants PAGEREF _Toc323552350 \h 104Figure 26. Notched box-and-Whisker plot of amylin levels at birth and postnatal day 5 in healthy preterm infants PAGEREF _Toc323552351 \h 106Figure 27. Comparison Box-and-Whisker plot of amylin level in term and preterm infants at birth PAGEREF _Toc323552352 \h 108Figure 28. Comparison Box-and-Whisker plot of serum amylin level in term and preterm infants on postnatal day 5 PAGEREF _Toc323552353 \h 109Figure 29. The correlation graph showing line of best fit to assess the degree of association between paired umbilical cord venous amylin (x axis) and umbilical cord arterial amylin (Y axis) PAGEREF _Toc323552354 \h 110Figure 30. Bland Altman method comparison plot of paired venous and arterial levels PAGEREF _Toc323552355 \h 111Figure 31. Bland Altman method comparison, percentage difference plot, of paired venous and arterial levels PAGEREF _Toc323552356 \h 112Figure 32. The correlation graph showing line of best fit to assess the degree of association between paired umbilical cord insulin (x axis) and umbilical cord amylin (Y axis) in healthy preterm and term infants PAGEREF _Toc323552357 \h 114Figure 33. The correlation graph showing line of best fit to assess the degree of association between gestational age at birth (x axis) and umbilical cord amylin (Y axis) PAGEREF _Toc323552358 \h 115Figure 34. The correlation graph showing line of best fit to assess the degree of association between birth weight (x axis) and umbilical cord amylin (Y axis) PAGEREF _Toc323552359 \h 116Figure 35. Study B Gantt chart PAGEREF _Toc323552360 \h 124Figure 36. Study B-flow diagram of participants and blood samples PAGEREF _Toc323552361 \h 125Figure 37. Box-and-whisker plot of umbilical cord amylin levels in term IMDM infants PAGEREF _Toc323552362 \h 127Figure 38. Box-and-whisker plot of Guthrie amylin levels in term IMDM infants PAGEREF _Toc323552363 \h 129Figure 39. Comparison Box-and-Whisker plot of amylin levels at birth and postnatal day 5 in term IMDMs PAGEREF _Toc323552364 \h 131Figure 40. Box-and-whisker plot of umbilical cord amylin levels in preterm IMDM infants PAGEREF _Toc323552365 \h 133Figure 41. Box-and-whisker plot of Guthrie amylin levels in preterm IMDM infants PAGEREF _Toc323552366 \h 135Figure 42. Comparison box-and-whisker plot of amylin concentration at birth and postnatal day 5 in preterm IMDM PAGEREF _Toc323552367 \h 137Figure 43. Comparison box-and-whisker plot of amylin concentration in umbilical cord and Guthrie blood in term and preterm IMDM PAGEREF _Toc323552368 \h 138Figure 44. Comparison box-and-whisker plot of amylin levels at birth and postnatal day 5 between term IMDM and healthy term infants (controls) PAGEREF _Toc323552369 \h 140Figure 45. Comparison box-and-whisker plot of amylin levels at birth and postnatal day 5 between preterm IMDM and healthy preterm infants (controls) PAGEREF _Toc323552370 \h 142Figure 46. The correlation graph showing line of best fit to assess the degree of association between umbilical cord insulin (x axis) and umbilical cord amylin (Y axis) from paired umbilical cord blood samples of healthy and IMDM preterm and term infants PAGEREF _Toc323552371 \h 143Figure 47. Study C Gantt chart PAGEREF _Toc323552372 \h 154Figure 48. Study C-Flow diagram of participants and blood samples PAGEREF _Toc323552373 \h 155Figure 49. Box and whisker plot of amylin levels (y-axis) in feed-intolerant (nTOL) and feed-tolerant (TOL) neonates (x-axis) PAGEREF _Toc323552374 \h 158Figure 50. Box and whisker plot of percentage GRV (y axis) in feed-intolerant (nTOL) and feed-tolerant (TOL) neonates (x axis) PAGEREF _Toc323552375 \h 159Figure 51. The box and whisker plot of days to reach full feeds (Y axis) in feed-intolerant (nTOL) and feed-tolerant (TOL) neonates (X axis) PAGEREF _Toc323552376 \h 160Figure 52. Correlation graph showing line of best fit to assess the degree of association between amylin concentration (y axis) and % GRV (x axis) in feed-intolerant (nTOL) group PAGEREF _Toc323552377 \h 161Figure 53. The correlation graph showing line of best fit to assess the degree of association between amylin concentration (y axis) and days to reach full enteral feeds (x axis) in nTOL group PAGEREF _Toc323552378 \h 162Figure 54. The correlation graph showing line of best fit to assess the degree of association between days to discharge (x axis) and amylin concentration (Y axis) in the feed-intolerant (nTOL) group PAGEREF _Toc323552379 \h 163Figure 55. The correlation graph showing line of best fit to assess the degree of association between % GRV (x axis) and amylin levels (y axis) in feed-tolerant (TOL) group PAGEREF _Toc323552380 \h 164Figure 56. The correlation graph showing line of best fit to assess the degree of association between days to full enteral feeds (x axis) and amylin levels (Y axis) in feed-tolerant (TOL) group PAGEREF _Toc323552381 \h 165Figure 57. The correlation graph showing line of best fit to assess the degree of association between days to discharge (x axis) and amylin levels (Y axis) in the feed-tolerant (TOL) group PAGEREF _Toc323552382 \h 166Figure 58. Proposed pathway of amylin action PAGEREF _Toc323552383 \h 168Key to Tables TOC \h \z \c "Table" Table 1. Study Objectives & Outcome Variables PAGEREF _Toc323552384 \h 25Table 2. Study A Summary PAGEREF _Toc323552385 \h 91Table 3. Summary statistic of amylin concentration and demographic characteristics at birth in healthy term infants PAGEREF _Toc323552386 \h 95Table 4. Summary statistic of amylin concentration and demographic characteristics at postnatal day 5 in healthy term infants PAGEREF _Toc323552387 \h 97Table 5. Demographic characteristics of healthy term infants at birth and postnatal day 5 PAGEREF _Toc323552388 \h 99Table 6. Summary statistic of amylin concentration and demographic characteristics at birth in healthy preterm infants PAGEREF _Toc323552389 \h 101Table 7. Summary statistic of amylin concentration and demographic characteristics at postnatal day 5 in healthy preterm infants PAGEREF _Toc323552390 \h 103Table 8. Demographic charateristics of healthy preterm infants at birth and postnatal day 5. PAGEREF _Toc323552391 \h 105Table 9. Comparison of demography and amylin levels in healthy term and preterm infants at birth and postnatal day 5 PAGEREF _Toc323552392 \h 107Table 10. Study B summary PAGEREF _Toc323552393 \h 123Table 11. Summary statistic of amylin concentration and demographic characteristics at birth in term IMDM infants PAGEREF _Toc323552394 \h 126Table 12. Summary statistic of amylin concentration and demographic characteristics on postnatal day 5 in term IMDM infants PAGEREF _Toc323552395 \h 128Table 13. Demographic characteristic of term IMDM at birth and postnatal day 5 PAGEREF _Toc323552396 \h 130Table 14. Summary statistic of amylin concentration and demographic characteristics at birth in preterm IMDM infants PAGEREF _Toc323552397 \h 132Table 15. Summary statistic of amylin concentration and demographic characteristics at postnatal day 5 in preterm IMDM infants PAGEREF _Toc323552398 \h 134Table 16. Demographic characteristics of preterm IMDM at birth and postnatal day 5 PAGEREF _Toc323552399 \h 136Table 17. Demographic characteristics and serum amylin levels of term healthy controls and term IMDM at birth and postnatal day 5 PAGEREF _Toc323552400 \h 139Table 18. Demographic characteristics and serum amylin levels of preterm healthy controls and preterm IMDM at birth and postnatal day 5 PAGEREF _Toc323552401 \h 141Table 19. Study C summary PAGEREF _Toc323552402 \h 153Table 20. Baseline characteristics at the time of blood sampling of preterm neonates defined as feed-intolerant (nTOL) and feed-tolerant (TOL) PAGEREF _Toc323552403 \h 156Table 21. Serum amylin levels, % GRV, days to reach full feeds and length of stay in feed-intolerant (nTOL) and feed-tolerant (TOL) neonates PAGEREF _Toc323552404 \h 157Key to Appendices TOC \h \z \c "Appendix" Appendix 1.Basic principle of luminescent ELISA PAGEREF _Toc323552405 \h 190Appendix 2. Human Amylin (Total) ELISA KIT and Assay Procedure PAGEREF _Toc323552406 \h 193Appendix 3. Characteristics of Human Amylin (Total) ELISA Kit PAGEREF _Toc323552407 \h 196Appendix 4. Research protocol for ethics approval, South Sheffield Research Ethics Committee PAGEREF _Toc323552408 \h 199Appendix 5. Research protocol for ethics approval, Doncaster Research Ethics Committee PAGEREF _Toc323552409 \h 205Appendix 6. Child participation information leaflet (Study A & B) PAGEREF _Toc323552410 \h 210Appendix 7. Child participation information leaflet (Study C) Royal Hallamshire Hospital PAGEREF _Toc323552411 \h 213Appendix 8. Child participation information leaflet (Study C) Doncaster Royal Infirmary PAGEREF _Toc323552412 \h 216Appendix 9. Study A & B Consent form PAGEREF _Toc323552413 \h 219Appendix 10. Study C Consent form PAGEREF _Toc323552414 \h 220Appendix 11. Advert for Study A PAGEREF _Toc323552415 \h 221Appendix 12. Advert for Study B PAGEREF _Toc323552416 \h 222Appendix 13. Advert for Study C PAGEREF _Toc323552417 \h 223Appendix 14. Case report form Study A PAGEREF _Toc323552418 \h 224Appendix 15. Case report form Study B PAGEREF _Toc323552419 \h 225Appendix 16. Case report form Study C PAGEREF _Toc323552420 \h 226Key to AbbreviationsAC 66Amylin antagonist, also known as salmon calcitonin AC187Amylin antagonistACSAAntral cross sectional areaADPAdenosine diphosphateAMY 1, AMY 2 and AMY 3 Amylin receptorsATPAdenosine triphosphateBMIBody Mass IndexCPAPContinuous positive airway pressureCTCalcitoninCTRCalcitonin receptorCGRPCalcitonin gene related peptideCVCoefficient of variationC.F.UCCKColony forming unitCholecystokininCRFCase Report FormDBSDried blood spotEGGElectrogastrographyELISAEnzyme linked Immunosorbent AssayELBWExtremely low birth weight infantsFDAFood and drug administration, USA4-MUB4-Methylumbelliferyl PhosphateGDMGestational diabetes mellitusGIPGlucagon inhibitory peptideGLP-1 Glucagon like peptide 1GLP-2Glucagon like peptide 2GRVGastric residual volumesGLUT 1 and GLUT 2Glucose transportersGSK 3Glycogen synthase kinase 3IGFInsulin like growth factorIGFBPInsulin like growth factor binding proteinIMDM Infant of mothers whose pregnancy was complicated by diabetes mellitusIAPPIslet amyloid polypeptideKATPATP sensitive potassium channelMMCMigrating motor complexNECNecrotising enterocolitisnTOLPreterm infants with feed intolerancePC2Protein convertase 2PK-PDPharmacokinetic-PharmacodynamicPYYPeptide YYRAMPReceptor activity modifying proteinsRFURelative Fluorescent UnitRIARadioimmunoassaysCTSalmon calcitonin, amylin antagonist TBSTris Buffered SalineTOLPreterm infants without feed intoleranceTPNTotal parenteral nutritionVLBWVery low birth weight infantsOverview & BackgroundForewordNeonatologists often struggle to attain full enteral nutrition in majority of preterm infants with very low birth weight due to common occurrence of feed intolerance PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWRkeTwvQXV0aG9yPjxZZWFyPjIwMDA8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Reddy, Deorari et al. 2000; ElHennawy, Sparks et al. 2003; Patole, Rao et al. 2005) characterised by large gastric residual volumes (GRV) with or without associated clinical manifestations PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXRvbGU8L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Frank and Sosenko 1988; Hack, Breslau et al. 1991; Ehrenkranz, Younes et al. 1999; Hack, Schluchter et al. 2003; Cooke, Ainsworth et al. 2004; Hay 2008). The resultant increased morbidity and hospital stay increases the cost of treatment ADDIN EN.CITE <EndNote><Cite><Author>Reddy</Author><Year>2000</Year><RecNum>201</RecNum><record><rec-number>201</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">201</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Reddy, P. S.</author><author>Deorari, A. K.</author><author>Bal, C. S.</author><author>Paul, V. K.</author><author>Singh, M.</author></authors></contributors><auth-address>Departments of Pediatrics and Nuclear Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110 029, India.</auth-address><titles><title>A double-blind placebo-controlled study on prophylactic use of cisapride on feed intolerance and gastric emptying in preterm neonates</title><secondary-title>Indian Pediatr</secondary-title></titles><pages>837-44</pages><volume>37</volume><number>8</number><edition>2000/08/22</edition><keywords><keyword>Cisapride/*therapeutic use</keyword><keyword>Double-Blind Method</keyword><keyword>Food Hypersensitivity/physiopathology/*prevention & control</keyword><keyword>*Gastric Emptying</keyword><keyword>Gastroesophageal Reflux/physiopathology/*prevention & control</keyword><keyword>Gastrointestinal Agents/*therapeutic use</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature</keyword><keyword>Infant, Premature, Diseases/physiopathology/*prevention & control</keyword></keywords><dates><year>2000</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0019-6061 (Print)</isbn><accession-num>10951632</accession-num><urls><related-urls><url>;(Reddy, Deorari et al. 2000). The patho-physiology of feed intolerance in these high risk infants is poorly understood, limiting the therapeutic options. Delayed gastric emptying, intestinal immaturity, ileus of prematurity, and gastro-esophageal reflux may all play a role. It is not clear whether one or all of these mechanisms contribute to the observed feed intolerance. Thirty-seven per cent of infants born to mothers whose pregnancy was complicated by diabetes mellitus (IMDM) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaXR6bWlsbGVyPC9BdXRob3I+PFllYXI+MTk3ODwvWWVh
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ADDIN EN.CITE.DATA (Kitzmiller, Cloherty et al. 1978; Lee-Parritz 2004), and consequently cost of treatment. It is reasonable to acknowledge that clinical practise has significantly changed in the last three decades for diabetic mothers and their infants and thus the actual incidence of feed intolerance or poor feeding may not be as high as previously reported. This may also explain the apparent absence of published literature on feed intolerance in IMDM. However with increasing incidence of diabetes in the general population, the clinical burden of IMDM and associated illnesses including feed intolerance may also increase. Therefore there is a need to understand the aetiology and pathophysiology of feed intolerance in this group of infants to formulate appropriate therapeutic interventions. Amylin is a 37 amino acid peptide hormone belonging to the calcitonin gene related peptide super family that is co-secreted with insulin from the pancreatic ? cells in response to enteral nutrient intake ADDIN EN.CITE <EndNote><Cite><Author>Rink</Author><Year>1993</Year><RecNum>47</RecNum><record><rec-number>47</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">47</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rink, T. J.</author><author>Beaumont, K.</author><author>Koda, J.</author><author>Young, A.</author></authors></contributors><auth-address>Amylin Pharmaceuticals Inc., San Diego, CA 92121.</auth-address><titles><title>Structure and biology of amylin</title><secondary-title>Trends Pharmacol Sci</secondary-title></titles><pages>113-8</pages><volume>14</volume><number>4</number><edition>1993/04/01</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>*Amyloid/chemistry/deficiency</keyword><keyword>Animals</keyword><keyword>Diabetes Mellitus, Type 1/genetics</keyword><keyword>Diabetes Mellitus, Type 2/genetics</keyword><keyword>Humans</keyword><keyword>Models, Molecular</keyword><keyword>Molecular Sequence Data</keyword><keyword>Protein Structure, Tertiary</keyword></keywords><dates><year>1993</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0165-6147 (Print)</isbn><accession-num>8516954</accession-num><urls><related-urls><url>;(Rink, Beaumont et al. 1993). In conjunction to playing a role in glucose homeostasis, it is recognised as a potent inhibitor of gastric emptying ADDIN EN.CITE <EndNote><Cite><Author>Macdonald</Author><Year>1997</Year><RecNum>48</RecNum><record><rec-number>48</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">48</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Macdonald, I. A.</author></authors></contributors><auth-address>Department of Physiology and Pharmacology, University of Nottingham Medical School, UK.</auth-address><titles><title>Amylin and the gastrointestinal tract</title><secondary-title>Diabet Med</secondary-title></titles><periodical><full-title>Diabet Med</full-title></periodical><pages>S24-8</pages><volume>14 Suppl 2</volume><edition>1997/06/01</edition><keywords><keyword>Amyloid/*pharmacology/therapeutic use</keyword><keyword>Animals</keyword><keyword>Diabetes Mellitus/drug therapy</keyword><keyword>Digestive Physiology</keyword><keyword>Digestive System/*drug effects</keyword><keyword>Gastric Emptying/drug effects</keyword><keyword>Humans</keyword><keyword>Hypoglycemic Agents/*pharmacology/therapeutic use</keyword><keyword>Rats</keyword><keyword>Rats, Inbred BB</keyword><keyword>Rats, Wistar</keyword></keywords><dates><year>1997</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0742-3071 (Print)</isbn><accession-num>9212326</accession-num><urls><related-urls><url>(SICI)1096-9136(199706)14:2+<S24::AID-DIA399>3.0.CO;2-M</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Macdonald 1997). Amylin has been shown to delay gastric emptying in adult diabetic patients ADDIN EN.CITE <EndNote><Cite><Author>Hoppener</Author><Year>2000</Year><RecNum>136</RecNum><record><rec-number>136</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">136</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hoppener, J. W.</author><author>Ahren, B.</author><author>Lips, C. J.</author></authors></contributors><auth-address>Department of Internal Medicine, University Medical Center, Utrecht, The Netherlands. j.w.m.hoeppener@lab.azu.nl</auth-address><titles><title>Islet amyloid and type 2 diabetes mellitus</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>411-9</pages><volume>343</volume><number>6</number><edition>2000/08/10</edition><keywords><keyword>Amyloid/*antagonists & inhibitors/chemistry/genetics/physiology</keyword><keyword>Amyloidosis/complications/prevention & control</keyword><keyword>Animals</keyword><keyword>*Diabetes Mellitus, Type 2/drug therapy/etiology/pathology</keyword><keyword>Humans</keyword><keyword>Islets of Langerhans/pathology</keyword><keyword>Mice</keyword><keyword>Mice, Transgenic</keyword><keyword>Pancreatic Diseases/complications/prevention & control</keyword></keywords><dates><year>2000</year><pub-dates><date>Aug 10</date></pub-dates></dates><isbn>0028-4793 (Print)</isbn><accession-num>10933741</accession-num><urls><related-urls><url>;(Hoppener, Ahren et al. 2000) and critically ill children with feed intolerance ADDIN EN.CITE <EndNote><Cite><Author>Mayer</Author><Year>2002</Year><RecNum>206</RecNum><record><rec-number>206</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">206</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mayer, A. P.</author><author>Durward, A.</author><author>Turner, C.</author><author>Skellett, S.</author><author>Dalton, N.</author><author>Tibby, S. M.</author><author>Murdoch, I. A.</author></authors></contributors><auth-address>Department of Paediatric Intensive Care, Guy's Hospital, Saint Thomas Street, London, SE1 9RT, UK. amayer@.uk</auth-address><titles><title>Amylin is associated with delayed gastric emptying in critically ill children</title><secondary-title>Intensive Care Med</secondary-title></titles><pages>336-40</pages><volume>28</volume><number>3</number><edition>2002/03/21</edition><keywords><keyword>Acetaminophen/pharmacokinetics</keyword><keyword>Adolescent</keyword><keyword>Amyloid/blood/*pharmacology</keyword><keyword>Analgesics, Non-Narcotic/pharmacokinetics</keyword><keyword>Anti-Ulcer Agents/blood/*pharmacology</keyword><keyword>Area Under Curve</keyword><keyword>Blood Glucose/drug effects</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Gastric Emptying/*drug effects</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Insulin/blood</keyword><keyword>Intensive Care Units, Pediatric</keyword><keyword>Intestinal Absorption</keyword><keyword>Metabolic Clearance Rate</keyword><keyword>Prospective Studies</keyword></keywords><dates><year>2002</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0342-4642 (Print)</isbn><accession-num>11904665</accession-num><urls><related-urls><url>;(Mayer, Durward et al. 2002). There are no published data at the time of writing this dissertation on amylin and its role in the neonatal population. The focus of this dissertation is to establish whether amylin is responsible for feed intolerance in preterm infants and IMDM. Study RationaleAmylin is a potent inhibitor of gastric emptying that may be linked to the pathophysiology of feed intolerance in the neonatal population. Understanding its role in new-born population may help develop therapeutic interventions which could lead to improved nutrition and outcomes. Study HypothesesIt is hypothesized that serum amylin levels are raised in (i) infants of mothers whose pregnancy was complicated by diabetes and (ii) preterm infants with increased gastric residual volumes; and this is likely to be the principal cause of their feed intolerance.Study AimsThe overall aims of this study were to determine serum amylin levels in (i) healthy preterm and term infants (control population), (ii) preterm and term IMDM and (iii) preterm infants with feed intolerance compared to preterm infants without feed intolerance.Study ObjectivesPrimary ObjectivesThe specific primary objectives of this study as detailed in ( REF _Ref323115325 \h Table 1) were to determine serum amylin concentration (i) at birth and in the postnatal period in healthy preterm and term infants (ii) at birth and in the postnatal period in preterm and term IMDM and (iii) in preterm infants admitted to neonatal intensive care unit who subsequently experience feed intolerance compared to those who do not.Secondary ObjectivesThe specific secondary objectives of this study as detailed in ( REF _Ref323115325 \h Table 1) were to investigate (i) the relationship between amylin and birth weight / gestational age (ii) if amylin and insulin were indeed co-secreted (iii) agreement of amylin levels in paired umbilical cord arterial and venous blood (iv) the relationship of amylin concentrations with gastric residual volumes (GRV), time to reach full enteral feeds and length of hospital stay.Rationale for secondary objective (iii): Umbilical venous sampling is technically easy compared to umbilical arterial sampling and was chosen as the ideal route for taking blood for this study. However experience of fellow researchers whose studies involved blood sampling from umbilical cords suggested that occasionally it was difficult to gain access to the umbilical vein necessitating umbilical arterial sampling. Secondly umbilical venous blood is thought to represent blood from the placenta whilst umbilical arterial blood to represent baby’s blood. Hence the study team decided to investigate amylin levels in paired samples wherever possible to investigate differences if any in amylin levels to inform the current and future studies employing umbilical cord blood. Table 1. Study Objectives & Outcome VariablesPrimary ObjectivePrimary Outcome VariableTo determine serum amylin concentrations at birth and postnatal period in healthy preterm and term infants, at birth and postnatal period in preterm and term IMDM, andin preterm infants with and without feed intolerance. Amylin (median and interquartile range) concentration in pmol/L. Secondary ObjectivesSecondary Outcome VariablesTo investigate the relationship between serum amylin concentrations and gestational age and birth weightCorrelation CoefficientTo determine the relationship between amylin and insulin levels to confirm co-secretion Correlation Coefficient To determine agreement between paired umbilical arterial and venous amylin levelsCorrelation Coefficient and Bland Altman method comparison test To investigate the relationship between serum amylin concentrations and influential covariates (gastric residual volumes (GRV), time to full enteral feeds and length of hospital stay).Correlation Coefficient Literature Review: Amylin PeptideIntroduction & Background Amylin or Islet amyloid polypeptide (IAPP) was first discovered in 1987 and is a second beta cell hormone that is co-located and co-secreted with insulin from pancreas ( REF _Ref323117224 \h \* MERGEFORMAT Figure 1). The names ‘Amylin’ and ‘islet amyloid polypeptide’ are often used interchangeably in current literature. The difference in nomenclature is largely geographical; European researchers tend to prefer IAPP whereas American researchers prefer Amylin. To maintain consistency ‘IAPP’ is referred to as ‘Amylin’ throughout this dissertation.Figure 1. Amylin is the second beta cell hormoneThis slide shows pictures (on the left) demonstrating that amylin and insulin are both present in the beta cells of islet of pancreas. A graphical representation of the structure of the amylin molecule is shown on the right.Amylin Synthesis, Sources, Release & MetabolismAmylin is co-synthesized, co-packaged within the Golgi apparatus, and co-secreted within the secretory granule by the islet beta cells in response to elevations of plasma glucose following enteral nutrient intake PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db29wZXI8L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Rink, Beaumont et al. 1993; Cooper 1994; Wimalawansa 1997). Although the major site of amylin biosynthesis lies in the pancreatic islet beta cells, animal studies have identified secondary sites in the endocrine cells of gastric mucosa PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdWxkZXI8L0F1dGhvcj48WWVhcj4xOTk3PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Ferrier, Pierson et al. 1989; Fan, Westermark et al. 1994; Mulder, Leckstrom et al. 1995), and in the developing kidney ADDIN EN.CITE <EndNote><Cite><Author>Wookey</Author><Year>1998</Year><RecNum>32</RecNum><record><rec-number>32</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">32</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wookey, P. J.</author><author>Tikellis, C.</author><author>Nobes, M.</author><author>Casley, D.</author><author>Cooper, M. E.</author><author>Darby, I. A.</author></authors></contributors><auth-address>Department of Medicine, University of Melbourne, Bundoora, Victoria, Australia. wookey@austin.unimelb.edu.au</auth-address><titles><title>Amylin as a growth factor during fetal and postnatal development of the rat kidney</title><secondary-title>Kidney Int</secondary-title></titles><pages>25-30</pages><volume>53</volume><number>1</number><edition>1998/02/07</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Amyloid/analysis/genetics/*physiology</keyword><keyword>Animals</keyword><keyword>Cells, Cultured</keyword><keyword>Growth Substances/*physiology</keyword><keyword>Kidney/embryology/*growth & development</keyword><keyword>Molecular Sequence Data</keyword><keyword>RNA, Messenger/analysis</keyword><keyword>Rats</keyword><keyword>Rats, Sprague-Dawley</keyword></keywords><dates><year>1998</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0085-2538 (Print)</isbn><accession-num>9452996</accession-num><urls><related-urls><url>;(Wookey, Tikellis et al. 1998). Large number of amylin-immunoreactive cells were also found in the pyloric antrum, and a small number in the body of the stomach, duodenum and rectum in both man and rat ADDIN EN.CITE <EndNote><Cite><Author>Toshimori</Author><Year>1990</Year><RecNum>352</RecNum><record><rec-number>352</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">352</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Toshimori, H.</author><author>Narita, R.</author><author>Nakazato, M.</author><author>Asai, J.</author><author>Mitsukawa, T.</author><author>Kangawa, K.</author><author>Matsuo, H.</author><author>Matsukura, S.</author></authors></contributors><auth-address>Department of Internal Medicine, Miyazaki Medical College, Japan.</auth-address><titles><title>Islet amyloid polypeptide (IAPP) in the gastrointestinal tract and pancreas of man and rat</title><secondary-title>Cell Tissue Res</secondary-title></titles><periodical><full-title>Cell Tissue Res</full-title></periodical><pages>401-6</pages><volume>262</volume><number>3</number><edition>1990/12/01</edition><keywords><keyword>Adult</keyword><keyword>Amyloid/immunology/*metabolism</keyword><keyword>Animals</keyword><keyword>Diabetes Mellitus, Type 1/metabolism</keyword><keyword>Diabetes Mellitus, Type 2/metabolism</keyword><keyword>Digestive System/cytology/*metabolism</keyword><keyword>Humans</keyword><keyword>Immune Sera/immunology</keyword><keyword>Immunohistochemistry/methods</keyword><keyword>Male</keyword><keyword>Pancreas/cytology/*metabolism</keyword><keyword>Rats</keyword><keyword>Rats, Inbred Strains</keyword></keywords><dates><year>1990</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0302-766X (Print)
0302-766X (Linking)</isbn><accession-num>2078850</accession-num><urls><related-urls><url>;(Toshimori, Narita et al. 1990). Amylin peptide may be prepared in vitro from diabetic pancreas by solubilisation of amyloid and isolation of the peptide by gel filtration and reverse phase chromatography. Amylin may also be produced by recombinant DNA techniques using the disclosed nucleic acid sequences. However one of the major problems with amylin is its spontaneous ability to deamidate and aggregate ADDIN EN.CITE <EndNote><Cite><Author>Nilsson</Author><Year>2002</Year><RecNum>76</RecNum><record><rec-number>76</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">76</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nilsson, M. R.</author><author>Driscoll, M.</author><author>Raleigh, D. P.</author></authors></contributors><auth-address>Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York 11794-3400, USA.</auth-address><titles><title>Low levels of asparagine deamidation can have a dramatic effect on aggregation of amyloidogenic peptides: implications for the study of amyloid formation</title><secondary-title>Protein Sci</secondary-title></titles><pages>342-9</pages><volume>11</volume><number>2</number><edition>2002/01/16</edition><keywords><keyword>Amides/chemistry/*metabolism</keyword><keyword>Amyloid/*chemistry/metabolism</keyword><keyword>Asparagine/*chemistry/metabolism</keyword><keyword>Chromatography, High Pressure Liquid</keyword><keyword>Congo Red</keyword><keyword>Humans</keyword><keyword>Peptide Fragments/*chemistry/*metabolism</keyword><keyword>Protein Binding</keyword><keyword>Protein Conformation</keyword><keyword>Solutions</keyword><keyword>Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization</keyword><keyword>Spectroscopy, Fourier Transform Infrared</keyword></keywords><dates><year>2002</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0961-8368 (Print)</isbn><accession-num>11790844</accession-num><urls><related-urls><url>;(Nilsson, Driscoll et al. 2002) rendering it insoluble and toxic for human administration. Amylin release into the circulation is increased postprandially and is in proportion to the amount of digested food ADDIN EN.CITE <EndNote><Cite><Author>Bronsky</Author><Year>2002</Year><RecNum>56</RecNum><record><rec-number>56</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">56</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bronsky, J.</author><author>Chada, M.</author><author>Kotaska, K.</author><author>Prusa, R.</author></authors></contributors><auth-address>Ustav klinicke biochemie a patobiochemie 2. LF UK a FN Motol, Praha. bronsky@email.cz</auth-address><titles><title>[Amylin--its physiological role in humans]</title><secondary-title>Cesk Fysiol</secondary-title></titles><pages>176-80</pages><volume>51</volume><number>4</number><edition>2003/03/01</edition><keywords><keyword>Amyloid/*physiology</keyword><keyword>Animals</keyword><keyword>Blood Glucose/metabolism</keyword><keyword>Bone and Bones/metabolism</keyword><keyword>Diabetes Mellitus/blood</keyword><keyword>Eating/physiology</keyword><keyword>Glucagon/secretion</keyword><keyword>Humans</keyword></keywords><dates><year>2002</year><pub-dates><date>Dec</date></pub-dates></dates><orig-pub>Amylin--fyziologicka uloha v lidskem organismu.</orig-pub><isbn>1210-6313 (Print)</isbn><accession-num>12608111</accession-num><urls><related-urls><url>;(Bronsky, Chada et al. 2002). Oral and intravenous dextrose loads also promote amylin release possibly due to co-secretion with insulin in response to hyperglycemia. On the other hand, amylin release is inhibited by both hypoglycaemia and somatostatin ADDIN EN.CITE <EndNote><Cite><Author>Mitsukawa</Author><Year>1990</Year><RecNum>24</RecNum><record><rec-number>24</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">24</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mitsukawa, T.</author><author>Takemura, J.</author><author>Asai, J.</author><author>Nakazato, M.</author><author>Kangawa, K.</author><author>Matsuo, H.</author><author>Matsukura, S.</author></authors></contributors><auth-address>Third Department of Internal Medicine, Miyazaki Medical College, Japan.</auth-address><titles><title>Islet amyloid polypeptide response to glucose, insulin, and somatostatin analogue administration</title><secondary-title>Diabetes</secondary-title></titles><periodical><full-title>Diabetes</full-title></periodical><pages>639-42</pages><volume>39</volume><number>5</number><edition>1990/05/01</edition><keywords><keyword>Administration, Oral</keyword><keyword>Adult</keyword><keyword>Amyloid/*blood/metabolism</keyword><keyword>Drug Synergism</keyword><keyword>Female</keyword><keyword>Glucose/*pharmacology</keyword><keyword>Humans</keyword><keyword>Injections, Intravenous</keyword><keyword>Insulin/*pharmacology</keyword><keyword>Male</keyword><keyword>Octreotide/pharmacology</keyword><keyword>Radioimmunoassay</keyword><keyword>Somatostatin/*analogs & derivatives/pharmacology</keyword></keywords><dates><year>1990</year><pub-dates><date>May</date></pub-dates></dates><isbn>0012-1797 (Print)</isbn><accession-num>1970540</accession-num><urls><related-urls><url>;(Mitsukawa, Takemura et al. 1990).Amylin is co-released with insulin in a molar ratio of approximately 1 to 100 and its diurnal profile corresponds to insulin in healthy non-diabetic subjects in response to carbohydrate and protein containing meals ( REF _Ref323120499 \h \* MERGEFORMAT Figure 2) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb2RhIEpFPC9BdXRob3I+PFllYXI+MTk5NTwvWWVhcj48
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ADDIN EN.CITE.DATA (Butler, Chou et al. 1990; Mitsukawa, Takemura et al. 1990; Koda JE and JF 1995). Figure 2. Twenty four hour plasma profile of amylin and insulin in healthy adultsTwenty-four hour plasma profile of amylin is similar to insulin in healthy adults with low baseline levels that rapidly increase in association with increase in plasma glucose concentrations. Image courtesy of ADDIN EN.CITE <EndNote><Cite><Author>Koda JE</Author><Year>1995</Year><RecNum>315</RecNum><record><rec-number>315</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">315</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Koda JE, Fineman MS, Kolterman OG,</author><author>Caro JF</author></authors></contributors><titles><title>24 hour plasma amylin profiles are elevated in IGT subjects vs. normal controls (Abstract)</title><secondary-title>Diabetes </secondary-title></titles><periodical><full-title>Diabetes</full-title></periodical><pages>238A</pages><volume>44 (Suppl. 1)</volume><dates><year>1995</year></dates><urls></urls></record></Cite></EndNote>(Koda JE and JF 1995).In normal subjects plasma levels of amylin vary from fasting level of 5 pmol/L to 30 pmol/L postprandially ADDIN EN.CITE <EndNote><Cite><Author>Bronsky</Author><Year>2002</Year><RecNum>56</RecNum><record><rec-number>56</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">56</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bronsky, J.</author><author>Chada, M.</author><author>Kotaska, K.</author><author>Prusa, R.</author></authors></contributors><auth-address>Ustav klinicke biochemie a patobiochemie 2. LF UK a FN Motol, Praha. bronsky@email.cz</auth-address><titles><title>[Amylin--its physiological role in humans]</title><secondary-title>Cesk Fysiol</secondary-title></titles><pages>176-80</pages><volume>51</volume><number>4</number><edition>2003/03/01</edition><keywords><keyword>Amyloid/*physiology</keyword><keyword>Animals</keyword><keyword>Blood Glucose/metabolism</keyword><keyword>Bone and Bones/metabolism</keyword><keyword>Diabetes Mellitus/blood</keyword><keyword>Eating/physiology</keyword><keyword>Glucagon/secretion</keyword><keyword>Humans</keyword></keywords><dates><year>2002</year><pub-dates><date>Dec</date></pub-dates></dates><orig-pub>Amylin--fyziologicka uloha v lidskem organismu.</orig-pub><isbn>1210-6313 (Print)</isbn><accession-num>12608111</accession-num><urls><related-urls><url>;(Bronsky, Chada et al. 2002). There is no difference in the mean (SD) amylin concentration in lean subjects (3.4 ± 0.7 pmol/L) and obese subjects (4.7 ± 0.9 pmol/L) with normal glucose tolerance PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXJ0dGVyPC9BdXRob3I+PFllYXI+MTk5MTwvWWVhcj48
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ADDIN EN.CITE.DATA (Hartter, Svoboda et al. 1991; Reda, Geliebter et al. 2002). In contrast amylin secretion following sustacal meal was observed to be absent in patients with type 1 diabetes and impaired markedly in patients with type 2 diabetes on insulin therapy ( REF _Ref323136670 \h \* MERGEFORMAT Figure 3) ADDIN EN.CITE <EndNote><Cite><Author>Fineman MS</Author><Year>1996</Year><RecNum>316</RecNum><record><rec-number>316</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">316</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fineman MS, Giotta MP, Thompson RG, Kolterman OG, Koda JE</author></authors></contributors><titles><title>Amylin response following Sustacal? ingestion is diminished in type II diabetic patients treated with insulin (Abstract).</title><secondary-title>Diabetologia</secondary-title></titles><periodical><full-title>Diabetologia</full-title></periodical><pages>A149</pages><volume>39 (Suppl. 1)</volume><dates><year>1996</year></dates><urls></urls></record></Cite></EndNote>(Fineman MS 1996).Figure SEQ Figure \* ARABIC 3. Amylin response after a liquid sustacal meal in patients with type 1 & type 2 diabetes mellitusThe graph shows almost absence of amylin secretion in patients with type 1 diabetes, and its secretion is markedly impaired in insulin-requiring patients with type 2 diabetes. Image courtesy of ADDIN EN.CITE <EndNote><Cite><Author>Fineman MS</Author><Year>1996</Year><RecNum>316</RecNum><record><rec-number>316</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">316</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fineman MS, Giotta MP, Thompson RG, Kolterman OG, Koda JE</author></authors></contributors><titles><title>Amylin response following Sustacal? ingestion is diminished in type II diabetic patients treated with insulin (Abstract).</title><secondary-title>Diabetologia</secondary-title></titles><periodical><full-title>Diabetologia</full-title></periodical><pages>A149</pages><volume>39 (Suppl. 1)</volume><dates><year>1996</year></dates><urls></urls></record></Cite></EndNote>(Fineman MS 1996).In healthy adults during glucose stimulation, like insulin, amylin concentrations exhibit high-frequency oscillatory pattern of nonglycosylated as well as glycosylated forms ( REF _Ref323137161 \h \* MERGEFORMAT Figure 4). The amylin frequency (min/pulse), burst mass (pM/burst), burst amplitude (pM/min), and basal secretion (pM/min) were 6.3 ± 1.0, 1.63 ± 0.88, 0.77 ± 0.4 and 0.04 ± 0.2. Whether basal amylin concentrations also exhibit an oscillatory pattern is not known ADDIN EN.CITE <EndNote><Cite><Author>Juhl</Author><Year>2000</Year><RecNum>39</RecNum><record><rec-number>39</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">39</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Juhl, C. B.</author><author>Porksen, N.</author><author>Sturis, J.</author><author>Hansen, A. P.</author><author>Veldhuis, J. D.</author><author>Pincus, S.</author><author>Fineman, M.</author><author>Schmitz, O.</author></authors></contributors><auth-address>Department of Medicine M (Endocrinology and Diabetes), Arhus Kommunehospital, University Hospital of Aarhus, Denmark. cbj@dadlnet.dk</auth-address><titles><title>High-frequency oscillations in circulating amylin concentrations in healthy humans</title><secondary-title>Am J Physiol Endocrinol Metab</secondary-title></titles><periodical><full-title>Am J Physiol Endocrinol Metab</full-title></periodical><pages>E484-90</pages><volume>278</volume><number>3</number><edition>2000/03/11</edition><keywords><keyword>Adult</keyword><keyword>Amyloid/*blood/metabolism</keyword><keyword>Entropy</keyword><keyword>Female</keyword><keyword>Glycosylation</keyword><keyword>Humans</keyword><keyword>Insulin/blood</keyword><keyword>Male</keyword><keyword>Oscillometry</keyword><keyword>Osmolar Concentration</keyword><keyword>Reference Values</keyword></keywords><dates><year>2000</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0193-1849 (Print)</isbn><accession-num>10710503</accession-num><urls><related-urls><url>;(Juhl, Porksen et al. 2000).Figure SEQ Figure \* ARABIC 4. Representative concentration profiles of amylin (A), total amylin immunoreactivity (TAI) (B) and insulin (C)This graph shows concentration profiles of amylin, total amylin immunoreactivity and insulin during constant glucose infusion (2 mg/ kg / min). Image courtesy of ADDIN EN.CITE <EndNote><Cite><Author>Juhl</Author><Year>2000</Year><RecNum>39</RecNum><record><rec-number>39</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">39</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Juhl, C. B.</author><author>Porksen, N.</author><author>Sturis, J.</author><author>Hansen, A. P.</author><author>Veldhuis, J. D.</author><author>Pincus, S.</author><author>Fineman, M.</author><author>Schmitz, O.</author></authors></contributors><auth-address>Department of Medicine M (Endocrinology and Diabetes), Arhus Kommunehospital, University Hospital of Aarhus, Denmark. cbj@dadlnet.dk</auth-address><titles><title>High-frequency oscillations in circulating amylin concentrations in healthy humans</title><secondary-title>Am J Physiol Endocrinol Metab</secondary-title></titles><periodical><full-title>Am J Physiol Endocrinol Metab</full-title></periodical><pages>E484-90</pages><volume>278</volume><number>3</number><edition>2000/03/11</edition><keywords><keyword>Adult</keyword><keyword>Amyloid/*blood/metabolism</keyword><keyword>Entropy</keyword><keyword>Female</keyword><keyword>Glycosylation</keyword><keyword>Humans</keyword><keyword>Insulin/blood</keyword><keyword>Male</keyword><keyword>Oscillometry</keyword><keyword>Osmolar Concentration</keyword><keyword>Reference Values</keyword></keywords><dates><year>2000</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0193-1849 (Print)</isbn><accession-num>10710503</accession-num><urls><related-urls><url>;(Juhl, Porksen et al. 2000).The mean removal time of amylin in plasma is longer than insulin and similar to C-peptide ADDIN EN.CITE <EndNote><Cite><Author>Clodi</Author><Year>1998</Year><RecNum>25</RecNum><record><rec-number>25</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">25</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Clodi, M.</author><author>Thomaseth, K.</author><author>Pacini, G.</author><author>Hermann, K.</author><author>Kautzky-Willer, A.</author><author>Waldhusl, W.</author><author>Prager, R.</author><author>Ludvik, B.</author></authors></contributors><auth-address>Department of Medicine III, University of Vienna, Austria.</auth-address><titles><title>Distribution and kinetics of amylin in humans</title><secondary-title>Am J Physiol</secondary-title></titles><periodical><full-title>Am J Physiol</full-title></periodical><pages>E903-8</pages><volume>274</volume><number>5 Pt 1</number><edition>1998/06/05</edition><keywords><keyword>Adult</keyword><keyword>Amyloid/blood/*metabolism/pharmacokinetics</keyword><keyword>Half-Life</keyword><keyword>Humans</keyword><keyword>Kinetics</keyword><keyword>Male</keyword><keyword>Models, Biological</keyword><keyword>Tissue Distribution</keyword></keywords><dates><year>1998</year><pub-dates><date>May</date></pub-dates></dates><isbn>0002-9513 (Print)</isbn><accession-num>9612249</accession-num><urls><related-urls><url>;(Clodi, Thomaseth et al. 1998), despite amylin having a faster clearance rate than insulin at the kidney ADDIN EN.CITE <EndNote><Cite><Author>Thomaseth</Author><Year>1996</Year><RecNum>26</RecNum><record><rec-number>26</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">26</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Thomaseth, K.</author><author>Kautzky-Willer, A.</author><author>Ludvik, B.</author><author>Prager, R.</author><author>Pacini, G.</author></authors></contributors><auth-address>Institute of Systems Science, Padua, Italy.</auth-address><titles><title>Integrated mathematical model to assess beta-cell activity during the oral glucose test</title><secondary-title>Am J Physiol</secondary-title></titles><periodical><full-title>Am J Physiol</full-title></periodical><pages>E522-31</pages><volume>270</volume><number>3 Pt 1</number><edition>1996/03/01</edition><keywords><keyword>Amyloid/blood/secretion</keyword><keyword>Blood Glucose/*metabolism</keyword><keyword>C-Peptide/blood/*secretion</keyword><keyword>Dexamethasone/diagnostic use</keyword><keyword>Glucose Intolerance/blood/*physiopathology</keyword><keyword>*Glucose Tolerance Test</keyword><keyword>Humans</keyword><keyword>Hypertension/blood/*physiopathology</keyword><keyword>Insulin/blood/*secretion</keyword><keyword>Islets of Langerhans/*secretion</keyword><keyword>Kinetics</keyword><keyword>Liver/metabolism</keyword><keyword>Mathematics</keyword><keyword>*Models, Biological</keyword><keyword>Obesity/blood/physiopathology</keyword><keyword>Reference Values</keyword><keyword>Regression Analysis</keyword><keyword>Sensitivity and Specificity</keyword><keyword>Time Factors</keyword></keywords><dates><year>1996</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0002-9513 (Print)</isbn><accession-num>8638701</accession-num><urls><related-urls><url>;(Thomaseth, Kautzky-Willer et al. 1996). Amylin Structure, Gene & Relation to CGRP SuperfamilyHuman amylin has 37 amino-acid sequences KCNTATCATQRLANFLVHSSNNFGAILSSTNVGSNTY, with a disulfide bridge between cysteine residues 2 and 7 and is characterised by a NH2-terminal cyclic ring structure and an amidated COOH-terminus ( REF _Ref323117224 \h Figure 1, REF _Ref323138264 \h \* MERGEFORMAT Figure 6 & REF _Ref323158809 \h Figure 14). Both the amidated C terminus and the disulphide bridge are essential for the full biological activity of amylin PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb2JlcnRzPC9BdXRob3I+PFllYXI+MTk4OTwvWWVhcj48
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ADDIN EN.CITE.DATA (Cooper, Day et al. 1989; Roberts, Leighton et al. 1989). The dynamic alpha helix structure of human amylin is shown in REF _Ref323137503 \h \* MERGEFORMAT Figure 5.Figure SEQ Figure \* ARABIC 5. Alpha helix structure of human amylinImage courtesy of human amylin gene is located on the short arm of chromosome 12 ADDIN EN.CITE <EndNote><Cite><Author>Cooper</Author><Year>1989</Year><RecNum>38</RecNum><record><rec-number>38</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">38</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cooper, G. J.</author><author>Day, A. J.</author><author>Willis, A. C.</author><author>Roberts, A. N.</author><author>Reid, K. B.</author><author>Leighton, B.</author></authors></contributors><auth-address>Department of Biochemistry, University of Oxford, U.K.</auth-address><titles><title>Amylin and the amylin gene: structure, function and relationship to islet amyloid and to diabetes mellitus</title><secondary-title>Biochim Biophys Acta</secondary-title></titles><pages>247-58</pages><volume>1014</volume><number>3</number><edition>1989/12/14</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Amyloid/*genetics/metabolism</keyword><keyword>Animals</keyword><keyword>Base Sequence</keyword><keyword>Diabetes Mellitus, Type 1/*metabolism</keyword><keyword>Diabetes Mellitus, Type 2/*metabolism</keyword><keyword>*Genes</keyword><keyword>Humans</keyword><keyword>Islets of Langerhans/*metabolism</keyword><keyword>Molecular Sequence Data</keyword></keywords><dates><year>1989</year><pub-dates><date>Dec 14</date></pub-dates></dates><isbn>0006-3002 (Print)</isbn><accession-num>2690958</accession-num><urls><related-urls><url>(89)90220-6 [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Cooper, Day et al. 1989) and encodes the complete polypeptide precursor in two exons which are separated by an intron of approximately 5 kb transcribing an 89 amino acid precursor peptide ADDIN EN.CITE <EndNote><Cite><Author>Nishi</Author><Year>1989</Year><RecNum>18</RecNum><record><rec-number>18</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">18</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nishi, M.</author><author>Sanke, T.</author><author>Seino, S.</author><author>Eddy, R. L.</author><author>Fan, Y. S.</author><author>Byers, M. G.</author><author>Shows, T. B.</author><author>Bell, G. I.</author><author>Steiner, D. F.</author></authors></contributors><auth-address>Department of Biochemistry and Molecular Biology, University of Chicago, Illinois.</auth-address><titles><title>Human islet amyloid polypeptide gene: complete nucleotide sequence, chromosomal localization, and evolutionary history</title><secondary-title>Mol Endocrinol</secondary-title></titles><pages>1775-81</pages><volume>3</volume><number>11</number><edition>1989/11/01</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Amyloid/*genetics</keyword><keyword>Base Sequence</keyword><keyword>Calcitonin Gene-Related Peptide/genetics</keyword><keyword>Chromosome Mapping</keyword><keyword>*Chromosomes, Human, Pair 12</keyword><keyword>Genes</keyword><keyword>Humans</keyword><keyword>Molecular Sequence Data</keyword><keyword>Phylogeny</keyword><keyword>Protein Sorting Signals/genetics</keyword><keyword>Sequence Homology, Nucleic Acid</keyword></keywords><dates><year>1989</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0888-8809 (Print)</isbn><accession-num>2608057</accession-num><urls><related-urls><url>;(Nishi, Sanke et al. 1989). The proprotein convertase PC2 is primarily responsible for amylin processing within the secretory granule by converting the 89 aminoacid prohormone to the actively secreted 37 amino acid amylin ADDIN EN.CITE <EndNote><Cite><Author>Badman</Author><Year>1996</Year><RecNum>19</RecNum><record><rec-number>19</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">19</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Badman, M. K.</author><author>Shennan, K. I.</author><author>Jermany, J. L.</author><author>Docherty, K.</author><author>Clark, A.</author></authors></contributors><auth-address>Department of Human Anatomy, University of Oxford, UK.</auth-address><titles><title>Processing of pro-islet amyloid polypeptide (proIAPP) by the prohormone convertase PC2</title><secondary-title>FEBS Lett</secondary-title></titles><pages>227-31</pages><volume>378</volume><number>3</number><edition>1996/01/15</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Amyloid/*genetics/*metabolism</keyword><keyword>Animals</keyword><keyword>Aspartic Endopeptidases/genetics/metabolism</keyword><keyword>Furin</keyword><keyword>Humans</keyword><keyword>Molecular Sequence Data</keyword><keyword>Proprotein Convertase 2</keyword><keyword>Proprotein Convertases</keyword><keyword>Protein Biosynthesis</keyword><keyword>Protein Precursors/genetics/*metabolism</keyword><keyword>RNA, Messenger</keyword><keyword>Subtilisins/genetics/*metabolism</keyword><keyword>Transcription, Genetic</keyword><keyword>Xenopus</keyword></keywords><dates><year>1996</year><pub-dates><date>Jan 15</date></pub-dates></dates><isbn>0014-5793 (Print)</isbn><accession-num>8557106</accession-num><urls><related-urls><url>(95)01460-8 [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Badman, Shennan et al. 1996). Amylin belongs to the calcitonin gene related peptide superfamily ADDIN EN.CITE <EndNote><Cite><Author>Rink</Author><Year>1993</Year><RecNum>47</RecNum><record><rec-number>47</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">47</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rink, T. J.</author><author>Beaumont, K.</author><author>Koda, J.</author><author>Young, A.</author></authors></contributors><auth-address>Amylin Pharmaceuticals Inc., San Diego, CA 92121.</auth-address><titles><title>Structure and biology of amylin</title><secondary-title>Trends Pharmacol Sci</secondary-title></titles><pages>113-8</pages><volume>14</volume><number>4</number><edition>1993/04/01</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>*Amyloid/chemistry/deficiency</keyword><keyword>Animals</keyword><keyword>Diabetes Mellitus, Type 1/genetics</keyword><keyword>Diabetes Mellitus, Type 2/genetics</keyword><keyword>Humans</keyword><keyword>Models, Molecular</keyword><keyword>Molecular Sequence Data</keyword><keyword>Protein Structure, Tertiary</keyword></keywords><dates><year>1993</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0165-6147 (Print)</isbn><accession-num>8516954</accession-num><urls><related-urls><url>;(Rink, Beaumont et al. 1993) which in addition consists of calcitonin (CT), calcitonin gene-related peptide (CGRP) and adrenomedullin. CT and CGRP are derived from the CT/CGRP gene, which is encoded on chromosome 11. Chromosome 12 is thought to be an evolutionary duplication of chromosome 11 as amylin has 20% sequence homology with calcitonin and adrenomedullin and 44% homology with calcitonin gene-related peptide ADDIN EN.CITE <EndNote><Cite><Author>Bronsky</Author><Year>2002</Year><RecNum>56</RecNum><record><rec-number>56</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">56</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bronsky, J.</author><author>Chada, M.</author><author>Kotaska, K.</author><author>Prusa, R.</author></authors></contributors><auth-address>Ustav klinicke biochemie a patobiochemie 2. LF UK a FN Motol, Praha. bronsky@email.cz</auth-address><titles><title>[Amylin--its physiological role in humans]</title><secondary-title>Cesk Fysiol</secondary-title></titles><pages>176-80</pages><volume>51</volume><number>4</number><edition>2003/03/01</edition><keywords><keyword>Amyloid/*physiology</keyword><keyword>Animals</keyword><keyword>Blood Glucose/metabolism</keyword><keyword>Bone and Bones/metabolism</keyword><keyword>Diabetes Mellitus/blood</keyword><keyword>Eating/physiology</keyword><keyword>Glucagon/secretion</keyword><keyword>Humans</keyword></keywords><dates><year>2002</year><pub-dates><date>Dec</date></pub-dates></dates><orig-pub>Amylin--fyziologicka uloha v lidskem organismu.</orig-pub><isbn>1210-6313 (Print)</isbn><accession-num>12608111</accession-num><urls><related-urls><url>;(Bronsky, Chada et al. 2002). Importantly, a portion of the B-chain of insulin is strongly homologous to these four peptides. Thus amylin, CGRP, CT, and adrenomedullin are related to the insulin gene superfamily of peptides, which may all have diverged from a common ancestral gene during evolution and therefore may share some of the characteristics of insulin ADDIN EN.CITE <EndNote><Cite><Author>Wimalawansa</Author><Year>1997</Year><RecNum>154</RecNum><record><rec-number>154</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">154</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wimalawansa, S. J.</author></authors></contributors><auth-address>Department of Internal Medicine, University of Texas Medical Branch at Galveston 77555-1065, USA.</auth-address><titles><title>Amylin, calcitonin gene-related peptide, calcitonin, and adrenomedullin: a peptide superfamily</title><secondary-title>Crit Rev Neurobiol</secondary-title></titles><periodical><full-title>Crit Rev Neurobiol</full-title></periodical><pages>167-239</pages><volume>11</volume><number>2-3</number><edition>1997/01/01</edition><keywords><keyword>Adrenomedullin</keyword><keyword>Amino Acid Sequence</keyword><keyword>Amyloid/chemistry/genetics/*physiology</keyword><keyword>Animals</keyword><keyword>Calcitonin Gene-Related Peptide/chemistry/genetics/*physiology</keyword><keyword>Calcium/metabolism</keyword><keyword>Cardiovascular Physiological Phenomena</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lactation</keyword><keyword>Models, Molecular</keyword><keyword>Molecular Sequence Data</keyword><keyword>Nervous System Physiological Phenomena</keyword><keyword>Peptides/chemistry/genetics/*physiology</keyword><keyword>Pregnancy</keyword><keyword>Protein Conformation</keyword><keyword>Protein Structure, Secondary</keyword><keyword>Receptors, Calcitonin Gene-Related Peptide/chemistry/physiology</keyword><keyword>Sequence Alignment</keyword><keyword>Sequence Homology, Amino Acid</keyword></keywords><dates><year>1997</year></dates><isbn>0892-0915 (Print)</isbn><accession-num>9209829</accession-num><urls><related-urls><url>;(Wimalawansa 1997).Feto-Maternal Passage of AmylinInformation with regards to transplacental passage of amylin is lacking at the time of writing this dissertation. The molecular weight of human amylin is 3904 Da compared to 5808 Da for human insulin. Published literature regarding transplacental passage of insulin may shed some light on passage of amylin across feto-maternal barrier. Early in vitro studies suggested that insulin does not cross the human placenta PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LZWxsZXI8L0F1dGhvcj48WWVhcj4xOTY4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Keller and Krohmer 1968; Sabata, Frerichs et al. 1970). However a subsequent placental perfusion study demonstrated that a small amount of human insulin, representing 1–5% of 59, 104, 448, and 1,198 μU/ml insulin concentration in the maternal artery (corresponding to subcutaneous doses of insulin of approximately 14, 24, 104, and 278 units respectively), was transferred from the maternal to the fetal circulation ADDIN EN.CITE <EndNote><Cite><Author>Challier</Author><Year>1986</Year><RecNum>310</RecNum><record><rec-number>310</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">310</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Challier, J. C.</author><author>Hauguel, S.</author><author>Desmaizieres, V.</author></authors></contributors><titles><title>Effect of insulin on glucose uptake and metabolism in the human placenta</title><secondary-title>J Clin Endocrinol Metab</secondary-title></titles><periodical><full-title>J Clin Endocrinol Metab</full-title></periodical><pages>803-7</pages><volume>62</volume><number>5</number><edition>1986/05/01</edition><keywords><keyword>Biological Transport/drug effects</keyword><keyword>Female</keyword><keyword>Glucose/*metabolism</keyword><keyword>Humans</keyword><keyword>Insulin/metabolism/*pharmacology/physiology</keyword><keyword>Lactates/metabolism</keyword><keyword>Oxygen Consumption/drug effects</keyword><keyword>Placenta/drug effects/*metabolism</keyword><keyword>Pregnancy</keyword></keywords><dates><year>1986</year><pub-dates><date>May</date></pub-dates></dates><isbn>0021-972X (Print)
0021-972X (Linking)</isbn><accession-num>3514649</accession-num><urls><related-urls><url>;(Challier, Hauguel et al. 1986). Similarly maternal insulin lispro concentrations of ≥580 μU/ml (corresponding to subcutaneous dose of insulin lispro of approximately 75 units) led to a small transfer of insulin lispro across the placenta ADDIN EN.CITE <EndNote><Cite><Author>Boskovic</Author><Year>2003</Year><RecNum>312</RecNum><record><rec-number>312</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">312</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Boskovic, R.</author><author>Feig, D. S.</author><author>Derewlany, L.</author><author>Knie, B.</author><author>Portnoi, G.</author><author>Koren, G.</author></authors></contributors><auth-address>Division of Clinical Pharmacology and Toxicology, the Hospital for Sick Children, Toronto, Ontario, Canada.</auth-address><titles><title>Transfer of insulin lispro across the human placenta: in vitro perfusion studies</title><secondary-title>Diabetes Care</secondary-title></titles><periodical><full-title>Diabetes Care</full-title></periodical><pages>1390-4</pages><volume>26</volume><number>5</number><edition>2003/04/30</edition><keywords><keyword>Adult</keyword><keyword>Biological Transport</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Female</keyword><keyword>Fetal Blood/chemistry</keyword><keyword>Humans</keyword><keyword>Hypoglycemic Agents/blood/*pharmacokinetics</keyword><keyword>Insulin/*analogs & derivatives/blood/*pharmacokinetics</keyword><keyword>Maternal-Fetal Exchange/*physiology</keyword><keyword>Perfusion</keyword><keyword>Placenta/*physiology</keyword><keyword>Pregnancy</keyword></keywords><dates><year>2003</year><pub-dates><date>May</date></pub-dates></dates><isbn>0149-5992 (Print)
0149-5992 (Linking)</isbn><accession-num>12716794</accession-num><urls><related-urls><url>;(Boskovic, Feig et al. 2003). In summary both human insulin and insulin lispro are unlikely to transfer across term placenta at clinically relevant therapeutic doses. Thus it may be assumed that endogenous amylin molecule has similar characteristic to insulin with regards to the transplacental passage. Synthetic Analogue ‘Pramlintide’Human amylin is insoluble and potentially toxic for human administration as a replacement in diabetic patients. Therefore synthetic, soluble, non-aggregating, equipotent PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TeW1saW48L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Fineman, Weyer et al. 2002; Symlin 2005) amylin analogue pramlintide acetate (Symlin, Amylin Pharmaceuticals) was developed by substitution of 3 residues with proline at positions 25 (alanine), 28 (serine), and 29 (serine) as shown below in REF _Ref323138264 \h \* MERGEFORMAT Figure 6. Pramlintide acetate (Symlin) is formulated as a clear, isotonic, sterile solution for subcutaneous administration.Figure SEQ Figure \* ARABIC 6. Comparison of aminoacid sequence of amylin and pramlintideImage is courtesy of amylin, pramlintide decreases post-prandial glucagon secretion, slows gastric emptying, and increases satiety. In addition, pramlintide results in weight loss, allows patients to use less insulin, lowers average blood sugar levels, and substantially reduces blood sugar surges that occurs in diabetic patients immediately after eating PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaWRkbGU8L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Ratner, Want et al. 2002; Hollander, Levy et al. 2003; Riddle, Frias et al. 2007). The absolute bioavailability of a single subcutaneous dose of symlin is approximately 30 to 40% and approximately 40% of the drug is unbound in plasma and plasma concentrations peaks at 20 minutes, regardless of dose, and then declines over the subsequent 3 hours. It undergoes little or no hepatic metabolism and is cleared mainly via the kidneys, with a plasma half-life of 50 minutes ADDIN EN.CITE <EndNote><Cite><Author>Weyer</Author><Year>2001</Year><RecNum>147</RecNum><record><rec-number>147</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">147</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Weyer, C.</author><author>Maggs, D. G.</author><author>Young, A. A.</author><author>Kolterman, O. G.</author></authors></contributors><auth-address>Amylin Pharmaceuticals Inc, 9373 Towne Centre Drive, San Diego, CA 92121, USA. cweyer@</auth-address><titles><title>Amylin replacement with pramlintide as an adjunct to insulin therapy in type 1 and type 2 diabetes mellitus: a physiological approach toward improved metabolic control</title><secondary-title>Curr Pharm Des</secondary-title></titles><periodical><full-title>Curr Pharm Des</full-title></periodical><pages>1353-73</pages><volume>7</volume><number>14</number><edition>2001/07/27</edition><keywords><keyword>Amyloid/metabolism/pharmacokinetics/*therapeutic use</keyword><keyword>Animals</keyword><keyword>Anti-Ulcer Agents/metabolism/pharmacokinetics/*therapeutic use</keyword><keyword>Diabetes Mellitus, Type 1/*drug therapy/metabolism</keyword><keyword>Diabetes Mellitus, Type 2/*drug therapy/metabolism</keyword><keyword>Humans</keyword><keyword>Hypoglycemic Agents/pharmacokinetics/*therapeutic use</keyword><keyword>Insulin/metabolism/pharmacokinetics/*therapeutic use</keyword></keywords><dates><year>2001</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1381-6128 (Print)</isbn><accession-num>11472273</accession-num><urls><related-urls><url>;(Weyer, Maggs et al. 2001). Pramlintide has been approved for use by the US Food and Drug Administration (FDA) in 2005 in patients with type 1 and type 2 diabetes who use insulin ADDIN EN.CITE <EndNote><Cite><Author>Ryan</Author><Year>2005</Year><RecNum>146</RecNum><record><rec-number>146</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">146</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ryan, G. J.</author><author>Jobe, L. J.</author><author>Martin, R.</author></authors></contributors><auth-address>Clinical and Administrative Sciences, Southern School of Pharmacy, Mercer University, Atlanta, GA 30341, USA. ryan_gj@mercer.edu</auth-address><titles><title>Pramlintide in the treatment of type 1 and type 2 diabetes mellitus</title><secondary-title>Clin Ther</secondary-title></titles><pages>1500-12</pages><volume>27</volume><number>10</number><edition>2005/12/07</edition><keywords><keyword>Amyloid/administration & dosage/pharmacology/*therapeutic use</keyword><keyword>Blood Glucose/analysis</keyword><keyword>Clinical Trials as Topic</keyword><keyword>Diabetes Mellitus, Type 1/blood/*drug therapy</keyword><keyword>Diabetes Mellitus, Type 2/blood/*drug therapy</keyword><keyword>Drug Interactions</keyword><keyword>Drug Therapy, Combination</keyword><keyword>Glucagon/blood</keyword><keyword>Humans</keyword><keyword>Hypoglycemic Agents/pharmacology/*therapeutic use</keyword><keyword>Insulin/administration & dosage</keyword><keyword>Postprandial Period</keyword></keywords><dates><year>2005</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0149-2918 (Print)</isbn><accession-num>16330288</accession-num><urls><related-urls><url>(05)00197-9 [pii]
10.1016/j.clinthera.2005.10.009</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Ryan, Jobe et al. 2005). Hypoglycemia, nausea, vomiting, and anorexia were the most frequently reported adverse drug events associated with pramlintide therapy. Personal communication with Amylin Pharmaceuticals provided information regarding transplacental passage of pramlintide from studies performed on perfused human placenta. Term human placenta from uncomplicated pregnancy was obtained immediately after delivery. Pramlintide, at varying concentrations was introduced into the maternal reservoir. The maternal side of the placenta was perfused with constant concentration of pramlintide; the fetal circulation was closed. Samples were drawn from both the maternal and fetal circulations at regular intervals. The appearance of pramlintide in the fetal circulation was analyzed by a specific ELISA. The resulting data demonstrated that pramlintide had low potential (maternal to fetal ratio >1000/1) to cross the maternal-fetal placental barrier ADDIN EN.CITE <EndNote><Cite><Author>Amylin Pharmaceuticals</Author><Year>2003</Year><RecNum>195</RecNum><record><rec-number>195</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">195</key></foreign-keys><ref-type name="Personal Communication">26</ref-type><contributors><authors><author>Amylin Pharmaceuticals,</author></authors></contributors><titles><title>Transplacental passage of amylin</title></titles><dates><year>2003</year></dates><urls></urls></record></Cite></EndNote>(Amylin Pharmaceuticals 2003). These results however cannot be extrapolated directly to the endogenous amylin and therefore in vivo and in vitro studies are required to investigate transplacental passage.Amylin Receptors & Signal Transduction MechanismsThe calcitonin (CT) family of peptides utilize two seven transmembrane G protein-coupled receptors known as calcitonin receptor (CTR) and the calcitonin receptor-like receptor (CRLR). These receptors can dimerize with three different single transmembrane spanning proteins called Receptor activity-modifying protein (RAMP). When associated with a calcitonin receptor, RAMP alters its pharmacology from calcitonin-preferring to amylin-preferring. When co-expressed with RAMP1, RAMP2, or RAMP3 ADDIN EN.CITE <EndNote><Cite><Author>Hay</Author><Year>2004</Year><RecNum>53</RecNum><record><rec-number>53</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">53</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hay, D. L.</author><author>Christopoulos, G.</author><author>Christopoulos, A.</author><author>Sexton, P. M.</author></authors></contributors><auth-address>School of Biological Sciences, University of Auckland, Symonds Street, Auckland, New Zealand. dl.hay@auckland.ac.nz</auth-address><titles><title>Amylin receptors: molecular composition and pharmacology</title><secondary-title>Biochem Soc Trans</secondary-title></titles><pages>865-7</pages><volume>32</volume><number>Pt 5</number><edition>2004/10/21</edition><keywords><keyword>Animals</keyword><keyword>Cloning, Molecular</keyword><keyword>Gene Expression Regulation</keyword><keyword>Humans</keyword><keyword>Intracellular Signaling Peptides and Proteins</keyword><keyword>Membrane Proteins/chemistry</keyword><keyword>Peptides/chemistry</keyword><keyword>Protein Isoforms</keyword><keyword>RNA, Messenger/metabolism</keyword><keyword>Receptors, Calcitonin/chemistry</keyword><keyword>Receptors, Peptide/*chemistry/physiology</keyword><keyword>Signal Transduction</keyword></keywords><dates><year>2004</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0300-5127 (Print)</isbn><accession-num>15494035</accession-num><urls><related-urls><url> [pii]
10.1042/BST0320865</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Hay, Christopoulos et al. 2004), the CTR/RAMP complexes generate pharmacologically distinct amylin receptors, AMY1, AMY2, and AMY3, respectively ADDIN EN.CITE <EndNote><Cite><Author>Poyner</Author><Year>2002</Year><RecNum>325</RecNum><record><rec-number>325</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">325</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Poyner, D. R.</author><author>Sexton, P. M.</author><author>Marshall, I.</author><author>Smith, D. M.</author><author>Quirion, R.</author><author>Born, W.</author><author>Muff, R.</author><author>Fischer, J. A.</author><author>Foord, S. M.</author></authors></contributors><auth-address>Pharmaceutical Sciences Institute, Aston University, Birmingham, United Kingdom. d.r.poyner@aton.ac.uk</auth-address><titles><title>International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors</title><secondary-title>Pharmacol Rev</secondary-title></titles><periodical><full-title>Pharmacol Rev</full-title></periodical><pages>233-46</pages><volume>54</volume><number>2</number><edition>2002/05/31</edition><keywords><keyword>Animals</keyword><keyword>Humans</keyword><keyword>International Agencies</keyword><keyword>Receptors, Calcitonin/*classification</keyword><keyword>Receptors, Calcitonin Gene-Related Peptide/*classification</keyword><keyword>Receptors, Peptide/*classification</keyword><keyword>*Terminology as Topic</keyword></keywords><dates><year>2002</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0031-6997 (Print)
0031-6997 (Linking)</isbn><accession-num>12037140</accession-num><urls><related-urls><url>;(Poyner, Sexton et al. 2002) which bind with high affinity to amylin. The binding sites at nucleus accumbens and subfornical organ are composed of CTR/RAMP1 (AMY1) whereas the binding sites at area postrema are composed of CTR/RAMP3 (AMY3) ADDIN EN.CITE <EndNote><Cite><Author>Young</Author><Year>2005</Year><RecNum>313</RecNum><record><rec-number>313</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">313</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Young, A.</author></authors></contributors><auth-address>Amylin Pharmaceuticals, Inc., San Diego, California, USA.</auth-address><titles><title>Receptor pharmacology</title><secondary-title>Adv Pharmacol</secondary-title></titles><periodical><full-title>Adv Pharmacol</full-title></periodical><pages>47-65</pages><volume>52</volume><edition>2006/02/24</edition><keywords><keyword>Animals</keyword><keyword>Binding, Competitive</keyword><keyword>Humans</keyword><keyword>Intracellular Signaling Peptides and Proteins/metabolism/pharmacology</keyword><keyword>Membrane Proteins/metabolism/pharmacology</keyword><keyword>Peptide Fragments/metabolism/pharmacology</keyword><keyword>Receptors, Calcitonin/antagonists & inhibitors/metabolism</keyword><keyword>Receptors, Peptide/*antagonists & inhibitors/*metabolism</keyword></keywords><dates><year>2005</year></dates><isbn>1054-3589 (Print)
1054-3589 (Linking)</isbn><accession-num>16492540</accession-num><urls><related-urls><url>(05)52003-9 [pii]
10.1016/S1054-3589(05)52003-9</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Young 2005). Despite pharmacological evidence of amylin sensitivity in several peripheral tissues, selective amylin binding outside of the brain is observed only in the renal cortex.Amylin Receptor AntagonistPeptides such as AC187, salmon calcitonin (sCT), AC66, CGRP [8-37], which are typically analogues of truncated salmon calcitonin, have been developed as potent and selective amylin antagonists and have been useful in identifying amylinergic responses. Antagonism of a response with an order of potency of AC187> AC66 > CGRP [8-37] is suggestive that it is mediated via amylin receptors. Activation of a response with salmon calcitonin (sCT) > amylin > calcitonin gene-related peptide (CGRP) > mammalian CT suggests activation via the AMY1 receptor, while sCT = amylin >> CGRP > mammalian CT suggests activation via AMY3 receptors (Young A, 2005).AC-187 is particularly selective and potent at blocking amylin receptors ADDIN EN.CITE <EndNote><Cite><Author>Young</Author><Year>1994</Year><RecNum>164</RecNum><record><rec-number>164</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">164</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Young, A. A.</author><author>Gedulin, B.</author><author>Gaeta, L. S.</author><author>Prickett, K. S.</author><author>Beaumont, K.</author><author>Larson, E.</author><author>Rink, T. J.</author></authors></contributors><auth-address>Amylin Pharmaceuticals Inc, San Diego, CA 92121.</auth-address><titles><title>Selective amylin antagonist suppresses rise in plasma lactate after intravenous glucose in the rat. Evidence for a metabolic role of endogenous amylin</title><secondary-title>FEBS Lett</secondary-title></titles><pages>237-41</pages><volume>343</volume><number>3</number><edition>1994/05/02</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Amyloid/administration & dosage/*antagonists & inhibitors/physiology</keyword><keyword>Animals</keyword><keyword>Blood Glucose/analysis</keyword><keyword>Glucose/administration & dosage/*pharmacology</keyword><keyword>Injections, Intravenous</keyword><keyword>Insulin/blood</keyword><keyword>Lactates/*blood</keyword><keyword>Lactic Acid</keyword><keyword>Male</keyword><keyword>Molecular Sequence Data</keyword><keyword>Peptide Fragments</keyword><keyword>Peptides/*pharmacology</keyword><keyword>Rats</keyword><keyword>Rats, Sprague-Dawley</keyword></keywords><dates><year>1994</year><pub-dates><date>May 2</date></pub-dates></dates><isbn>0014-5793 (Print)</isbn><accession-num>8174707</accession-num><urls><related-urls><url>(94)80563-6 [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Young, Gedulin et al. 1994) and most often cited in studies using amylin antagonists. It also blocks amylin mediated excitatory effect on area postrema neurons and subfornical organ neurons. In addition it blocks amylin induced c-Fos expression in the area postrema PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaWVkaWdlcjwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+
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ADDIN EN.CITE.DATA (Riediger, Schmid et al. 2001). Biological Functions of AmylinAmylin has a number of biological functions both in animals and humans of which inhibition of post prandial glucagon secretion, delaying gastric emptying, and reduction of appetite and food intake are its most potent role. Amylin plays a vital role in maintaining glucose homeostasis by virtue of its activity on the stomach and glucagon secretion which is illustrated in REF _Ref323138956 \h Figure 7. Figure SEQ Figure \* ARABIC 7. Role of amylin in regulation of postprandial glycemiaThis slide demonstrates the actions of amylin in regulation of blood glucose in fed state. Following ingestion of food the rise in blood glucose stimulates the pancreas to secrete insulin along with amylin which proceeds through the circulation to reach the brain where it binds to nuclei to slow gastric emptying and decrease food intake both of which delay the delivery of nutrients to the circulation. In addition amylin reduces hyperglucagonemia in the postprandial period, thereby reducing the delivery of glucose from the liver into the circulation. Thus blood glucose is maintained by fine tuning of the rate of glucose appearance and glucose disappearance in the blood. Following ingestion of nutrient intake, glucose is released into the blood stream which stimulates the co-secretion of insulin and amylin from pancreatic beta cells. Amylin regulates postprandial glycaemia by suppression of glucagon release ADDIN EN.CITE <EndNote><Cite><Author>Ludvik</Author><Year>2003</Year><RecNum>323</RecNum><record><rec-number>323</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">323</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ludvik, B.</author><author>Thomaseth, K.</author><author>Nolan, J. J.</author><author>Clodi, M.</author><author>Prager, R.</author><author>Pacini, G.</author></authors></contributors><auth-address>Department of Medicine 3, University of Vienna Medical School, Austria. bernhard.ludvik@akh-wien.ac.at</auth-address><titles><title>Inverse relation between amylin and glucagon secretion in healthy and diabetic human subjects</title><secondary-title>Eur J Clin Invest</secondary-title></titles><periodical><full-title>Eur J Clin Invest</full-title></periodical><pages>316-22</pages><volume>33</volume><number>4</number><edition>2003/03/29</edition><keywords><keyword>Adult</keyword><keyword>Amyloid/*secretion</keyword><keyword>Blood Glucose/metabolism</keyword><keyword>Diabetes Mellitus, Type 2/etiology/*metabolism</keyword><keyword>Female</keyword><keyword>Glucagon/*secretion</keyword><keyword>Glucose/administration & dosage</keyword><keyword>Glucose Clamp Technique/methods</keyword><keyword>Humans</keyword><keyword>Islets of Langerhans/secretion</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword></keywords><dates><year>2003</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0014-2972 (Print)
0014-2972 (Linking)</isbn><accession-num>12662162</accession-num><urls><related-urls><url> [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Ludvik, Thomaseth et al. 2003), delaying gastric emptying PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb2x0ZXJtYW48L0F1dGhvcj48WWVhcj4xOTk1PC9ZZWFy
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ADDIN EN.CITE.DATA (Kolterman, Gottlieb et al. 1995; Young, Gedulin et al. 1995; Young 2005; Young 2005), inhibition of glucose release and hepatic glucose production ADDIN EN.CITE <EndNote><Cite><Author>Ludvik</Author><Year>1997</Year><RecNum>41</RecNum><record><rec-number>41</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">41</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ludvik, B.</author><author>Kautzky-Willer, A.</author><author>Prager, R.</author><author>Thomaseth, K.</author><author>Pacini, G.</author></authors></contributors><auth-address>Klinik fur Innere Medizin III, Abteilung fur Endokrinologie und Stoffwechsel, University of Vienna, Austria.</auth-address><titles><title>Amylin: history and overview</title><secondary-title>Diabet Med</secondary-title></titles><periodical><full-title>Diabet Med</full-title></periodical><pages>S9-13</pages><volume>14 Suppl 2</volume><edition>1997/06/01</edition><keywords><keyword>Amyloid/history/*physiology/secretion</keyword><keyword>Animals</keyword><keyword>Diabetes Mellitus, Type 2/etiology</keyword><keyword>Female</keyword><keyword>Glucose/metabolism</keyword><keyword>History, 20th Century</keyword><keyword>Homeostasis</keyword><keyword>Humans</keyword><keyword>Insulin/secretion</keyword><keyword>Male</keyword></keywords><dates><year>1997</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0742-3071 (Print)</isbn><accession-num>9212323</accession-num><urls><related-urls><url>(SICI)1096-9136(199706)14:2+<S9::AID-DIA397>3.0.CO;2-D</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Ludvik, Kautzky-Willer et al. 1997) and possibly by noncompetitively antagonizing the effect of insulin and increasing the activity of the glycogen synthase kinase 3 (GSK 3) ADDIN EN.CITE <EndNote><Cite><Author>Abaffy</Author><Year>2004</Year><RecNum>324</RecNum><record><rec-number>324</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">324</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Abaffy, T.</author><author>Cooper, G. J.</author></authors></contributors><auth-address>School of Biological Sciences, Faculty of Science, University of Auckland, 3A Symonds Street, Private Bag 92019, Auckland 1001, New Zealand. tabaffy@newssun.med.miami.edu</auth-address><titles><title>GSK3 involvement in amylin signaling in isolated rat soleus muscle</title><secondary-title>Peptides</secondary-title></titles><periodical><full-title>Peptides</full-title></periodical><pages>2119-25</pages><volume>25</volume><number>12</number><edition>2004/12/02</edition><keywords><keyword>Amyloid/pharmacology/*physiology</keyword><keyword>Animals</keyword><keyword>Calcitonin Gene-Related Peptide/pharmacology</keyword><keyword>Cyclic AMP/physiology</keyword><keyword>Deoxyglucose/metabolism</keyword><keyword>Glycogen/biosynthesis/metabolism</keyword><keyword>Glycogen Synthase Kinase 3/*metabolism</keyword><keyword>Insulin Resistance/physiology</keyword><keyword>Muscle, Skeletal/drug effects/*physiology</keyword><keyword>Rats</keyword></keywords><dates><year>2004</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0196-9781 (Print)
0196-9781 (Linking)</isbn><accession-num>15572200</accession-num><urls><related-urls><url>(04)00374-2 [pii]
10.1016/j.peptides.2004.08.016</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Abaffy and Cooper 2004). The most reported role in literature of amylin and pramlintide is inhibition of gastric emptying in animals PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DbGVtZW50aTwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+
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ADDIN EN.CITE.DATA (Young, Gedulin et al. 1995; Clementi, Caruso et al. 1996; Young, Gedulin et al. 1996), adult patients with type 1 and type 2 diabetes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb25nPC9BdXRob3I+PFllYXI+MTk5NzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Kong, King et al. 1997; Kong, Stubbs et al. 1998; Vella, Lee et al. 2002) and non-diabetic subjects ADDIN EN.CITE <EndNote><Cite><Author>Samsom</Author><Year>2000</Year><RecNum>327</RecNum><record><rec-number>327</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">327</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Samsom, M.</author><author>Szarka, L. A.</author><author>Camilleri, M.</author><author>Vella, A.</author><author>Zinsmeister, A. R.</author><author>Rizza, R. A.</author></authors></contributors><auth-address>Gastroenterology Research Unit, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA.</auth-address><titles><title>Pramlintide, an amylin analog, selectively delays gastric emptying: potential role of vagal inhibition</title><secondary-title>Am J Physiol Gastrointest Liver Physiol</secondary-title></titles><periodical><full-title>Am J Physiol Gastrointest Liver Physiol</full-title></periodical><pages>G946-51</pages><volume>278</volume><number>6</number><edition>2000/06/22</edition><keywords><keyword>Adult</keyword><keyword>Amyloid/*pharmacology</keyword><keyword>Blood Glucose/analysis</keyword><keyword>Colon/drug effects/physiology</keyword><keyword>Female</keyword><keyword>Gastric Emptying/*drug effects</keyword><keyword>Gastrointestinal Transit/drug effects</keyword><keyword>Humans</keyword><keyword>Intestine, Small/drug effects/physiology</keyword><keyword>Male</keyword><keyword>Neural Inhibition/*physiology</keyword><keyword>Pancreatic Polypeptide/blood</keyword><keyword>Time Factors</keyword><keyword>Vagus Nerve/*physiology</keyword></keywords><dates><year>2000</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0193-1857 (Print)
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ADDIN EN.CITE.DATA (Young, Gedulin et al. 1996). In particular, amylin is 15- to 20 fold more potent than GLP-1 and CCK PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Zb3VuZzwvQXV0aG9yPjxZZWFyPjE5OTY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Gedulin 1996; Young, Gedulin et al. 1996). It is also known to inhibit gastric acid secretion and maintain gastric mucosal integrity ADDIN EN.CITE <EndNote><Cite><Author>Young</Author><Year>2005</Year><RecNum>293</RecNum><record><rec-number>293</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">293</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Young, A.</author></authors></contributors><auth-address>Amylin Pharmaceuticals, Inc., San Diego, California, USA.</auth-address><titles><title>Effects on digestive secretions</title><secondary-title>Adv Pharmacol</secondary-title></titles><periodical><full-title>Adv Pharmacol</full-title></periodical><pages>123-50</pages><volume>52</volume><edition>2006/02/24</edition><keywords><keyword>Amyloid/*pharmacology/physiology</keyword><keyword>Animals</keyword><keyword>Anti-Ulcer Agents/pharmacology</keyword><keyword>Digestive System/*drug effects/metabolism</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Gastric Acid/secretion</keyword><keyword>Rats</keyword></keywords><dates><year>2005</year></dates><isbn>1054-3589 (Print)</isbn><accession-num>16492544</accession-num><urls><related-urls><url>(05)52007-6 [pii]
10.1016/S1054-3589(05)52007-6</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Young 2005). Amylin is also known to control the central mechanisms responsible for food intake and for the feeling of satiety and thirst. Amylin decreases food intake PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb3JsZXk8L0F1dGhvcj48WWVhcj4xOTkxPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Morley and Flood 1991; Lutz, Del Prete et al. 1994). Amylin appears to reduce food intake centrally by activation of receptors in area postrema, a circumventricular organ outside the blood brain barrier involved in regulating food intake and peripherally through augmenting the actions of other gut peptides such as CCK, glucagon, and bombesin, all of which inhibit food intake by stimulating ascending vagal fibers and secretion of amylin. In addition amylin may decrease food intake by inducing anorexia through its effect on brain by increasing the transport of the precursor tryptophan into the brain to inhibit feeding and increase satiation by serotonin action in the paraventricular nucleus, stimulating histamine H1 receptors, inhibition of stimulation of feeding by potent hypothalamic neuropeptide Y (NPY) and peripherally by inhibition of nitric oxide which is a major regulatory agent in the gastrointestinal tract ADDIN EN.CITE <EndNote><Cite><Author>Reda</Author><Year>2002</Year><RecNum>185</RecNum><record><rec-number>185</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">185</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Reda, T. K.</author><author>Geliebter, A.</author><author>Pi-Sunyer, F. X.</author></authors></contributors><auth-address>New York Obesity Research Center, Department of Medicine, St.-Luke's-Roosevelt Hospital Center, Columbia University-College of Physicians and Surgeons, New York, USA. tarekreda@</auth-address><titles><title>Amylin, food intake, and obesity</title><secondary-title>Obes Res</secondary-title></titles><pages>1087-91</pages><volume>10</volume><number>10</number><edition>2002/10/12</edition><keywords><keyword>Amyloid/chemistry/pharmacology/*physiology</keyword><keyword>Eating/*physiology</keyword><keyword>Female</keyword><keyword>Gastric Emptying/physiology</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Obesity/*metabolism</keyword><keyword>Satiety Response/physiology</keyword></keywords><dates><year>2002</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1071-7323 (Print)</isbn><accession-num>12376591</accession-num><urls><related-urls><url>;(Reda, Geliebter et al. 2002). Amylin significantly increased water intake in euhydrated rats by activating neurons in the subfornical organ of the brain suggesting amylin release during food intake may stimulate prandial drinking ADDIN EN.CITE <EndNote><Cite><Author>Riediger</Author><Year>1999</Year><RecNum>113</RecNum><record><rec-number>113</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">113</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Riediger, T.</author><author>Rauch, M.</author><author>Schmid, H. A.</author></authors></contributors><auth-address>Max-Planck-Institut fur physiologische und klinische Forschung, W. G. Kerckhoff-Institut, 61231 Bad Nauheim, Germany.</auth-address><titles><title>Actions of amylin on subfornical organ neurons and on drinking behavior in rats</title><secondary-title>Am J Physiol</secondary-title></titles><periodical><full-title>Am J Physiol</full-title></periodical><pages>R514-21</pages><volume>276</volume><number>2 Pt 2</number><edition>1999/02/10</edition><keywords><keyword>1-Sarcosine-8-Isoleucine Angiotensin II/pharmacology</keyword><keyword>Amyloid/*pharmacology</keyword><keyword>Angiotensin II/antagonists & inhibitors</keyword><keyword>Animals</keyword><keyword>Drinking Behavior/*drug effects</keyword><keyword>Electrophysiology</keyword><keyword>Losartan/pharmacology</keyword><keyword>Male</keyword><keyword>Neurons/*drug effects/physiology</keyword><keyword>Peptide Fragments</keyword><keyword>Peptides/pharmacology</keyword><keyword>Rats</keyword><keyword>Rats, Wistar</keyword><keyword>Receptors, Peptide/antagonists & inhibitors</keyword><keyword>Subfornical Organ/cytology/*drug effects</keyword></keywords><dates><year>1999</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0002-9513 (Print)</isbn><accession-num>9950932</accession-num><urls><related-urls><url>;(Riediger, Rauch et al. 1999).Amylin has also been found to be a growth factor for cells involved in bone metabolism PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db3JuaXNoPC9BdXRob3I+PFllYXI+MTk5NTwvWWVhcj48
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ADDIN EN.CITE.DATA (Cornish, Callon et al. 1995; Cornish, Callon et al. 1998) and differentiation of osteoclast ADDIN EN.CITE <EndNote><Cite><Author>Cornish</Author><Year>2001</Year><RecNum>94</RecNum><record><rec-number>94</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">94</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cornish, J.</author><author>Callon, K. E.</author><author>Bava, U.</author><author>Kamona, S. A.</author><author>Cooper, G. J.</author><author>Reid, I. R.</author></authors></contributors><auth-address>Department of Medicine and School of Biological Sciences, University of Auckland, Auckland, New Zealand. j.cornish@auckland.ac.nz</auth-address><titles><title>Effects of calcitonin, amylin, and calcitonin gene-related peptide on osteoclast development</title><secondary-title>Bone</secondary-title></titles><periodical><full-title>Bone</full-title></periodical><pages>162-8</pages><volume>29</volume><number>2</number><edition>2001/08/15</edition><keywords><keyword>Amyloid/*pharmacology</keyword><keyword>Animals</keyword><keyword>Autoradiography</keyword><keyword>Calcitonin/*pharmacology</keyword><keyword>Calcitonin Gene-Related Peptide/*pharmacology</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Osteoclasts/cytology/*drug effects</keyword><keyword>Rats</keyword></keywords><dates><year>2001</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>8756-3282 (Print)</isbn><accession-num>11502478</accession-num><urls><related-urls><url>(01)00494-X [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Cornish, Callon et al. 2001) and inhibition of bone resorption ADDIN EN.CITE <EndNote><Cite><Author>Bronsky</Author><Year>2002</Year><RecNum>56</RecNum><record><rec-number>56</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">56</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bronsky, J.</author><author>Chada, M.</author><author>Kotaska, K.</author><author>Prusa, R.</author></authors></contributors><auth-address>Ustav klinicke biochemie a patobiochemie 2. LF UK a FN Motol, Praha. bronsky@email.cz</auth-address><titles><title>[Amylin--its physiological role in humans]</title><secondary-title>Cesk Fysiol</secondary-title></titles><pages>176-80</pages><volume>51</volume><number>4</number><edition>2003/03/01</edition><keywords><keyword>Amyloid/*physiology</keyword><keyword>Animals</keyword><keyword>Blood Glucose/metabolism</keyword><keyword>Bone and Bones/metabolism</keyword><keyword>Diabetes Mellitus/blood</keyword><keyword>Eating/physiology</keyword><keyword>Glucagon/secretion</keyword><keyword>Humans</keyword></keywords><dates><year>2002</year><pub-dates><date>Dec</date></pub-dates></dates><orig-pub>Amylin--fyziologicka uloha v lidskem organismu.</orig-pub><isbn>1210-6313 (Print)</isbn><accession-num>12608111</accession-num><urls><related-urls><url>;(Bronsky, Chada et al. 2002) which helps increase bone density and bone mass ADDIN EN.CITE <EndNote><Cite><Author>Cornish</Author><Year>2002</Year><RecNum>321</RecNum><record><rec-number>321</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">321</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cornish, J.</author><author>Naot, D.</author></authors></contributors><auth-address>Department of Medicine, University of Auckland, Auckland, New Zealand. j.cornish@auckland.ac.nz</auth-address><titles><title>Amylin and adrenomedullin: novel regulators of bone growth</title><secondary-title>Curr Pharm Des</secondary-title></titles><periodical><full-title>Curr Pharm Des</full-title></periodical><pages>2009-21</pages><volume>8</volume><number>23</number><edition>2002/08/13</edition><keywords><keyword>Adrenomedullin</keyword><keyword>Amino Acid Sequence</keyword><keyword>Amyloid/*metabolism</keyword><keyword>Animals</keyword><keyword>Bone Development/drug effects/*physiology</keyword><keyword>Bone Remodeling/drug effects/physiology</keyword><keyword>Bone and Bones/cytology/drug effects/physiology</keyword><keyword>Cell Division</keyword><keyword>Cell Line</keyword><keyword>Molecular Sequence Data</keyword><keyword>Osteoblasts/cytology/physiology</keyword><keyword>Peptide Fragments/pharmacology</keyword><keyword>Peptide Hormones/*metabolism</keyword><keyword>Peptides/*metabolism</keyword><keyword>Receptors, Calcitonin/metabolism</keyword><keyword>Receptors, Calcitonin Gene-Related Peptide/metabolism</keyword></keywords><dates><year>2002</year></dates><isbn>1381-6128 (Print)
1381-6128 (Linking)</isbn><accession-num>12171515</accession-num><urls><related-urls><url>;(Cornish and Naot 2002). Amylin is found to be a growth factor for isolated fetal beta cells which may have a role in the development of fetal pancreas ADDIN EN.CITE <EndNote><Cite><Author>Karlsson</Author><Year>2001</Year><RecNum>92</RecNum><record><rec-number>92</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">92</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Karlsson, E.</author><author>Sandler, S.</author></authors></contributors><auth-address>Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden. Ella.Karlsson@medcellbiol.uu.se</auth-address><titles><title>Islet amyloid polypeptide promotes beta-cell proliferation in neonatal rat pancreatic islets</title><secondary-title>Diabetologia</secondary-title></titles><periodical><full-title>Diabetologia</full-title></periodical><pages>1015-8</pages><volume>44</volume><number>8</number><edition>2001/08/03</edition><keywords><keyword>Amyloid/*pharmacology</keyword><keyword>Animals</keyword><keyword>*Animals, Newborn</keyword><keyword>Apoptosis</keyword><keyword>Autoradiography</keyword><keyword>Cell Division/*drug effects</keyword><keyword>DNA/biosynthesis</keyword><keyword>Female</keyword><keyword>Gestational Age</keyword><keyword>In Situ Nick-End Labeling</keyword><keyword>Insulin/metabolism</keyword><keyword>Islets of Langerhans/*cytology/drug effects/metabolism</keyword><keyword>Pregnancy</keyword><keyword>Rats</keyword><keyword>Rats, Sprague-Dawley</keyword></keywords><dates><year>2001</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0012-186X (Print)</isbn><accession-num>11484079</accession-num><urls><related-urls><url>;(Karlsson and Sandler 2001).Amylin is a potent proliferation factor both during the development of proximal tubules ADDIN EN.CITE <EndNote><Cite><Author>Wookey</Author><Year>1998</Year><RecNum>32</RecNum><record><rec-number>32</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">32</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wookey, P. J.</author><author>Tikellis, C.</author><author>Nobes, M.</author><author>Casley, D.</author><author>Cooper, M. E.</author><author>Darby, I. A.</author></authors></contributors><auth-address>Department of Medicine, University of Melbourne, Bundoora, Victoria, Australia. wookey@austin.unimelb.edu.au</auth-address><titles><title>Amylin as a growth factor during fetal and postnatal development of the rat kidney</title><secondary-title>Kidney Int</secondary-title></titles><pages>25-30</pages><volume>53</volume><number>1</number><edition>1998/02/07</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Amyloid/analysis/genetics/*physiology</keyword><keyword>Animals</keyword><keyword>Cells, Cultured</keyword><keyword>Growth Substances/*physiology</keyword><keyword>Kidney/embryology/*growth & development</keyword><keyword>Molecular Sequence Data</keyword><keyword>RNA, Messenger/analysis</keyword><keyword>Rats</keyword><keyword>Rats, Sprague-Dawley</keyword></keywords><dates><year>1998</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0085-2538 (Print)</isbn><accession-num>9452996</accession-num><urls><related-urls><url>;(Wookey, Tikellis et al. 1998) and in the proliferation of adult epithelial cells PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYXJyaXM8L0F1dGhvcj48WWVhcj4xOTk3PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Harris, Cooper et al. 1997). Amylin at physiological doses has been shown to stimulate renin activity in both rats ADDIN EN.CITE <EndNote><Cite><Author>Wookey</Author><Year>1996</Year><RecNum>97</RecNum><record><rec-number>97</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">97</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wookey, P. J.</author><author>Tikellis, C.</author><author>Du, H. C.</author><author>Qin, H. F.</author><author>Sexton, P. M.</author><author>Cooper, M. E.</author></authors></contributors><auth-address>Department of Medicine, University of Melbourne, Victoria, Australia.</auth-address><titles><title>Amylin binding in rat renal cortex, stimulation of adenylyl cyclase, and activation of plasma renin</title><secondary-title>Am J Physiol</secondary-title></titles><periodical><full-title>Am J Physiol</full-title></periodical><pages>F289-94</pages><volume>270</volume><number>2 Pt 2</number><edition>1996/02/01</edition><keywords><keyword>Adenylate Cyclase/*metabolism</keyword><keyword>Amino Acid Sequence</keyword><keyword>Amyloid/antagonists & inhibitors/*metabolism/pharmacology</keyword><keyword>Animals</keyword><keyword>Binding Sites</keyword><keyword>Binding, Competitive</keyword><keyword>Calcitonin/metabolism</keyword><keyword>Calcitonin Gene-Related Peptide/metabolism</keyword><keyword>Chimera</keyword><keyword>Kidney Cortex/*metabolism</keyword><keyword>Molecular Sequence Data</keyword><keyword>Peptide Fragments/genetics/metabolism</keyword><keyword>Rats</keyword><keyword>Rats, Sprague-Dawley</keyword><keyword>Renin/*blood</keyword><keyword>Salmon</keyword></keywords><dates><year>1996</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0002-9513 (Print)</isbn><accession-num>8779889</accession-num><urls><related-urls><url>;(Wookey, Tikellis et al. 1996) and man ADDIN EN.CITE <EndNote><Cite><Author>Cooper</Author><Year>1995</Year><RecNum>98</RecNum><record><rec-number>98</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">98</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cooper, M. E.</author><author>McNally, P. G.</author><author>Phillips, P. A.</author><author>Johnston, C. I.</author></authors></contributors><auth-address>Department of Medicine, University of Melbourne, Austin & Repatriation Medical Centre, Heidelberg, Australia.</auth-address><titles><title>Amylin stimulates plasma renin concentration in humans</title><secondary-title>Hypertension</secondary-title></titles><pages>460-4</pages><volume>26</volume><number>3</number><edition>1995/09/01</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Amyloid/blood/*pharmacology</keyword><keyword>Calcitonin Gene-Related Peptide/pharmacology</keyword><keyword>Double-Blind Method</keyword><keyword>Humans</keyword><keyword>Insulin Resistance</keyword><keyword>Male</keyword><keyword>Renin/*genetics</keyword></keywords><dates><year>1995</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0194-911X (Print)</isbn><accession-num>7649582</accession-num><urls><related-urls><url>;(Cooper, McNally et al. 1995) and demonstrates a modest pressor effect PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db29wZXI8L0F1dGhvcj48WWVhcj4xOTk1PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Cooper, McNally et al. 1995; Haynes, Hodgson et al. 1997) possibly mediated by insulin-induced changes in rennin release ADDIN EN.CITE <EndNote><Cite><Author>Ikeda</Author><Year>2001</Year><RecNum>100</RecNum><record><rec-number>100</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">100</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ikeda, T.</author><author>Iwata, K.</author><author>Ochi, H.</author></authors></contributors><auth-address>School of Health Science, Faculty of Medicine, Tottori University, and Yonago Hakuai Hospital, Yonago, Japan.</auth-address><titles><title>Effect of insulin, proinsulin, and amylin on renin release from perfused rat kidney</title><secondary-title>Metabolism</secondary-title></titles><pages>763-6</pages><volume>50</volume><number>7</number><edition>2001/07/04</edition><keywords><keyword>Amyloid/*pharmacology</keyword><keyword>Angiotensins/analysis</keyword><keyword>Animals</keyword><keyword>Cyclic AMP/analysis</keyword><keyword>Hypertension/etiology</keyword><keyword>Insulin/*pharmacology/physiology</keyword><keyword>Kidney/*drug effects/metabolism</keyword><keyword>Male</keyword><keyword>Perfusion</keyword><keyword>Proinsulin/*pharmacology</keyword><keyword>Rats</keyword><keyword>Rats, Wistar</keyword><keyword>Renin/*metabolism</keyword></keywords><dates><year>2001</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0026-0495 (Print)</isbn><accession-num>11436178</accession-num><urls><related-urls><url>(01)04788-6 [pii]
10.1053/meta.2001.24200</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Ikeda, Iwata et al. 2001). In addition renal amylin binding sites in proximal tubules could be correlated with blood pressure in rat models of renal hypertension PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Xb29rZXk8L0F1dGhvcj48WWVhcj4xOTk4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Cao, Wookey et al. 1997; Wookey, Cao et al. 1997; Wookey, Cao et al. 1998; Wookey and Cooper 1998). Amylin has been reported to induce relaxation of aortic rings ADDIN EN.CITE <EndNote><Cite><Author>Luk'yantseva</Author><Year>2001</Year><RecNum>104</RecNum><record><rec-number>104</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">104</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Luk'yantseva, G. V.</author><author>Sergeev, I. Y.</author><author>Kopylova, G. N.</author><author>Samonina, G. E.</author><author>German, S. V.</author></authors></contributors><auth-address>Department of Human and Animal Physiology, Biological Faculty, M. V. Lomonosov Moscow State University.</auth-address><titles><title>Effect of amylin on the tone of rat aorta ring preparation</title><secondary-title>Bull Exp Biol Med</secondary-title></titles><pages>932-4</pages><volume>132</volume><number>4</number><edition>2002/01/10</edition><keywords><keyword>Acetylcholine/pharmacology</keyword><keyword>Amyloid/*pharmacology</keyword><keyword>Animals</keyword><keyword>Aorta/pathology</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Endothelium, Vascular/metabolism</keyword><keyword>Male</keyword><keyword>Muscle, Smooth/cytology</keyword><keyword>Nitric Oxide Synthase/metabolism</keyword><keyword>Norepinephrine/metabolism</keyword><keyword>Rats</keyword></keywords><dates><year>2001</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0007-4888 (Print)</isbn><accession-num>11782784</accession-num><urls><related-urls><url>;(Luk'yantseva, Sergeev et al. 2001), inhibit CCK induced contraction of smooth muscle cells PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PY2hpYWk8L0F1dGhvcj48WWVhcj4yMDAxPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Young, Rink et al. 1993; Bronsky, Chada et al. 2002) probably by inhibiting the secretion of the atrial natriuretic peptide through CGRP1 and CT receptors ADDIN EN.CITE <EndNote><Cite><Author>Piao</Author><Year>2004</Year><RecNum>322</RecNum><record><rec-number>322</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">322</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Piao, F. L.</author><author>Cao, C.</author><author>Han, J. H.</author><author>Kim, S. Z.</author><author>Cho, K. W.</author><author>Kim, S. H.</author></authors></contributors><auth-address>Department of Physiology, Institute for Medical Sciences, Chonbuk National University Medical School, 2-20 Keum-Am-Dong-San, Jeonju 561-180, South Korea.</auth-address><titles><title>Amylin-induced suppression of ANP secretion through receptors for CGRP1 and salmon calcitonin</title><secondary-title>Regul Pept</secondary-title></titles><periodical><full-title>Regul Pept</full-title></periodical><pages>159-66</pages><volume>117</volume><number>3</number><edition>2004/01/30</edition><keywords><keyword>Amyloid/*pharmacology</keyword><keyword>Animals</keyword><keyword>Atrial Function</keyword><keyword>Atrial Natriuretic Factor/antagonists & inhibitors/biosynthesis/*secretion</keyword><keyword>Blood Pressure</keyword><keyword>Calcitonin/*physiology</keyword><keyword>Diabetes Mellitus, Experimental/pathology</keyword><keyword>Down-Regulation</keyword><keyword>Male</keyword><keyword>Pulse</keyword><keyword>Rats</keyword><keyword>Receptors, Calcitonin/antagonists & inhibitors/*physiology</keyword><keyword>Receptors, Calcitonin Gene-Related Peptide/antagonists &</keyword><keyword>inhibitors/*physiology</keyword></keywords><dates><year>2004</year><pub-dates><date>Mar 15</date></pub-dates></dates><isbn>0167-0115 (Print)
0167-0115 (Linking)</isbn><accession-num>14749035</accession-num><urls><related-urls><url> [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Piao, Cao et al. 2004), and exerts anti-inflammatory activity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWxsPC9BdXRob3I+PFllYXI+MTk5OTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Hall and Brain 1999) possibly due to cross reactions with CGRP receptors ADDIN EN.CITE <EndNote><Cite><Author>Zhu</Author><Year>1991</Year><RecNum>215</RecNum><record><rec-number>215</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">215</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zhu, G. C.</author><author>Dudley, D. T.</author><author>Saltiel, A. R.</author></authors></contributors><auth-address>Department of Physiology, University of Michigan Medical School, Ann Arbor 48109.</auth-address><titles><title>Amylin increases cyclic AMP formation in L6 myocytes through calcitonin gene-related peptide receptors</title><secondary-title>Biochem Biophys Res Commun</secondary-title></titles><pages>771-6</pages><volume>177</volume><number>2</number><edition>1991/06/14</edition><keywords><keyword>Amyloid/*pharmacology</keyword><keyword>Animals</keyword><keyword>Brain/drug effects/metabolism</keyword><keyword>Calcitonin Gene-Related Peptide/*metabolism/pharmacology</keyword><keyword>Cell Line</keyword><keyword>Cell Membrane/drug effects/metabolism</keyword><keyword>Cyclic AMP/*metabolism</keyword><keyword>Liver/drug effects/metabolism</keyword><keyword>Muscles/drug effects/*metabolism</keyword><keyword>Peptide Fragments/pharmacology</keyword><keyword>Rats</keyword><keyword>Rats, Inbred Strains</keyword><keyword>Receptors, Calcitonin</keyword><keyword>Receptors, Cell Surface/drug effects/*metabolism</keyword></keywords><dates><year>1991</year><pub-dates><date>Jun 14</date></pub-dates></dates><isbn>0006-291X (Print)</isbn><accession-num>1646609</accession-num><urls><related-urls><url>;(Zhu, Dudley et al. 1991). Like CGRP amylin may also play a role in maternal sepsis and shock ADDIN EN.CITE <EndNote><Cite><Author>Parida</Author><Year>1998</Year><RecNum>256</RecNum><record><rec-number>256</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">256</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Parida, S. K.</author><author>Schneider, D. B.</author><author>Stoss, T. D.</author><author>Pauly, T. H.</author><author>McGillis, J. P.</author></authors></contributors><auth-address>Department of Pediatrics, University of Kentucky College of Medicine, Lexington 40536-0084, USA.</auth-address><titles><title>Elevated circulating calcitonin gene-related peptide in umbilical cord and infant blood associated with maternal and neonatal sepsis and shock</title><secondary-title>Pediatr Res</secondary-title></titles><periodical><full-title>Pediatr Res</full-title></periodical><pages>276-82</pages><volume>43</volume><number>2</number><edition>1998/02/25</edition><keywords><keyword>Adult</keyword><keyword>Calcitonin Gene-Related Peptide/*blood</keyword><keyword>Chromatography, High Pressure Liquid</keyword><keyword>Female</keyword><keyword>Fetal Blood/*chemistry</keyword><keyword>Gestational Age</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Newborn, Diseases/*blood</keyword><keyword>Infant, Premature</keyword><keyword>Male</keyword><keyword>Maternal-Fetal Exchange</keyword><keyword>Pregnancy</keyword><keyword>Radioimmunoassay</keyword><keyword>Shock, Septic/*blood</keyword></keywords><dates><year>1998</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0031-3998 (Print)</isbn><accession-num>9475297</accession-num><urls><related-urls><url>;(Parida, Schneider et al. 1998).Mechanisms of Amylin Action at Molecular levelExperimental investigations in rodents indicate that the gastrointestinal effects of amylin are mediated via a central pathway that involves the area postrema and visceral efferents of the vagus nerve. The area postrema in the brainstem which contains a high density of amylin binding sites (Figure 7) is exposed to changes in plasma amylin and specifically co-excited by glucose PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaWVkaWdlcjwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+
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ADDIN EN.CITE.DATA (Riediger, Schmid et al. 2002) because it does not have a blood-brain barrier ADDIN EN.CITE <EndNote><Cite><Author>Gross</Author><Year>1992</Year><RecNum>168</RecNum><record><rec-number>168</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">168</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Gross,PM</author></authors><secondary-authors><author>Ermisch A, Landgraf R, and Ruhle HJ</author></secondary-authors></contributors><titles><title>Circumventricular organ capillaries. In: Circumventricular Organs and Brain Fluid Environment</title></titles><section>219-233</section><dates><year>1992</year></dates><pub-location>Amsterdam, The Netherlands</pub-location><publisher>Elsevier</publisher><urls></urls></record></Cite></EndNote>(Gross 1992). As there is no unique amylin receptor gene, the most likely mechanism of amylin action at molecular level in the brain and elsewhere is likely to be through CTR and RAMPs bestowing functionality to the amylin receptors and binding sites ( REF _Ref323157264 \h \* MERGEFORMAT Figure 8). Figure 8. Amylin binding sites in rat brainAn audioradiograph of the rat brain demonstrating major binding sites containing amylin receptors in nucleus accumbens, the dorsal raphe, and the area postrema which are thought to be important in regulation of appetite as well as sympathetic and parasympathetic tone. In addition peripherally injected amylin strongly activates neurons of nucleus tractus solitarius PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaWVkaWdlcjwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+
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ADDIN EN.CITE.DATA (van der Kooy and Koda 1983; Shapiro and Miselis 1985). Selective lesioning of the area postrema and/or bilateral vagotomy abolishes the effect of amylin on gastric emptying ADDIN EN.CITE <EndNote><Cite><Author>Edwards</Author><Year>1998</Year><RecNum>165</RecNum><record><rec-number>165</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">165</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Edwards, G; Gedulin, BR; Jodka, C; Dilts, RP; Miller, CC; Young, A</author></authors></contributors><titles><title>Area postrema (AP)-lesions block the regulation of gastric emptying by amylin (Abstract)</title><secondary-title>Neurogastroenterol Motil</secondary-title></titles><periodical><full-title>Neurogastroenterol Motil</full-title></periodical><volume>10</volume><number>26A</number><dates><year>1998</year></dates><urls></urls></record></Cite><Cite><Author>Jodka</Author><Year>1996</Year><RecNum>166</RecNum><record><rec-number>166</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">166</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jodka, C; Green, D; Young, A; Gedulin, B</author></authors></contributors><titles><title>Amylin modulation of gastric emptying in rats depends upon an intact vagus nerve (Abstract)</title><secondary-title>Diabetes</secondary-title></titles><periodical><full-title>Diabetes</full-title></periodical><volume>45 (Suppl. 2)</volume><number>235A</number><dates><year>1996</year></dates><urls></urls></record></Cite></EndNote>(Jodka 1996; Edwards 1998) demonstrating the importance of this central pathway in mediating amylin’s physiological functions. In addition the effect of amylin to slow gastric emptying is overridden in the presence of hypoglycaemia ADDIN EN.CITE <EndNote><Cite><Author>Gedulin</Author><Year>1998</Year><RecNum>167</RecNum><record><rec-number>167</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">167</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gedulin, B. R.</author><author>Young, A. A.</author></authors></contributors><auth-address>Amylin Pharmaceuticals, San Diego, California 92121, USA.</auth-address><titles><title>Hypoglycemia overrides amylin-mediated regulation of gastric emptying in rats</title><secondary-title>Diabetes</secondary-title></titles><periodical><full-title>Diabetes</full-title></periodical><pages>93-7</pages><volume>47</volume><number>1</number><edition>1998/01/08</edition><keywords><keyword>3-O-Methylglucose/blood/metabolism</keyword><keyword>Amyloid/administration & dosage/pharmacology/*physiology</keyword><keyword>Animals</keyword><keyword>Blood Glucose/analysis/metabolism</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Gastric Emptying/*physiology</keyword><keyword>Glucose/administration & dosage/metabolism/pharmacology</keyword><keyword>Hypoglycemia/chemically induced/*physiopathology</keyword><keyword>Injections, Intravenous</keyword><keyword>Injections, Subcutaneous</keyword><keyword>Insulin/administration & dosage/adverse effects/pharmacology</keyword><keyword>Male</keyword><keyword>Phenolsulfonphthalein</keyword><keyword>Rats</keyword><keyword>Tritium</keyword></keywords><dates><year>1998</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0012-1797 (Print)</isbn><accession-num>9421380</accession-num><urls><related-urls><url>;(Gedulin and Young 1998). Amylin exerts its inhibitory action on glucagon by mechanisms extrinsic to pancreas ADDIN EN.CITE <EndNote><Cite><Author>Silvestre</Author><Year>2001</Year><RecNum>326</RecNum><record><rec-number>326</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">326</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Silvestre, R. A.</author><author>Rodriguez-Gallardo, J.</author><author>Jodka, C.</author><author>Parkes, D. G.</author><author>Pittner, R. A.</author><author>Young, A. A.</author><author>Marco, J.</author></authors></contributors><auth-address>Clinica Puerta de Hierro and Department of Physiology, Universidad Autonoma de Madrid, San Martin de Porres, 4 28035 Madrid, Spain.</auth-address><titles><title>Selective amylin inhibition of the glucagon response to arginine is extrinsic to the pancreas</title><secondary-title>Am J Physiol Endocrinol Metab</secondary-title></titles><periodical><full-title>Am J Physiol Endocrinol Metab</full-title></periodical><pages>E443-9</pages><volume>280</volume><number>3</number><edition>2001/02/15</edition><keywords><keyword>Amyloid/*pharmacology</keyword><keyword>Animals</keyword><keyword>Arginine/*pharmacology</keyword><keyword>Carbachol/pharmacology</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Glucagon/*secretion</keyword><keyword>Glucose/administration & dosage/pharmacology</keyword><keyword>Glucose Clamp Technique</keyword><keyword>Hypoglycemia/physiopathology</keyword><keyword>Islets of Langerhans/drug effects/secretion</keyword><keyword>Male</keyword><keyword>Pancreas/*drug effects/*secretion</keyword><keyword>Rats</keyword><keyword>Rats, Inbred Lew</keyword><keyword>Rats, Wistar</keyword><keyword>Vasoactive Intestinal Peptide/pharmacology</keyword></keywords><dates><year>2001</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0193-1849 (Print)
0193-1849 (Linking)</isbn><accession-num>11171599</accession-num><urls><related-urls><url>;(Silvestre, Rodriguez-Gallardo et al. 2001). Thus amylin contributes to metabolic control by regulating nutrient influx into the blood resulting in increased glucose disposal and slowing nutrient delivery and postprandial hyperglycemia. Two main regions of the circumventricular organs in the rat brain ( REF _Ref323409807 \h \* MERGEFORMAT Figure 9) namely subfornical organ and area postrema mediate peripheral variations in amylin levels via receptors including drinking PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaWVkaWdlcjwvQXV0aG9yPjxZZWFyPjE5OTk8L1llYXI+
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ADDIN EN.CITE.DATA (Lutz, Senn et al. 1998; Riediger, Schmid et al. 2001) respectively. Figure SEQ Figure \* ARABIC 9. Location of amylin action within circumventricular organs in rat brainThe circumventricular region contains a rich capillary plexus and has a fenestrated endothelium rendering the structures outside of the blood brain barrier. It is made up of 7 organs namely median eminence, organum vasculosum of the lamina terminalis, subfornical organ, choroid plexus, pineal gland, and subcommissural organ and area postrema. Image courtesy of peripherally applied amylin inhibits feeding through binding sites in area postrema and nucleus accumbens PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gUm9zc3VtPC9BdXRob3I+PFllYXI+MTk5NDwvWWVh
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ADDIN EN.CITE.DATA (Baldo and Kelley 2001) and is independent of vagal afferents ADDIN EN.CITE <EndNote><Cite><Author>Lutz</Author><Year>1995</Year><RecNum>170</RecNum><record><rec-number>170</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">170</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lutz, T. A.</author><author>Del Prete, E.</author><author>Scharrer, E.</author></authors></contributors><auth-address>Institute of Veterinary Physiology, University of Zuerich, Switzerland.</auth-address><titles><title>Subdiaphragmatic vagotomy does not influence the anorectic effect of amylin</title><secondary-title>Peptides</secondary-title></titles><periodical><full-title>Peptides</full-title></periodical><pages>457-62</pages><volume>16</volume><number>3</number><edition>1995/01/01</edition><keywords><keyword>Abdomen/*innervation</keyword><keyword>Amyloid/*pharmacology</keyword><keyword>Animals</keyword><keyword>Appetite Depressants/*pharmacology</keyword><keyword>Diaphragm/innervation</keyword><keyword>Feeding Behavior/*drug effects</keyword><keyword>Food Deprivation</keyword><keyword>Gastric Emptying/drug effects</keyword><keyword>Injections, Intraperitoneal</keyword><keyword>Male</keyword><keyword>Rats</keyword><keyword>Vagotomy</keyword><keyword>Vagus Nerve/*physiology</keyword></keywords><dates><year>1995</year></dates><isbn>0196-9781 (Print)</isbn><accession-num>7651899</accession-num><urls><related-urls><url>(94)00203-I [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Lutz, Del Prete et al. 1995). Amylin may induce anorexia through stimulating H1 receptors ADDIN EN.CITE <EndNote><Cite><Author>Mollet</Author><Year>2001</Year><RecNum>122</RecNum><record><rec-number>122</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">122</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mollet, A.</author><author>Lutz, T. A.</author><author>Meier, S.</author><author>Riediger, T.</author><author>Rushing, P. A.</author><author>Scharrer, E.</author></authors></contributors><auth-address>Institute of Veterinary Physiology, University of Zurich, 8057 Zurich, Switzerland.</auth-address><titles><title>Histamine H1 receptors mediate the anorectic action of the pancreatic hormone amylin</title><secondary-title>Am J Physiol Regul Integr Comp Physiol</secondary-title></titles><periodical><full-title>Am J Physiol Regul Integr Comp Physiol</full-title></periodical><pages>R1442-8</pages><volume>281</volume><number>5</number><edition>2001/10/20</edition><keywords><keyword>Amyloid/*pharmacology</keyword><keyword>Animals</keyword><keyword>Anorexia/metabolism</keyword><keyword>Body Weight</keyword><keyword>Calcitonin/pharmacology</keyword><keyword>Cholecystokinin/pharmacology</keyword><keyword>Eating/*drug effects</keyword><keyword>Histamine Antagonists/pharmacology</keyword><keyword>Leptin/pharmacology</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Mice, Knockout</keyword><keyword>Pancreas/chemistry</keyword><keyword>Piperidines/pharmacology</keyword><keyword>Receptors, Histamine H1/genetics/*metabolism</keyword></keywords><dates><year>2001</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0363-6119 (Print)</isbn><accession-num>11641114</accession-num><urls><related-urls><url>;(Mollet, Lutz et al. 2001) and this effect is attenuated with dopamine D2 receptor antagonists PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MdXR6PC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Morley and Flood 1994; Morley, Flood et al. 1995). In summary amylin is a neuroendocrine hormone which helps in regulating feeding behaviour by reducing meal size, increasing satiety and anorexia by stimulating neurons particularly in the area postrema and hindbrain. History of Discovery of AmylinAlthough the presence of amyloid deposits within the islet was first described at the beginning of the 20th century, it was not until 1987 that the structure of amylin was discovered PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZXN0ZXJtYXJrPC9BdXRob3I+PFllYXI+MTk4NzwvWWVh
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ADDIN EN.CITE.DATA (Cooper, Willis et al. 1987; Westermark, Wernstedt et al. 1987; Cooper, Leighton et al. 1988). The history leading to the discovery of amylin is an interesting story and began in 1869 when Paul Langerhans ADDIN EN.CITE <EndNote><Cite><Author>Langerhans</Author><Year>1869</Year><RecNum>132</RecNum><record><rec-number>132</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">132</key></foreign-keys><ref-type name="Thesis">32</ref-type><contributors><authors><author>Langerhans, P</author></authors></contributors><titles><title>Beitr?ge zur mikroskopischen Anatomie der Bauchspeicheldrüse. Inaugural-Dissertation</title></titles><dates><year>1869</year></dates><pub-location>Berlin:Gustav Lange</pub-location><urls></urls></record></Cite><Cite><Author>Morrison</Author><Year>1937</Year><RecNum>134</RecNum><record><rec-number>134</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">134</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Morrison, H</author></authors></contributors><titles><title>Contribution to the Microscopic Anatomy of the Pancreas 1937 By Paul Langerhans (Berlin, 1869). Reprint of the German original with an English translation and an introductory essay</title><secondary-title>Bull Inst Hist Med</secondary-title></titles><pages>259-297</pages><volume>5</volume><dates><year>1937</year></dates><urls></urls></record></Cite></EndNote>(Langerhans 1869; Morrison 1937) described the existence of acinar glandular cells and pairs or groups of small polygonal cells with round nuclei in the interacinar spaces of rabbit’s pancreas. Oscar Minkowski in 1889 observed the connection between pancreatic secretion and diabetes on depancreatized dogs ADDIN EN.CITE <EndNote><Cite><Author>Bliss</Author><Year>1982</Year><RecNum>1</RecNum><record><rec-number>1</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">1</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bliss, M.</author></authors></contributors><titles><title>Banting's, Best's, and Collip's accounts of the discovery of insulin</title><secondary-title>Bull Hist Med</secondary-title></titles><pages>554-68</pages><volume>56</volume><number>4</number><edition>1982/01/01</edition><keywords><keyword>Canada</keyword><keyword>History, 20th Century</keyword><keyword>Insulin/*history</keyword></keywords><dates><year>1982</year><pub-dates><date>Winter</date></pub-dates></dates><isbn>0007-5140 (Print)</isbn><accession-num>6760943</accession-num><urls><related-urls><url>;(Bliss 1982). It was Languesse E ADDIN EN.CITE <EndNote><Cite><Author>Languesse</Author><Year>1893</Year><RecNum>135</RecNum><record><rec-number>135</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">135</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Languesse,E</author></authors></contributors><titles><title><style face="normal" font="default" size="100%">Sur la formation des </style><style face="normal" font="Symbol" charset="2" size="100%">i</style><style face="normal" font="default" size="100%">lots de Langerhans dans le pancreas.</style></title><secondary-title>Comptes Rend Soc Biol</secondary-title></titles><pages>819-820</pages><volume>5 (series 9)</volume><dates><year>1893</year></dates><urls></urls></record></Cite></EndNote>(Languesse 1893) in 1893 who named the clumps of cells observed by Paul Langerhans as the ‘Islands or Islets of Langerhans’. Eugene Opie in 1889 was the first to describe "hyaline degeneration of the islands of Langerhans" in the pancreas of patients with hyperglycemia and in 1901 provided its pathological link to diabetes ADDIN EN.CITE <EndNote><Cite><Author>Opie</Author><Year>1901</Year><RecNum>7</RecNum><record><rec-number>7</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">7</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Opie, Eugene L.</author></authors></contributors><titles><title>The relation of diabetes mellitus to lesions of the pancreas: hyaline degeneration of the islands of Langerhans
</title><secondary-title>J Exp Med</secondary-title><short-title>The relation of diabetes mellitus to lesions of the pancreas</short-title></titles><pages>527-40</pages><number>5</number><section>527</section><dates><year>1901</year></dates><work-type>Journal article</work-type><urls></urls></record></Cite></EndNote>(Opie 1901). It was not until 1922 however, that a Canadian team comprising of Banting, Best, Macleod and Collip discovered insulin ADDIN EN.CITE <EndNote><Cite><Author>Banting</Author><Year>1922</Year><RecNum>139</RecNum><record><rec-number>139</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">139</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Banting, F.G.;Best, C.H.; Macleod, J.J.R</author></authors></contributors><titles><title>The internal secretion of the pancreas (Abstract). </title><secondary-title>Am J Physiol</secondary-title></titles><periodical><full-title>Am J Physiol</full-title></periodical><pages>479</pages><volume>59</volume><dates><year>1922</year></dates><urls></urls></record></Cite></EndNote>(Banting 1922). Thirty-three years later, in 1955, the protein structure of insulin was completely sequenced by Frederick Sanger ADDIN EN.CITE <EndNote><Cite><Author>Ryle</Author><Year>1955</Year><RecNum>140</RecNum><record><rec-number>140</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">140</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ryle, A. P.</author><author>Sanger, F.</author><author>Smith, L. F.</author><author>Kitai, R.</author></authors></contributors><titles><title>The disulphide bonds of insulin</title><secondary-title>Biochem J</secondary-title></titles><pages>541-56</pages><volume>60</volume><number>4</number><edition>1955/08/01</edition><keywords><keyword>*Insulin</keyword><keyword>*Sulfides</keyword></keywords><dates><year>1955</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0264-6021 (Print)</isbn><accession-num>13249947</accession-num><urls><related-urls><url>;(Ryle, Sanger et al. 1955). The amyloidal nature of the hyaline material described by Eugene Opie was established by Ahronheim in 1943 and later confirmed by Ehrlick and Ratner in 1961 ADDIN EN.CITE <EndNote><Cite><Author>Ahronheim</Author><Year>1943</Year><RecNum>9</RecNum><record><rec-number>9</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">9</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ahronheim, JH </author></authors></contributors><titles><title>Nature of hyaline material in pancreatic islets in diabetes mellitus. </title><secondary-title>Am J Pathol</secondary-title></titles><pages>873-82</pages><number>19</number><dates><year>1943</year></dates><work-type>journal article</work-type><urls></urls></record></Cite><Cite><Author>Ehrlich</Author><Year>1961</Year><RecNum>10</RecNum><record><rec-number>10</rec-number><foreign-keys><key app='EN' db-id='vpfft9er49eff4etdv0v2av1wvwvwpte09xx'>10</key></foreign-keys><ref-type name='Journal Article'>17</ref-type><contributors><authors><author>Ehrlich, JC</author><author>Ratner, IM</author></authors></contributors><titles><title>Amyloidosis of the islets of Langerhans. A restudy of islet hyaline in diabetic and non diabetic individuals.</title><secondary-title>Am J Pathol</secondary-title></titles><periodical><full-title>Am J Pathol</full-title></periodical><pages>49-59</pages><number>38</number><dates><year>1961</year></dates><urls></urls></record></Cite></EndNote>(Ahronheim 1943; Ehrlich and Ratner 1961). Westermark in 1973 demonstrated the fibrillar structure ADDIN EN.CITE <EndNote><Cite><Author>Westermark</Author><Year>1973</Year><RecNum>3</RecNum><record><rec-number>3</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">3</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Westermark, P.</author></authors></contributors><titles><title>Fine structure of islets of Langerhans in insular amyloidosis</title><secondary-title>Virchows Arch A Pathol Pathol Anat</secondary-title></titles><pages>1-18</pages><volume>359</volume><number>1</number><edition>1973/03/20</edition><keywords><keyword>Aged</keyword><keyword>Amyloidosis/*pathology</keyword><keyword>Capillaries/pathology</keyword><keyword>Cell Membrane</keyword><keyword>Diabetes Mellitus/pathology</keyword><keyword>Epithelial Cells</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Islets of Langerhans/blood supply/*pathology</keyword><keyword>Macrophages</keyword><keyword>Male</keyword><keyword>Mast Cells</keyword><keyword>Microscopy, Electron</keyword><keyword>Middle Aged</keyword><keyword>Pancreatic Diseases/pathology</keyword></keywords><dates><year>1973</year><pub-dates><date>Mar 20</date></pub-dates></dates><isbn>0042-6423 (Print)</isbn><accession-num>4632997</accession-num><urls><related-urls><url>;(Westermark 1973) of the hyaline staining material on electron microscopy. Importantly, in 1987 he also discovered that it was predominantly made up of a 37 amino acid monomer and referred to it as “islet amyloid polypeptide” (IAPP). Interestingly in the same year Cooper from another laboratory also discovered this 37 amino acid polypeptide in pancreatic amyloid deposits and named it “amylin” PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZXN0ZXJtYXJrPC9BdXRob3I+PFllYXI+MTk4NzwvWWVh
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ADDIN EN.CITE.DATA (Cooper, Willis et al. 1987; Westermark, Wernstedt et al. 1987; Cooper, Leighton et al. 1988). Association of Amylin with Islet Amyloid Deposits in DiabetesAmylin is associated with type 2 diabetes, a disease that has increased over the past two decades and now afflicts an estimated 100 million worldwide ADDIN EN.CITE <EndNote><Cite><Author>Hossain</Author><Year>2007</Year><RecNum>301</RecNum><record><rec-number>301</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">301</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hossain, P.</author><author>Kawar, B.</author><author>El Nahas, M.</author></authors></contributors><auth-address>Academic Nephrology Unit at the Sheffield Kidney Institute, University of Sheffield, Sheffield, United Kingdom.</auth-address><titles><title>Obesity and diabetes in the developing world--a growing challenge</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>213-5</pages><volume>356</volume><number>3</number><edition>2007/01/19</edition><keywords><keyword>*Developing Countries</keyword><keyword>*Diabetes Mellitus/economics/epidemiology/prevention & control</keyword><keyword>Humans</keyword><keyword>*Obesity/economics/epidemiology/prevention & control</keyword></keywords><dates><year>2007</year><pub-dates><date>Jan 18</date></pub-dates></dates><isbn>1533-4406 (Electronic)
0028-4793 (Linking)</isbn><accession-num>17229948</accession-num><urls><related-urls><url> [pii]
10.1056/NEJMp068177</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Hossain, Kawar et al. 2007). At post-mortem 95% patients with type 2 diabetes stain positive for amyloid deposits in the pancreas composed of mature, fibrillar amylin ADDIN EN.CITE <EndNote><Cite><Author>Hoppener</Author><Year>2000</Year><RecNum>136</RecNum><record><rec-number>136</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">136</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hoppener, J. W.</author><author>Ahren, B.</author><author>Lips, C. J.</author></authors></contributors><auth-address>Department of Internal Medicine, University Medical Center, Utrecht, The Netherlands. j.w.m.hoeppener@lab.azu.nl</auth-address><titles><title>Islet amyloid and type 2 diabetes mellitus</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>411-9</pages><volume>343</volume><number>6</number><edition>2000/08/10</edition><keywords><keyword>Amyloid/*antagonists & inhibitors/chemistry/genetics/physiology</keyword><keyword>Amyloidosis/complications/prevention & control</keyword><keyword>Animals</keyword><keyword>*Diabetes Mellitus, Type 2/drug therapy/etiology/pathology</keyword><keyword>Humans</keyword><keyword>Islets of Langerhans/pathology</keyword><keyword>Mice</keyword><keyword>Mice, Transgenic</keyword><keyword>Pancreatic Diseases/complications/prevention & control</keyword></keywords><dates><year>2000</year><pub-dates><date>Aug 10</date></pub-dates></dates><isbn>0028-4793 (Print)</isbn><accession-num>10933741</accession-num><urls><related-urls><url>;(Hoppener, Ahren et al. 2000). Since 1987 there has been a rapid increase in publications on amylin most probably due to the fact that islet amyloid in type 2 diabetes mellitus is strongly associated with islet beta cell loss PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KYWlrYXJhbjwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+
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ADDIN EN.CITE.DATA (Hayden and Tyagi 2001; Jaikaran and Clark 2001). Additionally, it is also acknowledged that amylin may be linked to the pathogenesis and therefore a potential target for the treatment of diabetes ADDIN EN.CITE <EndNote><Cite><Author>Schmitz</Author><Year>2004</Year><RecNum>306</RecNum><record><rec-number>306</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">306</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schmitz, O.</author><author>Brock, B.</author><author>Rungby, J.</author></authors></contributors><auth-address>Department of Clinical Pharmacology, The Bartholin Building, University of Aarhus, DK 8000 Aarhus C, Denmark. ole.schmitz@iekf.au.dk</auth-address><titles><title>Amylin agonists: a novel approach in the treatment of diabetes</title><secondary-title>Diabetes</secondary-title></titles><periodical><full-title>Diabetes</full-title></periodical><pages>S233-8</pages><volume>53 Suppl 3</volume><edition>2004/11/25</edition><keywords><keyword>Amyloid/*agonists/physiology/therapeutic use</keyword><keyword>Animals</keyword><keyword>Clinical Trials as Topic</keyword><keyword>Diabetes Mellitus/*drug therapy</keyword><keyword>Disease Models, Animal</keyword><keyword>Hemoglobin A, Glycosylated/drug effects/metabolism</keyword><keyword>Humans</keyword><keyword>Insulin/therapeutic use</keyword></keywords><dates><year>2004</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0012-1797 (Print)
0012-1797 (Linking)</isbn><accession-num>15561917</accession-num><urls><related-urls><url> [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Schmitz, Brock et al. 2004). Amyloidosis and Composition of Amyloid DepositsAmyloidosis refers to group of disorders characterised by abnormal deposition of amyloid proteins in organs and/or tissues. The clinical classification of amyloidosis includes primary (de novo), secondary (a complication of a previously existing disorder), familial, and isolated types. Out of the approximately 60 amyloid proteins which have been identified so far ADDIN EN.CITE <EndNote><Cite><Author>Mok</Author><Year>2007</Year><RecNum>142</RecNum><record><rec-number>142</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">142</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mok, K. H.</author><author>Pettersson, J.</author><author>Orrenius, S.</author><author>Svanborg, C.</author></authors></contributors><auth-address>Trinity College, School of Biochemistry and Immunology, University of Dublin, Dublin 2, Ireland.</auth-address><titles><title>HAMLET, protein folding, and tumor cell death</title><secondary-title>Biochem Biophys Res Commun</secondary-title></titles><pages>1-7</pages><volume>354</volume><number>1</number><edition>2007/01/16</edition><keywords><keyword>Animals</keyword><keyword>*Apoptosis/drug effects</keyword><keyword>Cell Survival/drug effects</keyword><keyword>Humans</keyword><keyword>Lactalbumin/*administration & dosage/*metabolism</keyword><keyword>Neoplasms/*drug therapy/*metabolism/pathology</keyword><keyword>Oleic Acids/*administration & dosage/*metabolism</keyword><keyword>Protein Folding</keyword></keywords><dates><year>2007</year><pub-dates><date>Mar 2</date></pub-dates></dates><isbn>0006-291X (Print)</isbn><accession-num>17223074</accession-num><urls><related-urls><url>(06)02800-2 [pii]
10.1016/j.bbrc.2006.12.167</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Mok, Pettersson et al. 2007), at least 36 have been associated in some way with a human disease ADDIN EN.CITE <EndNote><Cite><Author>Pettersson-Kastberg</Author><Year>2008</Year><RecNum>143</RecNum><record><rec-number>143</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">143</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pettersson-Kastberg, J.</author><author>Aits, S.</author><author>Gustafsson, L.</author><author>Mossberg, A.</author><author>Storm, P.</author><author>Trulsson, M.</author><author>Persson, F.</author><author>Hun Mok, K.</author><author>Svanborg, C.</author></authors></contributors><auth-address>Department of Microbiology, Immunology and Glycobiology (MIG), Institute of Laboratory Medicine, Lund University, Lund, Sweden.</auth-address><titles><title>Can misfolded proteins be beneficial? The HAMLET case</title><secondary-title>Ann Med</secondary-title></titles><pages>1-15</pages><edition>2008/11/06</edition><dates><year>2008</year><pub-dates><date>Nov 4</date></pub-dates></dates><isbn>1365-2060 (Electronic)</isbn><accession-num>18985467</accession-num><urls><related-urls><url> [pii]
10.1080/07853890802502614</electronic-resource-num><language>Eng</language></record></Cite></EndNote>(Pettersson-Kastberg, Aits et al. 2008) such as Bovine spongiform encephalopathy (prion protein PrPSc), Alzheimer’s disease (beta-amyloid), Parkinson’s (Alpha-synuclein) and Creutzfeldt-Jakob disease (prion protein PrPSc). A characteristic feature of amyloid deposit histologically is the positive staining with Congo red ( REF _Ref323158998 \h \* MERGEFORMAT Figure 10) ADDIN EN.CITE <EndNote><Cite><Author>Satoskar</Author><Year>2007</Year><RecNum>141</RecNum><record><rec-number>141</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">141</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Satoskar, A. A.</author><author>Burdge, K.</author><author>Cowden, D. J.</author><author>Nadasdy, G. M.</author><author>Hebert, L. A.</author><author>Nadasdy, T.</author></authors></contributors><auth-address>Department of Pathology, The Ohio State University Medical Center, Columbus, OH, USA.</auth-address><titles><title>Typing of amyloidosis in renal biopsies: diagnostic pitfalls</title><secondary-title>Arch Pathol Lab Med</secondary-title></titles><pages>917-22</pages><volume>131</volume><number>6</number><edition>2007/06/07</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Aged, 80 and over</keyword><keyword>Amyloid/*classification/metabolism</keyword><keyword>Amyloidosis/*diagnosis/metabolism</keyword><keyword>Biopsy</keyword><keyword>Diagnostic Errors/*prevention & control</keyword><keyword>Fluorescent Antibody Technique</keyword><keyword>Humans</keyword><keyword>Immunoenzyme Techniques</keyword><keyword>Immunoglobulin Light Chains/analysis</keyword><keyword>Kidney/metabolism/pathology</keyword><keyword>Kidney Diseases/*diagnosis/metabolism</keyword><keyword>Middle Aged</keyword><keyword>Serum Amyloid A Protein/analysis</keyword></keywords><dates><year>2007</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1543-2165 (Electronic)</isbn><accession-num>17550319</accession-num><urls><related-urls><url> [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Satoskar, Burdge et al. 2007) and birefringence on viewing with polarised light ( REF _Ref323159022 \h \* MERGEFORMAT Figure 11) ADDIN EN.CITE <EndNote><Cite><Author>Hayden</Author><Year>2001</Year><RecNum>11</RecNum><record><rec-number>11</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">11</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hayden, M. R.</author><author>Tyagi, S. C.</author></authors></contributors><auth-address>Department of Cardiovascular Atherosclerosis, Metabolism and Aging, Camdenton Community Health Center. Camdenton, MO 65020, USA. mrh29@</auth-address><titles><title>"A" is for amylin and amyloid in type 2 diabetes mellitus</title><secondary-title>JOP</secondary-title></titles><periodical><full-title>JOP</full-title></periodical><pages>124-39</pages><volume>2</volume><number>4</number><edition>2002/03/05</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Amyloid/chemistry/classification/*physiology/ultrastructure</keyword><keyword>Diabetes Mellitus, Type 2/*metabolism/pathology</keyword><keyword>Humans</keyword><keyword>Molecular Sequence Data</keyword></keywords><dates><year>2001</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1590-8577 (Electronic)</isbn><accession-num>11875249</accession-num><urls><related-urls><url> [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Hayden and Tyagi 2001).Figure SEQ Figure \* ARABIC 10. Amyloid deposit in pancreatic isletHigh power microscopic view showing a pancreatic islet with extensive deposition of a pink homogenous material (Congo red stain) that has features suggestive of amyloid surrounded by normal pancreatic acini. Image courtesy of SEQ Figure \* ARABIC 11. Amyloid deposit in lymph node showing birefringenceCongo red staining of amyloid deposit in the lymph node demonstrating green birefringence to polarised light. Image courtesy of patterns of amyloid vary between patients but each disease is characterized by a particular protein or polypeptide that aggregates in an ordered manner to form insoluble amyloid fibrils that are deposited in the tissues, where they have been associated with the pathology of the disease. These different proteins and peptides, are characterised by common structural features, whereby stacks of parallel peptide strands ADDIN EN.CITE <EndNote><Cite><Author>Jayasinghe</Author><Year>2004</Year><RecNum>302</RecNum><record><rec-number>302</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">302</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jayasinghe, S. A.</author><author>Langen, R.</author></authors></contributors><auth-address>Department of Biochemistry and Molecular Biology, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, California 90033, USA.</auth-address><titles><title>Identifying structural features of fibrillar islet amyloid polypeptide using site-directed spin labeling</title><secondary-title>J Biol Chem</secondary-title></titles><periodical><full-title>J Biol Chem</full-title></periodical><pages>48420-5</pages><volume>279</volume><number>46</number><edition>2004/09/11</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Amyloid/*chemistry/metabolism/*ultrastructure</keyword><keyword>Circular Dichroism</keyword><keyword>Cysteine/chemistry</keyword><keyword>Electron Spin Resonance Spectroscopy</keyword><keyword>Humans</keyword><keyword>Molecular Sequence Data</keyword><keyword>Molecular Structure</keyword><keyword>*Protein Conformation</keyword><keyword>Spin Labels</keyword></keywords><dates><year>2004</year><pub-dates><date>Nov 12</date></pub-dates></dates><isbn>0021-9258 (Print)
0021-9258 (Linking)</isbn><accession-num>15358791</accession-num><urls><related-urls><url> [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Jayasinghe and Langen 2004) run perpendicular to the fibril axis hydrogen-bond ADDIN EN.CITE <EndNote><Cite><Author>Sumner Makin</Author><Year>2004</Year><RecNum>303</RecNum><record><rec-number>303</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">303</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sumner Makin, O.</author><author>Serpell, L. C.</author></authors></contributors><auth-address>University of Cambridge, Structural Medicine Unit, Cambridge Institute for Medical Research and Department of Haematology, Hills Rd, Cambridge CB2 2XY, UK.</auth-address><titles><title>Structural characterisation of islet amyloid polypeptide fibrils</title><secondary-title>J Mol Biol</secondary-title></titles><periodical><full-title>J Mol Biol</full-title></periodical><pages>1279-88</pages><volume>335</volume><number>5</number><edition>2004/01/20</edition><keywords><keyword>Amyloid/*chemistry/ultrastructure</keyword><keyword>Anti-Ulcer Agents/*chemistry</keyword><keyword>Diabetes Mellitus, Type 2/pathology</keyword><keyword>Humans</keyword><keyword>Hydrogen Bonding</keyword><keyword>Islets of Langerhans/chemistry/ultrastructure</keyword><keyword>Microscopy, Electron</keyword><keyword>Molecular Structure</keyword><keyword>Peptide Fragments/*chemistry</keyword><keyword>Protein Structure, Secondary</keyword><keyword>X-Ray Diffraction</keyword></keywords><dates><year>2004</year><pub-dates><date>Jan 30</date></pub-dates></dates><isbn>0022-2836 (Print)
0022-2836 (Linking)</isbn><accession-num>14729343</accession-num><urls><related-urls><url> [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Sumner Makin and Serpell 2004) to form extended beta-sheets ( REF _Ref323158907 \h Figure 12). Figure SEQ Figure \* ARABIC 12. Extended cross-beta structure of amyloidExtended cross-beta sheet amyloid structure consisting of layers of aminoacid chains lying perpendicular to the fiber axis. Image courtesy of one of the major polypeptide components forming the monomeric unit of polymerized, aggregated, and beta pleated sheet structure of islet amyloid in type 2 diabetic patients is amylin ( REF _Ref323158835 \h \* MERGEFORMAT Figure 13) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib3BwZW5lcjwvQXV0aG9yPjxZZWFyPjIwMDA8L1llYXI+
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ADDIN EN.CITE.DATA (Hoppener, Ahren et al. 2000; Kajava, Aebi et al. 2005).Figure SEQ Figure \* ARABIC 13. Superpleated beta structure of amyloid fibrilsThe superpleated beta-structural model of amyloid fibrils of human amylin viewed along the fibril axis. Image courtesy of ADDIN EN.CITE <EndNote><Cite><Author>Kajava</Author><Year>2005</Year><RecNum>296</RecNum><record><rec-number>296</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">296</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kajava, A. V.</author><author>Aebi, U.</author><author>Steven, A. C.</author></authors></contributors><auth-address>Centre de Recherches de Biochimie Macromoleculaire, CNRS FRE-2593, 1919 Route de Mende, 34293 Montpellier Cedex 5, France. andrey.kajava@rs.fr</auth-address><titles><title>The parallel superpleated beta-structure as a model for amyloid fibrils of human amylin</title><secondary-title>J Mol Biol</secondary-title></titles><periodical><full-title>J Mol Biol</full-title></periodical><pages>247-52</pages><volume>348</volume><number>2</number><edition>2005/04/07</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Amyloid/*chemistry</keyword><keyword>Calcitonin/chemistry</keyword><keyword>Humans</keyword><keyword>*Models, Molecular</keyword><keyword>Molecular Sequence Data</keyword><keyword>Protein Structure, Quaternary</keyword><keyword>Protein Structure, Secondary</keyword><keyword>Sequence Alignment</keyword></keywords><dates><year>2005</year><pub-dates><date>Apr 29</date></pub-dates></dates><isbn>0022-2836 (Print)</isbn><accession-num>15811365</accession-num><urls><related-urls><url>(05)00191-9 [pii]
10.1016/j.jmb.2005.02.029</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Kajava, Aebi et al. 2005)Amylin is implicated in the pathogenesis of type 2 diabetes and Alzheimer’s due to its ability to form amyloid deposits leading to destruction of cell membranes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HcmVlbjwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Green, Goldsbury et al. 2004; Sedman, Allen et al. 2005). Amylin receptors may play an important role in the neurotoxic effects of amyloid beta and therefore its inhibition could be promising in the treatment of Alzheimer’s disease ADDIN EN.CITE <EndNote><Cite><Author>Kurganov</Author><Year>2004</Year><RecNum>318</RecNum><record><rec-number>318</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">318</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kurganov, B.</author><author>Doh, M.</author><author>Arispe, N.</author></authors></contributors><auth-address>Department of Anatomy, Physiology and Genetics, and Institute for Molecular Medicine, Uniformed Services University School of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Rd., Bethesda, MD 20814, USA.</auth-address><titles><title>Aggregation of liposomes induced by the toxic peptides Alzheimer's Abetas, human amylin and prion (106-126): facilitation by membrane-bound GM1 ganglioside</title><secondary-title>Peptides</secondary-title></titles><periodical><full-title>Peptides</full-title></periodical><pages>217-32</pages><volume>25</volume><number>2</number><edition>2004/04/06</edition><keywords><keyword>Amyloid/*chemistry</keyword><keyword>Amyloid beta-Protein/*chemistry</keyword><keyword>Animals</keyword><keyword>G(M1) Ganglioside/*chemistry</keyword><keyword>Humans</keyword><keyword>Lipids/chemistry</keyword><keyword>Liposomes/*chemistry</keyword><keyword>Phosphatidylserines/chemistry</keyword><keyword>Prions/*chemistry</keyword></keywords><dates><year>2004</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0196-9781 (Print)
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ADDIN EN.CITE.DATA (Jaikaran and Clark 2001; Jaikaran, Higham et al. 2001; Padrick and Miranker 2001). Amylin and its 10-residue fragment between amino acids 20 and 29 ( REF _Ref323158809 \h Figure 14) is known to spontaneously deamidate, and the presence of less than 5% of deamidation impurities leads to the formation of aggregates by the purified peptide that has the hallmarks of amyloid ADDIN EN.CITE <EndNote><Cite><Author>Nilsson</Author><Year>2002</Year><RecNum>76</RecNum><record><rec-number>76</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">76</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nilsson, M. R.</author><author>Driscoll, M.</author><author>Raleigh, D. P.</author></authors></contributors><auth-address>Department of Chemistry, State University of New York at Stony Brook, Stony Brook, New York 11794-3400, USA.</auth-address><titles><title>Low levels of asparagine deamidation can have a dramatic effect on aggregation of amyloidogenic peptides: implications for the study of amyloid formation</title><secondary-title>Protein Sci</secondary-title></titles><pages>342-9</pages><volume>11</volume><number>2</number><edition>2002/01/16</edition><keywords><keyword>Amides/chemistry/*metabolism</keyword><keyword>Amyloid/*chemistry/metabolism</keyword><keyword>Asparagine/*chemistry/metabolism</keyword><keyword>Chromatography, High Pressure Liquid</keyword><keyword>Congo Red</keyword><keyword>Humans</keyword><keyword>Peptide Fragments/*chemistry/*metabolism</keyword><keyword>Protein Binding</keyword><keyword>Protein Conformation</keyword><keyword>Solutions</keyword><keyword>Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization</keyword><keyword>Spectroscopy, Fourier Transform Infrared</keyword></keywords><dates><year>2002</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0961-8368 (Print)</isbn><accession-num>11790844</accession-num><urls><related-urls><url>;(Nilsson, Driscoll et al. 2002). Figure SEQ Figure \* ARABIC 14. Region responsible for amyloid formationThe primary structure of amylin showing region responsible for amyloid formation. Image courtesy of Laboratory AssaysStudies investigating the biological roles of amylin in health and disease require sensitive and specific assays capable of measuring amylin at the concentrations at which it circulates in plasma. Some of the Radioimmunoassay’s (RIAs) developed initially to measure human amylin were reported to be sensitive enough to detect fasting concentration of amylin. However RIA is labour intensive, time consuming taking up to 5 days, extraction and assay procedure could potentially introduce variability into the results and required up to 5 ml blood volume to obtain enough plasma before assay to extract amylin. This blood volume would be unsafe and thus prohibitive especially in preterm and very low birth weight population. To combat the problems highlighted with RIA, two sandwich-type immunoassays were developed which are considered to be rapid, sensitive, analyze large numbers of samples within a few hours and capable of measuring 0.5 to 2 pmol/L amylin in 50 ?L of plasma. Furthermore, these two assays exhibited limited cross reactivity (< 0.01 %) with other related peptides, detectable dynamic range of amylin concentration 2 to 100 pmol/L, average intraassay coefficient of variations (CVs) of <10%, average interassay CVs of <15%, and good linearity on dilution and recovery of added amylin. Thus the availability of these assays made it possible to study plasma amylin concentrations in various disease states in different age groups including neonatal population. Literature Review: Gastric EmptyingAnatomy and Physiology of Gastric Motor FunctionAn understanding of the pathogenesis of delayed gastric emptying may be helped by revisiting the anatomy and physiology of normal gastric motor function.The stomach is divided into cardia, fundus, body and pylorus each with different cells and functions. The oesophageal and pyloric sphincters help to keep the contents of the stomach contained. In adult humans, the anatomic capacity of stomach is about 45 ml which normally expands to hold about 1-3 litres of food. The stomach volume in the fetus is approximately 10 ml which increases to 18-21 ml by term PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OYWdhdGE8L0F1dGhvcj48WWVhcj4xOTk0PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Nagata, Koyanagi et al. 1994; Sase, Miwa et al. 2005). The anatomic capacity of new-born stomach depends on birth weight and varies from 22-38 ml in 1.5-4.0+ kg infants which increases to 45 ml in 1 week and 75 ml in 2 weeks postnatal age. The physiologic capacity is less than the anatomic capacity at birth, equals by day 5 and reaches 81 ml by day 10 in 2.0-4.0+ kg infants ADDIN EN.CITE <EndNote><Cite><Author>Scammon RE</Author><Year>1920</Year><RecNum>474</RecNum><record><rec-number>474</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">474</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Scammon RE, Doyle LO</author></authors></contributors><titles><title>Observations on the capacity of the stomach in the first ten days of postnatal life</title><secondary-title>Am J Dis Child</secondary-title></titles><periodical><full-title>Am J Dis Child</full-title></periodical><pages>516-538</pages><volume>20</volume><dates><year>1920</year></dates><urls></urls></record></Cite></EndNote>(Scammon RE 1920). The gastric motor function is controlled by parasympathetic and sympathetic nervous systems, enteric brain neurons and smooth muscle cells. Extrinsic neural controls by parasympathetic pathways are conveyed to the stomach and upper intestine through the vagal efferents arising in the dorsal motor nucleus of the vagus nerve, nucleus ambiguus and tractus solitaries which form characteristic bead chain like terminals in the myenteric plexus throughout the stomach and upper intestine but without directly innervating muscle ADDIN EN.CITE <EndNote><Cite><Author>Berthoug</Author><Year>1993</Year><RecNum>190</RecNum><record><rec-number>190</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">190</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Berthoug, HR; Neuhuber, WL</author></authors><secondary-authors><author>Tache, Y; Wingate, D; Burks, T</author></secondary-authors></contributors><titles><title>Distribution and morphology of vagal afferents and efferents supplying the digestive system. In: Innervation of the Gut: Pathophysiological Implications</title><secondary-title>Innervation of the Gut: Pathophysiological Implications</secondary-title></titles><dates><year>1993</year></dates><pub-location>Boca Raton </pub-location><publisher>CRC Press</publisher><urls></urls></record></Cite></EndNote>(Berthoug 1993). The vagus nerve regulates the distribution of food between proximal and distal regions of the stomach. The proximal stomach serves as a reservoir for solid foods and induces tonic pressure to facilitate liquid emptying. At the distal end of the stomach, the tone of the pylorus controls the rate at which the contents of the stomach are emptied into the small intestine. During fasting state both adults as well as term infants exhibit migrating motor complexes (MMCs) which are peristaltic waves originating in the stomach that progress through small intestine into colon approximately every 75-90 minutes and are interrupted by a meal. As the distal stomach grinds ingested solid foods, phasic and tonic pyloric pressures in conjunction with duodenal contractions slow gastric emptying, which in turn disrupts MMC to allow for normal digestion and absorption of nutrients ADDIN EN.CITE <EndNote><Cite><Author>Chaikomin</Author><Year>2006</Year><RecNum>336</RecNum><record><rec-number>336</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">336</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chaikomin, R.</author><author>Rayner, C. K.</author><author>Jones, K. L.</author><author>Horowitz, M.</author></authors></contributors><auth-address>Department of Medicine, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia.</auth-address><titles><title>Upper gastrointestinal function and glycemic control in diabetes mellitus</title><secondary-title>World J Gastroenterol</secondary-title></titles><periodical><full-title>World J Gastroenterol</full-title></periodical><pages>5611-21</pages><volume>12</volume><number>35</number><edition>2006/09/29</edition><keywords><keyword>Blood Glucose/*analysis</keyword><keyword>Diabetes Mellitus/blood/*physiopathology</keyword><keyword>Disease Progression</keyword><keyword>Gastric Emptying/physiology</keyword><keyword>Gastrointestinal Motility/physiology</keyword><keyword>Humans</keyword><keyword>Hyperglycemia/blood/physiopathology/*prevention & control</keyword><keyword>Hypoglycemia/blood/physiopathology/prevention & control</keyword><keyword>Upper Gastrointestinal Tract/*physiopathology</keyword></keywords><dates><year>2006</year><pub-dates><date>Sep 21</date></pub-dates></dates><isbn>1007-9327 (Print)
1007-9327 (Linking)</isbn><accession-num>17007012</accession-num><urls><related-urls><url>;(Chaikomin, Rayner et al. 2006). In summary, normal gastrointestinal motor function is a complex sequence of events that is controlled by an extrinsic nerve supply from the brain and spinal cord, the complex plexi within the wall of the stomach and intestine, and the effects of locally released amines and peptides that alter the excitability of the smooth muscle of the intestine. Abnormalities in any of these locations can lead to delayed gastric emptying. Regulation of Gastric EmptyingCarbohydrate absorption is crucial to understanding the control of gastric emptying. In the normal adult human, a moderately sized meal contains up to 50-100 g of glucose but the total amount of glucose in plasma is approximately 5 g ADDIN EN.CITE <EndNote><Cite><Author>Young</Author><Year>1995</Year><RecNum>183</RecNum><record><rec-number>183</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">183</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Young, A.</author><author>Pittner, R.</author><author>Gedulin, B.</author><author>Vine, W.</author><author>Rink, T.</author></authors></contributors><auth-address>Amylin Pharmaceuticals, San Diego, CA 91901, USA.</auth-address><titles><title>Amylin regulation of carbohydrate metabolism</title><secondary-title>Biochem Soc Trans</secondary-title></titles><pages>325-31</pages><volume>23</volume><number>2</number><edition>1995/05/01</edition><keywords><keyword>Adenylate Cyclase/metabolism</keyword><keyword>Adult</keyword><keyword>Amyloid/pharmacology/*physiology</keyword><keyword>Animals</keyword><keyword>*Carbohydrate Metabolism</keyword><keyword>Dietary Carbohydrates</keyword><keyword>Eating</keyword><keyword>Glucose/*metabolism</keyword><keyword>Homeostasis</keyword><keyword>Humans</keyword><keyword>Insulin/physiology</keyword><keyword>Intestinal Absorption</keyword><keyword>Lactates/metabolism</keyword><keyword>Liver/drug effects/metabolism</keyword><keyword>Models, Biological</keyword><keyword>Muscle, Skeletal/drug effects/metabolism</keyword></keywords><dates><year>1995</year><pub-dates><date>May</date></pub-dates></dates><isbn>0300-5127 (Print)</isbn><accession-num>7672355</accession-num><urls><related-urls><url>;(Young, Pittner et al. 1995). Thus without regulation of its absorption, glucose could easily exceed the normal level found in plasma. The glucose released into the blood stream following ingestion of food stimulates rapid secretion of insulin and simultaneous suppression of glucagon secretion. These reciprocal changes in islet hormones stimulate glucose uptake and suppress hepatic glucose production. At the same time, glucose transport and disposal are facilitated in peripheral tissues, mainly in muscle, and to some extent in kidney and adipose tissue PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LZWxsZXk8L0F1dGhvcj48WWVhcj4xOTg4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Kelley, Mitrakou et al. 1988; Meyer, Dostou et al. 2002). As blood glucose concentrations rise, the decelerated rate of gastric emptying contributes to maintenance of glucose homeostasis ADDIN EN.CITE <EndNote><Cite><Author>Barnett</Author><Year>1988</Year><RecNum>339</RecNum><record><rec-number>339</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">339</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Barnett, J. L.</author><author>Owyang, C.</author></authors></contributors><auth-address>Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor.</auth-address><titles><title>Serum glucose concentration as a modulator of interdigestive gastric motility</title><secondary-title>Gastroenterology</secondary-title></titles><periodical><full-title>Gastroenterology</full-title></periodical><pages>739-44</pages><volume>94</volume><number>3</number><edition>1988/03/01</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Blood Glucose/*analysis</keyword><keyword>Duodenum/physiopathology</keyword><keyword>*Gastrointestinal Motility</keyword><keyword>Humans</keyword><keyword>Hyperglycemia/physiopathology</keyword><keyword>Motilin/blood</keyword><keyword>Pyloric Antrum/physiopathology</keyword></keywords><dates><year>1988</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0016-5085 (Print)
0016-5085 (Linking)</isbn><accession-num>3338642</accession-num><urls><related-urls><url> [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Barnett and Owyang 1988). Furthermore, in the presence of acute hyperglycaemia, proximal gastric tone is diminished, frequency and propagation of antral pressure waves are suppressed, and pyloric contractions are stimulated, all of which contribute to the slowing of gastric emptying ADDIN EN.CITE <EndNote><Cite><Author>Meyer</Author><Year>2002</Year><RecNum>338</RecNum><record><rec-number>338</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">338</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Meyer, C.</author><author>Dostou, J. M.</author><author>Welle, S. L.</author><author>Gerich, J. E.</author></authors></contributors><auth-address>Department of Medicine, University of Rochester School of Medicine, Rochester, New York 14642, USA.</auth-address><titles><title>Role of human liver, kidney, and skeletal muscle in postprandial glucose homeostasis</title><secondary-title>Am J Physiol Endocrinol Metab</secondary-title></titles><periodical><full-title>Am J Physiol Endocrinol Metab</full-title></periodical><pages>E419-27</pages><volume>282</volume><number>2</number><edition>2002/01/15</edition><keywords><keyword>Blood Glucose/analysis</keyword><keyword>Female</keyword><keyword>Glucagon/blood</keyword><keyword>Glucose/*metabolism/pharmacokinetics</keyword><keyword>Homeostasis/*physiology</keyword><keyword>Humans</keyword><keyword>Insulin/blood</keyword><keyword>Kidney/metabolism/*physiology</keyword><keyword>Liver/metabolism/*physiology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Muscle, Skeletal/*physiology</keyword><keyword>*Postprandial Period</keyword></keywords><dates><year>2002</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0193-1849 (Print)
0193-1849 (Linking)</isbn><accession-num>11788375</accession-num><urls><related-urls><url>;(Meyer, Dostou et al. 2002) as a protective mechanism to control glucose efflux into the blood stream. Hence there seems to be matching of fluxes via ‘entero-insular loop’ to ensure regulated carbohydrate efflux from the stomach for absorption is approximately equal to the regulated insulin-mediated uptake from the plasma into peripheral tissue. This regulatory system which is essential for normal control of blood glucose is disrupted in amylin-deficient state such as type-1 diabetes.The rate of gastric emptying in adults is also influenced by a number of other factors, including the size, composition (fat versus carbohydrate) and type (liquid versus solid) of the meal PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db2xsaW5zPC9BdXRob3I+PFllYXI+MTk4MzwvWWVhcj48
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ADDIN EN.CITE.DATA (Moore, Christian et al. 1981; Collins, Horowitz et al. 1983), and activity of the gut hormones ADDIN EN.CITE <EndNote><Cite><Author>Macdonald</Author><Year>1997</Year><RecNum>48</RecNum><record><rec-number>48</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">48</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Macdonald, I. A.</author></authors></contributors><auth-address>Department of Physiology and Pharmacology, University of Nottingham Medical School, UK.</auth-address><titles><title>Amylin and the gastrointestinal tract</title><secondary-title>Diabet Med</secondary-title></titles><periodical><full-title>Diabet Med</full-title></periodical><pages>S24-8</pages><volume>14 Suppl 2</volume><edition>1997/06/01</edition><keywords><keyword>Amyloid/*pharmacology/therapeutic use</keyword><keyword>Animals</keyword><keyword>Diabetes Mellitus/drug therapy</keyword><keyword>Digestive Physiology</keyword><keyword>Digestive System/*drug effects</keyword><keyword>Gastric Emptying/drug effects</keyword><keyword>Humans</keyword><keyword>Hypoglycemic Agents/*pharmacology/therapeutic use</keyword><keyword>Rats</keyword><keyword>Rats, Inbred BB</keyword><keyword>Rats, Wistar</keyword></keywords><dates><year>1997</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0742-3071 (Print)</isbn><accession-num>9212326</accession-num><urls><related-urls><url>(SICI)1096-9136(199706)14:2+<S24::AID-DIA399>3.0.CO;2-M</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Macdonald 1997). Osmolarity and temperature of feed, posture, and stress also impact the gastric emptying rate PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CbGFpcjwvQXV0aG9yPjxZZWFyPjE5OTE8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Hunt and Knox 1968; Blair, Wing et al. 1991). Small meals empty more rapidly than large ones and a meal with a high fat content has a higher half time for gastric emptying than a meal with high carbohydrate content ADDIN EN.CITE <EndNote><Cite><Author>Sidery</Author><Year>1994</Year><RecNum>182</RecNum><record><rec-number>182</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">182</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sidery, M. B.</author><author>Macdonald, I. A.</author><author>Blackshaw, P. E.</author></authors></contributors><auth-address>Department of Physiology, University of Nottingham Medical School.</auth-address><titles><title>Superior mesenteric artery blood flow and gastric emptying in humans and the differential effects of high fat and high carbohydrate meals</title><secondary-title>Gut</secondary-title></titles><periodical><full-title>Gut</full-title></periodical><pages>186-90</pages><volume>35</volume><number>2</number><edition>1994/02/01</edition><keywords><keyword>Adult</keyword><keyword>Dietary Carbohydrates/*administration & dosage</keyword><keyword>Dietary Fats/*administration & dosage</keyword><keyword>Gastric Emptying/*physiology</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Mesenteric Artery, Superior/*physiology/ultrasonography</keyword><keyword>Regional Blood Flow/physiology</keyword></keywords><dates><year>1994</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0017-5749 (Print)</isbn><accession-num>8307468</accession-num><urls><related-urls><url>;(Sidery, Macdonald et al. 1994). The rate of gastric emptying of liquids is faster than that of solids ADDIN EN.CITE <EndNote><Cite><Author>Collins</Author><Year>1991</Year><RecNum>181</RecNum><record><rec-number>181</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">181</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Collins, P. J.</author><author>Houghton, L. A.</author><author>Read, N. W.</author><author>Horowitz, M.</author><author>Chatterton, B. E.</author><author>Heddle, R.</author><author>Dent, J.</author></authors></contributors><auth-address>Department of Nuclear Medicine, Royal Adelaide Hospital, South Australia.</auth-address><titles><title>Role of the proximal and distal stomach in mixed solid and liquid meal emptying</title><secondary-title>Gut</secondary-title></titles><periodical><full-title>Gut</full-title></periodical><pages>615-9</pages><volume>32</volume><number>6</number><edition>1991/06/01</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Cardia/physiology</keyword><keyword>Female</keyword><keyword>Gastric Emptying/*physiology</keyword><keyword>Glucose</keyword><keyword>Humans</keyword><keyword>Indium Radioisotopes</keyword><keyword>Male</keyword><keyword>Manometry</keyword><keyword>Middle Aged</keyword><keyword>Pressure</keyword><keyword>Pyloric Antrum/physiology</keyword><keyword>Pylorus/physiology</keyword><keyword>Technetium Tc 99m Sulfur Colloid</keyword><keyword>Time Factors</keyword></keywords><dates><year>1991</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0017-5749 (Print)</isbn><accession-num>2060870</accession-num><urls><related-urls><url>;(Collins, Houghton et al. 1991), and addition of soluble fiber to food delays gastric emptying rate PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ub3JzZG90dGlyPC9BdXRob3I+PFllYXI+MTk5MTwvWWVh
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ADDIN EN.CITE.DATA (Torsdottir, Alpsten et al. 1991; Frost, Brynes et al. 2003).Role of Other Gastrointestinal Peptides on Gastric EmptyingGastric emptying is modulated by feedback mechanisms arising from the interaction of nutrients from food with the small intestine ADDIN EN.CITE <EndNote><Cite><Author>Chaikomin</Author><Year>2006</Year><RecNum>336</RecNum><record><rec-number>336</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">336</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chaikomin, R.</author><author>Rayner, C. K.</author><author>Jones, K. L.</author><author>Horowitz, M.</author></authors></contributors><auth-address>Department of Medicine, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia.</auth-address><titles><title>Upper gastrointestinal function and glycemic control in diabetes mellitus</title><secondary-title>World J Gastroenterol</secondary-title></titles><periodical><full-title>World J Gastroenterol</full-title></periodical><pages>5611-21</pages><volume>12</volume><number>35</number><edition>2006/09/29</edition><keywords><keyword>Blood Glucose/*analysis</keyword><keyword>Diabetes Mellitus/blood/*physiopathology</keyword><keyword>Disease Progression</keyword><keyword>Gastric Emptying/physiology</keyword><keyword>Gastrointestinal Motility/physiology</keyword><keyword>Humans</keyword><keyword>Hyperglycemia/blood/physiopathology/*prevention & control</keyword><keyword>Hypoglycemia/blood/physiopathology/prevention & control</keyword><keyword>Upper Gastrointestinal Tract/*physiopathology</keyword></keywords><dates><year>2006</year><pub-dates><date>Sep 21</date></pub-dates></dates><isbn>1007-9327 (Print)
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ADDIN EN.CITE.DATA (Young, Gedulin et al. 1996). In contrast to amylin, Ghrelin is synthesised predominantly by the stomach and is the endogenous ligand for the growth hormone secretagogue receptor which is expressed in brain stem and hypothalamic nuclei PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb2ppbWE8L0F1dGhvcj48WWVhcj4xOTk5PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Kojima, Hosoda et al. 1999). Exogenous ghrelin causes large meals to be eaten PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Uc2Nob3A8L0F1dGhvcj48WWVhcj4yMDAwPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Tschop, Smiley et al. 2000; Wren, Seal et al. 2001; Wren, Small et al. 2001) and is a most potent stimulator of gastric contractions and emptying ADDIN EN.CITE <EndNote><Cite><Author>Hellstrom</Author><Year>2006</Year><RecNum>194</RecNum><record><rec-number>194</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">194</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hellstrom, P. M.</author><author>Gryback, P.</author><author>Jacobsson, H.</author></authors></contributors><auth-address>Department of Gastroenterology and Hepatology, Karolinska University Hospital, Solna, Sweden. Per.Hellstrom@ki.se</auth-address><titles><title>The physiology of gastric emptying</title><secondary-title>Best Pract Res Clin Anaesthesiol</secondary-title></titles><pages>397-407</pages><volume>20</volume><number>3</number><edition>2006/11/04</edition><keywords><keyword>Animals</keyword><keyword>Gastric Emptying/drug effects/*physiology</keyword><keyword>Gastrointestinal Hormones/pharmacology/secretion</keyword><keyword>Ghrelin</keyword><keyword>Glucagon-Like Peptide 1/pharmacology/secretion</keyword><keyword>Humans</keyword><keyword>Peptide Hormones/pharmacology/secretion</keyword><keyword>Stomach/metabolism/*physiology</keyword></keywords><dates><year>2006</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1753-3740 (Print)</isbn><accession-num>17080692</accession-num><urls><related-urls><url>;(Hellstrom, Gryback et al. 2006). Other gut hormones such as gastrin, PP, CCK, secretin, GLP-1, GLP-2, oxyntomodulin, and PYY also influence gastrointestinal motility and may potentiate amylin’s inhibition of gastric emptying ( REF _Ref323192471 \h \* MERGEFORMAT Figure 15). Figure SEQ Figure \* ARABIC 15. Site of synthesis of main gut hormones influencing appetite and gastric emptyingThese gut hormones may also potentiate amylin’s role in delaying gastric emptying. CCK, cholecystokinin; PYY, peptide YY; GLP1, glucagon-like peptide 1; GLP2, glucagon-like peptide 2. Image courtesy of ADDIN EN.CITE <EndNote><Cite><Author>Druce</Author><Year>2006</Year><RecNum>355</RecNum><record><rec-number>355</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">355</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Druce, M.</author><author>Bloom, S. R.</author></authors></contributors><auth-address>Department of Metabolic Medicine, Imperial College London, 6th Floor, Commonwealth Building, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.</auth-address><titles><title>The regulation of appetite</title><secondary-title>Arch Dis Child</secondary-title></titles><periodical><full-title>Arch Dis Child</full-title></periodical><pages>183-7</pages><volume>91</volume><number>2</number><edition>2006/01/24</edition><keywords><keyword>Adult</keyword><keyword>Animals</keyword><keyword>Appetite Regulation/*physiology</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Energy Metabolism/physiology</keyword><keyword>Gastrointestinal Hormones/physiology</keyword><keyword>Homeostasis/physiology</keyword><keyword>Hormones/physiology</keyword><keyword>Humans</keyword><keyword>Hypothalamus/physiology</keyword><keyword>Obesity/*physiopathology/therapy</keyword><keyword>Satiation/physiology</keyword></keywords><dates><year>2006</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1468-2044 (Electronic)
0003-9888 (Linking)</isbn><accession-num>16428368</accession-num><urls><related-urls><url> [pii]
10.1136/adc.2005.073759</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Druce and Bloom 2006)Diabetes and its Effects on Gastric EmptyingDiabetes is frequently associated with symptoms due to disturbances of gastrointestinal motility and/or sensation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CeXR6ZXI8L0F1dGhvcj48WWVhcj4yMDAxPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Samsom, Roelofs et al. 1998; Bytzer, Talley et al. 2001). Approximately 30%-50% of patients with long standing type 1 and type 2 diabetes show delayed gastric emptying PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ib3Jvd2l0ejwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+
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ADDIN EN.CITE.DATA (Samsom, Akkermans et al. 1997; Rayner, Samsom et al. 2001). Type 1 diabetes patients have delayed gastric emptying rates in response to hyperglycemia ADDIN EN.CITE <EndNote><Cite><Author>Schvarcz</Author><Year>1997</Year><RecNum>361</RecNum><record><rec-number>361</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">361</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schvarcz, E.</author><author>Palmer, M.</author><author>Aman, J.</author><author>Horowitz, M.</author><author>Stridsberg, M.</author><author>Berne, C.</author></authors></contributors><auth-address>Department of Internal Medicine, Orebro Medical Center Hospital, Sweden.</auth-address><titles><title>Physiological hyperglycemia slows gastric emptying in normal subjects and patients with insulin-dependent diabetes mellitus</title><secondary-title>Gastroenterology</secondary-title></titles><periodical><full-title>Gastroenterology</full-title></periodical><pages>60-6</pages><volume>113</volume><number>1</number><edition>1997/07/01</edition><keywords><keyword>Adult</keyword><keyword>Blood Glucose/*metabolism</keyword><keyword>Case-Control Studies</keyword><keyword>Diabetes Mellitus, Type 1/*physiopathology</keyword><keyword>Gastric Emptying/*physiology</keyword><keyword>Glucose Clamp Technique</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Stomach/radionuclide imaging</keyword><keyword>Technetium Tc 99m Aggregated Albumin/diagnostic use</keyword><keyword>Time Factors</keyword></keywords><dates><year>1997</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0016-5085 (Print)
0016-5085 (Linking)</isbn><accession-num>9207262</accession-num><urls><related-urls><url> [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Schvarcz, Palmer et al. 1997) including patients with autonomic neuropathy probably due to changes in antroduodenal motility ADDIN EN.CITE <EndNote><Cite><Author>Samsom</Author><Year>1997</Year><RecNum>360</RecNum><record><rec-number>360</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">360</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Samsom, M.</author><author>Akkermans, L. M.</author><author>Jebbink, R. J.</author><author>van Isselt, H.</author><author>vanBerge-Henegouwen, G. P.</author><author>Smout, A. J.</author></authors></contributors><auth-address>Department of Gastroenterology, University Hospital Utrecht, The Netherlands.</auth-address><titles><title>Gastrointestinal motor mechanisms in hyperglycaemia induced delayed gastric emptying in type I diabetes mellitus</title><secondary-title>Gut</secondary-title></titles><periodical><full-title>Gut</full-title></periodical><pages>641-6</pages><volume>40</volume><number>5</number><edition>1997/05/01</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Diabetes Mellitus, Type 1/*physiopathology</keyword><keyword>Duodenum/physiopathology</keyword><keyword>Female</keyword><keyword>*Gastric Emptying</keyword><keyword>*Gastrointestinal Motility</keyword><keyword>Humans</keyword><keyword>Hyperglycemia/*physiopathology</keyword><keyword>Male</keyword><keyword>Manometry</keyword><keyword>Middle Aged</keyword><keyword>Postprandial Period</keyword></keywords><dates><year>1997</year><pub-dates><date>May</date></pub-dates></dates><isbn>0017-5749 (Print)
0017-5749 (Linking)</isbn><accession-num>9203944</accession-num><urls><related-urls><url>;(Samsom, Akkermans et al. 1997). On the contrary, gastric emptying rate is accelerated in type 1 diabetics in insulin induced hypoglycaemia ADDIN EN.CITE <EndNote><Cite><Author>Schvarcz</Author><Year>1993</Year><RecNum>362</RecNum><record><rec-number>362</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">362</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schvarcz, E.</author><author>Palmer, M.</author><author>Aman, J.</author><author>Lindkvist, B.</author><author>Beckman, K. W.</author></authors></contributors><auth-address>Department of Internal Medicine, Orebro Medical Centre Hospital, Sweden.</auth-address><titles><title>Hypoglycaemia increases the gastric emptying rate in patients with type 1 diabetes mellitus</title><secondary-title>Diabet Med</secondary-title></titles><periodical><full-title>Diabet Med</full-title></periodical><pages>660-3</pages><volume>10</volume><number>7</number><edition>1993/08/01</edition><keywords><keyword>Adult</keyword><keyword>Blood Glucose/*metabolism</keyword><keyword>Diabetes Mellitus, Type 1/blood/drug therapy/*physiopathology</keyword><keyword>*Gastric Emptying/drug effects</keyword><keyword>Glucose Clamp Technique</keyword><keyword>Hemoglobin A, Glycosylated/analysis</keyword><keyword>Humans</keyword><keyword>Hypoglycemia/chemically induced/*physiopathology</keyword><keyword>Insulin/*adverse effects/pharmacology/therapeutic use</keyword><keyword>Male</keyword></keywords><dates><year>1993</year><pub-dates><date>Aug-Sep</date></pub-dates></dates><isbn>0742-3071 (Print)
0742-3071 (Linking)</isbn><accession-num>8403829</accession-num><urls><related-urls><url>;(Schvarcz, Palmer et al. 1993). Thus there is an inverse relationship between the rate of gastric emptying and the blood glucose concentration, so that emptying is slower during hyperglycaemia and faster during hypoglycaemia.Delayed gastric emptying also occurs frequently in type 2 diabetes mellitus partly due to increased plasma glucose concentrations PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaWVnbGVyPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48
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ADDIN EN.CITE.DATA (Kong, King et al. 1999) or accelerated ADDIN EN.CITE <EndNote><Cite><Author>Schwartz</Author><Year>1996</Year><RecNum>365</RecNum><record><rec-number>365</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">365</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schwartz, J. G.</author><author>Green, G. M.</author><author>Guan, D.</author><author>McMahan, C. A.</author><author>Phillips, W. T.</author></authors></contributors><auth-address>Department of Pathology, University of Texas Health Science Center at San Antonio 78284-7750, USA.</auth-address><titles><title>Rapid gastric emptying of a solid pancake meal in type II diabetic patients</title><secondary-title>Diabetes Care</secondary-title></titles><periodical><full-title>Diabetes Care</full-title></periodical><pages>468-71</pages><volume>19</volume><number>5</number><edition>1996/05/01</edition><keywords><keyword>Adult</keyword><keyword>Blood Glucose/metabolism</keyword><keyword>Case-Control Studies</keyword><keyword>Diabetes Mellitus, Type 2/blood/*physiopathology</keyword><keyword>*Dietary Carbohydrates</keyword><keyword>Eating</keyword><keyword>Female</keyword><keyword>*Gastric Emptying</keyword><keyword>Humans</keyword><keyword>Insulin/blood</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Reference Values</keyword><keyword>Time Factors</keyword></keywords><dates><year>1996</year><pub-dates><date>May</date></pub-dates></dates><isbn>0149-5992 (Print)
0149-5992 (Linking)</isbn><accession-num>8732711</accession-num><urls><related-urls><url>;(Schwartz, Green et al. 1996) gastric emptying rates have also been reported.Although a review reports increase in amylin level in gestational diabetes ADDIN EN.CITE <EndNote><Cite><Author>Ludvik</Author><Year>1997</Year><RecNum>41</RecNum><record><rec-number>41</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">41</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ludvik, B.</author><author>Kautzky-Willer, A.</author><author>Prager, R.</author><author>Thomaseth, K.</author><author>Pacini, G.</author></authors></contributors><auth-address>Klinik fur Innere Medizin III, Abteilung fur Endokrinologie und Stoffwechsel, University of Vienna, Austria.</auth-address><titles><title>Amylin: history and overview</title><secondary-title>Diabet Med</secondary-title></titles><periodical><full-title>Diabet Med</full-title></periodical><pages>S9-13</pages><volume>14 Suppl 2</volume><edition>1997/06/01</edition><keywords><keyword>Amyloid/history/*physiology/secretion</keyword><keyword>Animals</keyword><keyword>Diabetes Mellitus, Type 2/etiology</keyword><keyword>Female</keyword><keyword>Glucose/metabolism</keyword><keyword>History, 20th Century</keyword><keyword>Homeostasis</keyword><keyword>Humans</keyword><keyword>Insulin/secretion</keyword><keyword>Male</keyword></keywords><dates><year>1997</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0742-3071 (Print)</isbn><accession-num>9212323</accession-num><urls><related-urls><url>(SICI)1096-9136(199706)14:2+<S9::AID-DIA397>3.0.CO;2-D</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Ludvik, Kautzky-Willer et al. 1997), literature on the effects of gestational diabetes on gastric emptying is lacking. Because amylin is co-secreted by β-cells, individuals with diabetes have both insulin and amylin deficiency. Amylin deficiency is absolute in type 1 diabetics, whereas in type 2 diabetics, amylin levels increase in the early stage due to insulin resistance but decrease progressively in tandem with the decline in insulin secretion ADDIN EN.CITE <EndNote><Cite><Author>Edelman</Author><Year>2002</Year><RecNum>366</RecNum><record><rec-number>366</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">366</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Edelman, S. V.</author><author>Weyer, C.</author></authors></contributors><auth-address>Veterans Affairs Health Care Systems, V111G Endocrinology, University of California-San Diego, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. svedelman@vapop.ucsd.edu</auth-address><titles><title>Unresolved challenges with insulin therapy in type 1 and type 2 diabetes: potential benefit of replacing amylin, a second beta-cell hormone</title><secondary-title>Diabetes Technol Ther</secondary-title></titles><periodical><full-title>Diabetes Technol Ther</full-title></periodical><pages>175-89</pages><volume>4</volume><number>2</number><edition>2002/06/25</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Amyloid/chemistry/genetics/*therapeutic use</keyword><keyword>Animals</keyword><keyword>Blood Glucose/drug effects/metabolism</keyword><keyword>Diabetes Mellitus, Type 1/*drug therapy/physiopathology</keyword><keyword>Diabetes Mellitus, Type 2/*drug therapy/physiopathology</keyword><keyword>Homeostasis</keyword><keyword>Humans</keyword><keyword>Hypoglycemic Agents/therapeutic use</keyword><keyword>Insulin/*therapeutic use</keyword><keyword>Molecular Sequence Data</keyword><keyword>Protein Conformation</keyword></keywords><dates><year>2002</year></dates><isbn>1520-9156 (Print)
1520-9156 (Linking)</isbn><accession-num>12079621</accession-num><urls><related-urls><url>;(Edelman and Weyer 2002). However contrary to the expectation of accelerated gastric emptying, even patients with type 1 diabetes demonstrate delayed gastric emptying suggesting factors other than amylin play a role in control of gastric motility ADDIN EN.CITE <EndNote><Cite><Author>Heptulla</Author><Year>2008</Year><RecNum>477</RecNum><record><rec-number>477</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">477</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Heptulla, R. A.</author><author>Rodriguez, L. M.</author><author>Mason, K. J.</author><author>Haymond, M. W.</author></authors></contributors><auth-address>Department of Pediatrics, Division of Diabetes and Endocrinology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX 77030, USA. heptulla@bcm.tmc.edu</auth-address><titles><title>Gastric emptying and postprandial glucose excursions in adolescents with type 1 diabetes</title><secondary-title>Pediatr Diabetes</secondary-title></titles><periodical><full-title>Pediatr Diabetes</full-title></periodical><pages>561-6</pages><volume>9</volume><number>6</number><edition>2008/09/03</edition><keywords><keyword>Adolescent</keyword><keyword>Amyloid/*blood/deficiency</keyword><keyword>Blood Glucose/*metabolism</keyword><keyword>Diabetes Mellitus, Type 1/*physiopathology</keyword><keyword>Gastric Emptying/*physiology</keyword><keyword>Gastrointestinal Motility/drug effects</keyword><keyword>Glucagon/blood</keyword><keyword>Humans</keyword><keyword>Insulin/blood</keyword><keyword>Islet Amyloid Polypeptide</keyword><keyword>Postprandial Period</keyword></keywords><dates><year>2008</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1399-5448 (Electronic)
1399-543X (Linking)</isbn><accession-num>18761650</accession-num><urls><related-urls><url> [pii]
10.1111/j.1399-5448.2008.00430.x</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Heptulla, Rodriguez et al. 2008) in diabetic patients. Delayed gastric emptying in type 2 diabetes patients ADDIN EN.CITE <EndNote><Cite><Author>Hoppener</Author><Year>2000</Year><RecNum>136</RecNum><record><rec-number>136</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">136</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hoppener, J. W.</author><author>Ahren, B.</author><author>Lips, C. J.</author></authors></contributors><auth-address>Department of Internal Medicine, University Medical Center, Utrecht, The Netherlands. j.w.m.hoeppener@lab.azu.nl</auth-address><titles><title>Islet amyloid and type 2 diabetes mellitus</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>411-9</pages><volume>343</volume><number>6</number><edition>2000/08/10</edition><keywords><keyword>Amyloid/*antagonists & inhibitors/chemistry/genetics/physiology</keyword><keyword>Amyloidosis/complications/prevention & control</keyword><keyword>Animals</keyword><keyword>*Diabetes Mellitus, Type 2/drug therapy/etiology/pathology</keyword><keyword>Humans</keyword><keyword>Islets of Langerhans/pathology</keyword><keyword>Mice</keyword><keyword>Mice, Transgenic</keyword><keyword>Pancreatic Diseases/complications/prevention & control</keyword></keywords><dates><year>2000</year><pub-dates><date>Aug 10</date></pub-dates></dates><isbn>0028-4793 (Print)</isbn><accession-num>10933741</accession-num><urls><related-urls><url>;(Hoppener, Ahren et al. 2000) may be partly explained by raised amylin levels due to insulin resistance syndrome. Amylin’s synthetic analogue pramlintide slows liquid and solid gastric emptying by 1–2 hours through vagal inhibition in both type 1 and type 2 diabetic patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaGl0ZWhvdXNlPC9BdXRob3I+PFllYXI+MjAwMjwvWWVh
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ADDIN EN.CITE.DATA (Whitehouse, Kruger et al. 2002; Kellmeyer, Kesty et al. 2007).Thus gastric emptying in diabetes is influenced particularly by glycaemia with reciprocal relationship between the rate of gastric emptying and the blood glucose concentration. Factors other than and partly due to amylin seem to be responsible for the gastrointestinal symptoms associated with delayed gastric emptying in patients with type 1and type 2 diabetes respectively.Methods of Measurement of Gastric Emptying in HumansA variety of different techniques are available to study the rate of gastric emptying in humans. The majority of these tests are only applicable to adult patients. However methodological details and review of individual tests may help to establish relevance of these tests to the neonatal and paediatric setting. Early methods employed to measure gastric emptying such as dye dilution and single and double sampling gastric aspiration techniques ADDIN EN.CITE <EndNote><Cite><Author>George</Author><Year>1968</Year><RecNum>369</RecNum><record><rec-number>369</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">369</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>George, J. D.</author></authors></contributors><titles><title>New clinical method for measuring the rate of gastric emptying: the double sampling test meal</title><secondary-title>Gut</secondary-title></titles><periodical><full-title>Gut</full-title></periodical><pages>237-42</pages><volume>9</volume><number>2</number><edition>1968/04/01</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Digestion</keyword><keyword>Dye Dilution Technique</keyword><keyword>Female</keyword><keyword>Gastric Acidity Determination</keyword><keyword>Gastric Juice/secretion</keyword><keyword>*Gastric Lavage</keyword><keyword>*Gastrointestinal Motility</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Methods</keyword><keyword>Middle Aged</keyword><keyword>Peptic Ulcer/physiopathology</keyword><keyword>Secretory Rate</keyword><keyword>Stomach/*physiology</keyword></keywords><dates><year>1968</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0017-5749 (Print)
0017-5749 (Linking)</isbn><accession-num>4871724</accession-num><urls><related-urls><url>;(George 1968) are now almost obsolete due to the availability of more advanced techniques. Gastric emptying scintigraphy is considered gold standard as it is a physiologic, quantitative, non-invasive test for evaluating gastric emptying for both solids and liquids. It is validated in healthy subjects and also allows for assessment of intragastric distribution PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BYmVsbDwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Tougas, Chen et al. 2000; Abell, Camilleri et al. 2008; Abell, Camilleri et al. 2008). A radiolabelled 99mTc-sulphur colloid or 113mIn DTPA or 67Ga EDTA meal is ingested under standardized ambient noise, ambient light, and patient comfort. Imaging is performed while the patient is positioned constant either standing or sitting. The passage of the meal from the stomach to the small intestine is then followed by taking images at regular intervals with a gamma camera ADDIN EN.CITE <EndNote><Cite><Author>Macdonald</Author><Year>1997</Year><RecNum>48</RecNum><record><rec-number>48</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">48</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Macdonald, I. A.</author></authors></contributors><auth-address>Department of Physiology and Pharmacology, University of Nottingham Medical School, UK.</auth-address><titles><title>Amylin and the gastrointestinal tract</title><secondary-title>Diabet Med</secondary-title></titles><periodical><full-title>Diabet Med</full-title></periodical><pages>S24-8</pages><volume>14 Suppl 2</volume><edition>1997/06/01</edition><keywords><keyword>Amyloid/*pharmacology/therapeutic use</keyword><keyword>Animals</keyword><keyword>Diabetes Mellitus/drug therapy</keyword><keyword>Digestive Physiology</keyword><keyword>Digestive System/*drug effects</keyword><keyword>Gastric Emptying/drug effects</keyword><keyword>Humans</keyword><keyword>Hypoglycemic Agents/*pharmacology/therapeutic use</keyword><keyword>Rats</keyword><keyword>Rats, Inbred BB</keyword><keyword>Rats, Wistar</keyword></keywords><dates><year>1997</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0742-3071 (Print)</isbn><accession-num>9212326</accession-num><urls><related-urls><url>(SICI)1096-9136(199706)14:2+<S24::AID-DIA399>3.0.CO;2-M</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Macdonald 1997). The main disadvantages of this procedure are its cost and exposure to a small amount of radiation which would be a limitation for its use in neonates’ especially preterm infants. The basis of the bio impedance technique ADDIN EN.CITE <EndNote><Cite><Author>Savino</Author><Year>2004</Year><RecNum>373</RecNum><record><rec-number>373</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">373</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Savino, F.</author><author>Cresi, F.</author><author>Ferrigno, M.</author><author>Palumeri, E.</author><author>Oggero, R.</author><author>Silvestro, L.</author></authors></contributors><auth-address>Department of Paediatrics, University of Turin, Regina Margherita Children Hospital, Turin, Italy. francesco.savino@unito.it</auth-address><titles><title>Gastric emptying in infants: epigastric impedance versus scintigraphy</title><secondary-title>Acta Paediatr</secondary-title></titles><periodical><full-title>Acta Paediatr</full-title></periodical><pages>608-12</pages><volume>93</volume><number>5</number><edition>2004/06/04</edition><keywords><keyword>Electric Impedance/diagnostic use</keyword><keyword>Female</keyword><keyword>Gastric Emptying/*physiology</keyword><keyword>Gastrointestinal Tract/physiology/radionuclide imaging</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Male</keyword><keyword>Radionuclide Imaging/*methods</keyword><keyword>Technetium Tc 99m Sulfur Colloid/diagnostic use</keyword></keywords><dates><year>2004</year><pub-dates><date>May</date></pub-dates></dates><isbn>0803-5253 (Print)
0803-5253 (Linking)</isbn><accession-num>15174781</accession-num><urls><related-urls><url>;(Savino, Cresi et al. 2004) is that after the ingestion of fluids with a different conductivity from body tissues, the impedance to an electrical current through the upper abdomen changes, impedance increases as the stomach fills and decreases as it empties. The slope of the plot of impedance versus time is used to calculate the time for emptying half of the meal giving a value for impedance half-life. Epigastric impedance patterns closely correlated with scintigraphy in the measurement of gastric emptying in infants ADDIN EN.CITE <EndNote><Cite><Author>Savino</Author><Year>2004</Year><RecNum>373</RecNum><record><rec-number>373</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">373</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Savino, F.</author><author>Cresi, F.</author><author>Ferrigno, M.</author><author>Palumeri, E.</author><author>Oggero, R.</author><author>Silvestro, L.</author></authors></contributors><auth-address>Department of Paediatrics, University of Turin, Regina Margherita Children Hospital, Turin, Italy. francesco.savino@unito.it</auth-address><titles><title>Gastric emptying in infants: epigastric impedance versus scintigraphy</title><secondary-title>Acta Paediatr</secondary-title></titles><periodical><full-title>Acta Paediatr</full-title></periodical><pages>608-12</pages><volume>93</volume><number>5</number><edition>2004/06/04</edition><keywords><keyword>Electric Impedance/diagnostic use</keyword><keyword>Female</keyword><keyword>Gastric Emptying/*physiology</keyword><keyword>Gastrointestinal Tract/physiology/radionuclide imaging</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Male</keyword><keyword>Radionuclide Imaging/*methods</keyword><keyword>Technetium Tc 99m Sulfur Colloid/diagnostic use</keyword></keywords><dates><year>2004</year><pub-dates><date>May</date></pub-dates></dates><isbn>0803-5253 (Print)
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ADDIN EN.CITE.DATA (Ziegler, Schadewaldt et al. 1996). When octanoic acid (with solid meal) or acetate (with liquid meal) labelled with 13C is combined with different food substrates, these compounds pass unabsorbed through the stomach to the duodenum but are quickly absorbed in the small intestine and metabolized to 13CO2 in the liver. Appearance of 13CO2 in the breath marks gastric emptying, absorption and excretion of 13CO2. This methodology offers significant advantages over scintigraphy and other methods in terms of cost, accessibility, and avoidance of radioactive materials. Sensitivity and specificity of the 13C-octanoate breath test for measuring gastric emptying has been shown to be 75% and 86%, respectively PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaWVnbGVyPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48
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ADDIN EN.CITE.DATA (Ziegler, Schadewaldt et al. 1996). In addition, because of low intraindividual variability, breath tests may be best applied to tracking gastric emptying during therapeutic interventions. It is noteworthy that the 13C-octanoate exhalation times correlate with gastric emptying but do not represent real gastric emptying times and the results may depend on intact liver and pulmonary function. 13C-Spirulina platensis breath test PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WZWxsYTwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+PFJl
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Tm90ZT5=
ADDIN EN.CITE.DATA (Vella, Lee et al. 2002) is a slight variation to 13C-octanoate breath test, has recently been validated and deemed as reproducible as scintigraphy PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TemFya2E8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Szarka, Camilleri et al. 2008).Ultrasonography ADDIN EN.CITE <EndNote><Cite><Author>Holt</Author><Year>1986</Year><RecNum>198</RecNum><record><rec-number>198</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">198</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Holt, S.</author><author>Cervantes, J.</author><author>Wilkinson, A. A.</author><author>Wallace, J. H.</author></authors></contributors><titles><title>Measurement of gastric emptying rate in humans by real-time ultrasound</title><secondary-title>Gastroenterology</secondary-title></titles><periodical><full-title>Gastroenterology</full-title></periodical><pages>918-23</pages><volume>90</volume><number>4</number><edition>1986/04/01</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Female</keyword><keyword>*Gastric Emptying</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Stomach/*radionuclide imaging</keyword><keyword>*Ultrasonography</keyword></keywords><dates><year>1986</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0016-5085 (Print)</isbn><accession-num>3512357</accession-num><urls><related-urls><url> [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Holt, Cervantes et al. 1986) allows real-time changes in gastric motility and gastric emptying including transpyloric flow of liquid gastric contents, and accommodation in the proximal stomach PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXJrbWFuPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48
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ADDIN EN.CITE.DATA (Berstad, Hausken et al. 1996; Kim, Myung et al. 2000; Parkman, Hasler et al. 2004). Ultrasound measurements of gastric emptying is well validated in healthy subjects and showed a high correlation to scintigraphy in quantifying emptying including liquids of both low and high nutrients ADDIN EN.CITE <EndNote><Cite><Author>Benini</Author><Year>1999</Year><RecNum>379</RecNum><record><rec-number>379</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">379</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Benini, L.</author><author>Sembenini, C.</author><author>Heading, R. C.</author><author>Giorgetti, P. G.</author><author>Montemezzi, S.</author><author>Zamboni, M.</author><author>Di Benedetto, P.</author><author>Brighenti, F.</author><author>Vantini, I.</author></authors></contributors><auth-address>Department of Gastroenterology, Rehabilitation Hospital of Valeggio sM, University of Verona, Italy.</auth-address><titles><title>Simultaneous measurement of gastric emptying of a solid meal by ultrasound and by scintigraphy</title><secondary-title>Am J Gastroenterol</secondary-title></titles><periodical><full-title>Am J Gastroenterol</full-title></periodical><pages>2861-5</pages><volume>94</volume><number>10</number><edition>1999/10/16</edition><keywords><keyword>Adult</keyword><keyword>Dyspepsia/physiopathology/radionuclide imaging/ultrasonography</keyword><keyword>Female</keyword><keyword>Food</keyword><keyword>*Gastric Emptying</keyword><keyword>Gastroesophageal Reflux/physiopathology/radionuclide</keyword><keyword>imaging/ultrasonography</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Stomach/*radionuclide imaging/*ultrasonography</keyword></keywords><dates><year>1999</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0002-9270 (Print)
0002-9270 (Linking)</isbn><accession-num>10520834</accession-num><urls><related-urls><url> [pii]
10.1111/j.1572-0241.1999.01429.x</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Benini, Sembenini et al. 1999). Although ultrasound methodologies are relatively low cost and will not expose patients to radioactive materials, their performance is operator-dependent and these studies are reliable only for measurement of liquid emptying rates ADDIN EN.CITE <EndNote><Cite><Author>Parkman</Author><Year>2004</Year><RecNum>376</RecNum><record><rec-number>376</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">376</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Parkman, H. P.</author><author>Hasler, W. L.</author><author>Fisher, R. S.</author></authors></contributors><auth-address>Temple University School of Medicine, Philadelphia, PA, USA.</auth-address><titles><title>American Gastroenterological Association technical review on the diagnosis and treatment of gastroparesis</title><secondary-title>Gastroenterology</secondary-title></titles><periodical><full-title>Gastroenterology</full-title></periodical><pages>1592-622</pages><volume>127</volume><number>5</number><edition>2004/11/03</edition><keywords><keyword>Breath Tests</keyword><keyword>Diagnosis, Differential</keyword><keyword>Gastric Emptying</keyword><keyword>Gastrointestinal Motility</keyword><keyword>Gastroparesis/classification/*diagnosis/*therapy</keyword><keyword>Humans</keyword></keywords><dates><year>2004</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0016-5085 (Print)
0016-5085 (Linking)</isbn><accession-num>15521026</accession-num><urls><related-urls><url> [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Parkman, Hasler et al. 2004). Also, it does not permit determination of the phase of the meal that is being emptied from the stomach. Recently, 3D ultrasonography has been shown to provide a valid measure of gastric emptying of liquid meals in healthy subjects ADDIN EN.CITE <EndNote><Cite><Author>Gentilcore</Author><Year>2006</Year><RecNum>380</RecNum><record><rec-number>380</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">380</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gentilcore, D.</author><author>Hausken, T.</author><author>Horowitz, M.</author><author>Jones, K. L.</author></authors></contributors><auth-address>Royal Adelaide Hospital, University of Adelaide, Adelaide, SA, Australia.</auth-address><titles><title>Measurements of gastric emptying of low- and high-nutrient liquids using 3D ultrasonography and scintigraphy in healthy subjects</title><secondary-title>Neurogastroenterol Motil</secondary-title></titles><periodical><full-title>Neurogastroenterol Motil</full-title></periodical><pages>1062-8</pages><volume>18</volume><number>12</number><edition>2006/11/18</edition><keywords><keyword>Adult</keyword><keyword>Eating</keyword><keyword>Female</keyword><keyword>Gastric Emptying/*physiology</keyword><keyword>Humans</keyword><keyword>Imaging, Three-Dimensional</keyword><keyword>Male</keyword><keyword>Radionuclide Imaging/*methods</keyword><keyword>Radiopharmaceuticals/diagnostic use</keyword><keyword>Stomach/*radionuclide imaging/*ultrasonography</keyword><keyword>Technetium Tc 99m Sulfur Colloid/diagnostic use</keyword><keyword>Ultrasonography/*methods</keyword></keywords><dates><year>2006</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1350-1925 (Print)
1350-1925 (Linking)</isbn><accession-num>17109689</accession-num><urls><related-urls><url> [pii]
10.1111/j.1365-2982.2006.00830.x</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Gentilcore, Hausken et al. 2006). Real time ultrasound measurement of gastric antral cross sectional area (ACSA) was shown to be reproducible in the assessment of gastric emptying in preterm infants ADDIN EN.CITE <EndNote><Cite><Author>Ewer</Author><Year>1994</Year><RecNum>269</RecNum><record><rec-number>269</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">269</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ewer, A. K.</author><author>Durbin, G. M.</author><author>Morgan, M. E.</author><author>Booth, I. W.</author></authors></contributors><auth-address>Maternity Hospital, Birmingham.</auth-address><titles><title>Gastric emptying in preterm infants</title><secondary-title>Arch Dis Child Fetal Neonatal Ed</secondary-title></titles><periodical><full-title>Arch Dis Child Fetal Neonatal Ed</full-title></periodical><pages>F24-7</pages><volume>71</volume><number>1</number><edition>1994/07/01</edition><keywords><keyword>Animals</keyword><keyword>Birth Weight</keyword><keyword>Double-Blind Method</keyword><keyword>Female</keyword><keyword>*Gastric Emptying</keyword><keyword>Gestational Age</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature/*physiology</keyword><keyword>Male</keyword><keyword>Milk</keyword><keyword>Milk, Human</keyword><keyword>Time Factors</keyword><keyword>Ultrasonography</keyword></keywords><dates><year>1994</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1359-2998 (Print)</isbn><accession-num>8092865</accession-num><urls><related-urls><url>;(Ewer, Durbin et al. 1994). The technique is based on serial measurements of ACSA as it fills and empties during and after a feed. Ultrasound and scintigraphic techniques showed 90% concordance in subjects varying from 15 day infants to 10 year old children. The 10% discordant results were related to overlapping of duodenum and stomach during scintigraphy and shadowing of the gastric antrum by air during ultrasonography ADDIN EN.CITE <EndNote><Cite><Author>Gomes</Author><Year>2003</Year><RecNum>272</RecNum><record><rec-number>272</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">272</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gomes, H.</author><author>Hornoy, P.</author><author>Liehn, J. C.</author></authors></contributors><auth-address>Department of Paediatric Imaging, American Memorial Hospital, 49 rue Cognacq Jay, 51100 Reims, France. hgomes@chu-reims.fr</auth-address><titles><title>Ultrasonography and gastric emptying in children: validation of a sonographic method and determination of physiological and pathological patterns</title><secondary-title>Pediatr Radiol</secondary-title></titles><periodical><full-title>Pediatr Radiol</full-title></periodical><pages>522-9</pages><volume>33</volume><number>8</number><edition>2003/06/18</edition><keywords><keyword>Adolescent</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Female</keyword><keyword>Gastric Emptying/*physiology</keyword><keyword>Gastroesophageal Reflux/radionuclide imaging/*ultrasonography</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Infant, Newborn</keyword><keyword>Linear Models</keyword><keyword>Male</keyword><keyword>Prospective Studies</keyword><keyword>Reproducibility of Results</keyword><keyword>Stomach/radionuclide imaging/ultrasonography</keyword></keywords><dates><year>2003</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0301-0449 (Print)</isbn><accession-num>12811435</accession-num><urls><related-urls><url>;(Gomes, Hornoy et al. 2003). Magnetic resonance imaging is another non-invasive test that allows for measurement of gastric motility and emptying and can differentiate among an ingested meal, solid and liquid phases, gastric secretion, and air PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GZWlubGU8L0F1dGhvcj48WWVhcj4xOTk5PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Schwizer, Maecke et al. 1992; Feinle, Kunz et al. 1999). Although magnetic resonance imaging requires no exposure to radioactive materials, the procedure cost is high and it requires significant time for interpretation of test results ADDIN EN.CITE <EndNote><Cite><Author>Parkman</Author><Year>2004</Year><RecNum>376</RecNum><record><rec-number>376</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">376</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Parkman, H. P.</author><author>Hasler, W. L.</author><author>Fisher, R. S.</author></authors></contributors><auth-address>Temple University School of Medicine, Philadelphia, PA, USA.</auth-address><titles><title>American Gastroenterological Association technical review on the diagnosis and treatment of gastroparesis</title><secondary-title>Gastroenterology</secondary-title></titles><periodical><full-title>Gastroenterology</full-title></periodical><pages>1592-622</pages><volume>127</volume><number>5</number><edition>2004/11/03</edition><keywords><keyword>Breath Tests</keyword><keyword>Diagnosis, Differential</keyword><keyword>Gastric Emptying</keyword><keyword>Gastrointestinal Motility</keyword><keyword>Gastroparesis/classification/*diagnosis/*therapy</keyword><keyword>Humans</keyword></keywords><dates><year>2004</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0016-5085 (Print)
0016-5085 (Linking)</isbn><accession-num>15521026</accession-num><urls><related-urls><url> [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Parkman, Hasler et al. 2004).The appearance of paracetamol in the systemic circulation is an indirect method of determining the rate of gastric emptying. Because paracetomol after oral administration is not absorbed from the stomach but is rapidly absorbed from the small intestine, the area under the serum concentration curve (AUC) is determined by the rate of gastric emptying ADDIN EN.CITE <EndNote><Cite><Author>Heading</Author><Year>1973</Year><RecNum>384</RecNum><record><rec-number>384</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">384</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Heading, R. C.</author><author>Nimmo, J.</author><author>Prescott, L. F.</author><author>Tothill, P.</author></authors></contributors><titles><title>The dependence of paracetamol absorption on the rate of gastric emptying</title><secondary-title>Br J Pharmacol</secondary-title></titles><periodical><full-title>Br J Pharmacol</full-title></periodical><pages>415-21</pages><volume>47</volume><number>2</number><edition>1973/02/01</edition><keywords><keyword>Acetaminophen/blood/*metabolism/urine</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Half-Life</keyword><keyword>Humans</keyword><keyword>Intestinal Absorption</keyword><keyword>Kinetics</keyword><keyword>Middle Aged</keyword><keyword>Stomach/*physiology</keyword><keyword>Time Factors</keyword></keywords><dates><year>1973</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0007-1188 (Print)
0007-1188 (Linking)</isbn><accession-num>4722050</accession-num><urls><related-urls><url>;(Heading, Nimmo et al. 1973). Paracetamol absorption test ADDIN EN.CITE <EndNote><Cite><Author>van Wyk</Author><Year>1995</Year><RecNum>202</RecNum><record><rec-number>202</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">202</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>van Wyk, M.</author><author>Sommers, D. K.</author><author>Snyman, J. R.</author><author>Moncrieff, J.</author></authors></contributors><auth-address>Department of Pharmacology, University of Pretoria, South Africa.</auth-address><titles><title>The proportional cumulative area under the curve of paracetamol used as an index of gastric emptying in diabetic patients with symptoms of gastroparesis</title><secondary-title>Clin Exp Pharmacol Physiol</secondary-title></titles><pages>637-40</pages><volume>22</volume><number>9</number><edition>1995/09/01</edition><keywords><keyword>Acetaminophen/*pharmacokinetics</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Analgesics, Non-Narcotic/*pharmacokinetics</keyword><keyword>Diabetes Mellitus, Type 1/complications/*physiopathology</keyword><keyword>Diabetic Neuropathies/physiopathology</keyword><keyword>Dopamine Antagonists/pharmacology</keyword><keyword>Female</keyword><keyword>Gastric Emptying/*physiology</keyword><keyword>Gastroparesis/*diagnosis/etiology</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Metoclopramide/pharmacology</keyword><keyword>Middle Aged</keyword></keywords><dates><year>1995</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0305-1870 (Print)</isbn><accession-num>8542677</accession-num><urls><related-urls><url>;(van Wyk, Sommers et al. 1995) is simple, reproducible, and accurate bedside tool PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXllcjwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Heyland, Tougas et al. 1996; Heyland, Tougas et al. 1996) and even in pregnant women ADDIN EN.CITE <EndNote><Cite><Author>Stanley</Author><Year>1995</Year><RecNum>385</RecNum><record><rec-number>385</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">385</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Stanley, K.</author><author>Magides, A.</author><author>Arnot, M.</author><author>Bruce, C.</author><author>Reilly, C.</author><author>McFee, A.</author><author>Fraser, R.</author></authors></contributors><auth-address>University Department of Obstetrics, Northern General Hospital, Sheffield, UK.</auth-address><titles><title>Delayed gastric emptying as a factor in delayed postprandial glycaemic response in pregnancy</title><secondary-title>Br J Obstet Gynaecol</secondary-title></titles><periodical><full-title>Br J Obstet Gynaecol</full-title></periodical><pages>288-91</pages><volume>102</volume><number>4</number><edition>1995/04/01</edition><keywords><keyword>Acetaminophen/pharmacokinetics</keyword><keyword>Blood Glucose/*metabolism</keyword><keyword>Female</keyword><keyword>Gastric Emptying/*physiology</keyword><keyword>Humans</keyword><keyword>Insulin/metabolism</keyword><keyword>Longitudinal Studies</keyword><keyword>Postpartum Period/*physiology</keyword><keyword>Pregnancy/metabolism/*physiology</keyword></keywords><dates><year>1995</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0306-5456 (Print)
0306-5456 (Linking)</isbn><accession-num>7612510</accession-num><urls><related-urls><url>;(Stanley, Magides et al. 1995). The safety and reliability of the test in neonatal population is not known.The newest technology in measuring gastric emptying is a technique involving a non-digestible capsule or SmartPill that can record luminal pH, temperature and pressure during gastrointestinal transit, thus allowing measurement of gastric emptying times PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LdW88L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA (Husband and Husband 1969; Husband, Husband et al. 1970) or modified double sampling marker dilution technique ADDIN EN.CITE <EndNote><Cite><Author>George</Author><Year>1968</Year><RecNum>369</RecNum><record><rec-number>369</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">369</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>George, J. D.</author></authors></contributors><titles><title>New clinical method for measuring the rate of gastric emptying: the double sampling test meal</title><secondary-title>Gut</secondary-title></titles><periodical><full-title>Gut</full-title></periodical><pages>237-42</pages><volume>9</volume><number>2</number><edition>1968/04/01</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Digestion</keyword><keyword>Dye Dilution Technique</keyword><keyword>Female</keyword><keyword>Gastric Acidity Determination</keyword><keyword>Gastric Juice/secretion</keyword><keyword>*Gastric Lavage</keyword><keyword>*Gastrointestinal Motility</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Methods</keyword><keyword>Middle Aged</keyword><keyword>Peptic Ulcer/physiopathology</keyword><keyword>Secretory Rate</keyword><keyword>Stomach/*physiology</keyword></keywords><dates><year>1968</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0017-5749 (Print)
0017-5749 (Linking)</isbn><accession-num>4871724</accession-num><urls><related-urls><url>;(George 1968). Although the former method assessed the pattern of gastric emptying for an individual feed, the latter method however required repeated aspiration of gastric contents which may be unphysiological and not well tolerated in preterm infants ADDIN EN.CITE <EndNote><Cite><Author>Ewer</Author><Year>1994</Year><RecNum>269</RecNum><record><rec-number>269</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">269</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ewer, A. K.</author><author>Durbin, G. M.</author><author>Morgan, M. E.</author><author>Booth, I. W.</author></authors></contributors><auth-address>Maternity Hospital, Birmingham.</auth-address><titles><title>Gastric emptying in preterm infants</title><secondary-title>Arch Dis Child Fetal Neonatal Ed</secondary-title></titles><periodical><full-title>Arch Dis Child Fetal Neonatal Ed</full-title></periodical><pages>F24-7</pages><volume>71</volume><number>1</number><edition>1994/07/01</edition><keywords><keyword>Animals</keyword><keyword>Birth Weight</keyword><keyword>Double-Blind Method</keyword><keyword>Female</keyword><keyword>*Gastric Emptying</keyword><keyword>Gestational Age</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature/*physiology</keyword><keyword>Male</keyword><keyword>Milk</keyword><keyword>Milk, Human</keyword><keyword>Time Factors</keyword><keyword>Ultrasonography</keyword></keywords><dates><year>1994</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1359-2998 (Print)</isbn><accession-num>8092865</accession-num><urls><related-urls><url>;(Ewer, Durbin et al. 1994) and thus obsolete due to availability of newer non-invasive techniques. Radionuclide methods using radioactive low-dose markers such as 99mTc sulfur colloid or with 99mTc phytate ADDIN EN.CITE <EndNote><Cite><Author>Reddy</Author><Year>2000</Year><RecNum>201</RecNum><record><rec-number>201</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">201</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Reddy, P. S.</author><author>Deorari, A. K.</author><author>Bal, C. S.</author><author>Paul, V. K.</author><author>Singh, M.</author></authors></contributors><auth-address>Departments of Pediatrics and Nuclear Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi 110 029, India.</auth-address><titles><title>A double-blind placebo-controlled study on prophylactic use of cisapride on feed intolerance and gastric emptying in preterm neonates</title><secondary-title>Indian Pediatr</secondary-title></titles><pages>837-44</pages><volume>37</volume><number>8</number><edition>2000/08/22</edition><keywords><keyword>Cisapride/*therapeutic use</keyword><keyword>Double-Blind Method</keyword><keyword>Food Hypersensitivity/physiopathology/*prevention & control</keyword><keyword>*Gastric Emptying</keyword><keyword>Gastroesophageal Reflux/physiopathology/*prevention & control</keyword><keyword>Gastrointestinal Agents/*therapeutic use</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature</keyword><keyword>Infant, Premature, Diseases/physiopathology/*prevention & control</keyword></keywords><dates><year>2000</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0019-6061 (Print)</isbn><accession-num>10951632</accession-num><urls><related-urls><url>;(Reddy, Deorari et al. 2000) mixed with milk is a reliable and reproducible technique to assess gastric emptying in infants. However the costs of a gamma camera and exposure to ionising radiation are major disadvantages in neonates and children. Various factors influence gastric emptying in neonates. Using marker dilution technique in newborns, Husband et al showed that 5% glucose and starch emptied faster than 10% glucose and glucose solution of comparable energy content PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IdXNiYW5kPC9BdXRob3I+PFllYXI+MTk2OTwvWWVhcj48
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ADDIN EN.CITE.DATA (Husband and Husband 1969; Husband, Husband et al. 1970). Cavell using the same technique in healthy preterm infants showed that half the human milk and formula left the stomach in 25 and 51 minutes respectively ADDIN EN.CITE <EndNote><Cite><Author>Cavell</Author><Year>1979</Year><RecNum>388</RecNum><record><rec-number>388</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">388</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cavell, B.</author></authors></contributors><titles><title>Gastric emptying in preterm infants</title><secondary-title>Acta Paediatr Scand</secondary-title></titles><periodical><full-title>Acta Paediatr Scand</full-title></periodical><pages>725-30</pages><volume>68</volume><number>5</number><edition>1979/09/01</edition><keywords><keyword>Female</keyword><keyword>*Gastric Emptying</keyword><keyword>Humans</keyword><keyword>Indicator Dilution Techniques</keyword><keyword>Infant Food</keyword><keyword>Infant, Newborn</keyword><keyword>*Infant, Premature</keyword><keyword>Infant, Premature, Diseases/physiopathology</keyword><keyword>Male</keyword><keyword>Milk, Human</keyword></keywords><dates><year>1979</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0001-656X (Print)
0001-656X (Linking)</isbn><accession-num>393064</accession-num><urls><related-urls><url>;(Cavell 1979). Other researchers also used marker dilution technique and demonstrated delayed gastric emptying to increased calorific density ADDIN EN.CITE <EndNote><Cite><Author>Siegel</Author><Year>1984</Year><RecNum>389</RecNum><record><rec-number>389</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">389</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Siegel, M.</author><author>Lebenthal, E.</author><author>Krantz, B.</author></authors></contributors><titles><title>Effect of caloric density on gastric emptying in premature infants</title><secondary-title>J Pediatr</secondary-title></titles><periodical><full-title>J Pediatr</full-title></periodical><pages>118-22</pages><volume>104</volume><number>1</number><edition>1984/01/01</edition><keywords><keyword>Bottle Feeding</keyword><keyword>*Energy Intake</keyword><keyword>Female</keyword><keyword>*Gastric Emptying</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>*Infant, Premature</keyword><keyword>Male</keyword></keywords><dates><year>1984</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0022-3476 (Print)
0022-3476 (Linking)</isbn><accession-num>6690656</accession-num><urls><related-urls><url>;(Siegel, Lebenthal et al. 1984) and carbohydrate composition of feeds ADDIN EN.CITE <EndNote><Cite><Author>Siegel</Author><Year>1985</Year><RecNum>390</RecNum><record><rec-number>390</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">390</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Siegel, M.</author><author>Krantz, B.</author><author>Lebenthal, E.</author></authors></contributors><titles><title>Effect of fat and carbohydrate composition on the gastric emptying of isocaloric feedings in premature infants</title><secondary-title>Gastroenterology</secondary-title></titles><periodical><full-title>Gastroenterology</full-title></periodical><pages>785-90</pages><volume>89</volume><number>4</number><edition>1985/10/01</edition><keywords><keyword>Dietary Carbohydrates/*administration & dosage/pharmacology</keyword><keyword>Dietary Fats/*administration & dosage/pharmacology</keyword><keyword>Energy Intake</keyword><keyword>*Gastric Emptying</keyword><keyword>Glucose/analysis</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Infant Food/analysis</keyword><keyword>Infant, Newborn</keyword><keyword>*Infant, Premature</keyword><keyword>Intubation, Gastrointestinal</keyword><keyword>Lactose/analysis</keyword><keyword>Polymers/analysis</keyword><keyword>Stomach/drug effects/*physiology</keyword><keyword>Time Factors</keyword><keyword>Triglycerides/analysis</keyword></keywords><dates><year>1985</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0016-5085 (Print)
0016-5085 (Linking)</isbn><accession-num>4029558</accession-num><urls><related-urls><url> [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Siegel, Krantz et al. 1985) and presence of respiratory distress syndrome ADDIN EN.CITE <EndNote><Cite><Author>Victor</Author><Year>1975</Year><RecNum>400</RecNum><record><rec-number>400</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">400</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Victor, Y. H.</author></authors></contributors><titles><title>Effect of body position on gastric emptying in the neonate</title><secondary-title>Arch Dis Child</secondary-title></titles><periodical><full-title>Arch Dis Child</full-title></periodical><pages>500-4</pages><volume>50</volume><number>7</number><edition>1975/07/01</edition><keywords><keyword>Birth Weight</keyword><keyword>*Gastrointestinal Motility</keyword><keyword>Gestational Age</keyword><keyword>Humans</keyword><keyword>*Infant, Newborn</keyword><keyword>Infant, Premature</keyword><keyword>*Posture</keyword><keyword>Respiratory Distress Syndrome, Newborn/physiopathology</keyword></keywords><dates><year>1975</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1468-2044 (Electronic)
0003-9888 (Linking)</isbn><accession-num>1167062</accession-num><urls><related-urls><url>;(Victor 1975) and congenital heart disease ADDIN EN.CITE <EndNote><Cite><Author>Cavell</Author><Year>1981</Year><RecNum>391</RecNum><record><rec-number>391</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">391</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cavell, B.</author></authors></contributors><titles><title>Gastric emptying in infants with congenital heart disease</title><secondary-title>Acta Paediatr Scand</secondary-title></titles><periodical><full-title>Acta Paediatr Scand</full-title></periodical><pages>517-20</pages><volume>70</volume><number>4</number><edition>1981/07/01</edition><keywords><keyword>*Gastric Emptying</keyword><keyword>Heart Defects, Congenital/*physiopathology</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Infant Food</keyword><keyword>Infant, Newborn</keyword><keyword>Polyethylene Glycols/diagnostic use</keyword></keywords><dates><year>1981</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0001-656X (Print)
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ADDIN EN.CITE.DATA (Victor 1975; Blumenthal and Pildes 1979) on gastric emptying was less clear. Using ultrasonography, Ewer et al confirmed Cavell’s finding that breast milk emptied faster than formula milk in preterm infants ADDIN EN.CITE <EndNote><Cite><Author>Ewer</Author><Year>1994</Year><RecNum>269</RecNum><record><rec-number>269</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">269</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ewer, A. K.</author><author>Durbin, G. M.</author><author>Morgan, M. E.</author><author>Booth, I. W.</author></authors></contributors><auth-address>Maternity Hospital, Birmingham.</auth-address><titles><title>Gastric emptying in preterm infants</title><secondary-title>Arch Dis Child Fetal Neonatal Ed</secondary-title></titles><periodical><full-title>Arch Dis Child Fetal Neonatal Ed</full-title></periodical><pages>F24-7</pages><volume>71</volume><number>1</number><edition>1994/07/01</edition><keywords><keyword>Animals</keyword><keyword>Birth Weight</keyword><keyword>Double-Blind Method</keyword><keyword>Female</keyword><keyword>*Gastric Emptying</keyword><keyword>Gestational Age</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature/*physiology</keyword><keyword>Male</keyword><keyword>Milk</keyword><keyword>Milk, Human</keyword><keyword>Time Factors</keyword><keyword>Ultrasonography</keyword></keywords><dates><year>1994</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1359-2998 (Print)</isbn><accession-num>8092865</accession-num><urls><related-urls><url>;(Ewer, Durbin et al. 1994). The most likely reason for this observation was attributed to gut peptide content and composition of breast milk ADDIN EN.CITE <EndNote><Cite><Author>Lucas</Author><Year>1980</Year><RecNum>401</RecNum><record><rec-number>401</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">401</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lucas, A.</author><author>Sarson, D. L.</author><author>Blackburn, A. M.</author><author>Adrian, T. E.</author><author>Aynsley-Green, A.</author><author>Bloom, S. R.</author></authors></contributors><titles><title>Breast vs bottle: endocrine responses are different with formula feeding</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>1267-9</pages><volume>1</volume><number>8181</number><edition>1980/06/14</edition><keywords><keyword>*Bottle Feeding</keyword><keyword>*Breast Feeding</keyword><keyword>Female</keyword><keyword>Gastrointestinal Hormones/*blood</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Neurotensin/blood</keyword><keyword>Pancreatic Hormones/*blood</keyword></keywords><dates><year>1980</year><pub-dates><date>Jun 14</date></pub-dates></dates><isbn>0140-6736 (Print)
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ADDIN EN.CITE.DATA (ElHennawy, Sparks et al. 2003). The gastric emptying rate measured by 13C-octanoate breath test in preterm neonates was shown to be independent of milk amount ADDIN EN.CITE <EndNote><Cite><Author>Pozler</Author><Year>2003</Year><RecNum>207</RecNum><record><rec-number>207</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">207</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pozler, O.</author><author>Neumann, D.</author><author>Vorisek, V.</author><author>Bukac, J.</author><author>Bures, J.</author><author>Kokstein, Z.</author></authors></contributors><auth-address>Department of Pediatrics, Hradec Kralove, Czech Republic. pozler@lfhk.cuni.cz</auth-address><titles><title>Development of gastric emptying in premature infants. Use of the (13)C-octanoic acid breath test</title><secondary-title>Nutrition</secondary-title></titles><pages>593-6</pages><volume>19</volume><number>7-8</number><edition>2003/07/02</edition><keywords><keyword>Breath Tests</keyword><keyword>Carbon Isotopes/diagnostic use</keyword><keyword>Gastric Emptying/*physiology</keyword><keyword>Humans</keyword><keyword>Infant Food</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature/*physiology</keyword><keyword>Kinetics</keyword><keyword>Mass Spectrometry</keyword><keyword>Milk, Human/metabolism</keyword><keyword>Octanoic Acids/diagnostic use/metabolism</keyword></keywords><dates><year>2003</year><pub-dates><date>Jul-Aug</date></pub-dates></dates><isbn>0899-9007 (Print)</isbn><accession-num>12831944</accession-num><urls><related-urls><url> [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Pozler, Neumann et al. 2003). Similarly, gastric emptying was not affected by changes in feed osmolarity, volume, or energy density individually in preterm infants in a study by Ramirez et al. However reducing osmolality combined with increasing feed volume increased gastric emptying ADDIN EN.CITE <EndNote><Cite><Author>Ramirez</Author><Year>2006</Year><RecNum>404</RecNum><record><rec-number>404</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">404</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ramirez, A.</author><author>Wong, W. W.</author><author>Shulman, R. J.</author></authors></contributors><auth-address>Department of Pediatrics, University of Missouri, Columbia, MO, USA.</auth-address><titles><title>Factors regulating gastric emptying in preterm infants</title><secondary-title>J Pediatr</secondary-title></titles><periodical><full-title>J Pediatr</full-title></periodical><pages>475-9</pages><volume>149</volume><number>4</number><edition>2006/10/03</edition><keywords><keyword>Bottle Feeding</keyword><keyword>Breast Feeding</keyword><keyword>Energy Intake</keyword><keyword>Gastric Emptying/*physiology</keyword><keyword>Humans</keyword><keyword>Infant Formula/administration & dosage</keyword><keyword>Infant, Newborn</keyword><keyword>*Infant, Premature</keyword><keyword>Osmolar Concentration</keyword></keywords><dates><year>2006</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0022-3476 (Print)
0022-3476 (Linking)</isbn><accession-num>17011317</accession-num><urls><related-urls><url>(06)00466-5 [pii]
10.1016/j.jpeds.2006.05.028</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Ramirez, Wong et al. 2006). Notably right lateral position increased gastric emptying in preterm infants ADDIN EN.CITE <EndNote><Cite><Author>Omari</Author><Year>2004</Year><RecNum>405</RecNum><record><rec-number>405</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">405</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Omari, T. I.</author><author>Rommel, N.</author><author>Staunton, E.</author><author>Lontis, R.</author><author>Goodchild, L.</author><author>Haslam, R. R.</author><author>Dent, J.</author><author>Davidson, G. P.</author></authors></contributors><auth-address>Department of Paediatrics, University of Adelaide, Center for Paediatric and Adolescent Gastroenterology, Neonatal Medicine Unit, Women's and Children's Hospital, North Adelaide Australia. taher.omar@adelaide.edu.au</auth-address><titles><title>Paradoxical impact of body positioning on gastroesophageal reflux and gastric emptying in the premature neonate</title><secondary-title>J Pediatr</secondary-title></titles><periodical><full-title>J Pediatr</full-title></periodical><pages>194-200</pages><volume>145</volume><number>2</number><edition>2004/08/04</edition><keywords><keyword>Electric Impedance</keyword><keyword>Female</keyword><keyword>*Gastric Emptying</keyword><keyword>Gastroesophageal Reflux/*physiopathology</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature, Diseases/*physiopathology</keyword><keyword>Male</keyword><keyword>Manometry</keyword><keyword>*Posture</keyword><keyword>Time Factors</keyword></keywords><dates><year>2004</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0022-3476 (Print)
0022-3476 (Linking)</isbn><accession-num>15289766</accession-num><urls><related-urls><url>(04)00422-6 [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Omari, Rommel et al. 2004).Thus ultrasonography ADDIN EN.CITE <EndNote><Cite><Author>Ewer</Author><Year>1994</Year><RecNum>269</RecNum><record><rec-number>269</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">269</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ewer, A. K.</author><author>Durbin, G. M.</author><author>Morgan, M. E.</author><author>Booth, I. W.</author></authors></contributors><auth-address>Maternity Hospital, Birmingham.</auth-address><titles><title>Gastric emptying in preterm infants</title><secondary-title>Arch Dis Child Fetal Neonatal Ed</secondary-title></titles><periodical><full-title>Arch Dis Child Fetal Neonatal Ed</full-title></periodical><pages>F24-7</pages><volume>71</volume><number>1</number><edition>1994/07/01</edition><keywords><keyword>Animals</keyword><keyword>Birth Weight</keyword><keyword>Double-Blind Method</keyword><keyword>Female</keyword><keyword>*Gastric Emptying</keyword><keyword>Gestational Age</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature/*physiology</keyword><keyword>Male</keyword><keyword>Milk</keyword><keyword>Milk, Human</keyword><keyword>Time Factors</keyword><keyword>Ultrasonography</keyword></keywords><dates><year>1994</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1359-2998 (Print)</isbn><accession-num>8092865</accession-num><urls><related-urls><url>;(Ewer, Durbin et al. 1994), (13)C-octanoic acid breath test ADDIN EN.CITE <EndNote><Cite><Author>Pozler</Author><Year>2003</Year><RecNum>207</RecNum><record><rec-number>207</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">207</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pozler, O.</author><author>Neumann, D.</author><author>Vorisek, V.</author><author>Bukac, J.</author><author>Bures, J.</author><author>Kokstein, Z.</author></authors></contributors><auth-address>Department of Pediatrics, Hradec Kralove, Czech Republic. pozler@lfhk.cuni.cz</auth-address><titles><title>Development of gastric emptying in premature infants. Use of the (13)C-octanoic acid breath test</title><secondary-title>Nutrition</secondary-title></titles><pages>593-6</pages><volume>19</volume><number>7-8</number><edition>2003/07/02</edition><keywords><keyword>Breath Tests</keyword><keyword>Carbon Isotopes/diagnostic use</keyword><keyword>Gastric Emptying/*physiology</keyword><keyword>Humans</keyword><keyword>Infant Food</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature/*physiology</keyword><keyword>Kinetics</keyword><keyword>Mass Spectrometry</keyword><keyword>Milk, Human/metabolism</keyword><keyword>Octanoic Acids/diagnostic use/metabolism</keyword></keywords><dates><year>2003</year><pub-dates><date>Jul-Aug</date></pub-dates></dates><isbn>0899-9007 (Print)</isbn><accession-num>12831944</accession-num><urls><related-urls><url> [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Pozler, Neumann et al. 2003) and epigastric impedance ADDIN EN.CITE <EndNote><Cite><Author>Savino</Author><Year>2004</Year><RecNum>373</RecNum><record><rec-number>373</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">373</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Savino, F.</author><author>Cresi, F.</author><author>Ferrigno, M.</author><author>Palumeri, E.</author><author>Oggero, R.</author><author>Silvestro, L.</author></authors></contributors><auth-address>Department of Paediatrics, University of Turin, Regina Margherita Children Hospital, Turin, Italy. francesco.savino@unito.it</auth-address><titles><title>Gastric emptying in infants: epigastric impedance versus scintigraphy</title><secondary-title>Acta Paediatr</secondary-title></titles><periodical><full-title>Acta Paediatr</full-title></periodical><pages>608-12</pages><volume>93</volume><number>5</number><edition>2004/06/04</edition><keywords><keyword>Electric Impedance/diagnostic use</keyword><keyword>Female</keyword><keyword>Gastric Emptying/*physiology</keyword><keyword>Gastrointestinal Tract/physiology/radionuclide imaging</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Male</keyword><keyword>Radionuclide Imaging/*methods</keyword><keyword>Technetium Tc 99m Sulfur Colloid/diagnostic use</keyword></keywords><dates><year>2004</year><pub-dates><date>May</date></pub-dates></dates><isbn>0803-5253 (Print)
0803-5253 (Linking)</isbn><accession-num>15174781</accession-num><urls><related-urls><url>;(Savino, Cresi et al. 2004) have gained popularity to monitor gastric emptying in premature infants and children both in research and clinical settings mainly due to the non-invasive nature of the technique and correlation with well-known techniques. The conflicting data on gastric emptying in new-born and preterm infants may be due to different methods of analysis and feed types used. Literature Review: Feed Intolerance in Preterm InfantsScale of the ProblemProvision of adequate nutrition for growth and development is a cornerstone of the care of preterm infants. However feed intolerance is a common problem and a major hurdle in optimising enteral nutrition in preterm neonates undergoing intensive care. Attempts to reach full enteral feeds in these infants are frequently limited by increased residual feeds in the stomach with or without other manifestations such as abdominal distension, bile stained aspirates, or lack of stooling. These manifestations in preterm infants are not exclusive to feed intolerance and can be experienced in other common clinical conditions such as infection and necrotising enterocolitis. Additionally the symptoms and signs of feed intolerance are difficult to quantify accurately and are prone to subjective variability. Thus the quoted incidence of feed intolerance in literature varies from up to 50% of ELBW infants PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FbEhlbm5hd3k8L0F1dGhvcj48WWVhcj4yMDAzPC9ZZWFy
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ADDIN EN.CITE.DATA (Gross 1983; Gross and Slagle 1993; Premji, Wilson et al. 1997). Under nutrition at critical stages of development may lead to short stature, organ growth failure, and later adverse behavioural and cognitive outcomes ADDIN EN.CITE <EndNote><Cite><Author>Hay</Author><Year>2008</Year><RecNum>417</RecNum><record><rec-number>417</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">417</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hay, W. W., Jr.</author></authors></contributors><auth-address>Department of Pediatrics, Perinatal Research Center, Colorado Clinical Translational Science Institute, University of Colorado School of Medicine, University of Colorado Denver, Aurora, Colorado 80045, USA. bill.hay@uchsc.edu</auth-address><titles><title>Strategies for feeding the preterm infant</title><secondary-title>Neonatology</secondary-title></titles><periodical><full-title>Neonatology</full-title></periodical><pages>245-54</pages><volume>94</volume><number>4</number><edition>2008/10/07</edition><keywords><keyword>Amino Acids/metabolism</keyword><keyword>Glucose/administration & dosage/metabolism</keyword><keyword>Humans</keyword><keyword>Infant Formula/*administration & dosage/methods</keyword><keyword>Infant Nutritional Physiological Phenomena</keyword><keyword>Infant, Newborn</keyword><keyword>*Infant, Premature</keyword><keyword>*Infant, Very Low Birth Weight</keyword><keyword>Lipids/administration & dosage</keyword><keyword>Parenteral Nutrition/*methods</keyword><keyword>Proteins/administration & dosage/metabolism</keyword></keywords><dates><year>2008</year></dates><isbn>1661-7819 (Electronic)
1661-7800 (Linking)</isbn><accession-num>18836284</accession-num><urls><related-urls><url> [pii]
10.1159/000151643</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Hay 2008). Therefore establishing full enteral feeds quickly in high risk preterm neonates has become a priority in neonatal intensive care ADDIN EN.CITE <EndNote><Cite><Author>Patole</Author><Year>2005</Year><RecNum>45</RecNum><record><rec-number>45</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">45</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Patole, S.</author><author>Rao, S.</author><author>Doherty, D.</author></authors></contributors><auth-address>Department of Neonatal Paediatrics, King Edward Memorial Hospital for Women, University of Western Australia, Perth, Western Australia 6008. skpatole@</auth-address><titles><title>Erythromycin as a prokinetic agent in preterm neonates: a systematic review</title><secondary-title>Arch Dis Child Fetal Neonatal Ed</secondary-title></titles><periodical><full-title>Arch Dis Child Fetal Neonatal Ed</full-title></periodical><pages>F301-6</pages><volume>90</volume><number>4</number><edition>2005/05/19</edition><keywords><keyword>Erythromycin/*therapeutic use</keyword><keyword>Gastrointestinal Agents/*therapeutic use</keyword><keyword>Gastrointestinal Diseases/*drug therapy</keyword><keyword>Gastrointestinal Motility/*drug effects</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature</keyword><keyword>Infant, Premature, Diseases/*drug therapy</keyword></keywords><dates><year>2005</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1359-2998 (Print)</isbn><accession-num>15899929</accession-num><urls><related-urls><url> [pii]
10.1136/adc.2004.065250</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Patole, Rao et al. 2005). Physiology of Gastric and Gastrointestinal Motility in Preterm InfantsMature gastrointestinal motility and migrating motor complexes depends on a complex interaction of neural and hormonal control mechanisms which are influenced by gestational age. By 34 weeks of gestation these MMCs are of variable length, with clear intervals and being increasingly propagated and except for the considerably shorter periodicity of 20-40 minutes, the MMC has adult characteristics at term gestation including interruption by feeding PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcnlhbnQ8L0F1dGhvcj48WWVhcj4xOTgyPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Chen, Co et al. 1997; Liang, Co et al. 1998; Riezzo, Indrio et al. 2000). A recent study has shown mature EGG as early as 34 weeks gestation ADDIN EN.CITE <EndNote><Cite><Author>Riezzo</Author><Year>2009</Year><RecNum>403</RecNum><record><rec-number>403</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">403</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Riezzo, G.</author><author>Indrio, F.</author><author>Raimondi, F.</author><author>Montagna, O.</author><author>Salvia, G.</author><author>Massimo, B.</author><author>Polimeno, L.</author><author>Cavallo, L.</author><author>Francavilla, R.</author></authors></contributors><auth-address>Department of Pediatrics, University of Bari Policlinico, Piazza G Cesare, 70124, Bari, Italy. f.indrio@neonatologia.uniba.it.</auth-address><titles><title>Maturation of gastric electrical activity, gastric emptying and intestinal permeability in preterm newborns during the first month of life</title><secondary-title>Ital J Pediatr</secondary-title></titles><periodical><full-title>Ital J Pediatr</full-title></periodical><pages>6</pages><volume>35</volume><number>1</number><edition>2009/06/06</edition><dates><year>2009</year></dates><isbn>1824-7288 (Electronic)</isbn><accession-num>19490663</accession-num><urls><related-urls><url> [pii]
10.1186/1824-7288-35-6</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Riezzo, Indrio et al. 2009). Fasting antral motor activity however is comparable in preterm and term neonates and the degree of antroduodenal coordination improves simultaneously towards term ADDIN EN.CITE <EndNote><Cite><Author>Ittmann</Author><Year>1992</Year><RecNum>406</RecNum><record><rec-number>406</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">406</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ittmann, P. I.</author><author>Amarnath, R.</author><author>Berseth, C. L.</author></authors></contributors><auth-address>Department of Pediatrics, Mayo Clinic, Rochester, Minnesota 55905.</auth-address><titles><title>Maturation of antroduodenal motor activity in preterm and term infants</title><secondary-title>Dig Dis Sci</secondary-title></titles><periodical><full-title>Dig Dis Sci</full-title></periodical><pages>14-9</pages><volume>37</volume><number>1</number><edition>1992/01/01</edition><keywords><keyword>Duodenum/growth & development/*physiology</keyword><keyword>*Gastrointestinal Motility</keyword><keyword>Humans</keyword><keyword>Infant, Newborn/growth & development/*physiology</keyword><keyword>Infant, Premature/growth & development/*physiology</keyword><keyword>Manometry/methods</keyword><keyword>Perfusion</keyword><keyword>Pyloric Antrum/growth & development/*physiology</keyword></keywords><dates><year>1992</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0163-2116 (Print)
0163-2116 (Linking)</isbn><accession-num>1728520</accession-num><urls><related-urls><url>;(Ittmann, Amarnath et al. 1992). Definition of Feed IntoleranceThere are no universally agreed-upon criteria to define feed intolerance in preterm infants. Feed intolerance in preterm infants usually manifests as residual feeds in the stomach prior to the next scheduled feed and may be associated with vomiting, regurgitation, bile stained aspirates and abdominal distension PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWhhdHNjaDwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+
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ADDIN EN.CITE.DATA (Akintorin, Kamat et al. 1997; Kliegman 1999; Rayyis, Ambalavanan et al. 1999; Dollberg, Kuint et al. 2000; Jadcherla and Kliegman 2002; Mihatsch, von Schoenaich et al. 2002). Of these, most clinicians consider vomiting, abdominal distension, and increased gastric residual volume as the ‘triad’ for defining feed intolerance. The literature definitions of feed intolerance in preterm infants mostly include an assessment of gastric residual volume (GRV) probably because it may indicate rapidity of gastric emptying. Furthermore majority of preterm and VLBW infants admitted to the neonatal unit need gastric tube placement and it is common practice to check the gastric residuals prior to the next scheduled feed. The significance of these GRV however may depend upon various factors (both systemic and local) including feeding method (continuous or bolus), feeding volume, feeding type (breast milk versus formula), feeding duration and birth weight and gestation of the infant. GRV are also dependent upon the technique of aspiration and body positions ADDIN EN.CITE <EndNote><Cite><Author>Geraldo V</Author><Year>1997</Year><RecNum>426</RecNum><record><rec-number>426</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">426</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Geraldo V, Pyati S, Joseph T, Pildes RS. </author></authors></contributors><titles><title>Gastric residual (GR): reliability of the measurement.</title><secondary-title>Pediatr Res.</secondary-title></titles><periodical><full-title>Pediatr Res.</full-title></periodical><pages>150A</pages><volume>41</volume><dates><year>1997</year></dates><urls></urls></record></Cite></EndNote>(Geraldo V 1997) and may be subject to variability. It is therefore not surprising that the definition of feed intolerance in preterm infants is varied in literature with several dynamic and fixed definitions based on assessment of prefeed residual volumes, the colour of these GRVs, and associated clinical manifestations such as abdominal distension, vomiting, blood in stool, and apnoea with bradycardia PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NaWhhdHNjaDwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+
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ADDIN EN.CITE.DATA (Akintorin, Kamat et al. 1997; Rayyis, Ambalavanan et al. 1999; Dollberg, Kuint et al. 2000; Mihatsch, von Schoenaich et al. 2002). Dynamic definitions of feed intolerance include GRV of > 20% ADDIN EN.CITE <EndNote><Cite><Author>Dollberg</Author><Year>2000</Year><RecNum>87</RecNum><record><rec-number>87</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">87</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dollberg, S.</author><author>Kuint, J.</author><author>Mazkereth, R.</author><author>Mimouni, F. B.</author></authors></contributors><auth-address>Department of Neonatology, Lis Maternity Hospital, Tel Aviv, Israel.</auth-address><titles><title>Feeding tolerance in preterm infants: randomized trial of bolus and continuous feeding</title><secondary-title>J Am Coll Nutr</secondary-title></titles><periodical><full-title>J Am Coll Nutr</full-title></periodical><pages>797-800</pages><volume>19</volume><number>6</number><edition>2001/02/24</edition><keywords><keyword>Enteral Nutrition/*methods</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature</keyword><keyword>Infant, Very Low Birth Weight/*physiology</keyword><keyword>Prospective Studies</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2000</year><pub-dates><date>Nov-Dec</date></pub-dates></dates><isbn>0731-5724 (Print)</isbn><accession-num>11194534</accession-num><urls><related-urls><url>;(Dollberg, Kuint et al. 2000) of the previous 4 hour feed volume, > 50% PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2hhbmxlcjwvQXV0aG9yPjxZZWFyPjE5OTk8L1llYXI+
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ADDIN EN.CITE.DATA (Wang, Hung et al. 1997; Dollberg, Kuint et al. 2000) of a 2 hour bolus feed volume, or as a total GRV > 10% of the previous day feed volume ADDIN EN.CITE <EndNote><Cite><Author>Slagle</Author><Year>1988</Year><RecNum>245</RecNum><record><rec-number>245</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">245</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Slagle, T. A.</author><author>Gross, S. J.</author></authors></contributors><auth-address>Department of Pediatrics, SUNY Health Science Center, Syracuse 13210.</auth-address><titles><title>Effect of early low-volume enteral substrate on subsequent feeding tolerance in very low birth weight infants</title><secondary-title>J Pediatr</secondary-title></titles><periodical><full-title>J Pediatr</full-title></periodical><pages>526-31</pages><volume>113</volume><number>3</number><edition>1988/09/01</edition><keywords><keyword>Apgar Score</keyword><keyword>Birth Weight</keyword><keyword>Clinical Trials as Topic</keyword><keyword>Enteral Nutrition/adverse effects/*methods</keyword><keyword>Enterocolitis, Pseudomembranous/etiology</keyword><keyword>Humans</keyword><keyword>Infant Food</keyword><keyword>*Infant, Low Birth Weight</keyword><keyword>Infant, Newborn</keyword><keyword>Intensive Care Units, Neonatal</keyword><keyword>Parenteral Nutrition</keyword><keyword>Prospective Studies</keyword><keyword>Random Allocation</keyword></keywords><dates><year>1988</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0022-3476 (Print)</isbn><accession-num>3137320</accession-num><urls><related-urls><url>;(Slagle and Gross 1988). Fixed definitions of feed intolerance include GRV > 2ml of undigested formula ADDIN EN.CITE <EndNote><Cite><Author>Silvestre</Author><Year>1996</Year><RecNum>244</RecNum><record><rec-number>244</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">244</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Silvestre, M. A.</author><author>Morbach, C. A.</author><author>Brans, Y. W.</author><author>Shankaran, S.</author></authors></contributors><auth-address>Department of Pediatrics, Wayne State University School of Medicine, Hutzel Hospital, Detroit, Michigan, USA.</auth-address><titles><title>A prospective randomized trial comparing continuous versus intermittent feeding methods in very low birth weight neonates</title><secondary-title>J Pediatr</secondary-title></titles><periodical><full-title>J Pediatr</full-title></periodical><pages>748-52</pages><volume>128</volume><number>6</number><edition>1996/06/01</edition><keywords><keyword>Body Weight/physiology</keyword><keyword>Energy Intake/physiology</keyword><keyword>Enteral Nutrition/*methods</keyword><keyword>Humans</keyword><keyword>*Infant Food</keyword><keyword>Infant Nutritional Physiological Phenomena</keyword><keyword>Infant, Newborn</keyword><keyword>*Infant, Very Low Birth Weight</keyword><keyword>Male</keyword></keywords><dates><year>1996</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0022-3476 (Print)</isbn><accession-num>8648531</accession-num><urls><related-urls><url> [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Silvestre, Morbach et al. 1996), > 2ml or any bilious coloured aspirate ADDIN EN.CITE <EndNote><Cite><Author>Dunn</Author><Year>1988</Year><RecNum>243</RecNum><record><rec-number>243</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">243</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dunn, L.</author><author>Hulman, S.</author><author>Weiner, J.</author><author>Kliegman, R.</author></authors></contributors><auth-address>Department of Pediatrics, Case Western Reserve University, Rainbow Babies and Childrens Hospital, Cleveland, OH 44106.</auth-address><titles><title>Beneficial effects of early hypocaloric enteral feeding on neonatal gastrointestinal function: preliminary report of a randomized trial</title><secondary-title>J Pediatr</secondary-title></titles><periodical><full-title>J Pediatr</full-title></periodical><pages>622-9</pages><volume>112</volume><number>4</number><edition>1988/04/01</edition><keywords><keyword>Alkaline Phosphatase/blood</keyword><keyword>Bilirubin/analysis</keyword><keyword>Body Weight</keyword><keyword>*Enteral Nutrition</keyword><keyword>Glucose Tolerance Test</keyword><keyword>Humans</keyword><keyword>Infant Food</keyword><keyword>Infant, Low Birth Weight/*physiology</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature/physiology</keyword><keyword>Infant, Premature, Diseases/diet therapy</keyword><keyword>Parenteral Nutrition</keyword><keyword>Prospective Studies</keyword><keyword>Random Allocation</keyword><keyword>gamma-Glutamyltransferase/blood</keyword></keywords><dates><year>1988</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0022-3476 (Print)</isbn><accession-num>2895173</accession-num><urls><related-urls><url>;(Dunn, Hulman et al. 1988), or > 3 ml/kg or any green coloured aspirate ADDIN EN.CITE <EndNote><Cite><Author>Meetze</Author><Year>1992</Year><RecNum>242</RecNum><record><rec-number>242</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">242</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Meetze, W. H.</author><author>Valentine, C.</author><author>McGuigan, J. E.</author><author>Conlon, M.</author><author>Sacks, N.</author><author>Neu, J.</author></authors></contributors><auth-address>Department of Pediatrics, University of Florida College of Medicine, Gainesville.</auth-address><titles><title>Gastrointestinal priming prior to full enteral nutrition in very low birth weight infants</title><secondary-title>J Pediatr Gastroenterol Nutr</secondary-title></titles><periodical><full-title>J Pediatr Gastroenterol Nutr</full-title></periodical><pages>163-70</pages><volume>15</volume><number>2</number><edition>1992/08/01</edition><keywords><keyword>Eating</keyword><keyword>Enterocolitis, Pseudomembranous/etiology</keyword><keyword>Female</keyword><keyword>Food Hypersensitivity/etiology</keyword><keyword>Gastrins/blood</keyword><keyword>Humans</keyword><keyword>*Infant, Low Birth Weight</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature</keyword><keyword>Male</keyword><keyword>*Parenteral Nutrition, Total/adverse effects/methods</keyword><keyword>Prospective Studies</keyword><keyword>Random Allocation</keyword><keyword>Weight Gain</keyword></keywords><dates><year>1992</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0277-2116 (Print)</isbn><accession-num>1403464</accession-num><urls><related-urls><url>;(Meetze, Valentine et al. 1992). Critical assessment of these publications revealed small sample size and variable birth weights and gestations, arbitrarily developed definitions based on consensus among the study staff and the attending neonatologists ADDIN EN.CITE <EndNote><Cite><Author>Akintorin</Author><Year>1997</Year><RecNum>89</RecNum><record><rec-number>89</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">89</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Akintorin, S. M.</author><author>Kamat, M.</author><author>Pildes, R. S.</author><author>Kling, P.</author><author>Andes, S.</author><author>Hill, J.</author><author>Pyati, S.</author></authors></contributors><auth-address>Department of Pediatrics, Cook County Children's Hospital, Chicago, IL 60612, USA.</auth-address><titles><title>A prospective randomized trial of feeding methods in very low birth weight infants</title><secondary-title>Pediatrics</secondary-title></titles><periodical><full-title>Pediatrics</full-title></periodical><pages>E4</pages><volume>100</volume><number>4</number><edition>1998/04/03</edition><keywords><keyword>Birth Weight</keyword><keyword>Digestion</keyword><keyword>Energy Intake</keyword><keyword>Enteral Nutrition/*methods</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Infant Care</keyword><keyword>Infant, Newborn</keyword><keyword>*Infant, Very Low Birth Weight/physiology</keyword><keyword>Male</keyword><keyword>Prospective Studies</keyword></keywords><dates><year>1997</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1098-4275 (Electronic)</isbn><accession-num>9310537</accession-num><urls><related-urls><url>;(Akintorin, Kamat et al. 1997), use of variable dilutions of formula feeds and hypocaloric feeds PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DdXJyYW88L0F1dGhvcj48WWVhcj4xOTg4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Currao, Cox et al. 1988; Silvestre, Morbach et al. 1996), variable feed types, duration, and method of feeding (all studies), and prolonged period of nil by mouth and TPN use with variable feed advancement rate ADDIN EN.CITE <EndNote><Cite><Author>Slagle</Author><Year>1988</Year><RecNum>245</RecNum><record><rec-number>245</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">245</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Slagle, T. A.</author><author>Gross, S. J.</author></authors></contributors><auth-address>Department of Pediatrics, SUNY Health Science Center, Syracuse 13210.</auth-address><titles><title>Effect of early low-volume enteral substrate on subsequent feeding tolerance in very low birth weight infants</title><secondary-title>J Pediatr</secondary-title></titles><periodical><full-title>J Pediatr</full-title></periodical><pages>526-31</pages><volume>113</volume><number>3</number><edition>1988/09/01</edition><keywords><keyword>Apgar Score</keyword><keyword>Birth Weight</keyword><keyword>Clinical Trials as Topic</keyword><keyword>Enteral Nutrition/adverse effects/*methods</keyword><keyword>Enterocolitis, Pseudomembranous/etiology</keyword><keyword>Humans</keyword><keyword>Infant Food</keyword><keyword>*Infant, Low Birth Weight</keyword><keyword>Infant, Newborn</keyword><keyword>Intensive Care Units, Neonatal</keyword><keyword>Parenteral Nutrition</keyword><keyword>Prospective Studies</keyword><keyword>Random Allocation</keyword></keywords><dates><year>1988</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0022-3476 (Print)</isbn><accession-num>3137320</accession-num><urls><related-urls><url>;(Slagle and Gross 1988). All the studies used excessive GRV, either determined by % of the previous feeding volume or an absolute volume, as a proxy for feeding intolerance and the authors provided no physiological basis or demonstrated correlation with the known measures of gastric emptying or gastrointestinal motility or relevance to clinical outcomes. Even when definition seemed comprehensive the clinical significance of each of the criteria for feeding intolerance was not determined (Mihatsch, von Schoenaich et al 2002; Dollberg, Kuint et al 2000; Rayyis, Ambalavanan et al 1999; Akintorin, Kamat et al 1997). A study which did attempt to investigate the impact of high GRV and colour in a cohort of ELBW infants showed that threshold GRV of 2ml/3ml and green, milky, or clear GRV had no significant impact on feeding volume on day 14 ADDIN EN.CITE <EndNote><Cite><Author>Mihatsch</Author><Year>2002</Year><RecNum>50</RecNum><record><rec-number>50</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">50</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mihatsch, W. A.</author><author>von Schoenaich, P.</author><author>Fahnenstich, H.</author><author>Dehne, N.</author><author>Ebbecke, H.</author><author>Plath, C.</author><author>von Stockhausen, H. B.</author><author>Muche, R.</author><author>Franz, A.</author><author>Pohlandt, F.</author></authors></contributors><auth-address>Division of Neonatology and Pediatric Critical Care Medicine, Department of Pediatrics, University of Ulm, Ulm, Germany.</auth-address><titles><title>The significance of gastric residuals in the early enteral feeding advancement of extremely low birth weight infants</title><secondary-title>Pediatrics</secondary-title></titles><periodical><full-title>Pediatrics</full-title></periodical><pages>457-9</pages><volume>109</volume><number>3</number><edition>2002/03/05</edition><keywords><keyword>Algorithms</keyword><keyword>*Enteral Nutrition/methods</keyword><keyword>*Gastrointestinal Contents/chemistry</keyword><keyword>Humans</keyword><keyword>Infant Food/analysis</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature</keyword><keyword>*Infant, Very Low Birth Weight</keyword><keyword>Milk, Human</keyword><keyword>Regression Analysis</keyword><keyword>*Stomach</keyword></keywords><dates><year>2002</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1098-4275 (Electronic)</isbn><accession-num>11875141</accession-num><urls><related-urls><url>;(Mihatsch, von Schoenaich et al. 2002). However, the median feeding volume of 103 (0-166) ml/kg birth weight on day 14 in the study was far below volumes aimed for in current practice which may have contributed to gut hypomotility. Additionally, the results cannot be generalised for infants fed at an incremental rate > 12ml/kg/day or with a different formula.On the other hand, threshold or % prefeed GRV was assessed against objectives measures of gastric emptying in critically ill children and adults PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXllcjwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Mayer, Durward et al. 2002; ElHennawy, Sparks et al. 2003; Gomes, Hornoy et al. 2003; Pozler, Neumann et al. 2003). Using GRV > 125% of previous 4 hour feed volume or > 150 ml as indicative of feed intolerance, Mayer et al showed correlation with delayed gastric emptying measured by paracetamol absorption test. However the study sample sizes were small PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXllcjwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Mayer, Durward et al. 2002; ElHennawy, Sparks et al. 2003; Gomes, Hornoy et al. 2003; Pozler, Neumann et al. 2003) and the study cohort was of wide ranging age and weight ADDIN EN.CITE <EndNote><Cite><Author>Mayer</Author><Year>2002</Year><RecNum>206</RecNum><record><rec-number>206</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">206</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mayer, A. P.</author><author>Durward, A.</author><author>Turner, C.</author><author>Skellett, S.</author><author>Dalton, N.</author><author>Tibby, S. M.</author><author>Murdoch, I. A.</author></authors></contributors><auth-address>Department of Paediatric Intensive Care, Guy's Hospital, Saint Thomas Street, London, SE1 9RT, UK. amayer@.uk</auth-address><titles><title>Amylin is associated with delayed gastric emptying in critically ill children</title><secondary-title>Intensive Care Med</secondary-title></titles><pages>336-40</pages><volume>28</volume><number>3</number><edition>2002/03/21</edition><keywords><keyword>Acetaminophen/pharmacokinetics</keyword><keyword>Adolescent</keyword><keyword>Amyloid/blood/*pharmacology</keyword><keyword>Analgesics, Non-Narcotic/pharmacokinetics</keyword><keyword>Anti-Ulcer Agents/blood/*pharmacology</keyword><keyword>Area Under Curve</keyword><keyword>Blood Glucose/drug effects</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Gastric Emptying/*drug effects</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Insulin/blood</keyword><keyword>Intensive Care Units, Pediatric</keyword><keyword>Intestinal Absorption</keyword><keyword>Metabolic Clearance Rate</keyword><keyword>Prospective Studies</keyword></keywords><dates><year>2002</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0342-4642 (Print)</isbn><accession-num>11904665</accession-num><urls><related-urls><url>;(Mayer, Durward et al. 2002). Thus the definition of feed intolerance in the literature varies and is arbitrarily based mainly on an assessment of prefeed gastric residual volumes, the colour of these GRVs, and the associated clinical manifestation. Although a high pre-prandial GRV or green GR are generally regarded as significant markers of feed intolerance, its clinical significance is yet to be determined. It is unclear if they are predictive of serious disease such as necrotising enterocolitis, a delayed time to achieve full enteric alimentation, or developmental physiologic expectations when feeding the preterm infants. Patho-Physiology of Feed IntoleranceFeed intolerance is rarely observed in well term infants most likely due to controlled gastrointestinal motility which matures as gestational age increases PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZXJzZXRoPC9BdXRob3I+PFllYXI+MTk4OTwvWWVhcj48
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ADDIN EN.CITE.DATA (Tomomasa, Itoh et al. 1985; Berseth 1989; Berseth 1990; Berseth 1996). The gastrointestinal tract has formed and has completed its rotation back into the abdominal cavity by 10 weeks of gestation. The fetus can swallow amniotic fluid by 16 weeks and gastrointestinal motor activity is present before 24 weeks but organized peristalsis is not established until 29-30 weeks. At 32-34 weeks coordinated sucking and swallowing develops and by term the fetus swallows about 150 ml/kg/day of amniotic fluid containing carbohydrates, protein, fat, electrolytes, immunoglobulin’s and growth factors which plays an important role in development of gastrointestinal function. Preterm birth interrupts this development. In the postnatal period the lack of enteric intake leads to decreased circulating gut peptides, slower enterocyte turnover and nutrient transport, decreased bile acid secretion; even when nutrients are provided parenterally. There is increased susceptibility to infection due to impaired barrier function by intestinal epithelium, lack of colonization by normal commensal flora and colonization by pathogenic organisms. Physiologic studies have shown a lack of the propagative phase III of the MMC in the duodenum of preterm infants less than 32 weeks gestational age ADDIN EN.CITE <EndNote><Cite><Author>al Tawil</Author><Year>1996</Year><RecNum>420</RecNum><record><rec-number>420</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">420</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>al Tawil, Y.</author><author>Berseth, C. L.</author></authors></contributors><auth-address>Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.</auth-address><titles><title>Gestational and postnatal maturation of duodenal motor responses to intragastric feeding</title><secondary-title>J Pediatr</secondary-title></titles><periodical><full-title>J Pediatr</full-title></periodical><pages>374-81</pages><volume>129</volume><number>3</number><edition>1996/09/01</edition><keywords><keyword>Birth Weight</keyword><keyword>Cross-Sectional Studies</keyword><keyword>Duodenum/*physiology</keyword><keyword>*Enteral Nutrition</keyword><keyword>Fasting/physiology</keyword><keyword>*Gastrointestinal Motility</keyword><keyword>Gestational Age</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature/*physiology</keyword><keyword>Manometry</keyword></keywords><dates><year>1996</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0022-3476 (Print)
0022-3476 (Linking)</isbn><accession-num>8804326</accession-num><urls><related-urls><url>(96)70069-0 [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(al Tawil and Berseth 1996). Additionally, very immature infants also have poor gastroduodenal coordination and excessive quiescence in motor activity ADDIN EN.CITE <EndNote><Cite><Author>Jadcherla</Author><Year>2002</Year><RecNum>85</RecNum><record><rec-number>85</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">85</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jadcherla, S. R.</author><author>Kliegman, R. M.</author></authors></contributors><auth-address>Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA.</auth-address><titles><title>Studies of feeding intolerance in very low birth weight infants: definition and significance</title><secondary-title>Pediatrics</secondary-title></titles><periodical><full-title>Pediatrics</full-title></periodical><pages>516-7</pages><volume>109</volume><number>3</number><edition>2002/03/05</edition><keywords><keyword>Animals</keyword><keyword>*Enteral Nutrition</keyword><keyword>Enterocolitis, Necrotizing/diagnosis</keyword><keyword>*Gastrointestinal Contents</keyword><keyword>Gastrointestinal Motility</keyword><keyword>Humans</keyword><keyword>Infant Food/analysis</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature</keyword><keyword>*Infant, Very Low Birth Weight</keyword><keyword>Milk, Human</keyword><keyword>*Stomach/physiology</keyword></keywords><dates><year>2002</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1098-4275 (Electronic)</isbn><accession-num>11875150</accession-num><urls><related-urls><url>;(Jadcherla and Kliegman 2002) and non-propagated contractions of the gastrointestinal tract. Furthermore, control systems of gastrointestinal motility are immature in preterm animals because interstitial cells of Cajal (ICC), nerve, and muscle control systems are not fully differentiated PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KYWRjaGVybGE8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFy
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ADDIN EN.CITE.DATA (Daniel and Wang 1999; Jadcherla and Kliegman 2002). Therefore immaturity of the gastrointestinal tract due to premature birth has been proposed as the main cause of feed intolerance in preterm infants ADDIN EN.CITE <EndNote><Cite><Author>Ng</Author><Year>2008</Year><RecNum>424</RecNum><record><rec-number>424</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">424</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ng, E.</author><author>Shah, V. S.</author></authors></contributors><auth-address>Department of Newborn and Developmental Paediatrics, Sunnybrook Health Sciences Centre, C/O Women's College Hospital, 76 Grenville Street, Toronto, Ontario, Canada, M5S1B2. eugene.ng@sunnybrook.ca</auth-address><titles><title>Erythromycin for the prevention and treatment of feeding intolerance in preterm infants</title><secondary-title>Cochrane Database Syst Rev</secondary-title></titles><periodical><full-title>Cochrane Database Syst Rev</full-title></periodical><pages>CD001815</pages><number>3</number><edition>2008/07/23</edition><keywords><keyword>Erythromycin/adverse effects/*therapeutic use</keyword><keyword>Gastrointestinal Agents/adverse effects/*therapeutic use</keyword><keyword>Gastrointestinal Diseases/*drug therapy</keyword><keyword>*Gastrointestinal Motility</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature</keyword><keyword>Infant, Premature, Diseases/*drug therapy</keyword><keyword>Randomized Controlled Trials as Topic</keyword></keywords><dates><year>2008</year></dates><isbn>1469-493X (Electronic)
1361-6137 (Linking)</isbn><accession-num>18646077</accession-num><urls><related-urls><url>;(Ng and Shah 2008).Prefeed gastric residual volumes (GRV) and bilious residuals may reflect poor gastric emptying, duodeno-gastric reflux, and gastroduodenal hypomotility ADDIN EN.CITE <EndNote><Cite><Author>Jadcherla</Author><Year>2002</Year><RecNum>85</RecNum><record><rec-number>85</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">85</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jadcherla, S. R.</author><author>Kliegman, R. M.</author></authors></contributors><auth-address>Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA.</auth-address><titles><title>Studies of feeding intolerance in very low birth weight infants: definition and significance</title><secondary-title>Pediatrics</secondary-title></titles><periodical><full-title>Pediatrics</full-title></periodical><pages>516-7</pages><volume>109</volume><number>3</number><edition>2002/03/05</edition><keywords><keyword>Animals</keyword><keyword>*Enteral Nutrition</keyword><keyword>Enterocolitis, Necrotizing/diagnosis</keyword><keyword>*Gastrointestinal Contents</keyword><keyword>Gastrointestinal Motility</keyword><keyword>Humans</keyword><keyword>Infant Food/analysis</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature</keyword><keyword>*Infant, Very Low Birth Weight</keyword><keyword>Milk, Human</keyword><keyword>*Stomach/physiology</keyword></keywords><dates><year>2002</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1098-4275 (Electronic)</isbn><accession-num>11875150</accession-num><urls><related-urls><url>;(Jadcherla and Kliegman 2002). Although not proven, it is likely that colonic motility is also slow and delayed in VLBW infants as supported by delayed stooling pattern, and emesis in bowel obstruction or functional ileus ADDIN EN.CITE <EndNote><Cite><Author>Jadcherla</Author><Year>2002</Year><RecNum>85</RecNum><record><rec-number>85</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">85</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jadcherla, S. R.</author><author>Kliegman, R. M.</author></authors></contributors><auth-address>Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI 53226, USA.</auth-address><titles><title>Studies of feeding intolerance in very low birth weight infants: definition and significance</title><secondary-title>Pediatrics</secondary-title></titles><periodical><full-title>Pediatrics</full-title></periodical><pages>516-7</pages><volume>109</volume><number>3</number><edition>2002/03/05</edition><keywords><keyword>Animals</keyword><keyword>*Enteral Nutrition</keyword><keyword>Enterocolitis, Necrotizing/diagnosis</keyword><keyword>*Gastrointestinal Contents</keyword><keyword>Gastrointestinal Motility</keyword><keyword>Humans</keyword><keyword>Infant Food/analysis</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature</keyword><keyword>*Infant, Very Low Birth Weight</keyword><keyword>Milk, Human</keyword><keyword>*Stomach/physiology</keyword></keywords><dates><year>2002</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1098-4275 (Electronic)</isbn><accession-num>11875150</accession-num><urls><related-urls><url>;(Jadcherla and Kliegman 2002). Although historically hypoglycaemia has been the clinical concern, hyperglycaemia is also a well-documented problem in the perinatal period in VLBW infants. This hyperglycaemia is a marker of insulin resistance and relative insulin deficiency and may reflect the prolonged catabolism observed in VLBW infants ADDIN EN.CITE <EndNote><Cite><Author>Beardsall</Author><Year>2007</Year><RecNum>425</RecNum><record><rec-number>425</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">425</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Beardsall, K.</author><author>Dunger, D.</author></authors></contributors><auth-address>Department of Paediatrics, University of Cambridge, Addenbrooke's Hospital NHS Trust, Cambridge, UK. Kb274@cam.ac.uk</auth-address><titles><title>The physiology and clinical management of glucose metabolism in the newborn</title><secondary-title>Endocr Dev</secondary-title></titles><periodical><full-title>Endocr Dev</full-title></periodical><pages>124-37</pages><volume>12</volume><edition>2007/10/10</edition><keywords><keyword>Delivery, Obstetric</keyword><keyword>Female</keyword><keyword>Fetus/*physiology</keyword><keyword>Glucose/*metabolism</keyword><keyword>Humans</keyword><keyword>Hyperglycemia/epidemiology</keyword><keyword>Infant, Newborn/*physiology</keyword><keyword>Infant, Very Low Birth Weight</keyword><keyword>Pregnancy</keyword></keywords><dates><year>2007</year></dates><isbn>1421-7082 (Print)
1421-7082 (Linking)</isbn><accession-num>17923775</accession-num><urls><related-urls><url> [pii]
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ADDIN EN.CITE.DATA (Mericq 2006; Mericq 2006). These infants are unable to suppress glucose production within a large range of glucose and insulin concentrations, insulin secretory response is inappropriate, insulin processing is immature and there is an increased ratio of the glucose transporters Glut-1/Glut-2 in fetal tissues, which limits sensitivity and hepatocyte reaction to increments in glucose/insulin concentration during hyperglycaemia ADDIN EN.CITE <EndNote><Cite><Author>Mericq</Author><Year>2006</Year><RecNum>434</RecNum><record><rec-number>434</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">434</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mericq, V.</author></authors></contributors><auth-address>Institute of Maternal and Child Research, Faculty of Medicine, University of Chile, Santiago. vmericq@med.uchile.cl</auth-address><titles><title>Prematurity and insulin sensitivity</title><secondary-title>Horm Res</secondary-title></titles><periodical><full-title>Horm Res</full-title></periodical><pages>131-6</pages><volume>65 Suppl 3</volume><edition>2006/04/14</edition><keywords><keyword>Child Development</keyword><keyword>Female</keyword><keyword>Fetal Growth Retardation/physiopathology</keyword><keyword>Glucose/metabolism</keyword><keyword>Glucose Metabolism Disorders/*physiopathology</keyword><keyword>Homeostasis</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature/*physiology</keyword><keyword>Infant, Small for Gestational Age</keyword><keyword>Pregnancy</keyword></keywords><dates><year>2006</year></dates><isbn>0301-0163 (Print)
0301-0163 (Linking)</isbn><accession-num>16612126</accession-num><urls><related-urls><url> [pii]
10.1159/000091518</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Mericq 2006). Although unproven, it is plausible that relative insulin resistance in preterm VLBW may induce hyperamylinemia which may be responsible for feed intolerance by delaying gastric emptying. In conclusion, prematurity may predispose to feed intolerance due to immaturity of gastrointestinal motor activity PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CaXNzZXQ8L0F1dGhvcj48WWVhcj4xOTg4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Bisset, Watt et al. 1988; Berseth 1989; Reddy, Deorari et al. 2000; Patole, Rao et al. 2005), and delayed gastric emptying and whole intestinal transit PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Fcm5zdDwvQXV0aG9yPjxZZWFyPjE5ODk8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Gupta and Brans 1978; Cavell 1982; Ernst, Rickard et al. 1989). Relative insulin resistance and hyperamylinaemia may also be responsible for feed intolerance in these neonates which is an emerging theory and hypothesis and subject of investigation of this dissertation. Management of Feed IntoleranceA range of management strategies currently exists for preventing and/or minimizing feed intolerance in preterm neonates reflecting the dilemma surrounding the definition and significance of signs of feed intolerance due to gastrointestinal hypomotility on one end and the fear of NEC on the other end of the spectrum. Additionally, the relationship of feed intolerance and gastro-esophageal reflux is unclear and therefore often used interchangeably. Furthermore due to the absence of robust diagnostic tests authors have resorted to surrogate markers of gastrointestinal motility such as gastric residuals and time to reach full enteral feeds to assess efficacy of therapeutic interventions. The following paragraphs provide critical appraisal of current literature on the management of feed intolerance in preterm infants. Prokinetic agents are often used in an attempt to overcome the functional immaturity by speeding up gastric emptying and increasing small intestinal motility. Until July 2000, cisapride was the mainstay of therapy in preterm infants with feed intolerance and/or gastro-oesophageal reflux. Due to reports of prolongation of the QT interval with occasional fatal cardiac arrythmias and sudden death, cisapride was taken off the market and restricted to a limited access programme supervised by a paediatric gastroenterologist PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWNsZW5uYW48L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFy
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ADDIN EN.CITE.DATA (Gounaris, Costalos et al. 2010; Maclennan, Augood et al. 2010). Metoclopromide and domperidone, dopamine antagonists, started to be widely prescribed soon after PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DbGFyazwvQXV0aG9yPjxZZWFyPjIwMDY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Putnam, Orenstein et al. 1992; Hibbs and Lorch 2006). There have been no adequately powered controlled trials of metoclopramide use in preterm neonate. Similarly efficacy data of domperidone in preterm infants is lacking. The few studies with domperidone are old and methodologically poor. In contrast the side effects profile is similar to those of cisapride with prolonged QT interval, sudden death and theoretical risk of neurological adverse effects. A recent small crossover study of domperidone use in 22 preterm infants showed faster gastric emptying rate measured by ultrasound antral cross sectional area half-value time (in minutes) n the domperidone group ADDIN EN.CITE <EndNote><Cite><Author>Gounaris</Author><Year>2010</Year><RecNum>432</RecNum><record><rec-number>432</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">432</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gounaris, A.</author><author>Costalos, C.</author><author>Varchalama, E.</author><author>Kokori, F.</author><author>Grivea, I. N.</author><author>Konstantinidi, K.</author><author>Syrogiannopoulos, G. A.</author></authors></contributors><auth-address>NICU, General Hospital 'Agios Panteleimon', Nikea, Greece.</auth-address><titles><title>Gastric emptying of preterm neonates receiving domperidone</title><secondary-title>Neonatology</secondary-title></titles><periodical><full-title>Neonatology</full-title></periodical><pages>56-60</pages><volume>97</volume><number>1</number><edition>2009/08/04</edition><keywords><keyword>Antiemetics/*pharmacology</keyword><keyword>Apgar Score</keyword><keyword>Birth Weight</keyword><keyword>Cross-Over Studies</keyword><keyword>Domperidone/*pharmacology</keyword><keyword>Female</keyword><keyword>Gastric Emptying/*drug effects/physiology</keyword><keyword>Gastrointestinal Diseases/*drug therapy/physiopathology</keyword><keyword>Gestational Age</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature/*physiology</keyword><keyword>Infant, Very Low Birth Weight/*physiology</keyword><keyword>Male</keyword><keyword>Treatment Outcome</keyword><keyword>Ultrasonography</keyword></keywords><dates><year>2010</year></dates><isbn>1661-7819 (Electronic)
1661-7800 (Linking)</isbn><accession-num>19648772</accession-num><urls><related-urls><url> [pii]
10.1159/000231517</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Gounaris, Costalos et al. 2010). However the study did not report on important clinical correlates of efficacy and long term safety. There have been no controlled trials of domperidone use in preterm infants. A plethora of publications soon followed on erythromycin use in the prevention and treatment of feeding intolerance in preterm infants. Erythromycin is a motilin agonist that exerts its prokinetic effect by stimulating propagative contractile activity in the interdigestive phase. Although previous studies demonstrated variable efficacy, a meta-analysis (three prevention and seven treatment studies) concluded that there is insufficient evidence to recommend the use of erythromycin in low or high doses for preterm infants with or at risk of feeding intolerance ADDIN EN.CITE <EndNote><Cite><Author>Ng</Author><Year>2008</Year><RecNum>424</RecNum><record><rec-number>424</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">424</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ng, E.</author><author>Shah, V. S.</author></authors></contributors><auth-address>Department of Newborn and Developmental Paediatrics, Sunnybrook Health Sciences Centre, C/O Women's College Hospital, 76 Grenville Street, Toronto, Ontario, Canada, M5S1B2. eugene.ng@sunnybrook.ca</auth-address><titles><title>Erythromycin for the prevention and treatment of feeding intolerance in preterm infants</title><secondary-title>Cochrane Database Syst Rev</secondary-title></titles><periodical><full-title>Cochrane Database Syst Rev</full-title></periodical><pages>CD001815</pages><number>3</number><edition>2008/07/23</edition><keywords><keyword>Erythromycin/adverse effects/*therapeutic use</keyword><keyword>Gastrointestinal Agents/adverse effects/*therapeutic use</keyword><keyword>Gastrointestinal Diseases/*drug therapy</keyword><keyword>*Gastrointestinal Motility</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature</keyword><keyword>Infant, Premature, Diseases/*drug therapy</keyword><keyword>Randomized Controlled Trials as Topic</keyword></keywords><dates><year>2008</year></dates><isbn>1469-493X (Electronic)
1361-6137 (Linking)</isbn><accession-num>18646077</accession-num><urls><related-urls><url>;(Ng and Shah 2008). Furthermore the same author concluded that although high dose regimens as a rescue therapy for established gastrointestinal dysmotility have consistently shown clinical benefit, further research is warranted to justify its widespread use due to the theoretical risks of prolonged antibiotic use (Ng et al 2011) and hypertrophic pyloric stenosis. Clinical trials followed to investigate interventions to promote intestinal maturation and enhance feeding tolerance and decrease time to reach full enteral feeding independent of parenteral nutrition. Systematic review of nine trials did not provide any evidence that early trophic feeding affected feed tolerance or growth rates in VLBW infants ADDIN EN.CITE <EndNote><Cite><Author>Bombell</Author><Year>2009</Year><RecNum>480</RecNum><record><rec-number>480</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">480</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bombell, S.</author><author>McGuire, W.</author></authors></contributors><auth-address>Centre for Newborn Care, Australian National University, Canberra Hospital, Canberra, Australia, ACT 2606.</auth-address><titles><title>Early trophic feeding for very low birth weight infants</title><secondary-title>Cochrane Database Syst Rev</secondary-title></titles><periodical><full-title>Cochrane Database Syst Rev</full-title></periodical><pages>CD000504</pages><number>3</number><edition>2009/07/10</edition><keywords><keyword>Adaptation, Physiological</keyword><keyword>Animals</keyword><keyword>Child Development/*physiology</keyword><keyword>Enteral Nutrition/adverse effects/*methods</keyword><keyword>Enterocolitis, Necrotizing/prevention & control</keyword><keyword>Humans</keyword><keyword>Infant Formula</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature</keyword><keyword>Infant, Very Low Birth Weight/growth & development/*physiology</keyword><keyword>*Milk</keyword><keyword>Milk, Human</keyword><keyword>Parenteral Nutrition/adverse effects/methods</keyword><keyword>Randomized Controlled Trials as Topic</keyword></keywords><dates><year>2009</year></dates><isbn>1469-493X (Electronic)
1361-6137 (Linking)</isbn><accession-num>19588318</accession-num><urls><related-urls><url>;(Bombell and McGuire 2009). Trials of supplementation of breast milk or formula milk with enzyme or hormone to improve short and long term effects of feed intolerance were also conducted. A randomized trial did not provide evidence of significant benefit to preterm infants from adding lactase to their feeds ADDIN EN.CITE <EndNote><Cite><Author>Tan-Dy</Author><Year>2005</Year><RecNum>478</RecNum><record><rec-number>478</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">478</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tan-Dy, C. R.</author><author>Ohlsson, A.</author></authors></contributors><auth-address>Special Care Nursery, Victoria General Hospital, 1 Hospital Way, Victoria, British Columbia, Canada, V8Z 6R5. Cherrie.Tan-Dy@</auth-address><titles><title>Lactase treated feeds to promote growth and feeding tolerance in preterm infants</title><secondary-title>Cochrane Database Syst Rev</secondary-title></titles><periodical><full-title>Cochrane Database Syst Rev</full-title></periodical><pages>CD004591</pages><number>2</number><edition>2005/04/23</edition><keywords><keyword>*Enteral Nutrition</keyword><keyword>Humans</keyword><keyword>Infant Nutritional Physiological Phenomena</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature/*growth & development</keyword><keyword>Lactase/*therapeutic use</keyword><keyword>*Parenteral Nutrition</keyword><keyword>Randomized Controlled Trials as Topic</keyword><keyword>Weight Gain</keyword></keywords><dates><year>2005</year></dates><isbn>1469-493X (Electronic)
1361-6137 (Linking)</isbn><accession-num>15846722</accession-num><urls><related-urls><url>;(Tan-Dy and Ohlsson 2005). A study of eight preterm infants who were given 4 U/kg/day insulin enterally from 4 to 28 days of age showed higher lactase activity and less feed intolerance (30% shorter time to full enteral feeds; fewer gastric residuals per infant) than the matched historical controls ADDIN EN.CITE <EndNote><Cite><Author>Shulman</Author><Year>2002</Year><RecNum>479</RecNum><record><rec-number>479</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">479</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shulman, R. J.</author></authors></contributors><auth-address>USDA/ARS Children's Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, and Texas Children's Hospital, Houston, Texas, USA. rshulman@bcm.tmc.edu</auth-address><titles><title>Effect of enteral administration of insulin on intestinal development and feeding tolerance in preterm infants: a pilot study</title><secondary-title>Arch Dis Child Fetal Neonatal Ed</secondary-title></titles><periodical><full-title>Arch Dis Child Fetal Neonatal Ed</full-title></periodical><pages>F131-3</pages><volume>86</volume><number>2</number><edition>2002/03/08</edition><keywords><keyword>Digestive System/drug effects/enzymology/*growth & development</keyword><keyword>Enteral Nutrition</keyword><keyword>Gastric Emptying/*drug effects</keyword><keyword>Humans</keyword><keyword>Infant Nutritional Physiological Phenomena/*physiology</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature/*physiology</keyword><keyword>Insulin/*pharmacology</keyword><keyword>Lactase</keyword><keyword>Pilot Projects</keyword><keyword>Time Factors</keyword><keyword>beta-Galactosidase/metabolism</keyword></keywords><dates><year>2002</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1359-2998 (Print)
1359-2998 (Linking)</isbn><accession-num>11882558</accession-num><urls><related-urls><url>;(Shulman 2002). However further large controlled studies are warranted before its use in preterm population. Recent literature abounds in the study of probiotics, prebiotics, or synbiotics in preterm infants primarily looking to improve growth and reduce mortality due to NEC and infections. Some of these trials reported on their effect on feed tolerance and/or days to reach full enteral feeds as a surrogate marker of feed tolerance. L. sporogenes supplementation at the dose of 350,000,000 c.f.u/day was not effective in reducing the incidence of death or NEC in VLBW infants; however, it could improve the feeding tolerance PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYXJpPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Sari, Dizdar et al. 2011). Although the time to reach full enteral feeds was significantly shorter in the early enteral probiotic group than in controls ADDIN EN.CITE <EndNote><Cite><Author>Deshpande</Author><Year>2007</Year><RecNum>482</RecNum><record><rec-number>482</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">482</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Deshpande, G.</author><author>Rao, S.</author><author>Patole, S.</author></authors></contributors><auth-address>Department of Neonatal Paediatrics, King Edward Memorial Hospital for Women, Subiaco, WA, Australia.</auth-address><titles><title>Probiotics for prevention of necrotising enterocolitis in preterm neonates with very low birthweight: a systematic review of randomised controlled trials</title><secondary-title>Lancet</secondary-title></titles><periodical><full-title>Lancet</full-title></periodical><pages>1614-20</pages><volume>369</volume><number>9573</number><edition>2007/05/15</edition><keywords><keyword>Double-Blind Method</keyword><keyword>Enteral Nutrition</keyword><keyword>Enterocolitis, Necrotizing/etiology/mortality/*prevention & control</keyword><keyword>Gestational Age</keyword><keyword>Humans</keyword><keyword>Infant Formula</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature</keyword><keyword>Infant, Very Low Birth Weight</keyword><keyword>Meta-Analysis as Topic</keyword><keyword>Probiotics/administration & dosage/metabolism/*therapeutic use</keyword><keyword>Randomized Controlled Trials as Topic</keyword></keywords><dates><year>2007</year><pub-dates><date>May 12</date></pub-dates></dates><isbn>1474-547X (Electronic)
0140-6736 (Linking)</isbn><accession-num>17499603</accession-num><urls><related-urls><url>(07)60748-X [pii]
10.1016/S0140-6736(07)60748-X</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Deshpande, Rao et al. 2007) an updated meta-analysis did not show this effect which was attributed to the significant heterogeneity among the included trials ADDIN EN.CITE <EndNote><Cite><Author>Deshpande</Author><Year>2010</Year><RecNum>483</RecNum><record><rec-number>483</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">483</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Deshpande, G.</author><author>Rao, S.</author><author>Patole, S.</author><author>Bulsara, M.</author></authors></contributors><auth-address>Department of Neonatal Paediatrics, King Edward Memorial Hospital for Women, Perth, Western Australia, Australia.</auth-address><titles><title>Updated meta-analysis of probiotics for preventing necrotizing enterocolitis in preterm neonates</title><secondary-title>Pediatrics</secondary-title></titles><periodical><full-title>Pediatrics</full-title></periodical><pages>921-30</pages><volume>125</volume><number>5</number><edition>2010/04/21</edition><keywords><keyword>Enteral Nutrition</keyword><keyword>Enterocolitis, Necrotizing/mortality/*prevention & control</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature, Diseases/mortality/*prevention & control</keyword><keyword>*Infant, Very Low Birth Weight</keyword><keyword>Probiotics/*therapeutic use</keyword><keyword>Randomized Controlled Trials as Topic</keyword><keyword>Survival Rate</keyword></keywords><dates><year>2010</year><pub-dates><date>May</date></pub-dates></dates><isbn>1098-4275 (Electronic)
0031-4005 (Linking)</isbn><accession-num>20403939</accession-num><urls><related-urls><url> [pii]
10.1542/peds.2009-1301</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Deshpande, Rao et al. 2010). The results of ProPrems trial PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYXJsYW5kPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48
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ADDIN EN.CITE.DATA (Rouge, Piloquet et al. 2009). Enteral supplementation of a prebiotic mixture consisting of neutral and acidic oligosaccharides decreased stool viscosity and stool pH with a trend towards increased stool frequency without demonstrating benefit on feed tolerance PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZXN0ZXJiZWVrPC9BdXRob3I+PFllYXI+MjAxMTwvWWVh
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ADDIN EN.CITE.DATA (Westerbeek, Hensgens et al. 2011). Evidence is still emerging with regards to the strain type, supplementation to breast or formula and dose, frequency and duration of prebiotics and probiotics in relation to its effects on feed intolerance and other important clinical outcomes including safety data. The ESPGHAN Committee on nutrition considers that the supplementation of formula with probiotics and/or prebiotics does not raise safety concerns but there is insufficient data to recommend routine supplementation and therefore is an important field of research ADDIN EN.CITE <EndNote><Cite><Author>Braegger</Author><Year>2011</Year><RecNum>487</RecNum><record><rec-number>487</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">487</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Braegger, C.</author><author>Chmielewska, A.</author><author>Decsi, T.</author><author>Kolacek, S.</author><author>Mihatsch, W.</author><author>Moreno, L.</author><author>Piescik, M.</author><author>Puntis, J.</author><author>Shamir, R.</author><author>Szajewska, H.</author><author>Turck, D.</author><author>van Goudoever, J.</author></authors></contributors><auth-address>University Children's Hospital, Zurich, Switzerland.</auth-address><titles><title>Supplementation of infant formula with probiotics and/or prebiotics: a systematic review and comment by the ESPGHAN committee on nutrition</title><secondary-title>J Pediatr Gastroenterol Nutr</secondary-title></titles><periodical><full-title>J Pediatr Gastroenterol Nutr</full-title></periodical><pages>238-50</pages><volume>52</volume><number>2</number><edition>2010/12/15</edition><keywords><keyword>Bacteria</keyword><keyword>Child Development/drug effects</keyword><keyword>Gastrointestinal Tract/*microbiology</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Infant Formula/*chemistry</keyword><keyword>Oligosaccharides/*administration & dosage/adverse effects/pharmacology</keyword><keyword>*Prebiotics/adverse effects</keyword><keyword>Probiotics/*administration & dosage/adverse effects/pharmacology</keyword><keyword>Safety</keyword></keywords><dates><year>2011</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1536-4801 (Electronic)
0277-2116 (Linking)</isbn><accession-num>21150647</accession-num><urls><related-urls><url>;(Braegger, Chmielewska et al. 2011).In clinical practice, failure of pharmacological intervention may necessitate trial of transpyloric feeding as a last resort. However transpyloric route cannot be recommended for preterm infants ADDIN EN.CITE <EndNote><Cite><Author>McGuire</Author><Year>2007</Year><RecNum>488</RecNum><record><rec-number>488</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">488</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>McGuire, W.</author><author>McEwan, P.</author></authors></contributors><auth-address>Australian National University Medical School, Department of Paediatrics and Child Health, Canberra Hospital Campus, Canberra, ACT 2606, Australia. william.mcguire@.au</auth-address><titles><title>Transpyloric versus gastric tube feeding for preterm infants</title><secondary-title>Cochrane Database Syst Rev</secondary-title></titles><periodical><full-title>Cochrane Database Syst Rev</full-title></periodical><pages>CD003487</pages><number>3</number><edition>2007/07/20</edition><keywords><keyword>Enteral Nutrition/*methods</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>*Infant, Premature</keyword><keyword>Pylorus</keyword><keyword>Randomized Controlled Trials as Topic</keyword></keywords><dates><year>2007</year></dates><isbn>1469-493X (Electronic)
1361-6137 (Linking)</isbn><accession-num>17636725</accession-num><urls><related-urls><url>;(McGuire and McEwan 2007) due to adverse effects such as greater incidence of gastrointestinal disturbances and some evidence of increased mortality. The fallback position when all intervention fails is to continue total parenteral nutrition until the feed intolerance settles. In conclusion management of feed intolerance in preterm infants is varied reflecting the dilemma surrounding the definition of feed intolerance. They include pharmacological and biological interventions the efficacy of which is variable. Further trials are awaited for evidence based management of this common condition.Literature Review: Gestational Diabetes MellitusDefinition of Gestational Diabetes MellitusGestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance with onset or first recognition during pregnancy ADDIN EN.CITE <EndNote><Cite><Author>Metzger</Author><Year>1998</Year><RecNum>445</RecNum><record><rec-number>445</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">445</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Metzger, B. E.</author><author>Coustan, D. R.</author></authors></contributors><auth-address>Northwestern University Medical School, Chicago, Illionois 60611, USA. bem@nwu.edu</auth-address><titles><title>Summary and recommendations of the Fourth International Workshop-Conference on Gestational Diabetes Mellitus. The Organizing Committee</title><secondary-title>Diabetes Care</secondary-title></titles><periodical><full-title>Diabetes Care</full-title></periodical><pages>B161-7</pages><volume>21 Suppl 2</volume><edition>1998/08/15</edition><keywords><keyword>*Diabetes, Gestational/diagnosis/epidemiology/therapy</keyword><keyword>Female</keyword><keyword>Glucose Intolerance</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Pregnancy</keyword><keyword>Pregnancy Outcome</keyword><keyword>Prevalence</keyword><keyword>United States/epidemiology</keyword></keywords><dates><year>1998</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0149-5992 (Print)
0149-5992 (Linking)</isbn><accession-num>9704245</accession-num><urls><related-urls><url>;(Metzger and Coustan 1998) Scale of the Problem3-10% of all pregnancies ADDIN EN.CITE <EndNote><Cite><Author>Hoffman</Author><Year>1998</Year><RecNum>438</RecNum><record><rec-number>438</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">438</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hoffman, L.</author><author>Nolan, C.</author><author>Wilson, J. D.</author><author>Oats, J. J.</author><author>Simmons, D.</author></authors></contributors><auth-address>Department of Diabetes and Endocrinology, Royal Hobart Hospital, Hobart, TAS.</auth-address><titles><title>Gestational diabetes mellitus--management guidelines. The Australasian Diabetes in Pregnancy Society</title><secondary-title>Med J Aust</secondary-title></titles><periodical><full-title>Med J Aust</full-title></periodical><pages>93-7</pages><volume>169</volume><number>2</number><edition>1998/08/13</edition><keywords><keyword>Blood Glucose Self-Monitoring</keyword><keyword>Delivery, Obstetric</keyword><keyword>Diabetes, Gestational/diagnosis/*therapy</keyword><keyword>Diet Therapy</keyword><keyword>Female</keyword><keyword>Follow-Up Studies</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Insulin/therapeutic use</keyword><keyword>Mass Screening/methods</keyword><keyword>Patient Education as Topic</keyword><keyword>Pregnancy</keyword><keyword>Pregnancy Outcome</keyword><keyword>Risk Factors</keyword></keywords><dates><year>1998</year><pub-dates><date>Jul 20</date></pub-dates></dates><isbn>0025-729X (Print)
0025-729X (Linking)</isbn><accession-num>9700346</accession-num><urls><related-urls><url>;(Hoffman, Nolan et al. 1998) experience GDM. This number may rise significantly in the next decade as the current significantly overweight paediatric population heads into their child-bearing years. GDM is not only associated with substantial rates of maternal adverse effects but also periconceptional, fetal, neonatal, and long term morbidities ADDIN EN.CITE <EndNote><Cite><Author>Nold</Author><Year>2004</Year><RecNum>439</RecNum><record><rec-number>439</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">439</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nold, J. L.</author><author>Georgieff, M. K.</author></authors></contributors><auth-address>Department of Pediatrics and Child Development, University of Minnesota, MMC 39, 420 Delaware Street SE, Minneapolis, MN 55455, USA.</auth-address><titles><title>Infants of diabetic mothers</title><secondary-title>Pediatr Clin North Am</secondary-title></titles><periodical><full-title>Pediatr Clin North Am</full-title></periodical><pages>619-37, viii</pages><volume>51</volume><number>3</number><edition>2004/05/26</edition><keywords><keyword>*Child Development</keyword><keyword>*Diabetes, Gestational</keyword><keyword>*Embryonic and Fetal Development</keyword><keyword>Female</keyword><keyword>Fertilization</keyword><keyword>Fetal Diseases/prevention & control</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Newborn, Diseases/prevention & control</keyword><keyword>Pregnancy</keyword><keyword>*Pregnancy in Diabetics</keyword><keyword>Prenatal Care</keyword></keywords><dates><year>2004</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0031-3955 (Print)
0031-3955 (Linking)</isbn><accession-num>15157588</accession-num><urls><related-urls><url> [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Nold and Georgieff 2004). Long-term adverse health outcomes reported among infants born to mothers with gestational diabetes (IMDM) include sustained impairment of glucose tolerance PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaWx2ZXJtYW48L0F1dGhvcj48WWVhcj4xOTk1PC9ZZWFy
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ADDIN EN.CITE.DATA (Silverman, Metzger et al. 1995), subsequent obesity ADDIN EN.CITE <EndNote><Cite><Author>Petitt</Author><Year>1985</Year><RecNum>441</RecNum><record><rec-number>441</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">441</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Petitt, D. J.</author><author>Bennett, P. H.</author><author>Knowler, W. C.</author><author>Baird, H. R.</author><author>Aleck, K. A.</author></authors></contributors><titles><title>Gestational diabetes mellitus and impaired glucose tolerance during pregnancy. Long-term effects on obesity and glucose tolerance in the offspring</title><secondary-title>Diabetes</secondary-title></titles><periodical><full-title>Diabetes</full-title></periodical><pages>119-22</pages><volume>34 Suppl 2</volume><edition>1985/06/01</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Birth Weight</keyword><keyword>Blood Glucose/*metabolism</keyword><keyword>Body Weight</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Female</keyword><keyword>Glucose Tolerance Test</keyword><keyword>Humans</keyword><keyword>Obesity/*etiology</keyword><keyword>Pregnancy</keyword><keyword>Pregnancy in Diabetics/*genetics</keyword></keywords><dates><year>1985</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0012-1797 (Print)
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ADDIN EN.CITE.DATA (Rizzo, Metzger et al. 1997; Rizzo, Silverman et al. 1997).Physiology of Insulin SecretionGlucose and several amino acids stimulate insulin secretion under physiologic conditions. The rate of insulin secretion is dependent on the ratio of ATP to?ADP within the pancreatic beta cell. An increase in the intracellular ATP/ADP ratio activates membrane ATP-sensitive potassium-dependent channels (KATPs) leading to closure of the potassium channel and depolarization of the cell membrane allowing influx of calcium through voltage-gated calcium channel resulting in insulin secretion. The rate of glucose entry into the beta cell exceeds its oxidation rate which is facilitated by a glucose transporter. The first rate-limiting step in glycolysis which is conversion of glucose to glucose-6-phosphate by the enzyme glucokinase regulates the rate of glucose oxidation and subsequent insulin secretion.Physiology of Gestational Diabetes MellitusPregnancy is a physiologic condition in which maternal glucose is the main energy substrate for intrauterine growth ADDIN EN.CITE <EndNote><Cite><Author>Combs</Author><Year>1992</Year><RecNum>444</RecNum><record><rec-number>444</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">444</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Combs, C. A.</author><author>Gunderson, E.</author><author>Kitzmiller, J. L.</author><author>Gavin, L. A.</author><author>Main, E. K.</author></authors></contributors><auth-address>Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco.</auth-address><titles><title>Relationship of fetal macrosomia to maternal postprandial glucose control during pregnancy</title><secondary-title>Diabetes Care</secondary-title></titles><periodical><full-title>Diabetes Care</full-title></periodical><pages>1251-7</pages><volume>15</volume><number>10</number><edition>1992/10/01</edition><keywords><keyword>Adult</keyword><keyword>Analysis of Variance</keyword><keyword>Birth Weight</keyword><keyword>Blood Glucose/*metabolism</keyword><keyword>Diabetic Diet</keyword><keyword>Eating</keyword><keyword>Energy Intake</keyword><keyword>Female</keyword><keyword>Fetal Macrosomia/epidemiology/*etiology</keyword><keyword>Gestational Age</keyword><keyword>Humans</keyword><keyword>Incidence</keyword><keyword>Infant, Newborn</keyword><keyword>Insulin/therapeutic use</keyword><keyword>Maternal Age</keyword><keyword>Pregnancy</keyword><keyword>Pregnancy in Diabetics/*blood/drug therapy/physiopathology</keyword></keywords><dates><year>1992</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0149-5992 (Print)
0149-5992 (Linking)</isbn><accession-num>1425084</accession-num><urls><related-urls><url>;(Combs, Gunderson et al. 1992). Early in pregnancy, increased levels of both oestrogen and progesterone act as counter-regulatory hormones affecting glucose homeostasis. As pregnancy progresses, human placental lactogen released by the syncytiotrophoblast leads to lipolysis and the subsequent release of glycerol and fatty acids which reduces maternal use of glucose and amino acid, thus preserving these substrates for the fetus. As placental growth and pregnancy continue, maternal insulin needs increase by 30% due to the release of increasing amounts of counter-insulin factors. Glucose and amino acids readily traverse the placental membrane while insulin is unable to cross materno-fetal barrier in physiological concentrations. In pregnancies complicated by diabetes, high concentrations of glucose, particularly after a meal, give rise to an increased nutrient transfer to the fetus. This results in beta-cell hyperplasia, stimulating an increased release of insulin which adversely influences birth weight with its pregnancy complications PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db21iczwvQXV0aG9yPjxZZWFyPjE5OTI8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Jovanovic-Peterson, Peterson et al. 1991; Combs, Gunderson et al. 1992). Strategies to Prevent Fetal and Neonatal HyperinsulinaemiaThe Diabetes Prevention Program randomised clinical trial showed reduction of diabetes incidence in high-risk adults by 58% with intensive lifestyle intervention and by 31% with metformin PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lbm93bGVyPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48
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ADDIN EN.CITE.DATA (Knowler, Barrett-Connor et al. 2002) the benefits of which persisted for at least 10 years PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lbm93bGVyPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48
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ADDIN EN.CITE.DATA (Knowler, Fowler et al. 2009). A randomised trial of dietary advice, blood glucose monitoring, and insulin therapy or routine care in women between 24 and 34 weeks' gestation who had gestational diabetes showed significantly lower serious perinatal complications such as death, shoulder dystocia, bone fracture, and nerve palsy PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Dcm93dGhlcjwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Dcm93dGhlcjwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+
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ADDIN EN.CITE.DATA (Crowther, Hiller et al. 2005). Continuous glucose monitoring during pregnancy is associated with improved glycaemic control in the third trimester, lower birth weight, and reduced risk of macrosomia PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdXJwaHk8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Murphy, Rayman et al. 2008). Compared to normal pregnant women in the low-glycaemic index group, women in the moderate-to-high glycaemic index group gave birth to infants who were heavier and had a higher birth centile, a higher ponderal index, and a higher prevalence of large-for-gestational age ADDIN EN.CITE <EndNote><Cite><Author>Moses</Author><Year>2006</Year><RecNum>451</RecNum><record><rec-number>451</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">451</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Moses, R. G.</author><author>Luebcke, M.</author><author>Davis, W. S.</author><author>Coleman, K. J.</author><author>Tapsell, L. C.</author><author>Petocz, P.</author><author>Brand-Miller, J. C.</author></authors></contributors><auth-address>Illawarra Area Health Service and Wollongong Hospital, Wollongong, NSW, Australia. robert.moses@sesiahs..au</auth-address><titles><title>Effect of a low-glycemic-index diet during pregnancy on obstetric outcomes</title><secondary-title>Am J Clin Nutr</secondary-title></titles><periodical><full-title>Am J Clin Nutr</full-title></periodical><pages>807-12</pages><volume>84</volume><number>4</number><edition>2006/10/07</edition><keywords><keyword>Adult</keyword><keyword>Birth Weight</keyword><keyword>Female</keyword><keyword>*Food Habits</keyword><keyword>*Glycemic Index</keyword><keyword>Humans</keyword><keyword>Mothers</keyword><keyword>Pregnancy</keyword><keyword>*Pregnancy Outcome</keyword><keyword>Pregnancy Trimester, First</keyword><keyword>Pregnancy Trimester, Second</keyword><keyword>Weight Gain</keyword></keywords><dates><year>2006</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0002-9165 (Print)
0002-9165 (Linking)</isbn><accession-num>17023707</accession-num><urls><related-urls><url> [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Moses, Luebcke et al. 2006). Low–glycaemic index diet for women with gestational diabetes also halved the number needing to use insulin, with no compromise of obstetric or fetal outcomes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb3NlczwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Moses, Barker et al. 2009). Both intensive lifestyle and metformin were highly effective in delaying or preventing diabetes in women with impaired glucose tolerance test and a history of gestational diabetes PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SYXRuZXI8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Ratner, Christophi et al. 2008). On the other hand, a multicentre randomised control trial of treatment of mild gestational diabetes did not significantly reduce the frequency of a composite outcome that included stillbirth or perinatal death and several neonatal complications; however it did reduce the risks of fetal overgrowth, shoulder dystocia, caesarean delivery, and hypertensive disorders PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MYW5kb248L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Landon, Spong et al. 2009). No substantial maternal or neonatal outcome differences were found with the use of glyburide or metformin compared with use of insulin in women with GDM ADDIN EN.CITE <EndNote><Cite><Author>Nicholson</Author><Year>2009</Year><RecNum>455</RecNum><record><rec-number>455</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">455</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nicholson, W.</author><author>Bolen, S.</author><author>Witkop, C. T.</author><author>Neale, D.</author><author>Wilson, L.</author><author>Bass, E.</author></authors></contributors><auth-address>Department of Gynecology and Obstetrics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. wnichol@jhmi.edu</auth-address><titles><title>Benefits and risks of oral diabetes agents compared with insulin in women with gestational diabetes: a systematic review</title><secondary-title>Obstet Gynecol</secondary-title></titles><periodical><full-title>Obstet Gynecol</full-title></periodical><pages>193-205</pages><volume>113</volume><number>1</number><edition>2008/12/24</edition><keywords><keyword>Acarbose/administration & dosage</keyword><keyword>Administration, Oral</keyword><keyword>Birth Weight/drug effects</keyword><keyword>Diabetes, Gestational/*drug therapy</keyword><keyword>Female</keyword><keyword>Glyburide/administration & dosage</keyword><keyword>Humans</keyword><keyword>Hypoglycemic Agents/*administration & dosage/adverse effects</keyword><keyword>Infant, Newborn</keyword><keyword>Insulin/adverse effects/*therapeutic use</keyword><keyword>Metformin/administration & dosage</keyword><keyword>Pregnancy</keyword></keywords><dates><year>2009</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0029-7844 (Print)
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ADDIN EN.CITE.DATA (Lain, Garabedian et al. 2009). In women with gestational diabetes at 20-33 weeks of gestation, metformin (alone or with supplemental insulin) as compared with insulin was not associated with increased perinatal complications ADDIN EN.CITE <EndNote><Cite><Author>Rowan</Author><Year>2008</Year><RecNum>457</RecNum><record><rec-number>457</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">457</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rowan, J. A.</author><author>Hague, W. M.</author><author>Gao, W.</author><author>Battin, M. R.</author><author>Moore, M. P.</author></authors></contributors><auth-address>National Women's Health, Auckland City Hospital, Grafton, Auckland, New Zealand. jrowan@internet.co.nz</auth-address><titles><title>Metformin versus insulin for the treatment of gestational diabetes</title><secondary-title>N Engl J Med</secondary-title></titles><periodical><full-title>N Engl J Med</full-title></periodical><pages>2003-15</pages><volume>358</volume><number>19</number><edition>2008/05/09</edition><keywords><keyword>Adult</keyword><keyword>Diabetes, Gestational/*drug therapy</keyword><keyword>Drug Therapy, Combination</keyword><keyword>Female</keyword><keyword>Gestational Age</keyword><keyword>Humans</keyword><keyword>Hypoglycemia/epidemiology</keyword><keyword>Hypoglycemic Agents/adverse effects/*therapeutic use</keyword><keyword>Infant, Newborn</keyword><keyword>Insulin/adverse effects/*therapeutic use</keyword><keyword>Jaundice, Neonatal/epidemiology</keyword><keyword>Metformin/adverse effects/*therapeutic use</keyword><keyword>Patient Satisfaction</keyword><keyword>Pregnancy</keyword><keyword>Pregnancy Complications, Cardiovascular</keyword><keyword>*Pregnancy Outcome</keyword><keyword>Premature Birth/epidemiology</keyword></keywords><dates><year>2008</year><pub-dates><date>May 8</date></pub-dates></dates><isbn>1533-4406 (Electronic)
0028-4793 (Linking)</isbn><accession-num>18463376</accession-num><urls><related-urls><url> [pii]
10.1056/NEJMoa0707193</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Rowan, Hague et al. 2008). Glucose control in women with gestational diabetes mellitus treated with metformin and/or insulin was strongly related to outcomes. The lowest risk of complications was seen when fasting capillary glucose was <4.9 mmol/l (mean ± SD 4.6 ± 0.3 mmol/l) compared with 4.9–5.3 mmol/l or higher and when 2-h postprandial glucose was 5.9–6.4 mmol/l (6.2 ± 0.2 mmol/l) or lower ADDIN EN.CITE <EndNote><Cite><Author>Rowan</Author><Year>2010</Year><RecNum>458</RecNum><record><rec-number>458</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">458</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rowan, J. A.</author><author>Gao, W.</author><author>Hague, W. M.</author><author>McIntyre, H. D.</author></authors></contributors><auth-address>National Women's Hospital, Auckland City Hospital, Auckland, New Zealand. jrowan@internet.co.nz</auth-address><titles><title>Glycemia and its relationship to outcomes in the metformin in gestational diabetes trial</title><secondary-title>Diabetes Care</secondary-title></titles><periodical><full-title>Diabetes Care</full-title></periodical><pages>9-16</pages><volume>33</volume><number>1</number><edition>2009/10/23</edition><keywords><keyword>Birth Weight</keyword><keyword>Diabetes Complications</keyword><keyword>Diabetes, Gestational/*drug therapy</keyword><keyword>Female</keyword><keyword>Gestational Age</keyword><keyword>Glucose Tolerance Test</keyword><keyword>Humans</keyword><keyword>Hypoglycemic Agents/*therapeutic use</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Small for Gestational Age</keyword><keyword>Insulin/therapeutic use</keyword><keyword>Metformin/*therapeutic use</keyword><keyword>Pregnancy</keyword><keyword>Pregnancy Outcome</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2010</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>1935-5548 (Electronic)
0149-5992 (Linking)</isbn><accession-num>19846793</accession-num><urls><related-urls><url> [pii]
10.2337/dc09-1407</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Rowan, Gao et al. 2010). Although treatment of GDM substantially reduced macrosomia at birth, it did not result in a change in BMI at age 4-5 years PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HaWxsbWFuPC9BdXRob3I+PFllYXI+MjAxMDwvWWVhcj48
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ADDIN EN.CITE.DATA (Gillman, Oakey et al. 2010).Thus strict control of blood sugar during pregnancy in GDM prevents fetal and neonatal hyperinsulinaemia and related complications but may not help in reversing intrauterine programming resulting in future adverse outcomes.Literature Review: IMDMScale of the ProblemCurrently, 3-10% of pregnancies are affected by abnormal glucose regulation and control. Of these cases, 80-88% are related to gestational diabetes mellitus. Of mothers with preexisting diabetes, 35% have been found to have type 1 diabetes mellitus, and 65% have been found to have type 2 diabetes mellitus. Notably infants born to mothers whose pregnancy was complicated by diabetes (gestational and types 1 and 2 diabetes) have experienced nearly 30-fold decrease in morbidity and mortality rates since the development of specialized maternal, fetal, and neonatal care for women with diabetes and their offspring. However adverse neonatal outcomes are still 3-9 times greater in infants born to mothers with preexisting types 1 and 2 diabetes compared to those of nondiabetic mothers ADDIN EN.CITE <EndNote><Cite><Author>Yang</Author><Year>2006</Year><RecNum>128</RecNum><record><rec-number>128</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">128</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Yang, J.</author><author>Cummings, E. A.</author><author>O'Connell, C.</author><author>Jangaard, K.</author></authors></contributors><auth-address>Department of Pediatrics, Izaak Walton Killam Health Centre and Dalhousie University, Halifax, Nova Scotia, Canada.</auth-address><titles><title>Fetal and neonatal outcomes of diabetic pregnancies</title><secondary-title>Obstet Gynecol</secondary-title></titles><periodical><full-title>Obstet Gynecol</full-title></periodical><pages>644-50</pages><volume>108</volume><number>3 Pt 1</number><edition>2006/09/02</edition><keywords><keyword>Adult</keyword><keyword>Cohort Studies</keyword><keyword>Confidence Intervals</keyword><keyword>Congenital Abnormalities/epidemiology</keyword><keyword>Diabetes Mellitus, Type 1/*complications</keyword><keyword>Diabetes Mellitus, Type 2/*complications</keyword><keyword>Female</keyword><keyword>Fetal Macrosomia/epidemiology</keyword><keyword>Humans</keyword><keyword>*Infant Mortality/trends</keyword><keyword>Infant, Newborn</keyword><keyword>Nova Scotia</keyword><keyword>Odds Ratio</keyword><keyword>Pregnancy</keyword><keyword>*Pregnancy Outcome/epidemiology</keyword><keyword>*Pregnancy in Diabetics</keyword><keyword>Pregnancy, High-Risk</keyword><keyword>Risk Factors</keyword></keywords><dates><year>2006</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0029-7844 (Print)</isbn><accession-num>16946226</accession-num><urls><related-urls><url> [pii]
10.1097/01.AOG.0000231688.08263.47</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Yang, Cummings et al. 2006). In mothers with insulin-dependent diabetes, the stillbirth and perinatal mortality rate is 5 times the rate in the general population, and neonatal and infant mortality rates are 15 times?and 3 times the rate in the general population, respectively. Major congenital malformations are found in 5-9% of affected infants and account for 30-50% of perinatal deaths of infants of mothers with gestational diabetes. IMDM (gestational, types 1 and 2 diabetes) are 3 times more likely to be born by caesarean delivery, twice as likely to suffer serious birth injury, and 4 times as likely to be admitted to a neonatal intensive care unit. In addition they are at increased risk of morbidity and mortality related to the abnormalities in fetal growth (either overgrowth or undergrowth), birth injuries, hypoglycaemia, hypocalcaemia, feed intolerance, polycythaemia and thrombocytopenia, jaundice, prematurity, respiratory distress syndrome, asymmetric septal hypertrophy, congenital malformations and intrapartum asphyxia. Physiology of Fetal HyperinsulaemiaThe physiology of fetal hyperinsulinaemia in mothers with gestational diabetes is explained by Pedersen hypothesis which states that maternal hyperglycemia results in fetal hyperglycemia as glucose readily traverses the placenta ADDIN EN.CITE <EndNote><Cite><Author>Pedersen</Author><Year>1977</Year><RecNum>460</RecNum><record><rec-number>460</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">460</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>J Pedersen</author></authors><secondary-authors><author>Williams and Wilkins</author></secondary-authors></contributors><titles><title>The pregnant diabetic and her newborn. </title></titles><edition>2nd edition.</edition><dates><year>1977</year></dates><pub-location>Baltimore</pub-location><publisher>Williams and Wilkins</publisher><urls></urls></record></Cite></EndNote>(Pedersen 1977). Before 20 weeks' gestation, fetal islet cells are not capable of responsive insulin secretion. After 20 weeks’ gestation, the fetus has a functioning pancreas and is responsible for its own glucose homeostasis. Therefore fetal hyperglycemia induces fetal pancreatic beta-cell hyperplasia with resultant hyperinsulinaemia. In addition, proinsulin hormones such as insulin like growth factor-1 [IGF-1] and insulin like growth factor–binding protein-3 [IGFBP-3] act as growth factors that, in the presence of increased fetal amino acids result in fetal macrosomia noted as early as 24 weeks' gestation. The combination of hyperglycaemia and insulin increases fetal fat and glycogen stores, resulting in weight increases marked by hepatosplenomegaly and cardiomegaly. Chronic fetal hyperglycaemia and hyperinsulinaemia increase the fetal basal metabolic rate and oxygen consumption, leading to a relative hypoxic state. The fetus responds by increasing oxygen-carrying capacity through increased erythropoietin production, potentially leading to polycythaemia. Prior to birth, elevated insulin levels may inhibit the maturational effect of cortisol on the lung, including the production of surfactant from type 2 pneumocytes. This puts the fetus at risk for developing respiratory distress syndrome after birth at a gestational age?when normal lung function is expected. Withdrawal of the transplacental supply of glucose after birth leads to a precipitous drop in the concentration of glucose; many require infusion of large quantities of glucose to maintain normal blood glucose levels.Feed Intolerance in IMDMFeed intolerance occurs in up to 37% of IMDM PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaXR6bWlsbGVyPC9BdXRob3I+PFllYXI+MTk3ODwvWWVh
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ADDIN EN.CITE.DATA (Kitzmiller, Cloherty et al. 1978) and a key reason for prolongation of hospital stay and parent-infant separation ADDIN EN.CITE <EndNote><Cite><Author>Lee-Parritz</Author><Year>2004</Year><RecNum>225</RecNum><record><rec-number>225</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">225</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Lee-Parritz, Cloherty JP</author></authors><secondary-authors><author>Cloherty JP, Eichenwald EC, Stark AR</author></secondary-authors><tertiary-authors><author>Cloherty, JP; Eichenwald, EC, Stark, AR</author></tertiary-authors></contributors><titles><title>Maternal conditions that affect the fetus: diabetes mellitus</title><secondary-title>Manual of Neonatal Care (Fifth Edition)</secondary-title></titles><pages>9-19</pages><dates><year>2004</year></dates><pub-location>Philadelphia, PA </pub-location><publisher>Lippincott Williams & Wilkins</publisher><urls></urls></record></Cite></EndNote>(Lee-Parritz 2004). It is often present in the absence of prematurity, respiratory distress, and polyhydramnios, and the incidence is similar among large-for-gestational-age and appropriate-for-gestational-age infants ADDIN EN.CITE <EndNote><Cite><Author>Lee-Parritz</Author><Year>2004</Year><RecNum>225</RecNum><record><rec-number>225</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">225</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Lee-Parritz, Cloherty JP</author></authors><secondary-authors><author>Cloherty JP, Eichenwald EC, Stark AR</author></secondary-authors><tertiary-authors><author>Cloherty, JP; Eichenwald, EC, Stark, AR</author></tertiary-authors></contributors><titles><title>Maternal conditions that affect the fetus: diabetes mellitus</title><secondary-title>Manual of Neonatal Care (Fifth Edition)</secondary-title></titles><pages>9-19</pages><dates><year>2004</year></dates><pub-location>Philadelphia, PA </pub-location><publisher>Lippincott Williams & Wilkins</publisher><urls></urls></record></Cite></EndNote>(Lee-Parritz 2004). This frequently observed problem of feed intolerance in IMDM is overshadowed by previously described morbidities (section 5.1) and therefore not widely reported. The management of feed intolerance in IMDM relies on tube feeding with or without intravenous dextrose solution until the infant establishes to demand oral feeds. The conservative approach to management may be due to the fact that the aetiology and pathophysiology of feed intolerance in IMDM is yet to be determined. Proposed Patho-Physiology of Feed intolerance in IMDMElevation of plasma amylin levels has been described in pregnant women with gestational diabetes mellitus ADDIN EN.CITE <EndNote><Cite><Author>Ludvik</Author><Year>1997</Year><RecNum>41</RecNum><record><rec-number>41</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">41</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ludvik, B.</author><author>Kautzky-Willer, A.</author><author>Prager, R.</author><author>Thomaseth, K.</author><author>Pacini, G.</author></authors></contributors><auth-address>Klinik fur Innere Medizin III, Abteilung fur Endokrinologie und Stoffwechsel, University of Vienna, Austria.</auth-address><titles><title>Amylin: history and overview</title><secondary-title>Diabet Med</secondary-title></titles><periodical><full-title>Diabet Med</full-title></periodical><pages>S9-13</pages><volume>14 Suppl 2</volume><edition>1997/06/01</edition><keywords><keyword>Amyloid/history/*physiology/secretion</keyword><keyword>Animals</keyword><keyword>Diabetes Mellitus, Type 2/etiology</keyword><keyword>Female</keyword><keyword>Glucose/metabolism</keyword><keyword>History, 20th Century</keyword><keyword>Homeostasis</keyword><keyword>Humans</keyword><keyword>Insulin/secretion</keyword><keyword>Male</keyword></keywords><dates><year>1997</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0742-3071 (Print)</isbn><accession-num>9212323</accession-num><urls><related-urls><url>(SICI)1096-9136(199706)14:2+<S9::AID-DIA397>3.0.CO;2-D</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Ludvik, Kautzky-Willer et al. 1997). Insulin resistance and hyperinsulinaemia probably due to hyperleptinemia has been demonstrated in IMDMs PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WZWxhLUh1ZXJ0YTwvQXV0aG9yPjxZZWFyPjIwMDg8L1ll
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ADDIN EN.CITE.DATA (Vela-Huerta, San Vicente-Santoscoy et al. 2008). It is plausible that this hyperinsulinaemia and insulin resistance may also predispose to hyperamylinaemia which may have a role to play in the pathogenesis of feed intolerance in IMDMs. This plausible mechanism and hypothesis is yet to be proven and a subject of investigation of this dissertation.Overview of Project PlanGeneral DesignThe overall project plan ( REF _Ref323197753 \h \* MERGEFORMAT Figure 16) was to test the hypothesis that amylin would be raised in neonates with clinical signs of feed intolerance. Figure SEQ Figure \* ARABIC 16. Project plan Gantt chart As there was no published information regarding amylin and its concentrations in the newborn, the first part of the study was to establish normative values of amylin at birth and postnatal period in term and well preterm infants. Measurement of amylin levels at more than one time point during the first weeks of life following birth would help in the assessment of its trend and decay with time. It was also essential to identify two or more time points after birth that would allow for blood collection to be undertaken without causing discomfort and pain to the study participants. Umbilical cord blood at birth and Guthrie blood on postnatal day 5 were identified as practically feasible time points requiring minimal or no intervention in the mother and the baby. This approach required collection of blood both in the hospital (from umbilical cords and at the time of Guthrie of in-house babies) and community setting (at the time of Guthrie of those babies discharged home from the hospital before day 5). A pilot study of community blood collection identified unacceptable compromises to the sampling process and maintenance of cold chain. Therefore the study plan was amended to abandon community blood collections. Umbilical cord blood could be collected from discarded cords immediately after birth without causing pain or discomfort to the mother and the baby. The blood for Guthrie test is collected from a heel-prick sample and is offered to all infants in the UK with the aim of screening for up to five disorders typically on day 5 after birth. Thus it was feasible to collect blood for amylin during routine Guthrie test minimizing pain and discomfort. A third time point in the 2nd week of postnatal life although necessary was deemed impractical due to logistical reasons around blood sampling and ethical concerns of blood collection purely for study purposes. Originally, the second part of the project was to determine amylin levels in feed intolerant infants of mothers whose pregnancy was complicated by diabetes mellitus. To address the hypothesis that amylin levels are raised in IMDM with feed intolerance, a case-control study of feed intolerant and feed tolerant IMDM was considered. However an audit showed that not all IMDM were admitted to the neonatal intensive care or special care baby unit. Additionally, not all admitted IMDM required gastric tube placement as part of their routine care. Insertion of gastric tube to measure prefeed gastric residual volumes was essential to define feed intolerance. This meant designing a new guideline for the purpose of the study with inherent ethical issues. Therefore case-control study design was abandoned in favor of a cohort or prospective observational study of IMDM as an appropriate alternative methodology to address the hypothesis. Thus if amylin levels were observed to be raised in IMDM then it was not necessary to provide proof of concept as amylin was shown in previous studies to be a potent inhibitor of gastric emptying. Measurement of amylin levels at more than one time point during the first weeks following birth would help analyse its trend and decay with time. It was therefore necessary to identify at least two points in time following birth of the IMDM for the bloods to be collected causing minimal discomfort and pain. Umbilical cord blood at birth and Guthrie blood on postnatal day 5 were identified as practically feasible time points requiring minimal or no intervention in the mother and the baby. A third time point for opportunistic blood collection was also agreed when IMDM were admitted to the neonatal intensive care unit or transitional care unit for IMDM related problems and needing routine blood sampling. The third part of the study was to test the hypothesis that amylin was raised in preterm infants with feed intolerance. A cohort study of preterm infants with feed intolerance alone may not conclusively address the hypothesis as measurement of gastric emptying times in addition to gastric residual volumes would have to be incorporated into the study design. Review of currently available tests to measure gastric emptying times at both the study centres were not considered to be practical, feasible and for some tests to be ethical: The expertise to measure gastric emptying time using currently available tests such as scintigraphy, ultrasonography, bio impedence, and 13C-octanoate breath test was not available at Doncaster General Hospital. Similarly bioimpedence technology and 13C-octanoate breath test were not available at Jessop Wing. Additionally the research team felt that serial ultrasonographic assessment of ACSA at Jessop Wing was not practical and feasible due to non-availability of radiology expertise out of hours and on weekends. Although gamma camera was available within the hospital building, the need to transfer the infants to the radiology department for this to be undertaken would put strain on existing resources in addition to a small risk of exposure to radiation. The question regarding safety of paracetomol in preterm infants and need for serial blood sampling for paracetomol absorption test would raise ethical concerns. A case-control study was therefore adopted to answer the hypothesis. Preterm infants less than 34 weeks are routinely admitted to the neonatal unit and most of these infants require naso/orogastric tube placement and routine blood sampling as part of their care. General Study Configuration and MethodologyThe study project involved observation of blood concentration of amylin in neonatal population and therefore did not require randomisation or blinding. The project was conducted simultaneously as three interrelated studies ( REF _Ref323199328 \h \* MERGEFORMAT Figure 17 & REF _Ref323199331 \h \* MERGEFORMAT Figure 18) for operational reasons and initially required a single-centre research ethics application. Figure SEQ Figure \* ARABIC 17. Study plan Gantt chartPROJECT TITLE: AMYLIN PEPTIDE: AN ASSOCIATION WITH FEED INTOLERANCE IN PRETERM NEONATES AND IMDMStudy AAmylin levels at birth and postnatal day 5 in healthy preterm and term infantsStudy BAmylin levels at birth and postnatal day 5 in preterm and term IMDM Study CAmylin levels in preterm infants with feed intoleranceSingle Centre Cohort StudyTwo Centre Case-Control StudyLabour ward, postnatal wards, Neonatal intensive care unit Jessop wing, Royal Hallamshire HospitalNeonatal intensive care unit Jessop wing, Royal Hallamshire Hospital & Doncaster General HospitalPrefeed GRV > 50% on 2 consecutive occasionsInclusion24-36 weeks gestation admitted to intensive care unit and requiring gastric tube feedingELISAAmylin levelsInsulin levels (where possible)Yes=nTOLNo=TOL0.5-1.0 ml blood collected from discarded umbilical cord, during routine collection and GuthriePlasma stored at -70 degrees Parental consent0.5-1.0 mlblood collected within an hour0.5-1.0 mlblood collected at the next routine collectionInclusion≥ 24 week gestation infants born without major antenatal or labour complications Inclusion≥ 24 weeks gestation born to mothers with diabetes mellitus (gestational, insulin or non-insulin dependent)Matched for birthweight, gestation, postnatal agePROJECT TITLE: AMYLIN PEPTIDE: AN ASSOCIATION WITH FEED INTOLERANCE IN PRETERM NEONATES AND IMDMStudy AAmylin levels at birth and postnatal day 5 in healthy preterm and term infantsStudy BAmylin levels at birth and postnatal day 5 in preterm and term IMDM Study CAmylin levels in preterm infants with feed intoleranceSingle Centre Cohort StudyTwo Centre Case-Control StudyLabour ward, postnatal wards, Neonatal intensive care unit Jessop wing, Royal Hallamshire HospitalNeonatal intensive care unit Jessop wing, Royal Hallamshire Hospital & Doncaster General HospitalPrefeed GRV > 50% on 2 consecutive occasionsInclusion24-36 weeks gestation admitted to intensive care unit and requiring gastric tube feedingELISAAmylin levelsInsulin levels (where possible)Yes=nTOLNo=TOL0.5-1.0 ml blood collected from discarded umbilical cord, during routine collection and GuthriePlasma stored at -70 degrees Parental consent0.5-1.0 mlblood collected within an hour0.5-1.0 mlblood collected at the next routine collectionInclusion≥ 24 week gestation infants born without major antenatal or labour complications Inclusion≥ 24 weeks gestation born to mothers with diabetes mellitus (gestational, insulin or non-insulin dependent)Matched for birthweight, gestation, postnatal ageFigure SEQ Figure \* ARABIC 18. General study methodologyThese three studies were planned to complete in 12 months; 10 months for recruitment and sample collection; and 2 months for completion of laboratory and data analysis.Study A was a single centre prospective observational study in well preterm and term infants to determine normal ranges of amylin in umbilical cord (birth) and Guthrie (postnatal day 5) blood. Study B was a single centre prospective observational study of IMDM to determine amylin levels in umbilical cord (birth), during routine blood sampling (neonatal intensive care stay) of admitted babies and Guthrie (postnatal day 5).Study C was a two centre case-control study to determine amylin levels in preterm infants admitted to the neonatal intensive care unit who subsequently developed feed intolerance and compared to amylin levels in birth weight, gestation and postnatal day of life matched preterm infants without feed intolerance. Some of these preterm infants were also recruited to study A. A second centre was enrolled to ensure the study was conducted to time lines.There were no modifications to the treatment of care received by the study infants. Blood samples for the study were obtained only when blood was being collected for routine clinical monitoring as this approach minimised discomfort to the infant. Doctors, nurses and midwifes working in the neonatal unit and labour ward performed routine blood sampling. Further training was imparted by the research team to nurses, midwives and doctors in blood collection, processing and storage. The transportation of the stored plasma to the laboratory was performed under controlled conditions using liquid nitrogen to maintain the cold chain. Ethics ConsiderationThe study was conducted according to the standards of International Conference on Harmonisation Good Clinical Practice Guideline, Research Ethics Committee regulations, Royal Hallamshire Hospital’s policies and procedures, and any applicable government regulations.The study protocol and any amendments were submitted to a properly constituted Ethics Committee (REC) for approval of the study conduct. The REC requested minor amendments to the protocol ( REF _Ref323198861 \h \* MERGEFORMAT Appendix 4 & REF _Ref323198864 \h \* MERGEFORMAT Appendix 5), information leaflets ( REF _Ref323198957 \h \* MERGEFORMAT Appendix 6, REF _Ref323198960 \h \* MERGEFORMAT Appendix 7 & REF _Ref323198963 \h \* MERGEFORMAT Appendix 8), and adverts ( REF _Ref323198981 \h \* MERGEFORMAT Appendix 11, REF _Ref323198983 \h \* MERGEFORMAT Appendix 12 & REF _Ref323198986 \h \* MERGEFORMAT Appendix 13) which were incorporated before final approval in writing. All parents/guardians were provided with an information sheet ( REF _Ref323198957 \h \* MERGEFORMAT Appendix 6, REF _Ref323198960 \h \* MERGEFORMAT Appendix 7, REF _Ref323198963 \h \* MERGEFORMAT Appendix 8) describing the elements of this study, with sufficient information for them to make an informed decision about their infant participating in this study. The parents/guardians completed and signed a consent form to indicate that they were giving consent for their infant to participate ( REF _Ref323536809 \h \* MERGEFORMAT Appendix 9 & REF _Ref323536812 \h \* MERGEFORMAT Appendix 10). It was made clear to the parents/guardians that the study will offer no direct benefit to their own child. Additionally they were free to withdraw their infant from the study at any time. Participants were discontinued from study at any time for safety reasons as judged by the investigator or clinician responsible for the child and when parents withdrew consent.The possible ethical considerations arising from the conduct of the study were: (1) Blood collection from umbilical cord attached to the baby. An amendment was accepted to collect the blood samples from the discarded umbilical cord to prevent discomfort, bleeding and possible parent-baby separation.(2) Consenting pregnant mothers in active labour. The ethics committee agreed for the blood to be collected from umbilical cords immediately after birth of the baby without prior consent. The study investigators may approach the mothers after delivery for consent and collected blood sample discarded if consent is refused. To circumvent this problem and to fulfil research governance obligations, the research team decided to amend the study plan to recruit mothers that were admitted for elective induction of labour or caesarean section and umbilical cord blood collected after informed and written consent. (3) The collection and possession of human tissue. The umbilical cords were disposed immediately after blood collection according to hospital policy. The left over plasma was disposed immediately after analysis. (4) Blood collection from preterm infants and volume of blood. Blood samples were obtained during times when blood was collected for routine clinical monitoring. This approach minimised any extra discomfort to the infant. All blood handling was performed as per guidance for the minimization of infection risk to both participants and investigators. Not more than 2 ml of blood was collected from any infant during the course of the study which was within the safe limit.Data Handling and Record KeepingConfidentiality: Information about study subjects was kept confidential and managed according to the requirements of the Data Protection Act, NHS Caldicott Guardian, The Research Governance Framework for Health and Social Care and Ethics Committee Approval. The chief investigator acted as custodian of the data.Each participant was assigned a unique study number, allocated for use on data collection forms, other documentation and the electronic database. The data collection form was the only form to contain identifying data and were treated as confidential documents and held securely in accordance with the relevant regulations. Access was restricted to those personnel approved by the chief investigator. Blood samples were sent to the laboratory for analysis labelled only with the unique identification number. Data were anonymised on a computer database for the study by using the subject identification number only and this anonymised data was used for the statistical analyses specific to this study.Data Collection Forms or Case Report Forms ( REF _Ref323218361 \h \* MERGEFORMAT Appendix 14, REF _Ref323262870 \h \* MERGEFORMAT Appendix 15 & REF _Ref323265048 \h \* MERGEFORMAT Appendix 16) recorded participants’ biochemistry and demographics. Relevant information was retrieved from an electronic patient database and patient notes. Infant data included demographic variables such as birth weight, gestation, and gender, and postnatal age, date of blood collection which were recorded for all neonates. Maternal data included medical, antenatal, and labour history. For Study C the neonatal data also included ventilation days, % GRV just prior to amylin sampling, time from initiation to full enteral feeds (defined as 150 ml/kg per day) and time to discharge. Additionally, inflammatory markers such as C-reactive protein, white cell count, and neutrophil cell count were also recorded nearest to the date of blood sampling. Incomplete datasets from subjects discontinued from the study were not used.Records Retention: Documents were stored in a locked cabinet with limited access. Good Clinical Practice Guidelines stipulated that for patients involved in clinical trials documentation should be retained for 25 years after conclusion of treatment. Benefits and RisksThere would be no health benefit to the participants themselves. The results obtained from this study will help to establish normative amylin data in healthy preterm and term infants. The study may also help unravel the pathophysiology of feed intolerance which may lead to intervention studies in IMDM and preterm infants. Blood was collected from discarded umbilical cords for study A and B. No more than a total of 2.0 ml of blood was collected during the whole study from each baby in study A, B & C. This is also an acceptable amount to take from a pre-term baby ADDIN EN.CITE <EndNote><Cite><Author>Directive</Author><Year>2008</Year><RecNum>40</RecNum><record><rec-number>40</rec-number><foreign-keys><key app="EN" db-id="vwvet955gwepeyewspz5rv5dsp9p02dxw2as">40</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Directive, 2001/20/EC </author></authors></contributors><titles><title>Recommendations of the ad hoc group for the development of implementing guidelines for Directive 2001/20/EC relating to good clinical practice in the conduct of clinical trials on medicinal products for human use. Ethical considerations for clinical trials on medicinal products conducted with the paediatric population. 2008.</title></titles><dates><year>2008</year></dates><urls></urls></record></Cite></EndNote>(Directive 2008). FundingThe investigators received ?5000 from Jessop Wing Baby Fund to complete the three studies. Three thousand and five hundred pounds was returned as only ?1500 was spent on the entire project. The money was utilized for the following: Amylin Kits?1440Serum tubes?50Technical staff time?0Trasylol?10Clinical Study A: Umbilical & Guthrie Amylin in Preterm and Term InfantsIntroductionThe aim of this study was to determine the normal range of serum amylin levels in healthy preterm and term neonates at birth and postnatal day 5. This approach required collection of blood both in the hospital (from umbilical cords and at the time of Guthrie of in-house babies) and community setting (at the time of Guthrie of those babies discharged home from the hospital before day 5). A pilot study of community blood collection however identified unacceptable compromises to the sampling process and maintenance of cold chain. Therefore the study aim was amended in favor of blood collection of those infants who remain in house on postnatal day 5. MethodologyStudy Design & SettingThis single centre prospective observation study was conducted at the University Hospitals of Sheffield NHS Trust, Jessop Wing neonatal and obstetric departments, over a one year period. Analysis of the blood samples were conducted in the Academic Unit of Reproductive and Developmental medicine located at Jessop Wing, Royal Hallamshire Hospital.ConsentThe Infants were recruited once informed consent was obtained from their parents/guardians. Infants whose parents refused consent were excluded from the study. Inclusion CriteriaAll infants born at a gestational age greater than 24 weeks were eligible for the study. We chose to use the term ‘healthy’ to identify well from unwell preterm neonates who were deemed clinically stable by the attending clinical team. Preterm infants between 35-37 weeks admitted to the neonatal unit, transitional care ward or postnatal ward were establishing feeds or required prophylactic antibiotics pending blood cultures. Preterm infants less than 35 weeks were admitted to the neonatal unit primarily because of prematurity and low birth weight were generally well and establishing feeds. Extremely premature neonates (e.g. 24 weeks) who were ventilated or required continuous positive airway pressure (CPAP) for poor respiratory effort were clinically stable, and therefore considered to be ‘healthy’ for inclusion into the study. Exclusion CriteriaThe Infant born to mother whose pregnancy was complicated by diabetes (including gestational, insulin dependent and non-insulin dependent diabetes mellitus). Deliveries associated with chorioamnionitis, or other significant antenatal or labour complications. Infants with congenital and chromosomal abnormality.Rationale for exclusion criteria: Amylin has been shown to have both vasodilator PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWxsPC9BdXRob3I+PFllYXI+MTk5OTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Hall and Brain 1999) and anti-inflammatory ADDIN EN.CITE <EndNote><Cite><Author>Clementi</Author><Year>1995</Year><RecNum>217</RecNum><record><rec-number>217</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">217</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Clementi, G.</author><author>Caruso, A.</author><author>Cutuli, V. M.</author><author>Prato, A.</author><author>de Bernardis, E.</author><author>Fiore, C. E.</author><author>Amico-Roxas, M.</author></authors></contributors><auth-address>Institute of Pharmacology, University of Catania School of Medicine, Italy.</auth-address><titles><title>Anti-inflammatory activity of amylin and CGRP in different experimental models of inflammation</title><secondary-title>Life Sci</secondary-title></titles><pages>PL193-7</pages><volume>57</volume><number>14</number><edition>1995/01/01</edition><keywords><keyword>Amyloid/*pharmacology</keyword><keyword>Analysis of Variance</keyword><keyword>Animals</keyword><keyword>Anti-Inflammatory Agents, Non-Steroidal/*pharmacology</keyword><keyword>Calcitonin Gene-Related Peptide/*pharmacology</keyword><keyword>Croton Oil</keyword><keyword>Inflammation/chemically induced/drug therapy</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Rats</keyword><keyword>Rats, Sprague-Dawley</keyword></keywords><dates><year>1995</year></dates><isbn>0024-3205 (Print)</isbn><accession-num>7564878</accession-num><urls><related-urls><url>;(Clementi, Caruso et al. 1995) properties. Since amylin shares 50% homology with calcitonin gene related peptide, which is recognised to be raised in acute inflammatory states such as trauma ADDIN EN.CITE <EndNote><Cite><Author>Onuoha</Author><Year>1999</Year><RecNum>255</RecNum><record><rec-number>255</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">255</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Onuoha, G. N.</author><author>Alpar, E. K.</author></authors></contributors><auth-address>The University of Birmingham, Department of Surgery, School of Medicine, Edgbaston, UK.</auth-address><titles><title>Calcitonin gene-related peptide and other neuropeptides in the plasma of patients with soft tissue injury</title><secondary-title>Life Sci</secondary-title></titles><pages>1351-8</pages><volume>65</volume><number>13</number><edition>1999/09/30</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Calcitonin Gene-Related Peptide/*blood</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Neuropeptide Y/blood</keyword><keyword>Neuropeptides/*blood</keyword><keyword>Soft Tissue Injuries/*blood</keyword><keyword>Substance P/blood</keyword></keywords><dates><year>1999</year></dates><isbn>0024-3205 (Print)</isbn><accession-num>10503954</accession-num><urls><related-urls><url> [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Onuoha and Alpar 1999), sepsis (neonatal and adult) ADDIN EN.CITE <EndNote><Cite><Author>Parida</Author><Year>1998</Year><RecNum>256</RecNum><record><rec-number>256</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">256</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Parida, S. K.</author><author>Schneider, D. B.</author><author>Stoss, T. D.</author><author>Pauly, T. H.</author><author>McGillis, J. P.</author></authors></contributors><auth-address>Department of Pediatrics, University of Kentucky College of Medicine, Lexington 40536-0084, USA.</auth-address><titles><title>Elevated circulating calcitonin gene-related peptide in umbilical cord and infant blood associated with maternal and neonatal sepsis and shock</title><secondary-title>Pediatr Res</secondary-title></titles><periodical><full-title>Pediatr Res</full-title></periodical><pages>276-82</pages><volume>43</volume><number>2</number><edition>1998/02/25</edition><keywords><keyword>Adult</keyword><keyword>Calcitonin Gene-Related Peptide/*blood</keyword><keyword>Chromatography, High Pressure Liquid</keyword><keyword>Female</keyword><keyword>Fetal Blood/*chemistry</keyword><keyword>Gestational Age</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Newborn, Diseases/*blood</keyword><keyword>Infant, Premature</keyword><keyword>Male</keyword><keyword>Maternal-Fetal Exchange</keyword><keyword>Pregnancy</keyword><keyword>Radioimmunoassay</keyword><keyword>Shock, Septic/*blood</keyword></keywords><dates><year>1998</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0031-3998 (Print)</isbn><accession-num>9475297</accession-num><urls><related-urls><url>;(Parida, Schneider et al. 1998), and hypotensive shock ADDIN EN.CITE <EndNote><Cite><Author>Joyce</Author><Year>1990</Year><RecNum>257</RecNum><record><rec-number>257</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">257</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Joyce, C. D.</author><author>Fiscus, R. R.</author><author>Wang, X.</author><author>Dries, D. J.</author><author>Morris, R. C.</author><author>Prinz, R. A.</author></authors></contributors><auth-address>Department of Surgery, Loyola University Medical Center, Maywood, Ill 60153.</auth-address><titles><title>Calcitonin gene-related peptide levels are elevated in patients with sepsis</title><secondary-title>Surgery</secondary-title></titles><pages>1097-101</pages><volume>108</volume><number>6</number><edition>1990/12/01</edition><keywords><keyword>Adult</keyword><keyword>Bacterial Infections/*blood/microbiology/physiopathology</keyword><keyword>Calcitonin Gene-Related Peptide/*blood</keyword><keyword>Female</keyword><keyword>Hemodynamics</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Reference Values</keyword></keywords><dates><year>1990</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0039-6060 (Print)</isbn><accession-num>2247835</accession-num><urls><related-urls><url>;(Joyce, Fiscus et al. 1990), it may also share these properties. We therefore excluded infants born to mothers with chorioamnionitis and those with significant antenatal and labour complications. Similarly, amylin levels are influenced by diabetes and therefore mothers whose pregnancy was complicated by diabetes were also excluded from the study. Study ProcedureThe research team approached the pregnant mothers for consent in the antenatal clinic and on admission to the labour ward prior to delivery. Mothers admitted to the labour ward for elective induction of labour and elective caesarean section were also approached. A pilot study highlighted concerns of consenting pregnant women during busy antenatal clinics and in active labour. Moreover it was acknowledged that pregnant mothers attending the antenatal clinics may not remember the information provided in the information leaflets at the time of admission to the labour ward. Therefore following feedback from mothers and midwives, pregnant women admitted for elective induction of labour and elective cesarean section were chosen as the target population. These pregnant mothers were identified by the research team from admission book and theatre lists in the antenatal ward and labour ward prior to elective induction of labour and elective caesarean section. The study was discussed with the prospective mothers and information leaflet provided. Written consent was obtained from mothers for collection of blood from umbilical cord and Guthrie bloods. Additionally, researchers also identified infants who were staying in the hospital for maternal reasons and who required Guthrie blood on day 5 and parents approached for consent. Blood was collected immediately after birth from umbilical cord stump that was clamped and separated from the baby. One to two ml of free flowing blood was collected from the umbilical vein and/or artery, were possible. The postnatal day 5 Guthrie blood was collected from in-house infants on the neonatal unit and postnatal wards and at home as a pilot for discharged babies. For in-house infants in the postnatal wards, special care baby unit and transitional care wards, 0.5-1.0 ml blood sample was collected from heel prick at the time of routine day 5 Guthrie. In infants admitted for neonatal intensive care, blood from capillary, vein or indwelling arterial catheters were obtained at the time of routine collection. Guthrie blood collection of term infants discharged home before their 5th day was conducted by their health visitors in the community. However community blood collection was abandoned due to the technical difficulty of maintaining cold chain and transporting the blood samples on ice. The study plan was therefore amended to recruit in-house infants alone who required Guthrie bloods during their stay in the neonatal intensive care, special care baby unit, transitional care and those staying in the hospital for maternal reasons. Study End PointThe study end point was reached once blood was collected at birth from the umbilical cord and postnatal period at the time of Guthrie test respectively. Sample Collection & StorageWhole blood was drawn into refrigerated EDTA tube containing 500 IU of aprotinin, a serine protease inhibitor, known to inhibit trypsin, chymotrypsin, plasmin, kallikrein, and thrombin. Addition of aprotinin helps to inhibit protein degradation prior to separation of plasma ADDIN EN.CITE <EndNote><Cite><Author>Mintz</Author><Year>1993</Year><RecNum>461</RecNum><record><rec-number>461</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">461</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mintz, G.R.</author></authors></contributors><titles><title>An irreversible serine protease inhibitor</title><secondary-title>BioPharm</secondary-title></titles><periodical><full-title>BioPharm</full-title></periodical><pages>34-38</pages><number>6</number><dates><year>1993</year></dates><urls></urls></record></Cite></EndNote>(Mintz 1993) which was obtained by centrifugation immediately at 1000 xg for 10 minutes in refrigerated centrifuge. The plasma specimens were stored at ≤ -70°C. Blood samples with gross haemolysis or lipaemia were discarded as these were known to affect amylin levels. Sample AnalysisLinco research laboratories supplied two amylin assay kits namely, “Human amylin kit” and “Total amylin kit”. These amylin kits had been validated for use with human plasma and were sensitive to 1 pmol. The “Human amylin kit” reflected biologically active amylin more faithfully than “Total amylin kit”. In some cell types the reduced form (disulphide bond broken) is not biologically active although it may act as a competitive inhibitor (receptor antagonist) of the unreduced form. Since the disulphide bond is sometimes reduced in physiological conditions, the “Total amylin kit” tended to be higher than the “Human amylin kit”. The “Total amylin kit” was however considered to be more robust when reassurance about the controls with regards to the sampling variables, time to separation, and storage was not absolutely certain. This is because the rearrangements of the thiols in blood sample were common when there were unavoidable delays in processing due to strict clinical protocol. The research team concluded that it was impossible to strictly control sampling variables, time to separation and storage. Furthermore amylin assay developer and biochemical scientist opined that the marginal higher estimation of plasma amylin by “Total amylin kit” was very small to affect study results and conclusions. Therefore on balance, the “Total Human amylin kit” was chosen for the project.All plasma samples were analysed for amylin, and where volume of plasma was sufficient, insulin assay was also performed. Plasma total amylin immunoreactivity was quantified using Human Amylin (Total) ELISA KIT, a monoclonal antibody based sandwich immunoassay system developed by LINCO Research, Inc. (Missouri, USA). After the receipt of the ELISA kit, all components were stored at 2-8°C. This ELISA has sensitivity of 1 pmol (in 50 ?l plasma) with an inter-assay coefficient of variation of 13-18% and intra-assay coefficient of variation of 2.5-5% at 50 pmol spiked concentration of amylin (Appendix 3). The basic steps of the assay are detailed in Appendix 2. Plasma immunoreactive insulin was measured by ELISA that has inter- and intra-assay coefficients of variation of 5.6% and 5.3% (BioSource Labs, Belgium) respectively. The principle of the sandwich ELISA ( REF _Ref323198845 \h \* MERGEFORMAT Appendix 1) is that the capture antibody and detection antibody binds to reduced or unreduced human amylin which is complexed with Streptavidin-Alkaline Phosphatase to form a sandwich. Substrate 4-Methylumbelliferyl Phosphate (MUP) is applied to the completed sandwich and fluorescent signal monitored at 355 nm/460 nm which is proportional to the amount of amylin present in the sample.Sample SizeA Priori statistical advice suggested a sample size of at least 200 observations from cord blood samples for the calculation of a reference interval ADDIN EN.CITE <EndNote><Cite><Author>Altman DG</Author><Year>1991</Year><RecNum>259</RecNum><record><rec-number>259</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">259</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Altman DG,</author></authors><secondary-authors><author>Altman DG</author></secondary-authors></contributors><titles><title>Practical statistics for medical research</title></titles><section>423</section><dates><year>1991</year></dates><pub-location>London </pub-location><publisher>Chapman and Hall, </publisher><urls></urls></record></Cite></EndNote>(Altman DG 1991).Statistical AnalysisStatistical analysis was performed using Medcalc version 11.4.4.0. 1993-2010. Data were assessed for normality using coefficient of skewness, coefficient of kurtosis, D’Agostino-Pearson and Kolmogorov-Smirnov tests. Non-parametric tests (such as Wilcoxon rank sum test & Mann-Whitney U test) were employed where data were non-normal and presented as median values with interquartile range (25th-75th centile). The data were analysed for group differences with chi-square or Fisher’s exact tests for the categorical variables and with t-tests for the continuous variables. Pearson’s and Spearman’s correlation coefficient was used to assess correlation between normally and non-normally distributed amylin and insulin levels respectively. A p value of less than 0.05 was considered significant. A Bland-Altman plot of difference between the methods (y axis) against their average (x axis) was used to measure agreement between the two sampling methods (cord arterial and cord venous). This method aims to investigate a possible relation between measurement error and the true value which is unknown. Therefore the mean, average discrepancy (bias), trend, and scatter of the two measurements are used as a guide to the comparability of the two methods. Data Collection & Case Report FormCase report forms ( REF _Ref323218361 \h \* MERGEFORMAT Appendix 14) of infants recruited into the study consisted of demographic details, clinical details, and time of blood sampling. Maternal details and clinical history were also entered on a CRF.Study Summary REF _Ref323218703 \h \* MERGEFORMAT Table 2 highlights the key features of the study.Table SEQ Table \* ARABIC 2. Study A SummaryTitleUmbilical and Guthrie amylin levels in healthy preterm and term infantsStudy DesignSingle centre, Prospective Observational StudyStudy Duration12 monthsObjectivesTo determine plasma amylin levels in healthy preterm and term infantsNumber of blood samples/ Participants200 umbilical cord samplesMain Inclusion CriteriaInfants ≥ 24 weeks gestationMain Exclusion CriteriaInfants born to mothers whose pregnancy was complicated by diabetesStatistical MethodologyMedian and interquartile ranges for summary statistics. Corelation Coefficient to evaluate the relationship between variables. Bland Altman test for method comparison between umbilical arterial and umbilical venous blood sampling methodOutcome variablePlasma amylin levelsMeasurement AssayELISA REF _Ref323219826 \h \* MERGEFORMAT Figure 19 below shows the overall study plan in a Gantt chart.Figure SEQ Figure \* ARABIC 19. Study A Gantt chartResults REF _Ref323221303 \h \* MERGEFORMAT Figure 20 below shows participant flow and collection of blood samples. Paired umbilical cord arterial blood where possible (n=26)14 mothers excluded due to significant perinatal complications196 mothers eligible(194 singleton & 2 twin)Paired umbilical cord arterial blood where possible (n=8)14 infants were inpatients for maternal reasons(Post caesarean section)25 infants were inpatient due to problems relating to prematurityHealthy Term infants (n=138)Cord Venous Amylin levels (181)Paired Cord Arterial Amylin levels (34)Paired Cord Insulin levels (33) Postnatal Day 5 Amylin levels (39)Umbilical cord venous blood (n=138)Healthy Preterm infants (n=43)Guthrie Blood D5 (n=14)Guthrie Blood D5 (n=25)Umbilical cord venous blood (n=43)3 infants excluded(2 Downs syndrome, 1 CDH)182 mothers consented(180 singleton & 2 twin)124 infants discharged on D118 infantsdischarged on D1184 infants eligibleELISAPaired umbilical cord arterial blood where possible (n=26)14 mothers excluded due to significant perinatal complications196 mothers eligible(194 singleton & 2 twin)Paired umbilical cord arterial blood where possible (n=8)14 infants were inpatients for maternal reasons(Post caesarean section)25 infants were inpatient due to problems relating to prematurityHealthy Term infants (n=138)Cord Venous Amylin levels (181)Paired Cord Arterial Amylin levels (34)Paired Cord Insulin levels (33) Postnatal Day 5 Amylin levels (39)Umbilical cord venous blood (n=138)Healthy Preterm infants (n=43)Guthrie Blood D5 (n=14)Guthrie Blood D5 (n=25)Umbilical cord venous blood (n=43)3 infants excluded(2 Downs syndrome, 1 CDH)182 mothers consented(180 singleton & 2 twin)124 infants discharged on D118 infantsdischarged on D1184 infants eligibleELISAFigure SEQ Figure \* ARABIC 20. Study A flow diagram of participants and blood samplesDuring the course of the study, 196 pregnant mothers (194 singleton and 2 twin gestation) were eligible for the study of whom 19 consented antenatally, 10 during early labour, and 169 prior to elective caesarean section and induction of labour. Fourteen mothers with singleton pregnancies subsequently developed severe perinatal complications (7 preeclampsia, 4 sepsis/chorioamnionitis, and 3 gestational diabetes requiring insulin therapy). Thus 182 mothers (180 singleton and 2 twin gestation) who consented gave birth to 184 infants. Three singleton mothers gave birth to infants who did not meet the inclusion criteria (2 Downs syndrome and 1 Congenital Diaphragmatic Hernia) and were therefore excluded from the study.Of the 181 infants who were eligible for blood collection, 138 were healthy term infants and 43 healthy preterm infants. Umbilical venous blood was collected from 138 term and 43 preterm infants. In addition, paired umbilical arterial blood was also collected from 26 term and 8 preterm infants. A total of 124 term and 18 preterm (> 35 weeks gestation) infants were discharged between D1-D4. Guthrie blood was collected from 14 term infants who were inpatient due to maternal reasons (post caesarean section) and 25 preterm infants who were inpatients due to problems associated with prematurity (9 feeding establishment, 5 temperature control, 7 mild respiratory distress, 4 monitoring for presumed sepsis). A total of 254 blood samples (181 umbilical cord venous, 34 paired (meaning when arterial blood was collected along with venous blood from the same umbilical cord where possible) umbilical cord arterial, and 39 Guthrie) were analysed for amylin levels. In addition, 33 paired umbilical cord blood samples were also analysed for insulin levels. The median (interquartile range) amylin concentration in 138 healthy term infants at birth (umbilical cord) was 6.10 (3.30-9.70) pmol/L. REF _Ref323222469 \h \* MERGEFORMAT Table 3 shows the summary statistics of amylin concentration, birth weight and gestation at birth (umbilical cord group) in healthy term infants. REF _Ref323222704 \h \* MERGEFORMAT Figure 21 provides the box and whisker plot showing distribution of individual amylin level at birth in 138 healthy term infants. Table SEQ Table \* ARABIC 3. Summary statistic of amylin concentration and demographic characteristics at birth in healthy term infants Healthy Term Infants(Umbilical Cord Group)Birth weight(Kg)Gestation(Weeks)Amylin(pmol/L)Median3.2839.006.1095% CI3.15?–?3.4238.00?-?39.005.20?-?7.4925-75 percentile (IQR)2.98?–?3.6738.00?-?40.003.30?-?9.70Min-Max1.86-4.6437-420.50-27.40Coefficient of Skewness-0.06(p=0.74)0.60(p=0.00)1.14(p<0.00)Coefficient of Kurtosis0.21(p=0.49)-0.43(p=0.26)1.49(p=0.01)*D-P test for Normal distribution0.75Accept0.00Reject<0.00Reject* D’Agostino-Pearson test Figure SEQ Figure \* ARABIC 21. Box-and-whisker plot of umbilical cord amylin levels in healthy term infantsThe central box represents the values from 25th to 75th percentile, middle line represents the median, and the vertical line joining the horizontal line extends from the minimum to the maximum value (range), excluding "outside" values which are displayed as separate points. An outside value is defined as a value that is smaller than the lower quartile minus 1.5 times the interquartile range, or larger than the upper quartile plus 1.5 times the interquartile range. D’Agostino test for normal distribution was rejected (p<0.0001).The amylin concentration in 14 healthy term infants on postnatal day 5 (Guthrie) was 5.65 (3.10-8.20) pmol/L ( REF _Ref323227278 \h \* MERGEFORMAT Table 4 & REF _Ref323227291 \h \* MERGEFORMAT Figure 22). Table SEQ Table \* ARABIC 4. Summary statistic of amylin concentration and demographic characteristics at postnatal day 5 in healthy term infants Healthy Term Infants(Guthrie Group)Birth weight(Kg)Gestation(Weeks)Amylin(pmol/L)Median3.4038.55.6595% CI3.11-3.5837.8-41.13.05-8.2325-75 percentile (IQR)3.12-3.5838-413.10-8.20Min-Max2.02-4.4237-421.4-21.0Coefficient of Skewness-0.67(p=0.24)0.52(p=0.35)1.97(p=0.00)Coefficient of Kurtosis3.23(p=0.05)-1.27(p=0.23)5.26(p=0.00)*DP test for Normal distributionp=0.05Rejectp=0.32Acceptp=0.00Reject* D’Agostino-Pearson testFigure SEQ Figure \* ARABIC 22. Box-and-whisker plot of Guthrie amylin levels in healthy term infantsThe central box represents 25th to 75th percentiles; middle line, median, and the vertical lines are limit lines (range) excluding "outside" value which is displayed as separate point. D’Agostino test for normal distribution was rejected (p value of p<0.003).There was no difference in the demographic characteristics and serum amylin levels at birth (umbilical cord) and postnatal day 5 (Guthrie) in healthy term infants ( REF _Ref323244001 \h \* MERGEFORMAT Table 5 & REF _Ref323244019 \h \* MERGEFORMAT Figure 23). Table SEQ Table \* ARABIC 5. Demographic characteristics of healthy term infants at birth and postnatal day 5Healthy Term infantsBirth (Umbilical Cord venous)Postnatal Day 5 (Guthrie)p valuen13814Amylin (pmol/L)6.10(3.30-9.70)5.65(3.10-8.20)*NSGestation (wks)39(38.0-40.0)38.5(38.0-41.0)*NSBirth Weight (kg)3.28(2.98-3.67)3.40(3.12-3.58)*NSGenderMale717Female677* NS- not significantMedian and interquartile range, Mann Whitney U testFigure SEQ Figure \* ARABIC 23. Notched box-and-whisker plot of amylin levels at birth and postnatal day 5 in healthy term infantsThe central box represents 25th to 75th percentiles; the middle line, median and a vertical line, limits (range), excluding "outside" values which are displayed as separate points. The confidence intervals for the medians are provided by notches surrounding the medians which overlap; therefore the medians are not significantly different at a ± 95% confidence level. To test the difference between two groups, Mann- Whitney U test for independent samples was used, p=0.58. REF _Ref323244116 \h \* MERGEFORMAT Table 6 shows the demographic characteristics in healthy preterm infants at birth. Although the group included preterm infants of 26 weeks gestation, the median gestational age at birth of 34 weeks suggests that the population studied were dominated by late preterm infants. The amylin level at birth (umbilical cord) in 43 healthy preterm infants was 4.60 (1.90-8.30) pmol/L ( REF _Ref323244116 \h \* MERGEFORMAT Table 6 & REF _Ref323244166 \h \* MERGEFORMAT Figure 24). Table SEQ Table \* ARABIC 6. Summary statistic of amylin concentration and demographic characteristics at birth in healthy preterm infantsHealthy Preterm Infants(Umbilical cord Group)Birth weight(Kg)Gestation(Weeks)Amylin(pmol/L)Median2.0534.004.6095% CI1.65-2.3033.00-34.393.16-6.1925-75 percentile (IQR)1.53-2.3930.50-35.001.90-8.30Min-Max0.83-3.9226-361.0-11.5Coefficient of Skewness0.52(p=0.13)-0.87(p=0.02)0.35(p=0.31)Coefficient of Kurtosis0.20(p=0.60)-0.36(p=0.47)-1.16(p=0.12)*DP test for Normal distributionp=0.29Acceptedp=0.05Rejectedp=0.18Accepted* D’Agostino-Pearson testFigure SEQ Figure \* ARABIC 24. Box-and-whisker plot of umbilical cord amylin levels at birth in healthy preterm infantsThe central box represents 25th to 75th percentiles; middle line, median, and the vertical lines, limit lines (range). D’Agostino test for normal distribution was accepted (p value of p=0.18).The amylin level on postnatal day 5 (Guthrie) was 6.9 (2.75-9.50) pmol/L ( REF _Ref323244238 \h \* MERGEFORMAT Table 7 & REF _Ref323244251 \h \* MERGEFORMAT Figure 25) in 25 healthy preterm infants. Table SEQ Table \* ARABIC 7. Summary statistic of amylin concentration and demographic characteristics at postnatal day 5 in healthy preterm infantsHealthy Preterm Infants(Guthrie Group)Birth weight(Kg)Gestation(Weeks)Amylin(pmol/L)Median1.7233.06.995% CI1.56-2.1432.14-34.002.90-8.5525-75 percentile (IQR)1.50-2.2430-352.75-9.50Min-Max0.83-2.7526-361.0-19.7Coefficient of Skewness0.00(p=0.99)-0.86(p=0.06)0.93(p=0.04)Coefficient of Kurtosis-0.62(p=0.37)-0.32(p=0.55)-0.08(p=0.73)*DP test for Normal distributionp=0.67Acceptedp=0.15Acceptedp=0.13Accepted* D’Agostino-Pearson testFigure SEQ Figure \* ARABIC 25. Box-and-whisker plot of amylin levels at postnatal day 5 in healthy preterm infantsThe central box represents the values from 25th to 75th percentile, middle line represents the median, and the horizontal line extends from the minimum to the maximum value, excluding "outside" value which is displayed as separate point. D’Agostino test for normal distribution was accepted (p value=0.13).There was no difference in the demographic characteristics and serum amylin levels of healthy preterm infants at birth (umbilical cord) and postnatal day 5 (Guthrie) ( REF _Ref323244339 \h \* MERGEFORMAT Table 8 & REF _Ref323244377 \h \* MERGEFORMAT Figure 26). Table SEQ Table \* ARABIC 8. Demographic charateristics of healthy preterm infants at birth and postnatal day 5. Healthy Preterm infantsBirth (Umbilical Cord venous)Postnatal Day 5 (Guthrie)P valuen4325Amylin (pmol/L)4.60 (1.90-8.30)6.9 (2.75-9.50)NSGestation (wks)34 (30.5 - 35.0)33.0 (30.0 - 35.0)NSBirth Weight (kg)2.05 (1.53 – 2.39)1.72 (1.50 - 2.24)NSGender Male2513Female1812NS- not significantMedian and interquartile range, Mann Whitney U testFigure SEQ Figure \* ARABIC 26. Notched box-and-Whisker plot of amylin levels at birth and postnatal day 5 in healthy preterm infantsThe central box represents 25th to 75th percentiles; the middle line, median; and vertical line the limits (range) excluding “outside" value which is displayed as a separate point. The confidence intervals for the medians are provided by notches surrounding the medians which overlap and therefore the medians are not significantly different at a ± 95% confidence level. Mann-Whitney U test for difference between the groups was not significant (p value=0.279). Independent sample t test was also not significant (p=0.07)The gestation and birth weight were significantly lower in preterm infants at birth (umbilical cord) and postnatal day 5 (Guthrie) compared to term infants. Amylin levels were significantly lower at birth (umbilical cord) but not on postnatal day 5 (Guthrie) in preterm infants when compared to term infants ( REF _Ref323244427 \h \* MERGEFORMAT Table 9 & REF _Ref323244447 \h \* MERGEFORMAT Figure 27 & REF _Ref323244451 \h \* MERGEFORMAT Figure 28). Table SEQ Table \* ARABIC 9. Comparison of demography and amylin levels in healthy term and preterm infants at birth and postnatal day 5Healthy TermBirthHealthy PretermBirthHealthy TermPostnatal Day 5Heathy PretermPostnatal Day 5p valuen138431425Amylin (pmol/L)6.10 (3.30 -9.70)*4.60 (1.90-8.30)5.65 (3.10-8.20)**6.90 (2.75-9.50)*p=0.04**p=0.63Gestation (wks)39 (38.0 - 40.0)*34 (30.5 - 35.0)38.5 (38.0-41.0)**33.0(30.0 - 35.0)*p<0.00**p<0.00Weight(kg)3.28 (2.98-3.67)*2.05 (1.53- 2.39)3.40 (3.12-3.58)**1.72 (1.50 - 2.24)*p<0.00**p<0.00GenderMale7125713Female6718712Median and interquartile range, Mann Whitney U testFigure SEQ Figure \* ARABIC 27. Comparison Box-and-Whisker plot of amylin level in term and preterm infants at birthThe central box represents 25th to 75th percentiles; the middle line, median; and vertical line, limits (range), excluding "outside" values. The confidence intervals for the medians are provided by means of notches surrounding the medians which do not overlap and therefore the medians are significantly different at a ± 95% confidence level, Mann-Whitney U test for independent samples was significant (p=0.04).Figure SEQ Figure \* ARABIC 28. Comparison Box-and-Whisker plot of serum amylin level in term and preterm infants on postnatal day 5The central box represents 25th to 75th percentiles; middle line, median; and vertical line, limits (range), excluding "outside" values. The notches about two medians overlap and therefore the medians are not significantly different at a ± 95% confidence level, Mann-Whitney U test for independent samples was not significant (p=0.93).Thus the study established reference interval for amylin concentrations at birth and postnatal day 5 in healthy term infants (6.10 (3.30-9.70) and 5.65 (3.10-8.20) pmol/L) and healthy preterm infants (4.60 (1.90-8.30) and 6.90 (2.75-9.50)) pmol/L respectively. Paired umbilical cord arterial and umbilical cord venous amylin levels were available from 34 infants. The median amylin level in 34 paired cord venous and arterial blood samples were 5.3 (2.97-10.17) and 5.8 (2.5-9.7) pmol/L respectively. The amylin levels in paired samples correlated positively (Spearman’s coefficient of rank correlation rho=0.94, 95% CI 0.89-0.97, p<0.0001) ( REF _Ref323244564 \h \* MERGEFORMAT Figure 29). Figure SEQ Figure \* ARABIC 29. The correlation graph showing line of best fit to assess the degree of association between paired umbilical cord venous amylin (x axis) and umbilical cord arterial amylin (Y axis)Since the distribution of cord venous amylin levels were non-normal, rank correlation was used. The data were ranked in order of size, and calculations were based on the ranks of corresponding values X and Y to provide Spearman correlation coefficient rho with p-value, and a 95% CI for rho, i.e. the range of values which contains the true correlation coefficient with 95% probability (n=34, r=0.98, 95% CI 0.96-0.99, p<0.0001).A Bland-Altman plot ( REF _Ref323244616 \h \* MERGEFORMAT Figure 30 & REF _Ref323244618 \h \* MERGEFORMAT Figure 31) or difference plot is a graphical method of the differences between cord venous and cord arterial amylin (y axis) against their average (x axis) to demonstrate agreement between the two sampling methods (cord venous versus cord arterial). Figure SEQ Figure \* ARABIC 30. Bland Altman method comparison plot of paired venous and arterial levelsThe plot is useful to reveal a relationship between the differences and the averages, to look for any systematic biases and to identify possible outliers. In this graphical method the differences between the two sampling techniques (Y axis) are plotted against the averages of the two techniques (X axis). Horizontal lines are drawn at the mean difference, and at the limits of agreement, which are defined as the mean difference plus and minus 1.96 times the standard deviation of the differences. Thus the average discrepancy between the two levels is -0.8 which is clinically small. The difference between the levels and scatter around the mean (bias) generally remain the same as the average increases (n=34, mean bias -0.8, and limits of agreement +2.8 to -4.4).Figure SEQ Figure \* ARABIC 31. Bland Altman method comparison, percentage difference plot, of paired venous and arterial levelsIn this graphical method the differences are expressed as percentages of the values on the axis (i.e. proportionally to the magnitude of measurements). This option is useful when there is an increase in variability of the differences as the magnitude of the measurement increases.The Bland-Altman method aims to investigate a possible relation between measurement error and the true value which is unknown. Therefore the mean, average discrepancy (bias), trend, and scatter of the two measurements are used as a guide to the comparability of the two methods. The Bland-Altman plot is interpreted informally by investigating the size of the average discrepancy between the methods (bias), the trend of the the difference between methods (tend to get larger (or smaller) as the average increases), and the consistency of variability across the graph (Does the scatter around the bias line get larger as the average gets higher?). Horizontal lines are drawn at the mean difference, and at the limits of agreement, which are defined as the mean difference plus and minus 1.96 times the standard deviation of the differences. If the differences within mean ± 1.96 SD are not clinically important, the two methods may be used interchangeably. The mean bias was -0.8 and the limits of agreement +2.8 to -4.4 which is clinically acceptable. Thus umbilical venous or arterial blood may be used to analyse amylin levels in both term and preterm infants. Paired amylin and insulin levels were analysed from 33 umbilical cord blood samples from healthy preterm and term infants. The median insulin level at 38.5 (37-40) week gestation and birth weight 3.14 kg (2.61-3.76) was 5.0 (3.00-8.25) mu/L. The amylin levels showed statistical correlation with insulin levels (rho= 0.46, 95% CI=0.14-0.69, p<0.006) ( REF _Ref323244807 \h \* MERGEFORMAT Figure 32). However analysis of REF _Ref323244807 \h \* MERGEFORMAT Figure 32 shows wide scatter suggesting this correlation is not strong. Figure SEQ Figure \* ARABIC 32. The correlation graph showing line of best fit to assess the degree of association between paired umbilical cord insulin (x axis) and umbilical cord amylin (Y axis) in healthy preterm and term infantsSince the distribution of cord amylin (DP test, p=0.002) and insulin (DP test, p=0.0004) levels were non-normal, rank correlation was used. The data are ranked in order of size, and calculations were based on the ranks of corresponding values X and Y to provide Spearman correlation coefficient (rho) with p-value, and a 95% CI for rho, i.e. the range of values which contains the true correlation coefficient with 95% probability (n=33, spearman’s rho= 0.46, 95% CI=0.14-0.69, p<0.006).The umbilical cord venous amylin levels correlated both with gestation ( REF _Ref323244894 \h \* MERGEFORMAT Figure 33, r=0.20, 95% CI= 0.04-0.35, p=0.012) and birth weight ( REF _Ref323244909 \h \* MERGEFORMAT Figure 34, r=0.21, 95% CI=0.05-0.36, p=0.002). Figure SEQ Figure \* ARABIC 33. The correlation graph showing line of best fit to assess the degree of association between gestational age at birth (x axis) and umbilical cord amylin (Y axis)Since the distribution of cord venous amylin levels were non-normal, rank correlation was used to calculate Spearman correlation coefficient rho with p-value, and a 95% CI for rho (n=181, Spearman’s rho=0.20, 95% CI= 0.04-0.35, p=0.012). Figure SEQ Figure \* ARABIC 34. The correlation graph showing line of best fit to assess the degree of association between birth weight (x axis) and umbilical cord amylin (Y axis)Since the distribution of cord amylin levels were non-normal, rank correlation was used to calculate Spearman correlation coefficient rho with p-value, and a 95% CI for rho (n=181, Spearman’s rho= 0.21, 95% CI=0.05-0.36, p=0.002).DiscussionThis single centre prospective observational study was the first to establish normal range of plasma amylin concentration in healthy term and preterm neonates at birth and at the fifth postnatal day. We chose to use the term ‘healthy’ to identify well from unwell preterm neonates who were deemed clinically stable by the attending clinical team. Term infants who stayed in the hospital for maternal reasons were well and did not need any medical interventions. Preterm infants between 35-37 weeks admitted to the neonatal unit, transitional care ward or postnatal ward were establishing feeds or required prophylactic antibiotics pending blood cultures. Preterm infants less than 35 weeks were admitted to the neonatal unit primarily because of prematurity and low birth weight were generally well and establishing feeds. Premature neonates who were ventilated or required continuous positive airway pressure (CPAP) for poor respiratory effort were clinically stable, and therefore included in the study. The plasma amylin levels at birth and postnatal day 5 in healthy term (6.10 and 5.65 pmol/L) and preterm infants (4.60 and 6.90 pmol/L) were similar to the levels observed (mean (SD)) in the paediatric (5.0 (1.94) pmol/l) and adult (5.0 (0.4) pmol/l) populations PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ba2ltb3RvPC9BdXRob3I+PFllYXI+MTk5MzwvWWVhcj48
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ADDIN EN.CITE.DATA (Mitsukawa, Takemura et al. 1990; Akimoto, Nakazato et al. 1993). There was no difference in amylin concentration and birth weight, gestation, and gender between the umbilical cord and Guthrie group in both term and preterm infants. The amylin concentration in umbilical cord of preterm infants however was lower than terms infants (6.10 versus 4.60) most probably due to small sample size and differences in birth weight. In adults, like insulin, amylin levels show variation depending on fasting or postprandial state. It is not known if a similar pattern also exists in neonatal population. It is plausible that the amylin levels observed on postnatal day 5 in this study may have been influenced by the timing of blood sampling in relation to the infants’ pre-prandial or post-prandial state. This is less likely as the amylin levels were similar between the cord and Guthrie groups. We were unable to study diurnal variation of amylin and the influence of feeding due to the limitation of the study protocol to opportunistic blood collection. We propose that plasma amylin levels in the neonatal period are due to endogenous production as explained previously in section REF _Ref323266965 \r \h 2.4 on page PAGEREF _Ref323267001 \h 27, and are in the range reported in the paediatric and adult populations. Agreement was shown between paired cord arterial and venous amylin levels; therefore either of the two sampling methods could be used to measure amylin. This observation will help future studies investigating amylin levels in umbilical cord blood. Although umbilical cord amylin levels showed statistically significant correlation with insulin levels, due to wide scatter of the data, we suggest that amylin secretion may be in some way associated with insulin. In our study, umbilical vein insulin level from 34 neonates was 36.0 pmol/L (22.0-63.5) which was higher than 21.0 pmol/L (14.0-33.0) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Pbmc8L0F1dGhvcj48WWVhcj4yMDAwPC9ZZWFyPjxSZWNO
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Tm90ZT4A
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Pbmc8L0F1dGhvcj48WWVhcj4yMDAwPC9ZZWFyPjxSZWNO
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Tm90ZT4A
ADDIN EN.CITE.DATA (Ong, Kratzsch et al. 2000) and in the range reported in previous studies (39.0±5 pmol/L and 33.0 pmol/L (24.0-41.0) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaG9tYXM8L0F1dGhvcj48WWVhcj4xOTY3PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Thomas, de Gasparo et al. 1967; Gesteiro, Bastida et al. 2009). Fetal growth and development is dependent on various growth factors such as insulin, growth hormone and insulin like growth factor. The umbilical venous plasma insulin concentration and fetal insulin/glucose ratio increase exponentially with gestation, reflecting maturation of the endocrine pancreas ADDIN EN.CITE <EndNote><Cite><Author>Economides</Author><Year>1990</Year><RecNum>465</RecNum><record><rec-number>465</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">465</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Economides, D. L.</author><author>Nicolaides, K. H.</author><author>Campbell, S.</author></authors></contributors><auth-address>Harris Birthright Research Centre for Fetal Medicine, King's College School of Medicine and Dentistry, Denmark Hill, London, UK.</auth-address><titles><title>Relation between maternal-to-fetal blood glucose gradient and uterine and umbilical Doppler blood flow measurements</title><secondary-title>Br J Obstet Gynaecol</secondary-title></titles><periodical><full-title>Br J Obstet Gynaecol</full-title></periodical><pages>543-4</pages><volume>97</volume><number>6</number><edition>1990/06/01</edition><keywords><keyword>Blood Flow Velocity</keyword><keyword>Blood Glucose/*metabolism</keyword><keyword>Female</keyword><keyword>Fetal Blood/*metabolism</keyword><keyword>Fetal Growth Retardation/*metabolism</keyword><keyword>Humans</keyword><keyword>Pregnancy/*metabolism</keyword><keyword>Ultrasonography</keyword><keyword>Umbilical Veins</keyword><keyword>Uterus/*blood supply</keyword></keywords><dates><year>1990</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0306-5456 (Print)
0306-5456 (Linking)</isbn><accession-num>2198923</accession-num><urls><related-urls><url>;(Economides, Nicolaides et al. 1990). Body weight at birth is related to the amount of functioning pancreatic tissue, with hyperinsulinemic babies being macrosomic and SGA babies having reduced amounts of pancreatic tissue ADDIN EN.CITE <EndNote><Cite><Author>Fowden</Author><Year>1989</Year><RecNum>467</RecNum><record><rec-number>467</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">467</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fowden, A. L.</author></authors></contributors><auth-address>Physiological Laboratory, Cambridge, UK.</auth-address><titles><title>The role of insulin in prenatal growth</title><secondary-title>J Dev Physiol</secondary-title></titles><periodical><full-title>J Dev Physiol</full-title></periodical><pages>173-82</pages><volume>12</volume><number>4</number><edition>1989/10/01</edition><keywords><keyword>Body Composition/physiology</keyword><keyword>Body Constitution/physiology</keyword><keyword>Embryonic and Fetal Development/*physiology</keyword><keyword>Humans</keyword><keyword>Insulin/*physiology</keyword></keywords><dates><year>1989</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0141-9846 (Print)
0141-9846 (Linking)</isbn><accession-num>2699324</accession-num><urls><related-urls><url>;(Fowden 1989). In this study, a positive correlation was observed between birth weight and umbilical vein insulin levels ADDIN EN.CITE <EndNote><Cite><Author>Delmis</Author><Year>1992</Year><RecNum>466</RecNum><record><rec-number>466</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">466</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Delmis, J.</author><author>Drazancic, A.</author><author>Ivanisevic, M.</author><author>Suchanek, E.</author></authors></contributors><auth-address>Department of Obstetrics and Gynecology, Medical School, University of Zagreb, Croatia.</auth-address><titles><title>Glucose, insulin, HGH and IGF-I levels in maternal serum, amniotic fluid and umbilical venous serum: a comparison between late normal pregnancy and pregnancies complicated with diabetes and fetal growth retardation</title><secondary-title>J Perinat Med</secondary-title></titles><periodical><full-title>J Perinat Med</full-title></periodical><pages>47-56</pages><volume>20</volume><number>1</number><edition>1992/01/01</edition><keywords><keyword>Amniotic Fluid/*metabolism</keyword><keyword>Blood Glucose/metabolism</keyword><keyword>Diabetes Mellitus, Type 1/blood</keyword><keyword>Female</keyword><keyword>Fetal Blood/*metabolism</keyword><keyword>Fetal Growth Retardation/*blood</keyword><keyword>Growth Hormone/blood/metabolism</keyword><keyword>Growth Substances/blood/*metabolism</keyword><keyword>Humans</keyword><keyword>Insulin/blood/metabolism</keyword><keyword>Insulin-Like Growth Factor I/metabolism</keyword><keyword>Pregnancy</keyword><keyword>Pregnancy in Diabetics/*blood</keyword><keyword>Umbilical Veins</keyword></keywords><dates><year>1992</year></dates><isbn>0300-5577 (Print)
0300-5577 (Linking)</isbn><accession-num>1608023</accession-num><urls><related-urls><url>;(Delmis, Drazancic et al. 1992). We also observed a direct correlation between amylin levels with ascending gestation and birth weight, finding shared with its cousin calcitonin gene related peptide ADDIN EN.CITE <EndNote><Cite><Author>Parida</Author><Year>1998</Year><RecNum>256</RecNum><record><rec-number>256</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">256</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Parida, S. K.</author><author>Schneider, D. B.</author><author>Stoss, T. D.</author><author>Pauly, T. H.</author><author>McGillis, J. P.</author></authors></contributors><auth-address>Department of Pediatrics, University of Kentucky College of Medicine, Lexington 40536-0084, USA.</auth-address><titles><title>Elevated circulating calcitonin gene-related peptide in umbilical cord and infant blood associated with maternal and neonatal sepsis and shock</title><secondary-title>Pediatr Res</secondary-title></titles><periodical><full-title>Pediatr Res</full-title></periodical><pages>276-82</pages><volume>43</volume><number>2</number><edition>1998/02/25</edition><keywords><keyword>Adult</keyword><keyword>Calcitonin Gene-Related Peptide/*blood</keyword><keyword>Chromatography, High Pressure Liquid</keyword><keyword>Female</keyword><keyword>Fetal Blood/*chemistry</keyword><keyword>Gestational Age</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Newborn, Diseases/*blood</keyword><keyword>Infant, Premature</keyword><keyword>Male</keyword><keyword>Maternal-Fetal Exchange</keyword><keyword>Pregnancy</keyword><keyword>Radioimmunoassay</keyword><keyword>Shock, Septic/*blood</keyword></keywords><dates><year>1998</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0031-3998 (Print)</isbn><accession-num>9475297</accession-num><urls><related-urls><url>;(Parida, Schneider et al. 1998). It is possible that amylin may play a similar role to insulin in the maturation of pancreas. Although amylin levels showed an association with birth weight and gestation, the precise clinical significance of this observation is unclear. Since amylin is co-secreted with insulin from pancreas, we assessed cord amylin levels in a cohort of small for gestational age infants to assess the possible influence of faltering intrauterine growth. The median amylin level in the umbilical cord blood of 23 small for gestational age infants with median birth weight 1.80 kg (1.50-2.12) and gestation 36 weeks (33-37) was 4.0 (1.20-7.60) pmol/L. Although the amylin levels were lower that the levels observed in term and preterm infants, this did not reach statistical significance. Amylin has been shown to be raised in rat intestinal ischaemic injury ADDIN EN.CITE <EndNote><Cite><Author>Phillips</Author><Year>2001</Year><RecNum>261</RecNum><record><rec-number>261</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">261</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Phillips, A. R.</author><author>Abu-Zidan, F. M.</author><author>Farrant, G. J.</author><author>Zwi, J. L.</author><author>Cooper, G. J.</author><author>Windsor, J. A.</author></authors></contributors><auth-address>Pancreatitis Research Group, Department of Surgery, University of Auckland, Auckland, New Zealand.</auth-address><titles><title>Plasma amylin concentration is related to the severity of intestinal ischemic injury in rats</title><secondary-title>Surgery</secondary-title></titles><pages>730-5</pages><volume>129</volume><number>6</number><edition>2001/06/08</edition><keywords><keyword>Amyloid/*blood</keyword><keyword>Animals</keyword><keyword>Blood Pressure</keyword><keyword>Body Temperature</keyword><keyword>Intestines/*blood supply</keyword><keyword>Ischemia/*blood</keyword><keyword>Male</keyword><keyword>Rats</keyword><keyword>Rats, Wistar</keyword><keyword>Reperfusion Injury/*blood</keyword></keywords><dates><year>2001</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0039-6060 (Print)</isbn><accession-num>11391372</accession-num><urls><related-urls><url>(01)07456-6 [pii]
10.1067/msy.2001.113892</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Phillips, Abu-Zidan et al. 2001), and may have a biologic role in sepsis ADDIN EN.CITE <EndNote><Cite><Author>Parida</Author><Year>1998</Year><RecNum>256</RecNum><record><rec-number>256</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">256</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Parida, S. K.</author><author>Schneider, D. B.</author><author>Stoss, T. D.</author><author>Pauly, T. H.</author><author>McGillis, J. P.</author></authors></contributors><auth-address>Department of Pediatrics, University of Kentucky College of Medicine, Lexington 40536-0084, USA.</auth-address><titles><title>Elevated circulating calcitonin gene-related peptide in umbilical cord and infant blood associated with maternal and neonatal sepsis and shock</title><secondary-title>Pediatr Res</secondary-title></titles><periodical><full-title>Pediatr Res</full-title></periodical><pages>276-82</pages><volume>43</volume><number>2</number><edition>1998/02/25</edition><keywords><keyword>Adult</keyword><keyword>Calcitonin Gene-Related Peptide/*blood</keyword><keyword>Chromatography, High Pressure Liquid</keyword><keyword>Female</keyword><keyword>Fetal Blood/*chemistry</keyword><keyword>Gestational Age</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Newborn, Diseases/*blood</keyword><keyword>Infant, Premature</keyword><keyword>Male</keyword><keyword>Maternal-Fetal Exchange</keyword><keyword>Pregnancy</keyword><keyword>Radioimmunoassay</keyword><keyword>Shock, Septic/*blood</keyword></keywords><dates><year>1998</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0031-3998 (Print)</isbn><accession-num>9475297</accession-num><urls><related-urls><url>;(Parida, Schneider et al. 1998). Future research investigating the role of amylin in feed intolerance, necrotising enterocolitis and sepsis in the neonatal population may benefit from normal values established by this study. The main strength of the study was adherence to study methodology with regards to sample processing, storage and analysis. In addition, an experienced technician who was blinded to the patient details performed all laboratory analyses. To be absolutely certain that protein degradation does not take place in the blood collected prior to centrifugation, separation and storage, EDTA tubes were primed with aprotinin which is a protease inhibitor. The major limitations of the study were selection bias towards inpatient infants especially of term infants in the Guthrie group which also contributed to the small sample size; and blood sampling covering first postnatal week alone. Serial amylin measurements beyond first week of life in preterm and term infants may have helped understand the influence of transplacental passage, diurnal variations, influence of feeds and decay time of amylin. In hindsight, maternal amylin may have also helped determine transplacental passage of amylin. However we could not accommodate this into the study design due to logistical reasons.ConclusionsThis single centre prospective observational study provides normative data of amylin levels in neonatal population. Further data from similar studies would be helpful in establishing a normal range. In healthy term infants, the median amylin level is 6.10 pmol/L at birth and 5.65 pmol/L at postnatal day 5. In healthy preterm infants, the median amylin level is 4.60 pmol/L at birth and 6.90 pmol/L at postnatal day 5. Umbilical cord venous amylin levels showed agreement with paired umbilical cord arterial amylin levels. Thus umbilical venous or arterial blood may be used to analyse amylin levels in term and preterm infants. The median insulin concentration in healthy preterm and term infants is 5.0 (3.00-8.25) mu/L and its correlation with amylin levels suggests an association and possibly co-secretion. Amylin levels demonstrate an association with gestation and birth weight, the exact significance of which is not clear. Clinical Study B: Umbilical and Guthrie Amylin in Preterm and Term IMDMIntroductionIn view of the physiological changes known to take place in fetus and neonate exposed to maternal diabetes, we hypothesised that amylin levels may be raised in new-born IMDM. The aim of this study was to determine serum amylin levels at birth (umbilical cord) and postnatal day 5 (Guthrie) in preterm and term IMDM. MethodologyStudy Design & SettingThis single-centre prospective observational study was conducted at the University Hospitals of Sheffield NHS Trust neonatal and obstetric department, over a one year period. Analysis of the blood samples was conducted in the Academic Unit of Reproductive and Developmental medicine located at Jessop Wing, Royal Hallamshire Hospital.ConsentInfants were recruited once informed consent was obtained from their parents/guardians. Infants whose parents refused consent were excluded from the study. Inclusion CriteriaInfant’s ≥ 24 weeks gestation at birth born to mothers whose pregnancies were complicated by diabetes mellitus (including gestational, insulin dependent and non-insulin dependent diabetes mellitus) were eligible for the study.Exclusion CriteriaDeliveries associated with chorioamnionitis, or other significant antenatal or labour complications.Infants with congenital and chromosomal abnormalityStudy ProcedureMothers whose pregnancies were complicated by diabetes were identified by the research team in the antenatal ward and labour ward before elective induction of labour and elective caesarean section. Information leaflet and consent were discussed with parents. Written consent was obtained for collection of blood from umbilical cord and during routine Guthrie. IMDM who stayed in the hospital for maternal reasons and requiring Guthrie bloods on day 5 were also identified. Additionally, IMDM admitted to the neonatal unit for monitoring of blood sugars were identified and parents approached for consent.Blood was collected immediately after birth from umbilical cord stump that was clamped and separated from the baby. One to two ml of free flowing blood was obtained from the umbilical vein and artery, where possible. Postnatal blood samples were collected at the time of routine day 5 Guthrie or during routine blood sampling (such as bedside glucose monitoring) from capillary, vein or indwelling arterial catheters as deemed necessary for routine collection. Study End PointThe infants were no longer followed up after collection of cord and postnatal bloods.Sample Collection & StorageA 0.5 to 1 ml whole blood was collected and processed as described in Study A, section REF _Ref323262620 \r \h 8.2.7 on page PAGEREF _Ref323262631 \h 83. Sample AnalysisAll samples were analysed for amylin, and where volume of plasma was sufficient, insulin assay was also carried out as described in study A, section REF _Ref323262405 \r \h 8.2.8 on page PAGEREF _Ref323262418 \h 83.Sample SizeAt least 21 IMDM were required, to detect a difference in means of 15, assuming a standard deviation of 13 with 5% two sided significance level and 90% power. The mean and standard deviation were derived from the data published by ADDIN EN.CITE <EndNote><Cite><Author>Mayer</Author><Year>2002</Year><RecNum>206</RecNum><record><rec-number>206</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">206</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mayer, A. P.</author><author>Durward, A.</author><author>Turner, C.</author><author>Skellett, S.</author><author>Dalton, N.</author><author>Tibby, S. M.</author><author>Murdoch, I. A.</author></authors></contributors><auth-address>Department of Paediatric Intensive Care, Guy's Hospital, Saint Thomas Street, London, SE1 9RT, UK. amayer@.uk</auth-address><titles><title>Amylin is associated with delayed gastric emptying in critically ill children</title><secondary-title>Intensive Care Med</secondary-title></titles><pages>336-40</pages><volume>28</volume><number>3</number><edition>2002/03/21</edition><keywords><keyword>Acetaminophen/pharmacokinetics</keyword><keyword>Adolescent</keyword><keyword>Amyloid/blood/*pharmacology</keyword><keyword>Analgesics, Non-Narcotic/pharmacokinetics</keyword><keyword>Anti-Ulcer Agents/blood/*pharmacology</keyword><keyword>Area Under Curve</keyword><keyword>Blood Glucose/drug effects</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Gastric Emptying/*drug effects</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Insulin/blood</keyword><keyword>Intensive Care Units, Pediatric</keyword><keyword>Intestinal Absorption</keyword><keyword>Metabolic Clearance Rate</keyword><keyword>Prospective Studies</keyword></keywords><dates><year>2002</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0342-4642 (Print)</isbn><accession-num>11904665</accession-num><urls><related-urls><url>;(Mayer, Durward et al. 2002)Statistical AnalysisStatistical analysis was performed using Medcalc version 11.4.4.0. 1993-2010. as described in study A, section REF _Ref323262786 \r \h 8.2.10 on page PAGEREF _Ref323262796 \h 84. Data Collection & Case Report FormCase report form ( REF _Ref323262870 \h \* MERGEFORMAT Appendix 15) of infants recruited into the study consisted of demography, clinical details, and time of blood sampling. Maternal details and clinical history were also entered on a CRF. Study Summary REF _Ref323262921 \h \* MERGEFORMAT Table 10 below highlights the key features of the study methodology.Table SEQ Table \* ARABIC 10. Study B summaryTitleUmbilical and Guthrie amylin levels in preterm and term IMDMStudy DesignProspective Observational Study Study Duration12 monthsStudy CentresSingle Centre ObjectivesTo determine plasma amylin levels in cord and Guthrie blood of IMDM infantsNumber of Samples/Participants21 IMDM infantsMain Inclusion CriteriaIMDM ≥ 24 weeks gestationStatistical MethodologyMedian and interquartile ranges and non-parametric tests. Correlation Coefficient was performed to evaluate the relationship between variables. Outcome variablePlasma amylin levelsMeasurement AssayELISA REF _Ref323263255 \h \* MERGEFORMAT Figure 35 below provides details of the study plan in a Gantt chart.Figure SEQ Figure \* ARABIC 35. Study B Gantt chartResultThe REF _Ref323263188 \h \* MERGEFORMAT Figure 36 below shows the participant flow and blood samples.Paired umbilical cord arterial blood (n=3)Term infants (n=17)Umbilical cord venous blood31 singleton mothers were eligible who consentedPaired umbilical cord arterial blood (n=3)Preterm infants (n=14)Umbilical cord venous bloodGuthrie blood (n=9)Guthrie blood (n=5)Cord Amylin (n=31)Guthrie Amylin (n=14)Paired insulin (n=6)Discharged on D1-4 (n=17)InpatientsFeed intolerance (n=4)Feed intolerance (n=8)Paired umbilical cord arterial blood (n=3)Term infants (n=17)Umbilical cord venous blood31 singleton mothers were eligible who consentedPaired umbilical cord arterial blood (n=3)Preterm infants (n=14)Umbilical cord venous bloodGuthrie blood (n=9)Guthrie blood (n=5)Cord Amylin (n=31)Guthrie Amylin (n=14)Paired insulin (n=6)Discharged on D1-4 (n=17)InpatientsFeed intolerance (n=4)Feed intolerance (n=8)Figure SEQ Figure \* ARABIC 36. Study B-flow diagram of participants and blood samplesThirty-one singleton mothers whose pregnancy was complicated by diabetes consented for the study. 20 mothers had gestational diabetes and 11 mothers had insulin dependent diabetes mellitus. Umbilical cord blood was collected from 17 term infants and 14 preterm infants. Of these seventeen infants were discharged between days 1-4. Guthrie blood was collected from 5 term and 9 preterm inpatient infants who were admitted to the neonatal unit for respiratory distress, hypoglycemia, prematurity, or feeding problems. The null hypothesis of the study was that there was no difference in amylin concentration at birth and postnatal day 5 between preterm and term IMDM and preterm and term healthy infants (controls). The median (interquartile range) amylin concentration at birth (umbilical cord) in term IMDM was 34.30 (28.35-50.00) pmol/L ( REF _Ref323263340 \h \* MERGEFORMAT Table 11 & REF _Ref323263364 \h \* MERGEFORMAT Figure 37). Table SEQ Table \* ARABIC 11. Summary statistic of amylin concentration and demographic characteristics at birth in term IMDM infantsTerm IMDM(umbilical cord Group)Birth weight(kg)Gestation(weeks)Amylin (pmol/L)Median3.7439.0034.3095% CI3.44-3.9838.00?-?39.9832.79-47.3925-75 percentile (IQR)3.41?–?4.0737.75-?40.0028.35-50.00Min-Max2.51-4.8537-4222.10-70.10Coefficient of Skewness-0.25(p=0.62)0.58(p=0.26)0.59(p=0.25)Coefficient of Kurtosis-0.13(p=0.71)-0.21(p=0.66)-0.65(p=0.417)*D-P test for Normal distribution0.82Accept0.49Accept0.38Accept* D’Agostino-Pearson testFigure SEQ Figure \* ARABIC 37. Box-and-whisker plot of umbilical cord amylin levels in term IMDM infantsThe central box represents 25th to 75th percentile, middle line represents the median, and the vertical line represents range. D’Agostino-Pearson test for normal distribution of amylin levels was accepted (p=0.38).The plasma amylin level in term IMDM on postnatal day 5 (Guthrie) was 25.20 (22.20?–?48.75) pmol/L ( REF _Ref323263462 \h \* MERGEFORMAT Table 12 & REF _Ref323263484 \h \* MERGEFORMAT Figure 38). Table SEQ Table \* ARABIC 12. Summary statistic of amylin concentration and demographic characteristics on postnatal day 5 in term IMDM infantsTerm IMDM (Guthrie Group)Birth weight(kg)Gestation(weeks)Amylin (pmol/L)Median3.533725.2095% CI2.67?–?4.6735.22?–?40.7712.18?–?56.2925-75 percentile (IQR)3.21?–?4.4337?–?38.2522.20?–?48.75Min-Max2.51-4.4637-4217.10-60.00Coefficient of Skewness-0.54(p=0.74)2.230.85Coefficient of Kurtosis-0.522(p=0.75)5.00(p=0.02)-0.988 (p=0.59)*D-P test for Normal distributionSample size too smallSample size too smallSample size too small* D’Agostino-Pearson testFour of five infants in the Guthrie group also had feed intolerance at the time of blood collection.Figure SEQ Figure \* ARABIC 38. Box-and-whisker plot of Guthrie amylin levels in term IMDM infantsThe central box represents the values from 25th to 75th percentile, middle line represents the median, and the vertical line joining the horizontal line extends from the minimum to the maximum value (range). The sample size was too small to test normal distribution.There was no difference in the demographic characteristics and plasma amylin levels of term IMDM at birth (umbilical cord) and postnatal day 5 (Guthrie) as shown in REF _Ref323263551 \h \* MERGEFORMAT Table 13 & REF _Ref323263571 \h \* MERGEFORMAT Figure 39. Table SEQ Table \* ARABIC 13. Demographic characteristic of term IMDM at birth and postnatal day 5Term IMDMGroupBirth(Umbilical Cord)Postnatal Day 5 (Guthrie)p valuen175Amylin (pmol/L)34.30(28.35-50.00)25.20(22.20-48.75)*NSGestation (wks)39(37.75-40.00)37(37-38.25)*NSWeight (kg)3.74(3.41-4.07)3.53(3.21-4.43)*NSGender Male82*NSFemale93*NS* NS-not significantMedian and interquartile range, Mann Whitney U testFigure SEQ Figure \* ARABIC 39. Comparison Box-and-Whisker plot of amylin levels at birth and postnatal day 5 in term IMDMsMann-Whitney test for independent samples was not significant, p=0.25.In preterm IMDM, amylin level at birth (umbilical cord) was 32.0 (18.65-44.27) pmol/L ( REF _Ref323263631 \h \* MERGEFORMAT Table 14 & REF _Ref323263645 \h \* MERGEFORMAT Figure 40). Table SEQ Table \* ARABIC 14. Summary statistic of amylin concentration and demographic characteristics at birth in preterm IMDM infantsPreterm IMDM (umbilical cord group)Birth weight(kg)Gestation(weeks)Amylin(pmol/L) Median2.883432.0095% CI1.97-3.5133?–?35.4618.51?–45.3825-75 percentile (IQR)1.97-3.3533 –?35.2518.65-44.27Min-Max0.82-4.2126-3613.90-90.00Coefficient of Skewness-0.19(p=0.73)-1.69(p=0.00)1.25(p<0.04)Coefficient of Kurtosis-0.56(p=0.49)2.91(p=0.05)1.28(p=0.24)*D-P test for Normal distribution0.74Accept0.00Reject<0.06Accept* D’Agostino-Pearson testFigure SEQ Figure \* ARABIC 40. Box-and-whisker plot of umbilical cord amylin levels in preterm IMDM infantsThe central box represents 25th to 75th percentile, middle line represents the median, and the vertical line represents range. D’Agostino-Pearson test for normal distribution of amylin levels was accepted (p=0.06).In preterm IMDM, amylin level on postnatal day 5 (Guthrie) was 23.4 (15.37-46.57) pmol/L ( REF _Ref323263713 \h \* MERGEFORMAT Table 15 & REF _Ref323263730 \h \* MERGEFORMAT Figure 41). Table SEQ Table \* ARABIC 15. Summary statistic of amylin concentration and demographic characteristics at postnatal day 5 in preterm IMDM infantsPreterm IMDM (Guthrie group)Amylin (pmol/L)Birth weight(kg)Gestation(weeks)Median23.42.613495% CI13.84?-?82.011.53?-?4.0233.00 -?36.0025-75 percentile (IQR)15.37?-?46.571.96?-?3.9238.0?-?40.0Min-Max4.90-92.000.82-4.2126-36Coefficient of Skewness1.38(p<0.05)-0.05(p=0.92)-1.45(p=0.03)Coefficient of Kurtosis0.38(p=0.64)-1.22(p=0.30)1.58(p=0.22)*D-P test for Normal distribution0.14Accept0.59Accept0.05Accept* D’Agostino-Pearson testFigure SEQ Figure \* ARABIC 41. Box-and-whisker plot of Guthrie amylin levels in preterm IMDM infantsThe central box represents 25th to 75 percentile, middle line represents the median, and the vertical line represents range. D’Agostino-Pearson test for normal distribution of amylin levels was accepted (p=0.14).At the time of Guthrie blood collection, eight of nine preterm IMDM were experiencing feed intolerance.There was no difference in the demographic characteristics and amylin levels of preterm IMDM at birth (umbilical cord) and postnatal day 5 (Guthrie) as shown in REF _Ref323263792 \h \* MERGEFORMAT Table 16 & REF _Ref323263808 \h \* MERGEFORMAT Figure 42.Table SEQ Table \* ARABIC 16. Demographic characteristics of preterm IMDM at birth and postnatal day 5Preterm IMDMBirth(Umbilical cord)Postnatal day 5(Guthrie)P valuen149Amylin (pmol/L)32.0(18.65-44.27)23.4(15.37-46.57)*NSGestation (wks)34(33-35.25)34(38-40)*NSWeight (kg)2.88(1.93-3.35)2.61(1.96-3.92)*NSGender *NSMale95Female54* NS-not significantMedian and interquartile range, Mann Whitney U testFigure SEQ Figure \* ARABIC 42. Comparison box-and-whisker plot of amylin concentration at birth and postnatal day 5 in preterm IMDMMann-Whitney test for independent samples did not reach statistical significance, p=0.48. REF _Ref323263868 \h \* MERGEFORMAT Figure 43 below summarises the serum amylin levels at birth and postnatal day 5 in term and preterm IMDM. There was no statistical difference in plasma amylin levels between term and preterm IMDM at birth (p=0.25) and postnatal day 5 (p=0.64). Figure SEQ Figure \* ARABIC 43. Comparison box-and-whisker plot of amylin concentration in umbilical cord and Guthrie blood in term and preterm IMDMMann-Whitney test for independent samples was not significant, cord group p=0.25 and Guthrie group p=0.64.There was no baseline difference in the demographic characteristics at birth (umbilical cord) and postnatal day 5 (Guthrie) between term IMDM and term healthy controls ( REF _Ref323263923 \h \* MERGEFORMAT Table 17). However, the median amylin level at birth in term IMDM was significantly increased at 34.30 pmol/L compared to 6.10 pmol/L in term healthy controls (p <0.0001). Similarly, the median amylin level at postnatal day 5 in term IMDM was also significantly increased at 25.20 pmol/L compared to 5.65 pmol/L in term healthy controls (p < 0.0001) ( REF _Ref323263963 \h \* MERGEFORMAT Figure 44).Table SEQ Table \* ARABIC 17. Demographic characteristics and serum amylin levels of term healthy controls and term IMDM at birth and postnatal day 5Term Controls BirthTerm IMDMBirthTerm Controls Postnatal Day 5Term IMDMPostnatal Day 5p valuen13817145Amylin (pmol/L)6.10(3.30-9.70)*34.30(28.35-50.00)5.65(3.10-8.20)**25.20(22.20-48.75)*p<0.00**p<0.00Gestation (wks)39.00(38.00-40.00)39(37.75-40.00)38.5(38.00-41.00)37.0(37-38.25)NSWeight(kg)3.28(2.98-3.67)3.74(3.41-4.07)3.40(3.12-3.58)3.53(3.21-4.43)NSGenderMale71872Female67973NS-not significantMedian and interquartile range, Mann Whitney U test Figure SEQ Figure \* ARABIC 44. Comparison box-and-whisker plot of amylin levels at birth and postnatal day 5 between term IMDM and healthy term infants (controls)Mann-Whitney test for independent samples was significant, cord group p<0.0001 and Guthrie group p <0.001.The null hypothesis was therefore rejected. Thus amylin levels are significantly raised in term IMDM both at birth and postnatal day 5 when compared to term healthy control infants.There was no difference in the demographic characteristics at birth (umbilical cord) and postnatal day 5 (Guthrie) in preterm IMDM and preterm healthy controls ( REF _Ref323264020 \h \* MERGEFORMAT Table 18). However, the median amylin level at birth in preterm IMDM was significantly increased at 32.00 pmol/L compared to 4.60 pmol/L in preterm healthy controls (p<0.0001). Similarly, the median amylin level at postnatal day 5 in preterm IMDM was also significantly increased at 23.40 pmol/L compared to 6.90 pmol/L in preterm healthy controls (p <0.0001) ( REF _Ref323264064 \h \* MERGEFORMAT Figure 45).Table SEQ Table \* ARABIC 18. Demographic characteristics and serum amylin levels of preterm healthy controls and preterm IMDM at birth and postnatal day 5Preterm ControlsBirthPreterm IMDMBirthPreterm ControlsPostnatal Day 5Preterm IMDMPostnatal Day 5p valuen4314259Amylin (pmol/L)4.60(1.90-8.30)*32.00(18.65-44.27)6.90(2.75-9.50)**23.40 (15.37-46.57)*p<0.00**p<0.00Gestation (wks)34(30.5 - 35.0)34(33-35.25)33(30.0 - 35.0)34(38-40)NSWeight(kg)2.05(1.53-2.39)2.88(1.97-3.35)1.72(1.50 - 2.29)2.61(1.96-3.92)NSGenderNSMale259135Female185124NS-not significantMedian and interquartile range, Mann Whitney U testFigure SEQ Figure \* ARABIC 45. Comparison box-and-whisker plot of amylin levels at birth and postnatal day 5 between preterm IMDM and healthy preterm infants (controls)Mann-Whitney test for independent samples was significant, cord group p <0.0001 and Guthrie group p<0.0001.The null hypothesis was therefore rejected. Thus serum amylin levels are significantly raised in preterm IMDM both at birth and postnatal day 5 when compared to healthy preterm infants (controls).Paired amylin and insulin levels were analysed from 3 IMDM preterm and 3 IMDM term infants from umbilical cord blood samples. The median insulin level was 10.5 (8.0-16.5) mu/L. Increased positive correlation was observed when this data were combined with paired amylin and insulin levels from healthy preterm and term infants (n=39, Spearman’s rho= 0.56, 95% CI=0.29-0.74, p<0.0001) ( REF _Ref323264147 \h \* MERGEFORMAT Figure 46). Figure SEQ Figure \* ARABIC 46. The correlation graph showing line of best fit to assess the degree of association between umbilical cord insulin (x axis) and umbilical cord amylin (Y axis) from paired umbilical cord blood samples of healthy and IMDM preterm and term infantsSince the distribution of cord venous amylin levels were non-normal, data were ranked in order of size, and calculations were based on the ranks of corresponding values X and Y to provide Spearman correlation coefficient rho with p-value, and a 95% CI for rho, (n=39, Spearman’s rho= 0.56, 95% CI=0.29-0.74, p<0.0001).Thus the median insulin level in preterm and term IMDM was twice (n=6, 10.5 (8.0-16.5) mu/L) the level observed in healthy preterm and term infants (n=33, 5.0 (3.00-8.25) mu/L) and its correlation with amylin levels confirms an association and possibly co-secretion. DiscussionThis single centre prospective observational study was the first to determine plasma amylin concentrations in term and preterm IMDM at birth and fifth postnatal day. An alternative to observational methodology would have been case-control study, IMDM with feed intolerance (cases) compared to IMDM without feed intolerance (controls). Case-control study incorporating objective assessment of gastric emptying in the study methodology may have added validity to the study results. However not all infants with feed intolerance were admitted to the neonatal unit or necessitated introduction of oro/nasogastric tube, a prerequisite to identify infants with feed intolerance. Furthermore, the issues of funding, technical expertise and ethical concerns of performing gastric emptying tests in neonatal setup were considered as major limiting factors. Interestingly, 4/5 term infants who required admission to the neonatal unit for monitoring of blood sugars were also found to have feed intolerance with increased prefeed gastric residual volumes and frequent vomiting. 8/9 preterm infants were also experiencing feed intolerance at the time of Guthrie blood collection. Due to small number of the admitted infants who were also experiencing feed intolerance we could not draw meaningful relationship of amylin levels to the degree of feed intolerance or resolution of symptoms of feed intolerance. In addition we could not identify any obvious differences in the characteristics of IMDM who experienced feed intolerance with those who did not. It is possible that minor but important differences in relation to the degree of feed tolerance and amylin levels were missed as we did not set out to study objective measures of feed intolerance. Further studies are warranted to shed more light on this topic.In this study serum amylin levels obtained from cord and Guthrie blood were significantly raised in infants born to mothers whose pregnancy was complicated by diabetes and these levels were comparable to those reported in critically ill children with feed intolerance ADDIN EN.CITE <EndNote><Cite><Author>Mayer</Author><Year>2002</Year><RecNum>206</RecNum><record><rec-number>206</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">206</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mayer, A. P.</author><author>Durward, A.</author><author>Turner, C.</author><author>Skellett, S.</author><author>Dalton, N.</author><author>Tibby, S. M.</author><author>Murdoch, I. A.</author></authors></contributors><auth-address>Department of Paediatric Intensive Care, Guy's Hospital, Saint Thomas Street, London, SE1 9RT, UK. amayer@.uk</auth-address><titles><title>Amylin is associated with delayed gastric emptying in critically ill children</title><secondary-title>Intensive Care Med</secondary-title></titles><pages>336-40</pages><volume>28</volume><number>3</number><edition>2002/03/21</edition><keywords><keyword>Acetaminophen/pharmacokinetics</keyword><keyword>Adolescent</keyword><keyword>Amyloid/blood/*pharmacology</keyword><keyword>Analgesics, Non-Narcotic/pharmacokinetics</keyword><keyword>Anti-Ulcer Agents/blood/*pharmacology</keyword><keyword>Area Under Curve</keyword><keyword>Blood Glucose/drug effects</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Gastric Emptying/*drug effects</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Insulin/blood</keyword><keyword>Intensive Care Units, Pediatric</keyword><keyword>Intestinal Absorption</keyword><keyword>Metabolic Clearance Rate</keyword><keyword>Prospective Studies</keyword></keywords><dates><year>2002</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0342-4642 (Print)</isbn><accession-num>11904665</accession-num><urls><related-urls><url>;(Mayer, Durward et al. 2002). We suggest that these high serum amylin levels observed in IMDM may be partially responsible for the feed intolerance seen in this population. This is in keeping with the physiological action of amylin, as it is 15–20 times more potent than other known inhibitors of gastric motility ADDIN EN.CITE <EndNote><Cite><Author>Young</Author><Year>1997</Year><RecNum>158</RecNum><record><rec-number>158</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">158</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Young, A.</author></authors></contributors><auth-address>Amylin Pharmaceuticals, Inc., San Diego, CA 92121, USA.</auth-address><titles><title>Role of amylin in nutrient intake - animal studies</title><secondary-title>Diabet Med</secondary-title></titles><periodical><full-title>Diabet Med</full-title></periodical><pages>S14-8</pages><volume>14 Suppl 2</volume><edition>1997/06/01</edition><keywords><keyword>Amyloid/pharmacology/*physiology/therapeutic use</keyword><keyword>Animal Nutritional Physiological Phenomena</keyword><keyword>Animals</keyword><keyword>Diabetes Mellitus/drug therapy</keyword><keyword>Disease Models, Animal</keyword><keyword>Eating/drug effects</keyword><keyword>Gastric Emptying/drug effects</keyword><keyword>Glucagon/metabolism</keyword><keyword>Humans</keyword><keyword>Hypoglycemic Agents/pharmacology/therapeutic use</keyword><keyword>Receptors, Peptide/antagonists & inhibitors</keyword></keywords><dates><year>1997</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0742-3071 (Print)</isbn><accession-num>9212324</accession-num><urls><related-urls><url>(SICI)1096-9136(199706)14:2+<S14::AID-DIA398>3.0.CO;2-Q</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Young 1997). There are a number of possible explanations for such high levels observed in IMDM. Amylin is deficient in type 1 diabetes mellitus and is present in excess in conditions in which insulin is hyper-secreted ADDIN EN.CITE <EndNote><Cite><Author>Rink</Author><Year>1993</Year><RecNum>47</RecNum><record><rec-number>47</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">47</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rink, T. J.</author><author>Beaumont, K.</author><author>Koda, J.</author><author>Young, A.</author></authors></contributors><auth-address>Amylin Pharmaceuticals Inc., San Diego, CA 92121.</auth-address><titles><title>Structure and biology of amylin</title><secondary-title>Trends Pharmacol Sci</secondary-title></titles><pages>113-8</pages><volume>14</volume><number>4</number><edition>1993/04/01</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>*Amyloid/chemistry/deficiency</keyword><keyword>Animals</keyword><keyword>Diabetes Mellitus, Type 1/genetics</keyword><keyword>Diabetes Mellitus, Type 2/genetics</keyword><keyword>Humans</keyword><keyword>Models, Molecular</keyword><keyword>Molecular Sequence Data</keyword><keyword>Protein Structure, Tertiary</keyword></keywords><dates><year>1993</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0165-6147 (Print)</isbn><accession-num>8516954</accession-num><urls><related-urls><url>;(Rink, Beaumont et al. 1993). It would therefore seem plausible that transient neonatal hyperinsulinaemia in IMDM as a consequence of in-utero hyperglycaemia, may also stimulate hypersecretion of endogenous amylin. This is further supported by evidence of co-secretion of amylin and insulin, shown by the positive correlation between amylin and insulin in study A and Study B (n=39, spearman’s rho= 0.56, 95% CI=0.29-0.74, p<0.0001) and previous studies PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SaW5rPC9BdXRob3I+PFllYXI+MTk5MzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Rink, Beaumont et al. 1993; Mayer, Durward et al. 2002). Moreover, the median insulin level in preterm and term IMDM was twice (n=6, 10.5 (8.0-16.5) mu/L) the level observed in healthy preterm and term infants (n=33, 5.0 (3.00-8.25) mu/L) suggesting possible fetal and neonatal hyperinsulinaemia. Unfortunately we were unable to obtain sufficient sample volumes for analysis of paired amylin and insulin on the fifth postnatal day. It is plausible that the amylin levels observed on postnatal day 5 in preterm and term IMDM in this study may have been influenced by the timing of blood sampling in relation to the infants’ pre-prandial or post-prandial state. This is less likely as the amylin levels were similar between the cord and Guthrie groups in both preterm and term IMDM. We were unable to study diurnal variation of amylin and the influence of feeding due to the limitation of the study protocol to opportunistic blood collection. Although, the median amylin levels on the fifth postnatal day were lower than umbilical cord samples at birth in both preterm and term IMDM, they did not reach statistical significance. This is most likely to be due to small sample size and comparatively lower gestation and birth weight possibly due to a selection bias towards blood collection of inpatient neonates in the Guthrie group. However a more plausible explanation for this gradual decline in Guthrie amylin levels in preterm and term IMDM is possibly explained by declining hyperinsulinaemic environment. This would also coincide with the time course of resolution of the feed intolerance observed in 4 term IMDM infants who were discharged by day 7 established to full feeds. We did not set out to study these infants in more detail and therefore cannot draw any meaningful conclusions about specific factors relevant to the group of infants who displayed feed intolerance. The observed serum amylin levels in preterm and term IMDMs on the fifth postnatal day (23.4 and 25.20 pmol/L) were still above the normal range observed in healthy preterm and term infants (6.90 and 5.65 pmol/L). The high amylin levels in IMDM further support the theory that transplacental passage either does not occur or is minimal as serum amylin levels are subnormal in diabetic patients PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb2RhPC9BdXRob3I+PFllYXI+MTk5MjwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Ludvik, Lell et al. 1991; Sanke, Hanabusa et al. 1991; Koda, Fineman et al. 1992; Akimoto, Nakazato et al. 1993). Thus the observed increased amylin levels in IMDM would seem to represent endogenous amylin production.AC187 is a truncated amylin peptide antagonist that acts by selectively and potently blocking amylin receptors ADDIN EN.CITE <EndNote><Cite><Author>Young</Author><Year>1994</Year><RecNum>164</RecNum><record><rec-number>164</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">164</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Young, A. A.</author><author>Gedulin, B.</author><author>Gaeta, L. S.</author><author>Prickett, K. S.</author><author>Beaumont, K.</author><author>Larson, E.</author><author>Rink, T. J.</author></authors></contributors><auth-address>Amylin Pharmaceuticals Inc, San Diego, CA 92121.</auth-address><titles><title>Selective amylin antagonist suppresses rise in plasma lactate after intravenous glucose in the rat. Evidence for a metabolic role of endogenous amylin</title><secondary-title>FEBS Lett</secondary-title></titles><pages>237-41</pages><volume>343</volume><number>3</number><edition>1994/05/02</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Amyloid/administration & dosage/*antagonists & inhibitors/physiology</keyword><keyword>Animals</keyword><keyword>Blood Glucose/analysis</keyword><keyword>Glucose/administration & dosage/*pharmacology</keyword><keyword>Injections, Intravenous</keyword><keyword>Insulin/blood</keyword><keyword>Lactates/*blood</keyword><keyword>Lactic Acid</keyword><keyword>Male</keyword><keyword>Molecular Sequence Data</keyword><keyword>Peptide Fragments</keyword><keyword>Peptides/*pharmacology</keyword><keyword>Rats</keyword><keyword>Rats, Sprague-Dawley</keyword></keywords><dates><year>1994</year><pub-dates><date>May 2</date></pub-dates></dates><isbn>0014-5793 (Print)</isbn><accession-num>8174707</accession-num><urls><related-urls><url>(94)80563-6 [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Young, Gedulin et al. 1994). The biological actions of amylin in IMDM need to be elucidated prior to evaluation of pharmacological blockade of this peptide as a potential therapeutic option. The strength of the study was strict adherence to study protocol with regards to sample processing and storage. However, a major limitation of the study was selection bias to inpatient IMDM which also contributed to small numbers especially in the Guthrie group. Although it was possible to collect serial blood for amylin levels beyond first week of postnatal life, we did not include this in our methodology fearing refusal by the ethics committee. Inclusion in the study methodology of maternal amylin concentration and serial amylin measurements in preterm and term IMDM may have helped understand the influence of transplacental passage, diurnal variations, possible influence of feeds and decay time of amylin. Moreover, this study did not attempt to correlate amylin levels with objective measures of gastric emptying and feed intolerance or its resolution. This is an important limitation of the study and may be considered in the design of future studies. In conclusion, we have presented evidence in support of our hypothesis that amylin levels are raised in preterm and term IMDM which may contribute to the observed feed intolerance. ConclusionsThe amylin levels in term and preterm IMDM at birth and postnatal day 5 were significantly higher than levels observed in healthy preterm and term controls. Amylin by virtue of its potent inhibition of gastric emptying may play a role in the pathogenesis of feed intolerance in this group of infants.The cord insulin levels in preterm and term IMDM were twice the levels observed in the cord blood from healthy preterm and term infants. These levels correlated positively with amylin levels which suggest an association with insulin secretion. Clinical Study C: Amylin Levels in Preterm infants with Feed Intolerance IntroductionAmylin is a potent inhibitor of gastric emptying and its elevated levels are shown to be associated with delayed gastric emptying in critically ill children with feed intolerance ADDIN EN.CITE <EndNote><Cite><Author>Mayer</Author><Year>2002</Year><RecNum>206</RecNum><record><rec-number>206</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">206</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mayer, A. P.</author><author>Durward, A.</author><author>Turner, C.</author><author>Skellett, S.</author><author>Dalton, N.</author><author>Tibby, S. M.</author><author>Murdoch, I. A.</author></authors></contributors><auth-address>Department of Paediatric Intensive Care, Guy's Hospital, Saint Thomas Street, London, SE1 9RT, UK. amayer@.uk</auth-address><titles><title>Amylin is associated with delayed gastric emptying in critically ill children</title><secondary-title>Intensive Care Med</secondary-title></titles><pages>336-40</pages><volume>28</volume><number>3</number><edition>2002/03/21</edition><keywords><keyword>Acetaminophen/pharmacokinetics</keyword><keyword>Adolescent</keyword><keyword>Amyloid/blood/*pharmacology</keyword><keyword>Analgesics, Non-Narcotic/pharmacokinetics</keyword><keyword>Anti-Ulcer Agents/blood/*pharmacology</keyword><keyword>Area Under Curve</keyword><keyword>Blood Glucose/drug effects</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Gastric Emptying/*drug effects</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Insulin/blood</keyword><keyword>Intensive Care Units, Pediatric</keyword><keyword>Intestinal Absorption</keyword><keyword>Metabolic Clearance Rate</keyword><keyword>Prospective Studies</keyword></keywords><dates><year>2002</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0342-4642 (Print)</isbn><accession-num>11904665</accession-num><urls><related-urls><url>;(Mayer, Durward et al. 2002). We hypothesized that preterm neonates with feed intolerance evidenced by increased prefeed GRV (surrogate marker for delayed gastric emptying) may have high plasma amylin concentrations. The main objective of this study was to determine serum amylin concentrations in preterm neonates with and without feed intolerance. MethodologyStudy Design & SettingThis two-centre case-control study was conducted at the University Hospitals of Sheffield NHS Trust and Doncaster General Hospital neonatal departments, over a one year period. Analyses of the blood samples were conducted in the Academic Unit of Reproductive and Developmental medicine located at Jessop Wing, Royal Hallamshire Hospital. ConsentInfants were recruited once informed consent was obtained from their parents/guardians. Infants whose parents refused consent were excluded from the study. Inclusion CriteriaPreterm infants between 24-36 weeks gestation at birth admitted to the neonatal intensive care unit and requiring gastric tube placement andPreterm infants who were receiving > 30 ml/kg or > 25% of total fluid intake as enteral feeds through a gastric tube. Exclusion CriteriaDeliveries associated with intrauterine growth retardation, abnormal antenatal Doppler assessment (risk factors for NEC which may influence amylin levels), maternal infection, chorioamnionitis, pre-eclampsia and significant labour complications (maternal inflammatory conditions which may influence amylin levels). Infants born to mothers whose pregnancy were complicated by diabetes mellitus (due to conclusions of Study B). Infants with congenital abnormalities, chromosomal abnormalities (possible bias due to association with feed intolerance), structural gastrointestinal abnormalities, necrotising enterocolitis, and sepsis (possible bias due to association with feed intolerance and in addition may influence amylin levels).Infants requiring administration of prokinetic agents including erythromycin. Exclusive breast feeding infants in who prefeed gastric residual volume cannot be determined.Haemoglobin less than 7 g/dl (due avoid further blood loss). Rationale for study exclusion criteria: Amylin is raised in IMDM as shown in study B, acute inflammatory conditions, maternal and neonatal sepsis, and in rat intestinal ischaemic injury (possible role in necrotising enterocolitis). 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ADDIN EN.CITE.DATA (Joyce, Fiscus et al. 1990; Clementi, Caruso et al. 1995; Parida, Schneider et al. 1998; Hall and Brain 1999; Onuoha and Alpar 1999; Phillips, Abu-Zidan et al. 2001; Kairamkonda, Deorukhkar et al. 2005). This data from animal and human studies of conditions which may influence amylin concentrations informed the study exclusion criteria. Study ProcedureThe feeding regime of the neonates was dictated by the local guideline. Expressed breast milk (EBM) was encouraged, and formula feed was used if breast milk was not available. The neonates were fed every hour and the volumes increased as clinically tolerated but not more than 20mls/kg birth weight/day. Every four hours pre-feed GRV were recorded as a percentage of the previous feed volume. Abdominal girth, colour of gastric residuals and emesis were also noted. If this GRV was greater than 50% on two consecutive occasions, neonates were classified as feed-intolerant (nTOL). The further management of these neonates was up to the attending neonatologist. Researcher or responsible consultant identified preterm infants who were receiving > 30 ml/kg or > 25% of total fluid intake as enteral feeds through a gastric tube. Parents were approached for consent and information leaflets provided. In neonates with feed intolerance (nTOL), 0.5-1 ml blood was collected from capillary, vein, or indwelling arterial catheters as deemed necessary for routine collection; within 2 hours of the second big (> 50%) prefeed GRV. Feed-tolerant (TOL) neonates served as controls. The researchers identified TOL infants matched for gestational age and birth weight and wherever possible postnatal age with nTOL infants. 0.5-1 ml blood was collected from these neonates at the time of next routine collection. All blood handling was performed as per guidance for the minimization of infection risk to both participants and investigators.Definition of feed intoleranceInfants whose Gastric Residual Volume (GRV) was greater than 50% on two consecutive occasions were identified as feed-intolerant (nTOL). We chose this definition of feed intolerance partly due to personal and published observation by Mayer et al ADDIN EN.CITE <EndNote><Cite><Author>Mayer</Author><Year>2002</Year><RecNum>206</RecNum><record><rec-number>206</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">206</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mayer, A. P.</author><author>Durward, A.</author><author>Turner, C.</author><author>Skellett, S.</author><author>Dalton, N.</author><author>Tibby, S. M.</author><author>Murdoch, I. A.</author></authors></contributors><auth-address>Department of Paediatric Intensive Care, Guy's Hospital, Saint Thomas Street, London, SE1 9RT, UK. amayer@.uk</auth-address><titles><title>Amylin is associated with delayed gastric emptying in critically ill children</title><secondary-title>Intensive Care Med</secondary-title></titles><pages>336-40</pages><volume>28</volume><number>3</number><edition>2002/03/21</edition><keywords><keyword>Acetaminophen/pharmacokinetics</keyword><keyword>Adolescent</keyword><keyword>Amyloid/blood/*pharmacology</keyword><keyword>Analgesics, Non-Narcotic/pharmacokinetics</keyword><keyword>Anti-Ulcer Agents/blood/*pharmacology</keyword><keyword>Area Under Curve</keyword><keyword>Blood Glucose/drug effects</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Gastric Emptying/*drug effects</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Insulin/blood</keyword><keyword>Intensive Care Units, Pediatric</keyword><keyword>Intestinal Absorption</keyword><keyword>Metabolic Clearance Rate</keyword><keyword>Prospective Studies</keyword></keywords><dates><year>2002</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0342-4642 (Print)</isbn><accession-num>11904665</accession-num><urls><related-urls><url>;(Mayer, Durward et al. 2002) who defined critically ill children as feed-intolerant on the basis of GRV greater than 125% 4 hour after a feed challenge which correlated with three objective measures of gastric emptying. In addition, based on the assumption that stomach empty’s every 2 hours, we concluded that in infants in our study who were fed every hour, GRV of more than 50% on 2 consecutive occasions would improve the sensitivity of the definition. This definition was different from previously reported in that the target GRV had to be proved on 2 consecutive occasions which we felt would improve the accuracy and sensitivity to the definition. It was also acknowledged that the proportion of feed that may be aspirated is strongly influenced by the size of the feed and hence the inclusion criteria was limited to those preterm infants who were receiving > 30 ml/kg or > 25% of total fluid intake as enteral feeds. Thus the minimal feed volume at any given time was more than 2mls even in the smallest infant. Definition of feed toleranceInfants with minimal (prefeed GRV <50%) or no GRV for > 24 hours were identified as feed tolerant (TOL). Study End PointThe infants were no longer followed up after collection of bloods. Sample Collection & StorageA 0.5 to 1 ml whole blood was drawn into ice-cooled EDTA tube containing 500 IU of aprotinin. The separation of plasma and storage was performed as explained in Study A, section REF _Ref323264902 \r \h 8.2.7 on page PAGEREF _Ref323264925 \h 83. Sample AnalysisAll samples were analysed as described previously in section REF _Ref323264976 \r \h 8.2.8 on page PAGEREF _Ref323264981 \h 83.Sample SizeTo detect a minimum difference of 15 pmol/L between the feed tolerant (TOL) and intolerant (nTOL) groups, with a power of 90%, assuming a standard deviation of 13, a total number of 20 neonates per group had to be recruited for significance levels of 5% (a=0.05). The mean and standard deviation for the sample size calculation was based on data from previous studies in neonates and children PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYWlyYW1rb25kYTwvQXV0aG9yPjxZZWFyPjIwMDU8L1ll
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ADDIN EN.CITE.DATA (Mayer, Durward et al. 2002; Kairamkonda, Deorukhkar et al. 2005)Statistical AnalysisStatistical analysis was performed using Medcalc version 11.4.4.0. 1993-2010. Individual group data were assessed for normal distribution by applying coefficient of Skewness and Kurtosis and D’Agostino-Pearson test. The coefficient of Skewness and Kurtosis is a measure for the degree of symmetry and peakedness/flatness respectively in the variable distribution. The D'Agostino-Pearson test ADDIN EN.CITE <EndNote><Cite><Author>Sheskin</Author><Year>2003</Year><RecNum>468</RecNum><record><rec-number>468</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">468</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Sheskin, D J</author></authors></contributors><titles><title>Handbook of parametric and nonparametric statistical procedures</title></titles><edition>3rd</edition><section>1231</section><dates><year>2003</year></dates><publisher>Boca Raton: Chapman & Hall /CRC</publisher><urls></urls></record></Cite></EndNote>(Sheskin 2003) computes a single p-value for the combination of the coefficients of Skewness and Kurtosis. The tests for normal distribution were accepted when the p value was > 0.05. Normal data were analysed for group differences with chi-square or Fisher’s exact tests for the categorical variables and with t-tests for the continuous variables. Median and interquartile range (25th–75th centile) and non-parametric tests such as Wilcoxon rank sum test & Mann-Whitney U test were employed where data were non-normal. Pearson’s correlation coefficient (r) or Spearman’s rank test (rho) was used to assess correlation between variables with parametric and non-parametric distribution respectively. A p value of less than 0.05 was considered significant. Data Collection & Case Report FormThe Case report form ( REF _Ref323265048 \h \* MERGEFORMAT Appendix 16) of infants recruited into the study consisted of demography, clinical details, and time of blood sampling. Maternal details and clinical history were also entered on a CRF. Study Summary REF _Ref323265086 \h \* MERGEFORMAT Table 19 & REF _Ref323265099 \h \* MERGEFORMAT Figure 47 below highlight the key features of the study methodology and Gantt chart respectively.Table SEQ Table \* ARABIC 19. Study C summaryTitleAmylin levels in preterm infants with feed intoleranceStudy MethodologyCase-Control StudyStudy Duration12 monthsStudy CentresTwo Centre ObjectivesTo determine plasma amylin levels in preterm infants with feed intoleranceNumber of Participants20 nTOL and 20 TOLMain Inclusion CriteriaPreterm infants (24-36 weeks) admitted to the neonatal intensive care unit and requiring gastric tube feeding Statistical MethodologyMedian and interquartile ranges and non-parametric tests. Correlation Coefficient will be performed to evaluate the relationship between variablesOutcome variablePlasma amylin levelsMeasurement AssayELISAFigure SEQ Figure \* ARABIC 47. Study C Gantt chart Results REF _Ref323265191 \h \* MERGEFORMAT Figure 48 below shows study participant flow and timing of blood collection. 70 preterm infants were eligible for the study once they met the selection criteria. Blood was collected from 34 feed intolerant (nTOL) and 36 feed tolerant (TOL) infants. 4 blood samples in the nTOL and 6 in the TOL group were heavily hemolysed and therefore discarded. Thirty blood samples in each group were available for further analysis. Enteral feeds >30ml/kg or>25% of total fluid intakeConsent obtained from parents of preterm neonates (24-36 weeks) with gastric tube placementn=70None or <50% prefeed GRV Study entry and consent Feed-tolerant (TOL)(n=30)Feed-intolerant (nTOL)(n=30)n=4 excluded Blood samples haemolysed & therefore unsuitable for analysisn=6 excluded Blood samples haemolysed & therefore unsuitable for analysisFeed-intolerant (nTOL)(n=34)Feed-tolerant (TOL)(n=36)>50% prefeed GRV on two consecutive occasionsStudy entry and consentEnteral feeds >30ml/kg or>25% of total fluid intakeConsent obtained from parents of preterm neonates (24-36 weeks) with gastric tube placementn=70None or <50% prefeed GRV Study entry and consent Feed-tolerant (TOL)(n=30)Feed-intolerant (nTOL)(n=30)n=4 excluded Blood samples haemolysed & therefore unsuitable for analysisn=6 excluded Blood samples haemolysed & therefore unsuitable for analysisFeed-intolerant (nTOL)(n=34)Feed-tolerant (TOL)(n=36)>50% prefeed GRV on two consecutive occasionsStudy entry and consentFigure SEQ Figure \* ARABIC 48. Study C-Flow diagram of participants and blood samplesThe null hypothesis of the study was that serum amylin levels in preterm infants with feed intolerance were no different to preterm infants without feed intolerance. There was no significant difference between the nTOL and TOL group with regards to baseline characteristics such as gestation, birth weight, gender, postnatal age, ventilation days, CPAP days, type of feed, blood glucose, white cell count and CRP (Table 20). Table SEQ Table \* ARABIC 20. Baseline characteristics at the time of blood sampling of preterm neonates defined as feed-intolerant (nTOL) and feed-tolerant (TOL)nTOL (n=34)TOL (n=36)p valuen3436Gestation (wks)29.5 (28-31)30.0 (29-33)0.33Birth weight (kg)1.30 (1.00-1.80)1.30 (1.10-1.80)0.62GenderMale (n)23240.64Female (n)11120.62Postnatal age (days)7.5 (4-10)9.5 (5-12)0.16Ventilation (days)1 (0-4)<1 (0-3)0.21CPAP (days)3 (0-4)2 (0-5)0.41Feed typeEBM (n)22240.12Formula (n)770.26Mixed (n)550.18Blood glucose (mmol/l)4.2 (3.5-4.9)3.9 (3.1-5.0)0.23White cell count (109/l)9.0 (7.5-10.4)8.3 (6.3-10.4)0.08C reactive protein (mg/l)6 (6-10)6 (6-10)0.51Data are presented as median (interquartile range)Amylin concentration, % GRV and time to full enteral feeds were significantly raised in nTOL compared to TOL group. However, there was no difference in length of hospital stay between nTOL and TOL group ( REF _Ref323265279 \h \* MERGEFORMAT Table 21).Table SEQ Table \* ARABIC 21. Serum amylin levels, % GRV, days to reach full feeds and length of stay in feed-intolerant (nTOL) and feed-tolerant (TOL) neonatesnTOL TOL P valuen3030Amylin (pmol/L)47.9 (21.4-79.8)8.7 (5.7-16)<0.00GRV (%)150 (100-350)5 (0-5)<0.00Time to full feeds (days)13.0 (10.0-16.0)6.5 (4.0-9.0)<0.00Length of hospital stay (days)52.5 (21-69)37 (20-50)0.08Data are presented as median [interquartile range]GRV (%)-percentage gastric residual volume prior to next scheduled feed measured prior to amylin samplingIn particular, median amylin level was significantly raised in nTOL group at 47.9 pmol/L compared to 8.7 pmol/L in TOL group. The null hypothesis was therefore rejected. Thus amylin levels in preterm infants with feed intolerance are significantly raised compared to preterm infants without feed intolerance. REF _Ref323265406 \h \* MERGEFORMAT Figure 49, REF _Ref323265408 \h \* MERGEFORMAT Figure 50 & REF _Ref323265410 \h \* MERGEFORMAT Figure 51 show box and whisker plots of plasma amylin, % GRV and time to reach full enteral feeds in nTOL and TOL group.Figure SEQ Figure \* ARABIC 49. Box and whisker plot of amylin levels (y-axis) in feed-intolerant (nTOL) and feed-tolerant (TOL) neonates (x-axis)D’Agostino-Pearson test for normal distribution for amylin levels was accepted for nTOL (p=0.21) and rejected for TOL (p<0.0001) group. The central box represents 25th to 75th percentile, middle line represents the median, and the vertical line, range, excluding "far out" values (red circles). Median amylin level was significantly raised in nTOL compared to TOL group (47.9 vs 8.7) (Mann-Whitney test for independent samples was significant, p value <0.0001).The details of the 2 outliers in the TOL group are as follows. The male infant with amylin level 76.1 pmol/L was born at 29+5 weeks gestation with birth weight 1.44 kg to a 33 year mother without any medical problems. He was fed expressed breast milk and was on caffeine at the time of blood collection on day 12. The male infant with amylin level 67.7 pmol/L was born at 29 weeks gestation with birth weight 1.14 kg to a 26 year mother who presented to labour ward with premature rupture of membranes for > 12 hours and abnormal cardiotocograph. The infant had initial features of hypoxic ischaemic encephalopathy which settled in three days. He was also treated for coagulase negative staphylococcal infection and abdominal distension with feed intolerance until day 12. He was fed nutriprem milk with occasional vomiting and was on caffeine at the time of blood collection on day 28.Figure SEQ Figure \* ARABIC 50. Box and whisker plot of percentage GRV (y axis) in feed-intolerant (nTOL) and feed-tolerant (TOL) neonates (x axis)D’Agostino-Pearson test for normal distribution was accepted for nTOL (p=0.105) and rejected for TOL (p<0.0001). The central box represents 25th to 75th percentile, middle line represents the median, and the vertical line represents range, excluding "outside" (black circles) and "far out" (red circles) values which are displayed as separate points. %GRV was significantly raised in nTOL compared to TOL (150% vs 5%) (Mann-Whitney test for independent samples was significant, p value <0.0001).Figure SEQ Figure \* ARABIC 51. The box and whisker plot of days to reach full feeds (Y axis) in feed-intolerant (nTOL) and feed-tolerant (TOL) neonates (X axis)D’Agostino-Pearson test for normal distribution was rejected for nTOL and TOL (p<0.001). The central box represents 25th to 75th percentile, middle line represents the median, and the vertical line represents range, excluding "outside" (black circles) and "far out" (red circles) values which are displayed as separate points. Days to reach full enteral feeds was significantly increased in nTOL compared to TOL group (13 days vs 5.5 days) (Mann-Whitney test for independent samples was significant, p value <0.0001).In the nTOL group, plasma amylin levels correlated with percentage gastric residual volumes ( REF _Ref323265567 \h \* MERGEFORMAT Figure 52), days to reach full enteral feed volume of 150 ml/kg/day ( REF _Ref323265583 \h \* MERGEFORMAT Figure 53) and days to discharge ( REF _Ref323265729 \h \* MERGEFORMAT Figure 54). Figure SEQ Figure \* ARABIC 52. Correlation graph showing line of best fit to assess the degree of association between amylin concentration (y axis) and % GRV (x axis) in feed-intolerant (nTOL) groupD’ Agostino-Pearson test for normal distribution was accepted for both % GRV (p=0.10) and amylin levels (p=0.21). n=30, Pearson correlation coefficient, r=0.78, p<0.0001, 95%CI 0.59-0.89. Figure SEQ Figure \* ARABIC 53. The correlation graph showing line of best fit to assess the degree of association between amylin concentration (y axis) and days to reach full enteral feeds (x axis) in nTOL groupD’ Agostino-Pearson test for normal distribution was rejected for days to reach full enteral feeds (p=0.001) and accepted for amylin levels (0.21). n=30, Spearmans coefficient of rank correlation rho=0.56, p=0.001, 95% CI 0.26-0.77.Figure SEQ Figure \* ARABIC 54. The correlation graph showing line of best fit to assess the degree of association between days to discharge (x axis) and amylin concentration (Y axis) in the feed-intolerant (nTOL) groupD’ Agostino-Pearson test for normal distribution was accepted for days to discharge (p=0.49) and amylin levels (0.21). n=30, Pearson’s correlation coefficient r=0.43, p=0.015, 95%CI 0.092-0.68. In the TOL group, plasma amylin levels did not correlate with percentage gastric residual volumes ( REF _Ref323265796 \h \* MERGEFORMAT Figure 55), days to reach full enteral feed volume of 150 ml/kg/day ( REF _Ref323265806 \h \* MERGEFORMAT Figure 56), and days to discharge ( REF _Ref323265817 \h \* MERGEFORMAT Figure 57).Figure SEQ Figure \* ARABIC 55. The correlation graph showing line of best fit to assess the degree of association between % GRV (x axis) and amylin levels (y axis) in feed-tolerant (TOL) groupD’Agostino-Pearson test for normal distribution was rejected for % GRV and amylin (p<0.001). n=30, Spearman’s coefficient of rank correlation rho=0.33, p=0.068, CI -0.025-0.622. Figure SEQ Figure \* ARABIC 56. The correlation graph showing line of best fit to assess the degree of association between days to full enteral feeds (x axis) and amylin levels (Y axis) in feed-tolerant (TOL) groupD’Agostino-Pearson test for normal distribution was rejected for days to reach full enteral feeds and amylin (p<0.001). n=30, Spearman’s coefficient of rank correlation rho=-0.003, p=0.98, CI -0.363-0.357.Figure SEQ Figure \* ARABIC 57. The correlation graph showing line of best fit to assess the degree of association between days to discharge (x axis) and amylin levels (Y axis) in the feed-tolerant (TOL) groupD’Agostino-Pearson test for normal distribution was accepted for days to discharge (p=0.11) and rejected for amylin (p<0.001). n=30, Spearman’s coefficient of rank correlation rho=-0.33, p=0.07, -0.61-0.03.In conclusion the study results confirm the hypothesis that plasma amylin levels are raised in preterm infants with feed intolerance. DiscussionUp to 67% preterm very low birth infants struggle to attain full enteral nutrition in the first few weeks of life ADDIN EN.CITE (Reddy, Deorari et al. 2000; ElHennawy, Sparks et al. 2003; Patole, Rao et al. 2005; Hay 2008). Feed intolerance is the common cause of this problem and is characterised by large gastric residual volumes (GRV) with or without associated clinical manifestations PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXRvbGU8L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Jadcherla and Kliegman 2002; Mihatsch, von Schoenaich et al. 2002; Patole 2005). Reliance on total parenteral nutrition during this period is usually not enough to maintain protein and lipid intake PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hcm92ZXI8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Donnell, Taylor et al. 2002; Kaufman, Gondolesi et al. 2003). Notably these infants may lag behind in protein and calorie intake by up to 6-8 weeks by the time they are ready to go home PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hcm92ZXI8L0F1dGhvcj48WWVhcj4yMDA4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA (Grover, Khashu et al. 2008) which may have adverse effects on their postnatal growth and neurodevelopment PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db29rZTwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Frank and Sosenko 1988; Hack, Breslau et al. 1991; Ehrenkranz, Younes et al. 1999; Hack, Schluchter et al. 2003; Cooke, Ainsworth et al. 2004; Hay 2008). Delayed gastric emptying, intestinal immaturity, ileus of prematurity, and gastro-esophageal reflux may all play a role. It is not clear whether one or all of these mechanisms contribute to the observed feed intolerance. This is the first study to evaluate the role of amylin as an inhibitor of gastric motility in feed intolerance in the neonatal intensive care setting. The results of this study support the hypothesis that plasma amylin levels are increased in neonates with delayed gastric emptying compared to controls and these levels correlate with increasing GRV. We propose that although poor gastric motility in premature neonates is probably multifactorial in origin, amylin may play a role in its pathophysiology. The amylin levels in nTOL were approximately 3.5 times that of TOL controls. These levels were comparable to those reported in critically ill children with feed intolerance ADDIN EN.CITE <EndNote><Cite><Author>Mayer</Author><Year>2002</Year><RecNum>206</RecNum><record><rec-number>206</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">206</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mayer, A. P.</author><author>Durward, A.</author><author>Turner, C.</author><author>Skellett, S.</author><author>Dalton, N.</author><author>Tibby, S. M.</author><author>Murdoch, I. A.</author></authors></contributors><auth-address>Department of Paediatric Intensive Care, Guy's Hospital, Saint Thomas Street, London, SE1 9RT, UK. amayer@.uk</auth-address><titles><title>Amylin is associated with delayed gastric emptying in critically ill children</title><secondary-title>Intensive Care Med</secondary-title></titles><pages>336-40</pages><volume>28</volume><number>3</number><edition>2002/03/21</edition><keywords><keyword>Acetaminophen/pharmacokinetics</keyword><keyword>Adolescent</keyword><keyword>Amyloid/blood/*pharmacology</keyword><keyword>Analgesics, Non-Narcotic/pharmacokinetics</keyword><keyword>Anti-Ulcer Agents/blood/*pharmacology</keyword><keyword>Area Under Curve</keyword><keyword>Blood Glucose/drug effects</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Gastric Emptying/*drug effects</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Insulin/blood</keyword><keyword>Intensive Care Units, Pediatric</keyword><keyword>Intestinal Absorption</keyword><keyword>Metabolic Clearance Rate</keyword><keyword>Prospective Studies</keyword></keywords><dates><year>2002</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0342-4642 (Print)</isbn><accession-num>11904665</accession-num><urls><related-urls><url>;(Mayer, Durward et al. 2002) and are amongst the highest reported levels in humans. This is in keeping with the physiological action of amylin, as it is 15-20 times more potent than other known inhibitors of gastric motility ADDIN EN.CITE <EndNote><Cite><Author>Young</Author><Year>1997</Year><RecNum>158</RecNum><record><rec-number>158</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">158</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Young, A.</author></authors></contributors><auth-address>Amylin Pharmaceuticals, Inc., San Diego, CA 92121, USA.</auth-address><titles><title>Role of amylin in nutrient intake - animal studies</title><secondary-title>Diabet Med</secondary-title></titles><periodical><full-title>Diabet Med</full-title></periodical><pages>S14-8</pages><volume>14 Suppl 2</volume><edition>1997/06/01</edition><keywords><keyword>Amyloid/pharmacology/*physiology/therapeutic use</keyword><keyword>Animal Nutritional Physiological Phenomena</keyword><keyword>Animals</keyword><keyword>Diabetes Mellitus/drug therapy</keyword><keyword>Disease Models, Animal</keyword><keyword>Eating/drug effects</keyword><keyword>Gastric Emptying/drug effects</keyword><keyword>Glucagon/metabolism</keyword><keyword>Humans</keyword><keyword>Hypoglycemic Agents/pharmacology/therapeutic use</keyword><keyword>Receptors, Peptide/antagonists & inhibitors</keyword></keywords><dates><year>1997</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0742-3071 (Print)</isbn><accession-num>9212324</accession-num><urls><related-urls><url>(SICI)1096-9136(199706)14:2+<S14::AID-DIA398>3.0.CO;2-Q</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Young 1997). The amylin levels in the TOL group (8.7 pmol/L) were comparable to the Guthrie levels in healthy preterm neonates (6.90 pmol/L). Although the median postnatal timing (9.5 days) of amylin sampling was delayed in TOL controls, this difference was not significant compared to nTOL group (7.5 days). The main reason for this delay was because the routine collection of blood in TOL controls was less frequent. However the blood samples from nTOL and TOL were treated in the same way and therefore did not bias the observed results. The proposed mechanism of action of amylin is outlined below in REF _Ref323265934 \h \* MERGEFORMAT Figure 58. It is plausible that amylin may play a similar role on gastric emptying in preterm neonates with feed intolerance. Figure SEQ Figure \* ARABIC 58. Proposed pathway of amylin actionNutrient intake into stomach not only stimulates insulin release but also amylin release which inhibits gastric emptying through brain centres regulating gastric motility. Amylin also inhibits glucagon release and further food intake, thus reducing endogenous glucose production in the postprandial period.The reason for increased amylin levels in nTOL neonates is unclear. We could only speculate the possible reasons for this hyperamylinemia in the nTOL group. As amylin is co-secreted with insulin under normal physiological conditions, an attractive hypothesis is that transient hyperinsulinemia and relative insulin resistance in nTOL infants may stimulate amylin release. This is based on the observation that many extremely preterm infants develop hyperglycemia in the first week of life during continuous glucose infusion due to relative insulin resistance and defective islet beta cell processing of proinsulin ADDIN EN.CITE <EndNote><Cite><Author>Mitanchez-Mokhtari</Author><Year>2004</Year><RecNum>267</RecNum><record><rec-number>267</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">267</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mitanchez-Mokhtari, D.</author><author>Lahlou, N.</author><author>Kieffer, F.</author><author>Magny, J. F.</author><author>Roger, M.</author><author>Voyer, M.</author></authors></contributors><auth-address>Service de Reanimation Pediatrique et Neonatale, Hopital Necker-Enfants Malades, Paris, France. delphine.mitanchez@nck.ap-hop-paris.fr</auth-address><titles><title>Both relative insulin resistance and defective islet beta-cell processing of proinsulin are responsible for transient hyperglycemia in extremely preterm infants</title><secondary-title>Pediatrics</secondary-title></titles><periodical><full-title>Pediatrics</full-title></periodical><pages>537-41</pages><volume>113</volume><number>3 Pt 1</number><edition>2004/03/03</edition><keywords><keyword>Blood Glucose</keyword><keyword>C-Peptide/blood</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Hyperglycemia/*blood/etiology</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature/physiology</keyword><keyword>Infant, Premature, Diseases/*blood/etiology</keyword><keyword>Insulin/administration & dosage/physiology</keyword><keyword>Insulin Resistance/*physiology</keyword><keyword>Islets of Langerhans/physiology</keyword><keyword>Male</keyword><keyword>Proinsulin/blood/*physiology</keyword><keyword>Prospective Studies</keyword></keywords><dates><year>2004</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1098-4275 (Electronic)</isbn><accession-num>14993546</accession-num><urls><related-urls><url>;(Mitanchez-Mokhtari, Lahlou et al. 2004). Furthermore compared with term neonates; proinsulin and C-peptide levels were higher in normoglycemic preterm infants less than 30 weeks (23.2 +/- 0.9 vs 18.9 +/- 2.71 pmol/L and 1.67 +/- 0.3 vs 0.62 +/- 0.12 nmol/L, respectively). In addition, among low birth weight infants, fat mobilization and beta oxidation of fatty acids in the liver is not suppressed by glucose stimulated insulin secretion suggesting decreased insulin sensitivity ADDIN EN.CITE <EndNote><Cite><Author>Hemachandra</Author><Year>1999</Year><RecNum>495</RecNum><record><rec-number>495</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">495</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hemachandra, A.H</author><author>Cowett, R.M</author></authors></contributors><titles><title>Neonatal hyperglycemia</title><secondary-title>Pediatrics in Review</secondary-title></titles><periodical><full-title>Pediatrics in Review</full-title></periodical><pages>e16 -e24</pages><volume>Vol. 20</volume><dates><year>1999</year><pub-dates><date>July</date></pub-dates></dates><work-type>Review</work-type><urls></urls></record></Cite></EndNote>(Hemachandra and Cowett 1999). 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ADDIN EN.CITE.DATA (Hawdon, Aynsley-Green et al. 1993; Mitanchez-Mokhtari, Lahlou et al. 2004). However we could not speculate the reasons for the absence of hyperinsulenemia and insulin resistance in the TOL infants. It is known that large intravenous dextrose loads may promote amylin release ADDIN EN.CITE <EndNote><Cite><Author>Mitsukawa</Author><Year>1990</Year><RecNum>24</RecNum><record><rec-number>24</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">24</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mitsukawa, T.</author><author>Takemura, J.</author><author>Asai, J.</author><author>Nakazato, M.</author><author>Kangawa, K.</author><author>Matsuo, H.</author><author>Matsukura, S.</author></authors></contributors><auth-address>Third Department of Internal Medicine, Miyazaki Medical College, Japan.</auth-address><titles><title>Islet amyloid polypeptide response to glucose, insulin, and somatostatin analogue administration</title><secondary-title>Diabetes</secondary-title></titles><periodical><full-title>Diabetes</full-title></periodical><pages>639-42</pages><volume>39</volume><number>5</number><edition>1990/05/01</edition><keywords><keyword>Administration, Oral</keyword><keyword>Adult</keyword><keyword>Amyloid/*blood/metabolism</keyword><keyword>Drug Synergism</keyword><keyword>Female</keyword><keyword>Glucose/*pharmacology</keyword><keyword>Humans</keyword><keyword>Injections, Intravenous</keyword><keyword>Insulin/*pharmacology</keyword><keyword>Male</keyword><keyword>Octreotide/pharmacology</keyword><keyword>Radioimmunoassay</keyword><keyword>Somatostatin/*analogs & derivatives/pharmacology</keyword></keywords><dates><year>1990</year><pub-dates><date>May</date></pub-dates></dates><isbn>0012-1797 (Print)</isbn><accession-num>1970540</accession-num><urls><related-urls><url>;(Mitsukawa, Takemura et al. 1990); however the study neonate’s received standard glucose maintenance and remained euglycemic. Although the major site of amylin biosynthesis is within pancreatic islet β cells, amylin secretion other than nutrient mediated stimulation cannot be ruled out. In addition, other potential physiological mediators of gastric emptying including GLP-1 and CCK may potentiate the actions of amylin ADDIN EN.CITE <EndNote><Cite><Author>Young</Author><Year>1997</Year><RecNum>158</RecNum><record><rec-number>158</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">158</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Young, A.</author></authors></contributors><auth-address>Amylin Pharmaceuticals, Inc., San Diego, CA 92121, USA.</auth-address><titles><title>Role of amylin in nutrient intake - animal studies</title><secondary-title>Diabet Med</secondary-title></titles><periodical><full-title>Diabet Med</full-title></periodical><pages>S14-8</pages><volume>14 Suppl 2</volume><edition>1997/06/01</edition><keywords><keyword>Amyloid/pharmacology/*physiology/therapeutic use</keyword><keyword>Animal Nutritional Physiological Phenomena</keyword><keyword>Animals</keyword><keyword>Diabetes Mellitus/drug therapy</keyword><keyword>Disease Models, Animal</keyword><keyword>Eating/drug effects</keyword><keyword>Gastric Emptying/drug effects</keyword><keyword>Glucagon/metabolism</keyword><keyword>Humans</keyword><keyword>Hypoglycemic Agents/pharmacology/therapeutic use</keyword><keyword>Receptors, Peptide/antagonists & inhibitors</keyword></keywords><dates><year>1997</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0742-3071 (Print)</isbn><accession-num>9212324</accession-num><urls><related-urls><url>(SICI)1096-9136(199706)14:2+<S14::AID-DIA398>3.0.CO;2-Q</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Young 1997). The effects of possible interaction of amylin with other gut peptides remain to be studied in preterm population. Transplacental passage giving rise to raised amylin levels in nTOL group seems unlikely as discussed previously in section REF _Ref323266079 \r \h \* MERGEFORMAT 2.4 on page PAGEREF _Ref323266089 \h 27.Studies A and B and a previous study ADDIN EN.CITE <EndNote><Cite><Author>Mayer</Author><Year>2002</Year><RecNum>206</RecNum><record><rec-number>206</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">206</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mayer, A. P.</author><author>Durward, A.</author><author>Turner, C.</author><author>Skellett, S.</author><author>Dalton, N.</author><author>Tibby, S. M.</author><author>Murdoch, I. A.</author></authors></contributors><auth-address>Department of Paediatric Intensive Care, Guy's Hospital, Saint Thomas Street, London, SE1 9RT, UK. amayer@.uk</auth-address><titles><title>Amylin is associated with delayed gastric emptying in critically ill children</title><secondary-title>Intensive Care Med</secondary-title></titles><pages>336-40</pages><volume>28</volume><number>3</number><edition>2002/03/21</edition><keywords><keyword>Acetaminophen/pharmacokinetics</keyword><keyword>Adolescent</keyword><keyword>Amyloid/blood/*pharmacology</keyword><keyword>Analgesics, Non-Narcotic/pharmacokinetics</keyword><keyword>Anti-Ulcer Agents/blood/*pharmacology</keyword><keyword>Area Under Curve</keyword><keyword>Blood Glucose/drug effects</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Gastric Emptying/*drug effects</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Insulin/blood</keyword><keyword>Intensive Care Units, Pediatric</keyword><keyword>Intestinal Absorption</keyword><keyword>Metabolic Clearance Rate</keyword><keyword>Prospective Studies</keyword></keywords><dates><year>2002</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0342-4642 (Print)</isbn><accession-num>11904665</accession-num><urls><related-urls><url>;(Mayer, Durward et al. 2002) showed correlation between serum amylin and insulin levels indicating a degree of preservation of pancreatic hormonal co-release. Although ideally we would like to have repeated this in this study we were limited ethically by the blood volume we could take in very low birth weight neonates. Unfortunately we were also unable to measure insulin resistance. It is plausible that the amylin levels observed in nTOL and TOL group in this study may have been influenced by the blood sampling time and relationship to the infants’ prandial state. This is less likely due to the observations highlighted in section heading REF _Ref323270005 \r \h 2.2 and previous study observations as highlighted in section heading REF _Ref323270139 \r \h 8.4 and REF _Ref323270164 \r \h 9.4. Notably twenty-three of thirty nTOL bloods were collected when the infants were nil by mouth and 7/30 before the next scheduled feed (reduced or same volume). Thus the observed amylin levels in nTOL could be considered as baseline and pre-prandial in the nTOL group. We did not observe an association of amylin levels to the timing of blood collection in the TOL group probably due to the short interval between scheduled feeds (1-2 hours). The mean stomach half emptying time in infants fed expressed breast milk was shorter than formula fed infants ADDIN EN.CITE <EndNote><Cite><Author>Ewer</Author><Year>1994</Year><RecNum>269</RecNum><record><rec-number>269</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">269</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ewer, A. K.</author><author>Durbin, G. M.</author><author>Morgan, M. E.</author><author>Booth, I. W.</author></authors></contributors><auth-address>Maternity Hospital, Birmingham.</auth-address><titles><title>Gastric emptying in preterm infants</title><secondary-title>Arch Dis Child Fetal Neonatal Ed</secondary-title></titles><periodical><full-title>Arch Dis Child Fetal Neonatal Ed</full-title></periodical><pages>F24-7</pages><volume>71</volume><number>1</number><edition>1994/07/01</edition><keywords><keyword>Animals</keyword><keyword>Birth Weight</keyword><keyword>Double-Blind Method</keyword><keyword>Female</keyword><keyword>*Gastric Emptying</keyword><keyword>Gestational Age</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature/*physiology</keyword><keyword>Male</keyword><keyword>Milk</keyword><keyword>Milk, Human</keyword><keyword>Time Factors</keyword><keyword>Ultrasonography</keyword></keywords><dates><year>1994</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1359-2998 (Print)</isbn><accession-num>8092865</accession-num><urls><related-urls><url>;(Ewer, Durbin et al. 1994). Additionally, gastric distension (which may be influenced by bolus or continuous milk feeds) may stimulate amylin release and resultant slowing of gastric emptying ADDIN EN.CITE <EndNote><Cite><Author>Reda</Author><Year>2002</Year><RecNum>185</RecNum><record><rec-number>185</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">185</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Reda, T. K.</author><author>Geliebter, A.</author><author>Pi-Sunyer, F. X.</author></authors></contributors><auth-address>New York Obesity Research Center, Department of Medicine, St.-Luke's-Roosevelt Hospital Center, Columbia University-College of Physicians and Surgeons, New York, USA. tarekreda@</auth-address><titles><title>Amylin, food intake, and obesity</title><secondary-title>Obes Res</secondary-title></titles><pages>1087-91</pages><volume>10</volume><number>10</number><edition>2002/10/12</edition><keywords><keyword>Amyloid/chemistry/pharmacology/*physiology</keyword><keyword>Eating/*physiology</keyword><keyword>Female</keyword><keyword>Gastric Emptying/physiology</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Obesity/*metabolism</keyword><keyword>Satiety Response/physiology</keyword></keywords><dates><year>2002</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1071-7323 (Print)</isbn><accession-num>12376591</accession-num><urls><related-urls><url>;(Reda, Geliebter et al. 2002). The types of milk feed were comparable between the groups and the neonates in both the study groups received intermittent bolus feeds. The percentage GRV is influenced by the absolute feed volume and feeding interval. It could be argued that the difference in % GRV simply reflects much smaller absolute feed volume in the nTOL group and therefore the amount of aspirate would be a much greater percentage. We do not think that the absolute feed volumes or intervals influenced % GRV observed between the groups as only 3 infants in the nTOL group had absolute feed volume less than 2 mls/hr. Amylin levels correlated with percentage GRV and time to reach full enteral feeds which were significantly increased in the nTOL group. Although it is conceivable that gestational age or birth weight might have been responsible for this association, a similar observation was not demonstrated in the TOL group. Furthermore both gestational age at birth and birth weight were not statistically different between nTOL and TOL groups. This has clinical significance since increased length of time to reach full enteral feeding is associated with a poorer neurological outcome ADDIN EN.CITE <EndNote><Cite><Author>Patole</Author><Year>2005</Year><RecNum>265</RecNum><record><rec-number>265</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">265</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Patole, S.</author></authors></contributors><auth-address>Department of Neonatal Paediatrics, King Edward Memorial Hospital for Women and University of Western Australia, Perth, Australia. Sanjay.Patole@health..au</auth-address><titles><title>Strategies for prevention of feed intolerance in preterm neonates: a systematic review</title><secondary-title>J Matern Fetal Neonatal Med</secondary-title></titles><pages>67-76</pages><volume>18</volume><number>1</number><edition>2005/08/18</edition><keywords><keyword>Enteral Nutrition/adverse effects/*methods</keyword><keyword>Enterocolitis, Necrotizing/*prevention & control</keyword><keyword>Food Hypersensitivity/*prevention & control</keyword><keyword>Humans</keyword><keyword>Infant Formula</keyword><keyword>Infant Nutritional Physiological Phenomena</keyword><keyword>Infant, Low Birth Weight</keyword><keyword>Infant, Newborn</keyword><keyword>*Infant, Premature</keyword><keyword>Parenteral Nutrition, Total/adverse effects/*methods</keyword></keywords><dates><year>2005</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1476-7058 (Print)</isbn><accession-num>16105795</accession-num><urls><related-urls><url> [pii]
10.1080/14767050500127724</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Patole 2005). Amylin may thus be used as an early marker of delayed enteral nutrition. Although the length of stay was increased in nTOL compared to TOL group, it did not reach statistical significance even after stratification by gestation and birth weight.Studies investigating feed intolerance in preterm population could be facilitated by the availability of a consistently reliable clinical or biochemical marker of feed intolerance. Percentage prefeed GRV to define feed intolerance has been validated in children and adults against more objective measures of gastric emptying including paracetamol absorption test, ultrasonography and scintigraphic techniques PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXllcjwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+PFJl
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ADDIN EN.CITE.DATA (Mayer, Durward et al. 2002; ElHennawy, Sparks et al. 2003; Gomes, Hornoy et al. 2003; Pozler, Neumann et al. 2003). We formulated a pragmatic definition of feed intolerance based on consensus opinion, physiology of gastric emptying in preterm infants and previously published definitions. Our definition of feed intolerance is similar to those used in previous trials PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OZzwvQXV0aG9yPjxZZWFyPjIwMDE8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA (Ng, So et al. 2001; Salhotra and Ramji 2004). Also the plasma amylin levels correlated with % GRV in the nTOL group adding validity to the definition of feed intolerance in this study. Thus more than 50% prefeed GRV may be used as a clinical indicator of delayed gastric emptying. With the prevailing fear of NEC and its association with feed intolerance most caregivers are often persuaded to investigate colour of prefeed GRV, abdominal distension, vomiting, the presence of blood in stool and apnoea and bradycardia. However the clinical significance of each of these criteria to establish feeding strategies and for feeding intolerance has yet to be determined. Most clinicians and nurses determine daily feeding strategy based on greenish aspirates, vomiting or abdominal girth. We also monitored and recorded abdominal girth, colour of the gastric residuals and emesis. Notably green gastric residuals in ELBW infants were not negatively correlated with feeding volume on day 14 ADDIN EN.CITE <EndNote><Cite><Author>Mihatsch</Author><Year>2002</Year><RecNum>50</RecNum><record><rec-number>50</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">50</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mihatsch, W. A.</author><author>von Schoenaich, P.</author><author>Fahnenstich, H.</author><author>Dehne, N.</author><author>Ebbecke, H.</author><author>Plath, C.</author><author>von Stockhausen, H. B.</author><author>Muche, R.</author><author>Franz, A.</author><author>Pohlandt, F.</author></authors></contributors><auth-address>Division of Neonatology and Pediatric Critical Care Medicine, Department of Pediatrics, University of Ulm, Ulm, Germany.</auth-address><titles><title>The significance of gastric residuals in the early enteral feeding advancement of extremely low birth weight infants</title><secondary-title>Pediatrics</secondary-title></titles><periodical><full-title>Pediatrics</full-title></periodical><pages>457-9</pages><volume>109</volume><number>3</number><edition>2002/03/05</edition><keywords><keyword>Algorithms</keyword><keyword>*Enteral Nutrition/methods</keyword><keyword>*Gastrointestinal Contents/chemistry</keyword><keyword>Humans</keyword><keyword>Infant Food/analysis</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Premature</keyword><keyword>*Infant, Very Low Birth Weight</keyword><keyword>Milk, Human</keyword><keyword>Regression Analysis</keyword><keyword>*Stomach</keyword></keywords><dates><year>2002</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1098-4275 (Electronic)</isbn><accession-num>11875141</accession-num><urls><related-urls><url>;(Mihatsch, von Schoenaich et al. 2002). Only seven infants in this study showed vomiting and abdominal distension (more than 2cm) at the time of sample collection (4 nTOL and 3 TOL). Although this is a small sample size, we did not see an association with NEC, a delayed time to achieve full enteral feeds, PDA or amylin levels. Amylin is raised in IMDM, and may be affected by intestinal ischaemic injury and acute inflammatory conditions PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYWlyYW1rb25kYTwvQXV0aG9yPjxZZWFyPjIwMDU8L1ll
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ADDIN EN.CITE.DATA (Joyce, Fiscus et al. 1990; Clementi, Caruso et al. 1995; Parida, Schneider et al. 1998; Hall and Brain 1999; Onuoha and Alpar 1999; Phillips, Abu-Zidan et al. 2001; Kairamkonda, Deorukhkar et al. 2005) influencing our exclusion criteria. The inflammatory markers such as C-reactive protein, white cell count and neutrophil count were comparable between the groups and therefore not attributable to the observed difference in the amylin levels. Amylin was found to be significantly elevated in the ischaemia-reperfusion group that had clamping of the superior mesenteric artery for 60 min followed by 15 min reperfusion (median 39 pM, range 30-44) compared with the Sham operated group that underwent laparotomy and isolation (without clamping) of the superior mesenteric artery (19 pM, range 15-45; Mann-Whitney U, p < 0.05) and the Control group that underwent no surgery (24 pM, range 15-55; p < 0. 01) ADDIN EN.CITE <EndNote><Cite><Author>Phillips</Author><Year>1999</Year><RecNum>493</RecNum><record><rec-number>493</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">493</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Phillips, A. R.</author><author>Abu-Zidan, F. M.</author><author>Bonham, M. J.</author><author>Simovic, M. O.</author><author>Cooper, G. J.</author><author>Windsor, J. A.</author></authors></contributors><auth-address>Pancreatitis Research Group, Department of Surgery, Faculty of Medicine and Health Science, University of Auckland, New Zealand. a.phillis@auckland.ac.nz</auth-address><titles><title>Intestinal ischaemia-reperfusion increases plasma amylin concentration in rats</title><secondary-title>Eur Surg Res</secondary-title></titles><periodical><full-title>Eur Surg Res</full-title></periodical><pages>457-64</pages><volume>31</volume><number>6</number><edition>2000/06/22</edition><keywords><keyword>Amyloid/*blood</keyword><keyword>Animals</keyword><keyword>Intestines/*blood supply/pathology</keyword><keyword>Ischemia/*blood/complications/pathology</keyword><keyword>Islet Amyloid Polypeptide</keyword><keyword>Male</keyword><keyword>Osmolar Concentration</keyword><keyword>Pancreatitis/complications</keyword><keyword>Rats</keyword><keyword>Rats, Wistar</keyword><keyword>Reperfusion Injury/*blood</keyword></keywords><dates><year>1999</year></dates><isbn>0014-312X (Print)
0014-312X (Linking)</isbn><accession-num>10861341</accession-num><urls><related-urls><url> [pii]</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Phillips, Abu-Zidan et al. 1999). The same researchers observed a positive correlation between the histologic score of the intestinal injury and the measured plasma amylin concentration (R = 0.48, P =.007) ADDIN EN.CITE <EndNote><Cite><Author>Phillips</Author><Year>2001</Year><RecNum>261</RecNum><record><rec-number>261</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">261</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Phillips, A. R.</author><author>Abu-Zidan, F. M.</author><author>Farrant, G. J.</author><author>Zwi, J. L.</author><author>Cooper, G. J.</author><author>Windsor, J. A.</author></authors></contributors><auth-address>Pancreatitis Research Group, Department of Surgery, University of Auckland, Auckland, New Zealand.</auth-address><titles><title>Plasma amylin concentration is related to the severity of intestinal ischemic injury in rats</title><secondary-title>Surgery</secondary-title></titles><pages>730-5</pages><volume>129</volume><number>6</number><edition>2001/06/08</edition><keywords><keyword>Amyloid/*blood</keyword><keyword>Animals</keyword><keyword>Blood Pressure</keyword><keyword>Body Temperature</keyword><keyword>Intestines/*blood supply</keyword><keyword>Ischemia/*blood</keyword><keyword>Male</keyword><keyword>Rats</keyword><keyword>Rats, Wistar</keyword><keyword>Reperfusion Injury/*blood</keyword></keywords><dates><year>2001</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0039-6060 (Print)</isbn><accession-num>11391372</accession-num><urls><related-urls><url>(01)07456-6 [pii]
10.1067/msy.2001.113892</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Phillips, Abu-Zidan et al. 2001). Thus amylin is increased in intestinal ischeamia and its levels are related to the degree of intestinal ischaemic injury in rats. However none of the infants in nTOL and TOL groups experienced necrotising enterocolitis or significant abdominal pathology. In addition, amylin levels were not associated with vomiting and abdominal distension (more than 2cm) in 4 nTOL and 3 TOL infants at the time of sample collection. Objective assessment of gastric emptying may have added validity to this study, however with intra-observer variability, safety, ethical issues, and the need for repeated blood sampling in our preterm population render these assessments prohibitive. Serial measurement of amylin levels may have helped to establish the critical amylin level associated with resolution of feed intolerance. However multiple samples could not be taken from this population. A degree of selection bias was unavoidable, as we aimed to include neonates with and without gastric stasis, reflective of our intensive care population. The strengths of the study were the adherence to sample processing and storage protocol and the blood samples were obtained during times when blood was collected for routine clinical monitoring which minimised any extra discomfort to the infant. This study has implications for future research in preterm infants with feed intolerance. In particular, further studies are warranted to establish beyond doubt that amylin is responsible for delayed gastric emptying in preterm neonates. Furthermore, although we established that neonates with feed intolerance have high amylin levels; it is unclear why amylin is increased in these preterm but well neonates. The possible areas of interest are the role of hyperinsulinemia, insulin resistance, amylin receptor insensitivity and other gut peptides. This study may also stimulate future research into the effect of bolus versus continuous feeds on amylin secretion (stretch receptors) and gastric emptying in preterm population. Amylin receptor antagonists are being developed for animal studies. It would be premature to discuss pharmacological blockade of amylin peptide as one of the therapeutic option in feed intolerance until further studies firmly establish the conclusions of this study. In addition considerable caution is warranted as it is not known if amylin by virtue of its association with feed intolerance in preterm infants plays a protective role on the immature gut. In addition there is a possibility of adverse effects due to the blockade of amylin’s other biological functions. ConclusionsAmylin by virtue of its inhibitory action on gastric emptying may play a role in its etiology. The study results confirmed the hypothesis that serum amylin levels are increased in preterm infants with feed intolerance compared to preterm infants without feed intolerance. Serum amylin concentration, percentage gastric residual volume and time to reach full enteral feeds were significantly raised in nTOL group compared to TOL group. Thus measurement of serum amylin level in preterm infants may have clinical and revenue implications. Definition of feed intolerance in preterm infants (> than 50% prefeed GRV prior to the next scheduled feed) correlated with amylin levels. Increased GRV may be associated with feed intolerance and may be a useful surrogate marker for feed intolerance in preterm neonates. Conclusions of the DissertationAmylin is a potent inhibitor of gastric emptying and plays an important role in glucose homeostasis. Feed intolerance is common in preterm infants and infants born to mothers whose pregnancy was complicated by diabetes. We therefore set out to test the hypothesis that serum amylin levels are increased in preterm infants with feed intolerance. We also hypothesized that serum amylin levels are raised in infants born to mothers whose pregnancy was complicated by diabetes.It was evident from literature that there was no uniform validated definition of feed intolerance in neonatal population. Additionally a gold standard test for gastric emptying in new-born population especially preterm infants was not available. Therefore a pragmatic definition of feed intolerance was formulated based on consensus opinion, physiology of gastric emptying in preterm infants and previous published literature.The primary aims of the study were to (i) establish normal serum amylin concentrations at birth and postnatal day 5 in healthy preterm and term infants (ii) determine amylin levels in infants of diabetic mothers and (iii) determine amylin levels in preterm infants with feed intolerance. The secondary aims were to (i) investigate if amylin and insulin were indeed co-secreted (ii) investigate agreement of serum amylin levels in paired umbilical cord arterial and venous blood (iii) investigate the relationship between serum amylin concentrations and gastric residual volumes (GRV) (iv) investigate the relationship between serum amylin concentrations and length of hospital stay.To meet the aims and objectives, three studies were designed and conducted in parallel. Prospective observational and case control study designs were adopted to answer the hypotheses. The median serum amylin levels in term infants at birth and postnatal day 5 were 6.10 (3.30-9.70) and 5.65 (3.10-8.20) pmol/L respectively. The median serum amylin in preterm infants at birth and postnatal day 5 were 4.60 (1.90-8.30) and 6.90 (2.75-9.50) pmol/L respectively. These levels were comparable to those seen in children and adults.Amylin like insulin may have ontogenetic significance as it correlated with both birth weight and gestation.Paired amylin levels agreed in umbilical cord arterial and venous blood. Either sampling method could therefore be used in future research involving amylin levels in cord bloods. Amylin and insulin levels correlated in paired blood samples suggesting an association between these peptides and possible co-secretion.Amylin levels were significantly increased at birth and postnatal day 5 in preterm (32.00 and 23.40) and term (34.30 and 25.20) infants born to mothers whose pregnancy was complicated by diabetes which may explain the observed feed intolerance.Amylin levels were significantly raised in preterm neonates with delayed gastric emptying compared to controls (47.9 vs 8.7 pmol/L). The serum amylin levels correlated with gastric residual volumes providing validity of GRV as a marker of feed intolerance due to delayed gastric emptying. Thus the study definition of feed intolerance (prefeed residual gastric volumes of more than 50% on 2 consecutive occasions) may be considered to be reliable for future studies. The serum amylin levels in preterm neonates also correlated with time to reach full enteral feeds and days to discharge which has clinical and revenue implications. Overall the study has achieved its intended aims and objectives. The study made original contribution to establishing normative data of amylin levels in the new-born population and explored its significance in infants born to mothers whose pregnancy was complicated by diabetes and preterm infants with feed intolerance. Implications for Future ResearchThere are several areas that I was able to identify during the course of this study that have implications for future research.One of the major handicaps to analytical studies in preterm population is the volume of blood required for ELISA and similar tests. Our study methodology was therefore restricted to opportunistic blood collections due to the volume of blood required especially in preterm infants. Dried blood spot (DBS) technology has been shown to be useful in pharmacokinetic-pharmacodynamic (PK-PD) studies including preterm population. Although this technology is expensive, future study designs limited by volume of blood collected in preterm infants should explore this technique. It is important to establish placental passage of amylin to make sense of the postnatal amylin concentrations we established in new-born population. Future studies of this hormone should investigate maternal amylin levels prior to birth of their baby. This is especially relevant in infants of diabetic mothers in addition to measurement of amylin levels from umbilical cord blood and serial postnatal samples. Alternatively studies on perfused human placenta at various amylin concentrations may help answer this question conclusively. Amylin is increased in rat intestinal ischaemia ADDIN EN.CITE <EndNote><Cite><Author>Phillips</Author><Year>2001</Year><RecNum>261</RecNum><record><rec-number>261</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">261</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Phillips, A. R.</author><author>Abu-Zidan, F. M.</author><author>Farrant, G. J.</author><author>Zwi, J. L.</author><author>Cooper, G. J.</author><author>Windsor, J. A.</author></authors></contributors><auth-address>Pancreatitis Research Group, Department of Surgery, University of Auckland, Auckland, New Zealand.</auth-address><titles><title>Plasma amylin concentration is related to the severity of intestinal ischemic injury in rats</title><secondary-title>Surgery</secondary-title></titles><pages>730-5</pages><volume>129</volume><number>6</number><edition>2001/06/08</edition><keywords><keyword>Amyloid/*blood</keyword><keyword>Animals</keyword><keyword>Blood Pressure</keyword><keyword>Body Temperature</keyword><keyword>Intestines/*blood supply</keyword><keyword>Ischemia/*blood</keyword><keyword>Male</keyword><keyword>Rats</keyword><keyword>Rats, Wistar</keyword><keyword>Reperfusion Injury/*blood</keyword></keywords><dates><year>2001</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0039-6060 (Print)</isbn><accession-num>11391372</accession-num><urls><related-urls><url>(01)07456-6 [pii]
10.1067/msy.2001.113892</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Phillips, Abu-Zidan et al. 2001) and may have a biologic role in sepsis ADDIN EN.CITE <EndNote><Cite><Author>Parida</Author><Year>1998</Year><RecNum>256</RecNum><record><rec-number>256</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">256</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Parida, S. K.</author><author>Schneider, D. B.</author><author>Stoss, T. D.</author><author>Pauly, T. H.</author><author>McGillis, J. P.</author></authors></contributors><auth-address>Department of Pediatrics, University of Kentucky College of Medicine, Lexington 40536-0084, USA.</auth-address><titles><title>Elevated circulating calcitonin gene-related peptide in umbilical cord and infant blood associated with maternal and neonatal sepsis and shock</title><secondary-title>Pediatr Res</secondary-title></titles><periodical><full-title>Pediatr Res</full-title></periodical><pages>276-82</pages><volume>43</volume><number>2</number><edition>1998/02/25</edition><keywords><keyword>Adult</keyword><keyword>Calcitonin Gene-Related Peptide/*blood</keyword><keyword>Chromatography, High Pressure Liquid</keyword><keyword>Female</keyword><keyword>Fetal Blood/*chemistry</keyword><keyword>Gestational Age</keyword><keyword>Humans</keyword><keyword>Infant, Newborn</keyword><keyword>Infant, Newborn, Diseases/*blood</keyword><keyword>Infant, Premature</keyword><keyword>Male</keyword><keyword>Maternal-Fetal Exchange</keyword><keyword>Pregnancy</keyword><keyword>Radioimmunoassay</keyword><keyword>Shock, Septic/*blood</keyword></keywords><dates><year>1998</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0031-3998 (Print)</isbn><accession-num>9475297</accession-num><urls><related-urls><url>;(Parida, Schneider et al. 1998). Future research exploring the role of amylin in necrotising enterocolitis and sepsis in the neonatal population may benefit from normal values established by our study.It is theorised that exposure to maternal diabetes and alterations in fetal glucose, insulin, or other factors results in altered fetal adaptation and changes in normal fetal programming ADDIN EN.CITE <EndNote><Cite><Author>Pettitt</Author><Year>1988</Year><RecNum>469</RecNum><record><rec-number>469</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">469</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pettitt, D. J.</author><author>Aleck, K. A.</author><author>Baird, H. R.</author><author>Carraher, M. J.</author><author>Bennett, P. H.</author><author>Knowler, W. C.</author></authors></contributors><auth-address>Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, Arizona 85014.</auth-address><titles><title>Congenital susceptibility to NIDDM. Role of intrauterine environment</title><secondary-title>Diabetes</secondary-title></titles><periodical><full-title>Diabetes</full-title></periodical><pages>622-8</pages><volume>37</volume><number>5</number><edition>1988/05/01</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Age Factors</keyword><keyword>Diabetes Mellitus, Type 2/epidemiology/*genetics</keyword><keyword>Fathers</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Indians, North American</keyword><keyword>Male</keyword><keyword>Mothers</keyword><keyword>Pregnancy</keyword><keyword>Pregnancy in Diabetics/*genetics</keyword></keywords><dates><year>1988</year><pub-dates><date>May</date></pub-dates></dates><isbn>0012-1797 (Print)
0012-1797 (Linking)</isbn><accession-num>3360218</accession-num><urls><related-urls><url>;(Pettitt, Aleck et al. 1988). Evidence of altered fetal programming (reduced insulin sensitivity) is shown to be present before birth in large for gestation neonates PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EeWVyPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA (Dyer, Rosenfeld et al. 2007). Thus high amylin levels in IMDM could be explained by hyperinsulinaemia. However the reason for increased amylin levels in feed intolerant preterm neonates is unclear. As amylin is co-secreted with insulin under normal physiological conditions, an attractive hypothesis that could be put to clinical test is that transient hyperinsulinemia and relative insulin resistance may stimulate amylin release. The adult gold standard of euglycemic clamp to study insulin resistance would not be feasible and safe in neonatal population due to the invasive nature of the procedure. However it is possible to study glucose/insulin and insulin/cortisol ratios ADDIN EN.CITE <EndNote><Cite><Author>Gesteiro</Author><Year>2009</Year><RecNum>463</RecNum><record><rec-number>463</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">463</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gesteiro, E.</author><author>Bastida, S.</author><author>Sanchez-Muniz, F. J.</author></authors></contributors><auth-address>Servicio de Analisis Clinicos, Hospital de Merida, Poligono Nueva Ciudad s/n, 06800, Merida, Badajoz, Spain.</auth-address><titles><title>Insulin resistance markers in term, normoweight neonates. The Merida cohort</title><secondary-title>Eur J Pediatr</secondary-title></titles><periodical><full-title>Eur J Pediatr</full-title></periodical><pages>281-8</pages><volume>168</volume><number>3</number><edition>2008/07/04</edition><keywords><keyword>Biological Markers/*blood</keyword><keyword>Blood Glucose</keyword><keyword>Body Mass Index</keyword><keyword>Cohort Studies</keyword><keyword>Female</keyword><keyword>Gestational Age</keyword><keyword>Growth Hormone/blood</keyword><keyword>Homeostasis</keyword><keyword>Humans</keyword><keyword>Hydrocortisone/blood</keyword><keyword>Infant, Newborn/*physiology</keyword><keyword>Insulin/blood</keyword><keyword>Insulin Resistance/*physiology</keyword><keyword>Insulin-Like Growth Factor I/metabolism</keyword><keyword>Male</keyword><keyword>Models, Biological</keyword><keyword>Reference Values</keyword><keyword>Spain</keyword></keywords><dates><year>2009</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>1432-1076 (Electronic)
0340-6199 (Linking)</isbn><accession-num>18597116</accession-num><urls><related-urls><url>;(Gesteiro, Bastida et al. 2009) to assess insulin resistance in neonatal population. Other possible areas of interest are the role of amylin receptor insensitivity and interaction with other gut peptides such as CCK, GLP-1, leptin and ghrelin. Other potential physiological mediators of gastric emptying including GLP-1 and CCK may potentiate the actions of amylin ADDIN EN.CITE <EndNote><Cite><Author>Young</Author><Year>1997</Year><RecNum>158</RecNum><record><rec-number>158</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">158</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Young, A.</author></authors></contributors><auth-address>Amylin Pharmaceuticals, Inc., San Diego, CA 92121, USA.</auth-address><titles><title>Role of amylin in nutrient intake - animal studies</title><secondary-title>Diabet Med</secondary-title></titles><periodical><full-title>Diabet Med</full-title></periodical><pages>S14-8</pages><volume>14 Suppl 2</volume><edition>1997/06/01</edition><keywords><keyword>Amyloid/pharmacology/*physiology/therapeutic use</keyword><keyword>Animal Nutritional Physiological Phenomena</keyword><keyword>Animals</keyword><keyword>Diabetes Mellitus/drug therapy</keyword><keyword>Disease Models, Animal</keyword><keyword>Eating/drug effects</keyword><keyword>Gastric Emptying/drug effects</keyword><keyword>Glucagon/metabolism</keyword><keyword>Humans</keyword><keyword>Hypoglycemic Agents/pharmacology/therapeutic use</keyword><keyword>Receptors, Peptide/antagonists & inhibitors</keyword></keywords><dates><year>1997</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0742-3071 (Print)</isbn><accession-num>9212324</accession-num><urls><related-urls><url>(SICI)1096-9136(199706)14:2+<S14::AID-DIA398>3.0.CO;2-Q</electronic-resource-num><language>eng</language></record></Cite></EndNote>(Young 1997). Therefore studies investigating the interaction with other gut peptides including ghrelin may help understand the conundrum of the pathophysiology of gastric emptying in new-born infants with feed intolerance. There is an urgent need for validation of non-invasive techniques for gastric emptying assessments in new-born infants and preterm extremely low birth weight infants. Employment of these validated tests of gastric emptying in future studies may add validity to the biological role of amylin and other gut peptides in the pathophysiology of feed intolerance in humans. Amylin release is also known to be influenced by gastric distension and stretch receptors. The results of this study may stimulate future research into the effect of bolus versus continuous feeds on amylin secretion (stretch receptors) and gastric emptying in preterm population. Amylin receptor antagonists are being developed for research purposes in animals. Amylin receptor blockade would seem to be one of the potential therapeutic options for feed intolerance in preterm infants. However considerable caution is warranted as it is not known if amylin by causing feed intolerance in preterm neonates has a protective role on the immature gastrointestinal tract. As highlighted before amylin has other important biological function in addition to gastric emptying and glucose homeostasis. Thus pharmacological blockade of this peptide as a potential therapeutic option could expose the preterm infant to greater risk of necrotising enterocolitis in addition to other possible adverse effects.Obesity is a worldwide problem with significant health and economic problems. Amylin by virtue of its central and peripheral action on the stomach acts as an anorectic hormone. Thus synthetic analogues of amylin may be developed as anorectic agents that may have therapeutic implications in the management of childhood and adult obesity. Publications arising from this Project Amylin peptide levels are raised in infants of diabetic mothers. Arch Dis Child. 2005 Dec; 90(12):1279-82 Amylin peptide is increased in preterm neonates with feed intolerance. Arch Dis Child Fetal Neonatal Ed. 2008 Jul; 93(4):F265-70 AppendicesAppendix SEQ Appendix \* ARABIC 1.Basic principle of luminescent ELISAThe basic steps in any luminescent ELISA are as follows:Antibodies or antigens are passively adsorbed to solid surfaces such as commercially available 96-well format microtiter plates for use in ELISA. As one of the reactants in the ELISA is attached to a solid-phase, the separation of bound and free reagents is made by simple washing procedures. The result of an ELISA is a color reaction that can be observed by eye and read rapidly using specially designed multichannel spectrophotometers allowing data to be stored and analysed statistically ADDIN EN.CITE <EndNote><Cite><Author>Crowther</Author><Year>1995</Year><RecNum>300</RecNum><record><rec-number>300</rec-number><foreign-keys><key app="EN" db-id="ta5tswtfof5ttmepssypfasxpfvzrevpz2f2">300</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>John R. Crowther</author></authors></contributors><titles><title>Methods in Molecular Biology</title><secondary-title>ELISA</secondary-title><tertiary-title>Methods in Molecular Biology</tertiary-title></titles><pages>35-61</pages><volume>Volume 42</volume><section>Basic Principles of ELISA</section><dates><year>1995</year></dates><publisher>Humana Press</publisher><isbn>1064-3745</isbn><urls></urls></record></Cite></EndNote>(Crowther 1995) . 3246120194945000239839512446000042652951701800Analyte-specific antibody00Analyte-specific antibody42672001095375Analyte00AnalyteStep 1. Analyte-specific antibody (capture antibody) is pre-coated onto a microplate. The sample is added and any analyte present is bound by the immobilized antibody.42081451628775Antibody-Analyte Conjugate00Antibody-Analyte Conjugate2684145196215000Step 2. An enzyme-linked analyte-specific detection antibody binds to a second epitope on the analyte forming the analyte-antibody complex.42462441679575Substrate- Light or Colour00Substrate- Light or Colour2684145197294500Step 3. Substrate is added and converted by the enzyme, thereby producing a colored product or light emission in direct proportion to the amount of analyte bound in the intial reaction (signal increases as concentration increases).Step 4. A standard curve is prepared from the data produced from the serial dilutions with concentration on the x axis (log scale) versus absorbance on the Y axis (linear). The concentration of the sample is interpolated from this standard curve.Nonlinear regression is often used to fit standard curves generated by ELISA assay which is based on competitive binding. The assaying compound competes for binding to an enzyme or antibody with a labeled compound. Therefore the standard curve is described by equations for competitive binding. One-site competitive binding curve is tried first. If that doesn’t fit the data well, sigmoid curves are tried, by entering the X values as the logarithms of concentrations. Choice of an equation is important when using nonlinear regression, if the equation does not describe a model that makes scientific sense; the results of nonlinear regression won’t make sense either. With standard curve calculations, the choice of an equation is less important because all one has to do is assess visually that the curve nicely fits the standard points.Appendix SEQ Appendix \* ARABIC 2. Human Amylin (Total) ELISA KIT and Assay ProcedureThe Human Amylin ELISA is a monoclonal antibody-based sandwich immunoassay for determining total amylin levels in human plasma. The capture antibody recognizes reduced human amylin and human amylin acid (deamidated amylin) but not the 1-20 fragment of amylin. The detection antibody binds to reduced or unreduced human amylin but not amylin acid and is complexed with streptavidin-alkaline phosphatase to form a sandwich. The substrate, 4-Methylumbelliferyl Phosphate (MUP), is applied to the completed sandwich and the fluorescent signal, monitored at 355 nm/460 nm, is proportional to the amount of amylin present in the sample. After receipt of the kit, all components of the kit were stored at 2-8 degrees centigrade. The assay is run in duplicate using 50 ?l of assay buffer and 50 ?l of Standard, Control, or Sample in each well. The assay procedure is as follows:The concentrated TBS (Tris Buffered Saline) wash buffer is diluted 10 fold by mixing the entire contents of the 10 X wash buffer with 270 ml deionized water.Standards and QCI and QC2 (lyophilized) vials is reconstituted with 250 ?l of deionoized water. The solution is mixed gently for at least 5 minutes to assure complete reconstitution.The microtitre assay plate is removed from the foil pouch and each well is filled with 300 ?l of diluted TBS wash buffer which is incubated at room temperature for 10 minutes without shaking.Wash buffer is decanted from the plate and the residual amount removed from all wells by inverting the plate and tapping it smartly onto absorbent towels several times. The well is not allowed to dry before proceeding to the next step.50 ?l of assay buffer is added to each well. 50 ?l Standards, Samples and Controls are added in duplicates. The wells are orientated as highlighted below. The plate is sealed and incubated at room temperature on the shaker for one hour. It is important to note that the incubation start time is the time as plate was loaded on the shaker, not from the time one started loading the plate with samples. The residual amount from all wells is decanted and removed by inverting the plate and tapping it smartly onto absorbent towels several times. Microtitre plate arrangements of wells is as shown below123456789101112A0 pM0 pM1 pM1 pM2 pM2 pM5 pM5 pM10 pM10 pM 40 pM40 pM B100 pM100 pMQC1QC1QC2QC2Sample 1Sample 1Sample 2Sample 2Sample 3Sample 3CDEFGHThe plate is washed 3 times with 300 ?l per well TBS wash buffer. The plate is decanted and tapped after each wash to remove residual buffer.100 ?l detection antibody is added to each well, plate is covered with sealer, and incubated on the shaker at room temperature for 2 hours.Near the completion of this incubation step, the substrate is hydrated by adding 1 ml deionized water to 10 mg, mixed well, and allowed to stand for 15 minutes with occasional mixing to assure complete dissolution. 105 ?l is removed from the reconstituted substrate and added to the 21 ml vial of substrate diluent, mixed well, referred to as substrate solution from here on.Detection antibody is decanted and the residual amount removed from all wells by inverting the plate and tapping it smartly onto absorbent towels several times.The plate is washed 3 times with 300 ?l per well TBS wash buffer, decanted and tapped after each wash, to remove residual buffer.100 ?l substrate solution is added to each well and incubated for 15 minutes at room temperature in the dark without shaking.A reading is taken and the RFU (Relative Fluorescence Unit) of the top standard point is noted; when the reading is 2000 RFU or greater, 50 ?l stop solution is added, gently mixed, and read on the fluorescence plate reader after 5 minutes.The RFU can be fitted directly to the concentration. If the curve fitting software is available, the best fit can be obtained with a linear-linear spline fit. Since this assay is a direct ELISA, the RFU is directly proportional to the concentration of total human amylin in the sample. It is important to note that when sample volumes assayed differ from 50 ?l, an appropriate mathematical adjustment must be made to accommodate for the dilution factor (e.g. if 25 ?l of sample is used, then calculated data must be multiplied by 2).Appendix SEQ Appendix \* ARABIC 3. Characteristics of Human Amylin (Total) ELISA KitThe human amylin ELISA kit had the following assay characteristics:Sensitivity: The lowest level of total human amylin that could be detected by this assay is 1 pM (50 ?l plasma sample size).Performance: The parameters expressed as mean ± standard deviation of assay performance are: ParametersMean ± SDED 8082 ± 2 pMED 5054 ± 5 pMED 202 6± 4 pMCrossreactivity: The cross reactivity of the assay is as follows:PeptidesPercentageHuman Glucagon<1%Human GLP-1<1%Human Insulin<1%Human Pancreatic Polypeptide<1%Human Adrenomedullin1%Human Calcitonin<1%Calcitonin Gene Related Peptide<1%Precision: The assay variation of Linco Human Amylin ELISA kits were studied at three different spiked concentrations of amylin in three different human plasma samples. The within variations was the mean from four duplicate determinations in a single assay. The between variation was the mean value of the mean of four duplicate determinations in each plasma across four assays. Within and between assay variation is as follows:Sample NoAmylin Added pMWithin % CVBetween % CV1202.611.9505.012.98014.811.522011.517.4502.517.8807.916.23207.817.6505.411.9807.313.0Recovery: Varying concentrations of Human Amylin were added to three human plasma samples and the amylin content was determined in four different ELISA assays. The % of recovery=observed amylin concentration/expected amylin concentration x 100%. Spike and recovery of total human amylin in human plasma was as follows:SampleSample Concentration (pM)Amylin% of Recovery13.25201045099809122.56209650898089311.232010150878090Linearity: Three human plasma samples with the indicated sample volumes were assayed in four different assays. Required amount of assay buffer was added to compensate for lost volumes below 50 ?l. The resulting dilution factors of 1.0, 1.25, 2.0, and 5.0 representing 50 ?l, 40 ?l, 25 ?l, and 10 ?l sample volumes assayed, respectively, were applied. The effect of plasma dilution was as follows:Sample NoVolume SampledExpected pMObserved pM%of Expected15022.3222.321004021.13952519.98901018.558325025.3425.351004022.30882520.54811021.058335020.5420.541004020.851012515.96781019.6596Appendix SEQ Appendix \* ARABIC 4. Research protocol for ethics approval, South Sheffield Research Ethics CommitteeTitle: Amylin peptide: Association with feed intolerance in preterm infants and IMDM- Observational & Case-Control StudyStudy Sponsor: University Hospitals of Sheffield NHS TrustStudy SummaryTitleAmylin peptide: Association with feed intolerance in preterm infants & IMDM Short TitleAmylin peptide MethodologyProspective Observational Study and Case-Control StudyStudy Duration12 monthsStudy CentresSingle Centre (Study A & B ) & Two Centre (Study C)ObjectivesTo determine serum amylin levels in well preterm and term infants (Study A), infants of diabetic mothers (Study B) and preterm infants with feed intolerance (Study C).Number of Samples/ParticipantsStudy A=200 samplesStudy B= 21 IDMStudy C= 20 nTOL and 20 TOLMain Inclusion Criteria1. Infants ≥ 24 weeks gestation2. Infants of diabetic mothers3. Preterm infants (24-36 weeks) admitted to the neonatal intensive care unit and requiring gastric tube feeding Statistical MethodologyMedian and interquartile ranges and non-parametric tests. Correlation Coefficient will be performed to evaluate the relationship between variables. Bland altman test will be applied for method comparison between umbilical arterial and umbilical venous blood sampling method. Outcome variableSerum amylin levels in pmol/lBackground: The goal of neonatal nutrition is the attainment of normal growth and development. However impairment of gastric motility is common in critically ill patients (1) and failure to establish enteral feeds in neonates necessitates the use of parenteral nutrition which carries a significant increased risk of morbidity and mortality (2). There is scant information on the mechanisms relating to feed intolerance in these patients, therefore limiting the therapeutic options.Insight into the regulation of gastric motility has been advanced by the recent discovery of ‘amylin’, a novel 37 amino-acid peptide hormone from the calcitonin gene-related peptide family. As a potent inhibitor of gastric emptying it plays an important physiological role in the control of carbohydrate absorption by regulating the efflux from the stomach to the small bowel. The pathophysiological role of amylin is well documented in adult patients with diabetes mellitus (1), where inappropriately high levels have been reported with delayed gastric emptying. There is no published data on amylin levels and its role in neonatal population. We aim to determine normal amylin levels in neonatal population and investigate its role in infants born to mothers whose pregnancies were complicated by diabetes (IMDM) & preterm infants with feed intolerance. Rationale and significance of the study: Up to 67% of infants weighing less than 1500 g (1-3) experience feed intolerance resulting in prolonged parenteral fluid therapy, increased hospital stay, increased risk of sepsis and consequently increased cost of treatment (4). Feed intolerance is also a major problem in IMDM (5). An increased prefeed gastric residual volume is a commonly used measure of feed intolerance in newborn infants.Decreased gastrointestinal motility can be multifactorial in origin, we hypothesize that amylin may have an important role to play in its pathophysiology. Amylin is novel “brain-gut peptide” which is co-secreted with insulin from the pancreas (6). In conjunction to playing a role in glucose homeostasis, it is a potent inhibitor of gastric emptying (7). A study in critically ill infants and children showed elevated amylin levels which correlated with delayed gastric emptying and feed intolerance (8). We aimed to investigate the role of amylin in newborn infants with feed intolerance which could potentially form the basis of a subsequent clinical trial. Research question: Is amylin elevated in neonates with feed intolerance (delayed gastric emptying)?Aims and Objectives: 1. To determine reference range of amylin at birth (umbilical cord) and at 5-7 days (Guthrie) in term and preterm neonates (Study A). 2. To determine amylin levels in IMDM (Study B). 3. To determine amylin in preterm neonates with feed intolerance (study C).Study design: Prospective observational and case-control study to be conducted simultaneously as 3 sub-studies. Study A- To establish normal ranges of cord and postnatal amylin levels, mothers will be recruited antenatally for umbilical cord blood and inpatient Guthrie blood. Study B- All infants of diabetic mothers will be recruited for cord bloods, Guthrie bloods, and opportunistic bloods taken at the time of routine glucose measurement. Study C- Preterm infants admitted to neonatal intensive care unit and requiring tube feeding will be recruited. Amylin levels of feed intolerant infants (case) will be compared to feed tolerant infants (control) Study population: Study A-Term and preterm infants > 24 weeks of gestation, Study B-Term IMDM and preterm IMDM > 24 weeks of gestation and Study C- Preterm infants > 24 weeks of gestationExclusion CriteriaInfants born less than 24 weeks gestationCongenital malformationChromosomal anomalyStructural gastrointestinal abnormalities and necrotising enterocolitisHaemoglobin less than 7 g/dlBreast feeding where feed volume cannot be determinedPrimary outcome measure: Serum amylin levels (pmol/l)Definition of feed tolerance: Feed intolerance will be defined as prefeed gastric residual volumes of greater than 50% of the previous feed on 2 consecutive occasions (4). Method of collection and analysis: 0.5 ml-1ml blood will be drawn into a tube containing EDTA with 500 IU of aprotinin per millilitre of blood and kept on ice before separation and stored at -70?C. All samples will be analysed for total amylin levels using monoclonal antibody-based sandwich immunoassay. The amylin ELISA kit is validated for the measurement of total amylin from EDTA human plasma samples. It has sensitivity to 1 pM and a standard range of 1-100 pM. Were possible, plasma immunoreactive insulin will be measured by ELISA. Blood glucose will be measured by the glucose oxidase method. The assays will be performed by technical team blinded to the patient data led by Mr R Fraser.Setting: Labour ward and neonatal intensive care unit, Jessop wing, Royal Hallamshire Hospital. Study C will also be conducted at the neonatal intensive care unit, Doncaster General Hospital.Consent: Parents will be recruited prior to delivery and written consent obtained.Study Plan: Estimated sample volume is 0.5-1.0 ml. Prefeed gastric aspirates are recorded as part of routine neonatal practise. Data will be collected with reference to method of nutrition, demographic data and medication at the time of sample collection.Study A: Mothers of babies having normal, preterm and LSCS deliveries will be recruited. Cord blood will be obtained immediately after delivery of these babies. A repeat sample will be taken at the same time as routine Guthrie from babies who are inpatients. These will be analysed for amylin and insulin. Study B: Cord and Guthrie blood and a daily sample taken at the time routine blood sugar (hypoglycaemia protocol) of infants of diabetic mothers, and will be analysed for amylin and insulin.Study C: Preterm infants with apparent feed intolerance will be recruited when delayed gastric emptying is observed. Samples for amylin, insulin and glucose will be taken at the next routine phlebotomy. Analysis: A sample size of 200 in study A and 20 each in study B and study C will have a 90% power to detect a difference in means of 15 (the difference between a group 1 mean of 37.7 and group 2 mean of 22.7) assuming that the common standard deviation is 13 using a two group t-test with a 0.05 two sided significance level. Benefits and risks: There will be no benefit to the babies included in the trial. However there are no known risks involved. The information we get from this study may help us to understand the mechanisms of delayed emptying of the stomach. Confidentiality: Patient data will be allocated a unique number and only the research team will have access to family identities. All patient information will be stored in locked filing cabinet and patient information will be stored on password protected PC’s at Jessop wing, Royal Hallamshire hospital. Resource RequirementsAmylin Kits ?270/Kit?1080Serum tubes?50Technical staff time?0Trasylol?10Dissemination and Outcome: The data will be presented at local, national and international meetings. The results will be published in pediatrics research journals.ReferencesDive A et al. Crit Care Med 1994;22:441-447Yu VY. Acta Med Port 1997;10(2-3):185-196Premji SS et al. Cisapride: A review of the evidence supporting its use in premature infants with feeding intolerance. Neonatal Netw 1997; 16: 17-21Gross SJ. Growth and biochemical response of preterm infants fed human milk or modified infant formula. N Engl J Med 1983; 308:237-241.Gross SJ et al. Feeding the low birth weight infant. Clin Perinatol 1993; 20: 193-209.Reddy PS et al. Double blind placebo controlled study on prophylactic use of cisapride on feed intolerance and gastric emptying in preterm neonates. Indian Pediatr 2000; 37: 837-844Kitzmiller J L. Am J Obstet Gynecol 1978; 131: 560.Ludvig B et al. Amylin: History and overview. Diabetic Med 1997; 14: S9-S13Macdonald IA. Amylin and the gastrointestinal tract. Diabetic Med 1997; 14: S24-S28.Mayer AP. Amylin is associated with delayed gastric emptying in critically ill children. Intensive Care Medicine. 2002; 28(3): 336-340. Appendix SEQ Appendix \* ARABIC 5. Research protocol for ethics approval, Doncaster Research Ethics CommitteeAmylin peptide: Association with feed intolerance in preterm infants- A Case-Control StudyStudy Sponsor: Doncaster General Hospital NHS TrustStudy SummaryTitleAmylin peptide: Association with feed intolerance in preterm infantsShort TitleAmylin peptide MethodologyCase-Control StudyStudy Duration12 monthsStudy CentreSingle Centre ObjectivesTo determine serum amylin levels in preterm infants with feed intolerance.Number of Samples/Participants20 nTOL and 20 TOLMain Inclusion CriteriaPreterm infants (24-36 weeks) admitted to the neonatal intensive care unit and requiring gastric tube feeding Statistical MethodologyMedian and interquartile ranges and non-parametric tests. Corelation Coefficient will be performed to evaluate the relationship between variables. Outcome variableSerum amylin levels in pmol/lBackground: The goal of neonatal nutrition is the attainment of normal growth and development. However impairment of gastric motility is common in critically ill patients (1). Failure to establish enteral feeds in neonates necessitates the use of parenteral nutrition which carries significantly increased risk of morbidity and mortality (2). There is scant information on the mechanisms relating to feed intolerance in these patients, therefore limiting the therapeutic options.Insight into the regulation of gastric motility has been advanced by the discovery of ‘amylin’, a novel 37 amino-acid peptide hormone from the calcitonin gene-related peptide family. As a potent inhibitor of gastric emptying it plays an important physiological role in the control of carbohydrate absorption by regulating the efflux from the stomach to the small bowel. The pathophysiological role of amylin is well documented in adult patients with diabetes mellitus (1), where inappropriately high levels have been reported with delayed gastric emptying. We have previously established normal serum amylin levels in umbilical cord and Guthrie blood samples from healthy preterm and term new-born infants. This study is planned to investigate the role of amylin in preterm infants with feed intolerance. Rationale and significance of the study: Feed intolerance has been reported in up to 67% of infants weighing less than 1500 g (1-3) resulting in prolonged parenteral fluid therapy, increased hospital stay, increased risk of sepsis and consequently increased cost of treatment (4). Decreased gastrointestinal motility can be multifactorial in origin, we hypothesize that amylin may have an important role to play in its pathophysiology. Amylin is a novel “brain-gut peptide” which is co-secreted with insulin from the pancreas (6). In conjunction to playing a role in glucose homeostasis, it is a potent inhibitor of gastric emptying (7). A study examining critically ill infants and children with feed intolerance showed elevated serum amylin levels (8). We aim to establish the association of feed intolerance to elevated amylin levels in the neonatal population which could potentially form the basis of a subsequent clinical trial using a commercially available amylin antagonist. Research question: Is amylin elevated in neonates with delayed gastric emptying?Aim and Objectives: To establish amylin levels in preterm neonates with delayed gastric emptying (feed intolerance).Study design: This is a case-control study. The cases will be preterm infants admitted to neonatal intensive care unit who subsequently develop feed intolerance. Preterm infants without feed intolerance matched for birth weight, gestation and postnatal age will be controls. Study population: Preterm infants between 24-36 weeks of gestationExclusion CriteriaCongenital malformation Chromosomal anomaly Structural gastrointestinal abnormalities and necrotising enterocolitisBreast feeding where feed volume cannot be determinedInfant born to mother whose pregnancy is complicated by diabetesPrimary outcome: Serum amylin levels in infants with and without feed intolerance.Definition of feed intolerance: In this population feed intolerance will be defined as, prefeed gastric residual volume (GRV) of greater than 50% of the previous feed (4), increase in the abdominal girth from baseline by more than 2 cm in the region of the epigastrium over 24 hours by regular monitoring and vomiting. Method of collection and analysis: Blood for amylin and insulin will be drawn into a tube containing EDTA with 500 IU of aprotinin per millilitre of blood and kept on ice before separation and stored at -70?C. The total amylin levels in human plasma are assayed using an ELISA monoclonal antibody-based sandwich immunoassay. The amylin ELISA kit is validated for the measurement of total amylin from EDTA human plasma samples. It has sensitivity to 1 pM and a standard range of 1-100 pM. Plasma immunoreactive insulin will be measured by ELISA. Blood glucose will be measured by the glucose oxidase method. The assays will be done by technical team under R Fraser who will be blinded to the patient data.Setting: Neonatal intensive care unit, Doncaster Royal InfirmaryConsent: Parents of infants admitted to the neonatal unit and requiring tube feeding will be approached for consent. Study Plan: All the infants admitted to the neonatal intensive care unit and requiring tube feeding will be eligible for the study. The feeding regime of the neonates will be dictated by the local guideline. Expressed breast milk (EBM) is encouraged, and formula feed is used if breast milk is not available. The neonates are fed every hour and the volumes increased as clinically tolerated but not more than 20mls/kg birth weight/day. Every four hours pre-feed GRV will be recorded as a percentage of the previous feed volume. Abdominal girth, colour of gastric residuals and emesis will also be noted. If this GRV is greater than 50% on two consecutive occasions, neonates will be classified as feed-intolerant (nTOL). The further management of these neonates is up to the attending neonatologist. Researcher or responsible consultant will identify preterm infants introduced to gastric tube feeding who are receiving > 30 ml/kg or > 25% of total fluid intake as enteral feeds. Parents will be approached for consent and information leaflets provided. Blood for amylin will be collected within 2 hours of the second big (> 50%) prefeed GRV in nTOL neonates. 0.5 ml blood will be collected from capillary, vein, or indwelling arterial catheters as deemed necessay for routine collection. Feed-tolerant (TOL) neonates matched for gestational age, birth weight and postnatal age will serve as controls. 0.5 ml blood for amylin in these neonates will be collected during their next routine collection. Data will be collected with reference to method of nutrition, demographic data and medication at the time of sample collection.Analysis: A sample size of 20 each in nTOL and TOL will have a 90% power to detect a difference in means of 15 (the difference between a group 1 mean of 37.7 and group 2 mean of 22.7) assuming that the common standard deviation is 13 using a two group t-test with a 0.05 two sided significance level. Benefits and risks: There will be no benefit to the babies included in the trial. However there are no known risks involved. The information we get from this study may help us to understand the mechanisms of delayed emptying of the stomach. Confidentiality: Patient data will be allocated a unique number and only the research team will have access to family identities. All patient information will be stored in locked filing cabinet and patient information will be stored on password protected PC’s at Women’s Hospital, Doncaster Royal InfirmaryResource RequirementsAmylin Kits ?270/Kit?270Serum tubes?50Trasylol?10Dissemination and Outcome: The data will be presented at local, national and international meetings. The results will be published in paediatrics research journals.ReferencesDive A et al. Crit Care Med 1994;22:441-447Yu VY. Acta Med Port 1997;10(2-3):185-196Premji SS et al. Cisapride: A review of the evidence supporting its use in premature infants with feeding intolerance. Neonatal Netw 1997; 16: 17-21Gross SJ. Growth and biochemical response of preterm infants fed human milk or modified infant formula. N Engl J Med 1983; 308:237-241.Gross SJ et al. Feeding the low birth weight infant. Clin Perinatol 1993; 20: 193-209.Reddy PS et al. Double blind placebo controlled study on prophylactic use of cisapride on feed intolerance and gastric emptying in preterm neonates. Indian Pediatr 2000; 37: 837-844Kitzmiller J L. Am J Obstet Gynecol 1978; 131: 560.Ludvig B et al. Amylin: History and overview. Diabetic Med 1997; 14: S9-S13Macdonald IA. Amylin and the gastrointestinal tract. Diabetic Med 1997; 14: S24-S28.Mayer AP. Amylin is associated with delayed gastric emptying in critically ill children. Intensive Care Medicine. 2002; 28(3): 336-340. Appendix SEQ Appendix \* ARABIC 6. Child participation information leaflet (Study A & B)CHILD PARTICIPATION INFORMATION LEAFLETNeonatal Intensive Care Unit, Jessop Wing, Royal Hallamshire HospitalStudy title: Amylin peptide: Association with feed intolerance in preterm infants and IMDM.What is this study about?You and your baby are being invited to take part in a research study. Before you decide whether to take part, it is important for you to understand why the research is being done and what it will involve. Please take time to read the following information carefully and discuss it with others if you wish. Ask us if there is anything that is not clear or you would like more information. Please take time to decide whether or not you wish to take part.What is the purpose of the study? Many critically ill babies admitted to the intensive care unit have major problems tolerating normal milk feeds. This is especially common in those babies born early (prematurely) and babies born to mothers with sugar intolerance (diabetes mellitus). We are presently investigating possible reasons why this may occur. One explanation is that a substance called AMYLIN present in the blood stream may be responsible. Amylin is a newly discovered hormone that potently inhibits the function of the stomach. Because good nutrition is crucial to the healing process in sick babies we are conducting a study to measure Amylin levels in the hope that this may shed some light on this difficult problem. If a relationship can be shown between blood Amylin levels and poor stomach function we could potentially develop treatments in the future to promote feeding, improve nutrition and hopefully hasten recovery time in critically ill babies. To study this chemical we aim to measure it in all babies born at this hospital at the time of routine blood taking for neonatal screening. Why has my baby been chosen?Your baby has been chosen because if he/she is not tolerating feeds or is slow to feed, we are trying to find out if the feed intolerance is due to increased blood amylin level.Do I have to take part?It is up to you to decide whether or not to take part. If you do decide to take part you will be given this information sheet to keep and be asked to sign a consent form. If you decide to take part you are still free to withdraw at any time and without giving a reason. This will not affect the standard of care your baby receives.What will happen if my baby takes part?If you decide to take part in the study the only change from routine management is that 0.5 ml (about 8 drops) of your baby’s blood would be taken during routine blood sampling, so causing no added distress or pain. Additionally a sample would be taken from umbilical cord after delivery (this causes no added distress or discomfort to your baby as the sample is taken after the cord is cut).What are the possible disadvantages and risks of taking part?We will collect no more than 0.5 ml blood. This is safe amount to take from your baby.What are the possible benefits of taking part? There will be no direct health benefit to your baby. What if something goes wrong? If you have any cause to complain about any aspect of the way in which you have been approached or treated during the course of this study, the normal National Health Service complaints mechanisms are available to you and are not compromised in any way because you have taken part in a research study. If you have any complaints or concerns please contact the project co-ordinator: (Dr Coombs on telephone 01142268387). Otherwise you can use the normal hospital complaints procedure and contact the following person: (Chris Welsh, Medical Director STH, 8 Beech Hill Road, Sheffield, S10 2SB, 0114 271 2178).Will my baby’s taking part in this study be kept confidential? All information, which is collected, about your baby during the course of the research will be kept strictly confidential. Any information about your baby, which leaves the hospital/surgery, will have your name and address removed so that you cannot be recognised from it. What will happen to the results of the research study? When the study finishes all the results will be analysed, which may lead to a publication in a medical journal. At no time will any identifying information will be published and all records will remain confidential. If you wish we will forward you the published report of the study.Who is organising and funding the research? The research is being organised by the neonatal intensive care unit at Jessops Wing, Royal Hallamshire hospital. There is no outside funding or financial incentive to this study.Who has reviewed the study? The study has been reviewed and approved by South Sheffield Ethics Committee.Who can I contact if I want to know more about the study?Drs V Kairamkonda & A Deorukhkar, Neonatal intensive care unit, Jessop Wing, Royal Hallamshire Hospital, Sheffield S10 2SF, Tel: 01142268322, Fax: 01142268449.Thank you for reading this information sheet.?Appendix SEQ Appendix \* ARABIC 7. Child participation information leaflet (Study C) Royal Hallamshire HospitalCHILD PARTICIPATION INFORMATION LEAFLETNeonatal Intensive Care Unit, Jessop Wing, Royal Hallamshire HospitalStudy title: Amylin peptide: Association with feed intolerance in preterm infants.What is the purpose of the study? Many critically ill babies admitted to the intensive care unit have major problems tolerating normal milk feeds. This is especially common in those babies born early (prematurely) and babies born to mothers with sugar intolerance (diabetes mellitus). We are presently investigating possible reasons why this may occur. One explanation is that a substance called AMYLIN present in the blood stream may be responsible. Amylin is a newly discovered hormone that potently inhibits the function of the stomach. Because good nutrition is crucial to the healing process in sick babies we are conducting a study to measure Amylin levels in the hope that this may shed some light on this difficult problem. If a relationship can be shown between blood Amylin levels and poor stomach function we could potentially in the future use drugs to block the action of Amylin in order to promote feeding, improve nutrition and hopefully hasten recovery time in critically ill babies. To study this chemical we aim to measure it in all preterm babies admitted to the intensive care with feed intolerance or who subsequently develop feed intolerance. Why has my baby been chosen?Your baby has been chosen because if he/she is not tolerating feeds or is slow to feed, we are trying to find out if the feed intolerance is due to increased blood amylin level.?Do I have to take part?It is up to you to decide whether or not to take part. If you do decide to take part you will be given this information sheet to keep and be asked to sign a consent form. If you decide to take part you are still free to withdraw at any time and without giving a reason. This will not affect the standard of care your baby receives.?What will happen if my baby takes part?If you decide to take part in the study the only change from routine management is that 0.5ml (about 8 drops) of your baby’s blood would be taken during routine blood sampling, so causing no added distress or pain. What are the side effects of taking part?None?What are the possible disadvantages and risks of taking part?None ?What are the possible benefits of taking part? None?What if something goes wrong?If you have any cause to complain about any aspect of the way in which you have been approached or treated during the course of this study, the normal National Health Service complaints mechanisms are available to you and are not compromised in any way because you have taken part in a research study. If you have any complaints or concerns please contact the project co-ordinator: (Dr Coombs on telephone 01142268387). Otherwise you can use the normal hospital complaints procedure and contact the following person: (Chris Welsh, Medical Director STH, 8 Beech Hill Road, Sheffield, S10 2SB, 0114 271 2178).?Will my baby’s taking part in this study be kept confidential?All information, which is collected, about your baby during the course of the research will be kept strictly confidential. Any information about your baby, which leaves the hospital/surgery, will have your name and address removed so that you cannot be recognised from it. ?What will happen to the results of the research study?When the study finishes all the results will be analysed, which may lead to a publication in a medical journal. At no time will any identifying information will be published and all records will remain confidential. If you wish we will forward you the published report of the study.?Who is organising and funding the research?The research is being organised by the neonatal intensive care unit at Jessops Wing, Royal Hallamshire Hospital. There is no outside funding or financial incentive to this study.?Who has reviewed the study?The study has been reviewed and approved by South Sheffield Ethics Committee. ?Contacts for Further InformationDrs V Kairamkonda & A Deorukhkar, Neonatal intensive care unit, Jessop Wing, Royal Hallamshire Hospital, Sheffield S10 2SF, Tel: 01142268322, Fax: 01142268449Thank you for reading this information sheet.?Appendix SEQ Appendix \* ARABIC 8. Child participation information leaflet (Study C) Doncaster Royal InfirmaryCHILD PARTICIPATION INFORMATION LEAFLETNeonatal Intensive Care Unit, Doncaster Royal Infirmary, Doncaster Study title: Amylin peptide: Association with feed intolerance in preterm infants.What is the purpose of the study?Many critically ill babies admitted to the intensive care unit have major problems tolerating normal milk feeds. This is especially common in those babies born early (prematurely) and babies born to mothers with sugar intolerance (diabetes mellitus). We are presently investigating possible reasons why this may occur. One explanation is that a substance called AMYLIN present in the blood stream may be responsible. Amylin is a newly discovered hormone that potently inhibits the function of the stomach. Because good nutrition is crucial to the healing process in sick babies we are conducting a study to measure Amylin levels in the hope that this may shed some light on this difficult problem. If a relationship can be shown between blood Amylin levels and poor stomach function we could potentially in the future use drugs to block the action of Amylin in order to promote feeding, improve nutrition and hopefully hasten recovery time in critically ill babies. To study this chemical we aim to measure it in all preterm babies admitted to the intensive care with feed intolerance or who subsequently develop feed intolerance.Why has my baby been chosen?Your baby has been chosen because if he/she is not tolerating feeds or is slow to feed, we are trying to find out if the feed intolerance is due to increased blood amylin level.Do I have to take part?It is up to you to decide whether or not to take part. If you do decide to take part you will be given this information sheet to keep and be asked to sign a consent form. If you decide to take part you are still free to withdraw at any time and without giving a reason. This will not affect the standard of care your baby receives.What will happen if my baby takes part?If you decide to take part in the study the only change from routine management is that 0.5ml (about 8 drops) of your baby’s blood would be taken during routine blood sampling, so causing no added distress or pain.What are the side effects of taking part?NoneWhat are the possible disadvantages and risks of taking part?None What are the possible benefits of taking part?NoneWhat if something goes wrong?If you have any cause to complain about any aspect of the way in which you have been approached or treated during the course of this study, the normal National Health Service complaints mechanisms are available to you and are not compromised in any way because you have taken part in a research study. If you have any complaints or concerns please contact the project co-ordinator: (Dr Anjum Deorukhkar on telephone 01302 366666 ext 3166). Will my baby’s taking part in this study be kept confidential?All information, which is collected, about your baby during the course of the research will be kept strictly confidential. Any information about your baby, which leaves the hospital/surgery, will have your name and address removed so that you cannot be recognised from it. What will happen to the results of the research study?When the study finishes all the results will be analysed, which may lead to a publication in a medical journal. At no time will any identifying information will be published and all records will remain confidential. If you wish we will forward you the published report of the study.Who is organising and funding the research?The research is being organised by the neonatal intensive care unit at Women’s Hospital Doncaster Royal Infirmary, Doncaster. There is no outside funding or financial incentive to this study.Who has reviewed the study?The South Sheffield Ethics Committee and the Doncaster Research Ethics Committee.Contacts for Further InformationDr. A Deorukhkar, Neonatal intensive care unit, Women’s Hospital DRI Doncaster, Telephone: 01302 366666 ext 3166Thank you for reading this information sheet.?Appendix SEQ Appendix \* ARABIC 9. Study A & B Consent formCONSENT FORM FOR PARTICIPATION OF CHILDTitle of Project: Amylin peptide: Association with feed intolerance in preterm infants and IMDM.Patient Identification Number:Centre Number:Study Number:Name of Researchers: V Kairamkonda, A Mayer, A Deorukhkar, R Coombs, R FraserPlease initial box4686300762000I confirm that I have read and understand the information sheet Version 14/8/00 for the above study and have had the opportunity to ask questions.468630014097000I understand that my participation is voluntary and that I am free to withdraw at any time, without giving any reason, without my medical care or legal rights being affected.46863006477000I understand that sections of any of my medical notes may be looked at by responsible individuals from research team or from regulatory authorities where it is relevant to my taking part in research. I give permission for these individuals to have access to my records.468630013525500I agree to take part in the above study._______________________________________ ___________________Name of PatientDateSignature_________________________________________ ___________________Name of Person taking consentDateSignatureOriginal to be kept in baby’s medical notes; 1 copy to parent; 1 copy for research fileAppendix SEQ Appendix \* ARABIC 10. Study C Consent formCONSENT FORM FOR PARTICIPATION OF CHILDTitle of Project: Amylin peptide: Association with feed intolerance in preterm infants.Patient Identification Number:Centre Number:Study Number:Name of Researchers: V Kairamkonda, A Mayer, A Deorukhkar, R Coombs, R FraserPlease initial box4686300762000I confirm that I have read and understand the information sheet Version 14/8/00 for the above study and have had the opportunity to ask questions.468630014097000I understand that my participation is voluntary and that I am free to withdraw at any time, without giving any reason, without my medical care or legal rights being affected.46863006477000I understand that sections of any of my medical notes may be looked at by responsible individuals from research team or from regulatory authorities where it is relevant to my taking part in research. I give permission for these individuals to have access to my records.468630013525500I agree to take part in the above study._______________________________________ ___________________Name of PatientDateSignature_________________________________________ ___________________Name of Person taking consentDateSignatureOriginal to be kept in baby’s medical notes; 1 copy to parent; 1 copy for research fileAppendix SEQ Appendix \* ARABIC 11. Advert for Study AAMYLIN STUDYDear ParentsFeed intolerance is a common problem in babies admitted to neonatal intensive care unit. Amylin is a newly discovered hormone that potently inhibits the function of the stomach. We are conducting a study to measure amylin levels in the hope that this may shed some light on this difficult problem.The study involves taking blood from your baby at birth from discarded umbilical cord and at day 5 routine Guthrie (few drops)If you would like further information or interested in taking part, please contact staff on the unit OR Dr Venkatesh Kairamkonda, Specialist Registrar 0114228456/68356 OR Dr Anjum Deorukhkar, clinical research fellow 0114228456/68356.Appendix SEQ Appendix \* ARABIC 12. Advert for Study BAMYLIN STUDY Dear ParentsFeed intolerance is a common problem in babies born to mothers whose pregnancy was complicated by diabetes. Amylin is a newly discovered hormone that potently inhibits the function of the stomach. We are conducting a study to measure amylin levels in the hope that this may shed some light on this difficult problem.The study involves taking blood from your baby at birth from discarded umbilical cord and at day 5 routine Guthrie (few drops)If you would like further information or interested in taking part, please contact staff on the unit OR Dr Venkatesh Kairamkonda, Specialist Registrar 0114228456/68356 OR Dr Anjum Deorukhkar, clinical research fellow 0114228456/68356.Appendix SEQ Appendix \* ARABIC 13. Advert for Study CAMYLIN STUDY Dear ParentsFeed intolerance is a common problem in babies admitted to neonatal intensive care unit. Amylin is a newly discovered hormone that potently inhibits the function of the stomach. We are conducting a study to measure amylin levels in the hope that this may shed some light on this difficult problem.The study involves taking a small sample of your baby’s blood during routine collection (few drops). If you would like further information or interested in taking part, please contact staff on the unit OR Dr Venkatesh Kairamkonda, Specialist Registrar 0114228456/68356 OR Dr Anjum Deorukhkar, clinical research fellow 0114228456/68356.Appendix SEQ Appendix \* ARABIC 14. Case report form Study ACASE REPORT FORM STUDY AStudy IDDateBaby details Patient StickerNameMale/FemaleDate of BirthHospital NumberAddressBaby DetailsBirth weightGestational ageGrowth TypeAGASGALGADate of blood samplingNumber of blood samplesCord blood sampleArterialVenousBothPostnatal blood sampleyesnoGuthrie sampleyesnoMode of deliveryAPGARAPGAR1APGAR5APGAR10ResuscitationyesnoETVentilation/CPAPyesnoSepsisyesnoMaternal DetailsMaternal DiagnosisPROMyesnoChorioamnionitisyesnoAntenatal steroidsyesnoMedicationsAppendix SEQ Appendix \* ARABIC 15. Case report form Study BCASE REPORT FORM STUDY BStudy IDDateBaby details Patient StickerNameMale/FemaleDate of BirthHospital NumberAddressBaby DetailsBirth weightGestational ageGrowth TypeAGASGALGADate of blood samplingNumber of blood samplesCord blood sampleArterialVenousBothPostnatal blood sampleyesnoGuthrie sampleyesnoMode of deliveryCSInstrumentalNormalAPGARAPGAR1APGAR5APGAR10ResuscitationyesnoETVentilation/CPAPyesyesSepsisyesnoFeed intoleranceyesnoMaternal DetailsMaternal DiagnosisDiabetes TypeGDMIDDMNIDDMPROMyesnoChorioamnionitisyesnoAntenatal steroidsyesnoMedicationsAppendix SEQ Appendix \* ARABIC 16. Case report form Study CCASE REPORT FORM STUDY CStudy IDDateBaby details Patient StickerNameMale/FemaleDate of BirthHospital NumberAddressBaby DetailsDOADODBirth weightGestational ageGrowth TypeAGASGALGADate of blood samplingNumber of blood samplesCord blood sampleArterialVenousBothPostnatal blood sampleyesnoGuthrie sampleyesnoMode of deliveryCSInstrumentalNormalAPGARAPGAR1APGAR5APGAR10ResuscitationyesnoET Ventilation/CPAPyesnoSepsisyesnoMedicationsTPNyesnoAge at feed intoleranceType of feedVolume of feedMethod of feed% aspirateColour of aspirateDays to full feedsDays to dischargeWCC (differential count)Platelet countCRPBlood cultureMaternal DetailsMaternal DiagnosisSignificant Antenatal/natal/postnatal historyyesnoPROMyesnoChorioamnionitisyesnoAntenatal steroidsyesnoMedicationsBibliography ADDIN EN.REFLIST Abaffy, T. and G. J. Cooper (2004). "GSK3 involvement in amylin signaling in isolated rat soleus muscle." Peptides 25(12): 2119-25.Abell, T. L., M. Camilleri, et al. (2008). 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