ME Australia



Widespread Pain and altered Renal Function in MECFS Patients.Neil R. McGregor1 PhD.Christopher W. Armstrong2 BSc.Donald P. Lewis3 MBBS.Henry L. Butt4 PhD.Paul R. Gooley2 PhD.Correspondence:Neil McGregorHonorary Senior Fellow Faculty of Medicine, Dentistry and Health Sciences,University of Melbourne4a Wilmot StreetMalvern East 3145Victoria, Australia.Email: neilm@unimelb.edu.auFaculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville VIC 3010, Australia. Telephone: 61 0412469832, email: neilm@unimelb.edu.auDepartment of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biochemistry Institute, 30 Flemington Road, Parkville, VIC 3010, Australia. Telephone: 61 383481421, email: prg@unimelb.edu.auCFS Discovery, Donvale Medical Centre, 90 Mitcham Road, Donvale, VIC 3111, Australia. Telephone: 61 398414500, email: dplewis@.auBioscreen (Aust) Pty Ltd, 5 Little Hyde Street, Yarraville, VIC 3013, Australia. Telephone: 61 396873355, email: hbutt@Abbreviations: FP Facial pain; NoFP No Facial Pain; MECFS Myalgic encephalomyelitis/Chronic Fatigue Syndrome; eGRF estimated glomelular Filtration rate; GRF Glomelular Filtration rateAbstract: Background: Widespread pain is noted in many patients with Chronic Fatigue Syndrome (MECFS), Fibromyalgia (FM) and Temporomandibular disorders (TMD). These conditions usually start as a localized condition and spread to a widespread pain condition with increasing illness duration. Purpose: To assess the changes in biochemistry associated with pain expression and alterations in renal function. Methods: Forty-seven MECFS patients and age/sex matched controls had: a clinical examination, completed questionnaires, standard serum biochemistry, glucose tolerance tests and serum and urine metabolomes in an observational study. Results: Increases in pain distribution were associated with reductions in serum essential amino acids, urea, serum sodium and increases in serum glucose and the 24-hour urine volume however the biochemistry was different for each pain area. Regression modelling revealed potential acetylation and methylation defects in the pain subjects. Conclusions: These findings confirm and extend our earlier findings. These changes appear consistent with repeated minor inflammatory mediated alterations in kidney function resulting in essential amino acid deprivation and inhibition of protein synthesis and genetic translation within tissues.Key Words: Fatigue Syndrome, Chronic; Fibromyalgia, Kidney Concentrating Ability; Facial Pain; Acetylation; Betaine;IntroductionChronic fatigue syndrome (MECFS) patients frequently report widespread musculoskeletal pain or fibromyalgia and Temporomandibular disorders (TMD) PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkFhcm9uPC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA 1. Importantly patients diagnosed to have fibromyalgia also report a high level of fatigue ADDIN REFMGR.CITE <Refman><Cite><Author>Goldenberg</Author><Year>1990</Year><RecNum>2415</RecNum><IDText>High frequency of fibromyalgia in patients with chronic fatigue seen in a primary care practice</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2415</Ref_ID><Title_Primary>High frequency of fibromyalgia in patients with chronic fatigue seen in a primary care practice</Title_Primary><Authors_Primary>Goldenberg,D.L.</Authors_Primary><Authors_Primary>Simms,R.W.</Authors_Primary><Authors_Primary>Geiger,A.</Authors_Primary><Authors_Primary>Komaroff,A.L.</Authors_Primary><Date_Primary>1990/3</Date_Primary><Keywords>Adult</Keywords><Keywords>Bone and Bones</Keywords><Keywords>Comparative Study</Keywords><Keywords>complications</Keywords><Keywords>diagnosis</Keywords><Keywords>epidemiology</Keywords><Keywords>Evaluation Studies</Keywords><Keywords>Fatigue</Keywords><Keywords>Fatigue Syndrome,Chronic</Keywords><Keywords>Female</Keywords><Keywords>Fibromyalgia</Keywords><Keywords>history</Keywords><Keywords>Human</Keywords><Keywords>methods</Keywords><Keywords>Middle Age</Keywords><Keywords>Muscles</Keywords><Keywords>Musculoskeletal Pain</Keywords><Keywords>Pain</Keywords><Keywords>pathology</Keywords><Keywords>Patients</Keywords><Keywords>Physical Examination</Keywords><Keywords>Primary Health Care</Keywords><Keywords>Support,Non-U.&apos;t</Keywords><Keywords>Support,U.&apos;t,P.H.S.</Keywords><Keywords>Syndrome</Keywords><Keywords>United States</Keywords><Reprint>Not in File</Reprint><Start_Page>381</Start_Page><End_Page>387</End_Page><Periodical>Arthritis Rheum.</Periodical><Volume>33</Volume><Issue>3</Issue><Address>Arthritis-Fibrositis Center, Newton-Wellesley Hospital, MA 02162</Address><Web_URL>PM:2317224</Web_URL><ZZ_JournalStdAbbrev><f name="System">Arthritis Rheum.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>2. A twin study of these conditions revealed that fatigued twins were >20 fold more likely to be diagnosed with fibromyalgia and 4 fold more likely to be diagnosed with TMD PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkFhcm9uPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA 3. Whilst the relationship between these conditions is observed very little is known of their underlying etiology or pathophysiology.A recent study of comorbidities using a group with Temporomandibular disorders (TMD) linked TMD severity and duration with widespread pain presentation, chronic fatigue syndrome (MECFS) and irritable bowel symptoms (IBS) PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkRhaGFuPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA 4 suggesting that they may have a common underlying mechanism as they exacerbate at the same time. These findings are consistent with our groups earlier studies linking the same potential comorbid conditions PFJlZm1hbj48Q2l0ZT48QXV0aG9yPk1jR3JlZ29yPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48

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ADDIN EN.CITE.DATA 5. In a previous study it was observed that widespread pain was associated with reductions in urinary excretion of amino acids and that serum sodium levels were associated with higher face pain score in females ADDIN REFMGR.CITE <Refman><Cite><Author>McGregor</Author><Year>2000</Year><RecNum>19307</RecNum><IDText>An investigation of the association between toxin-producing staphylococcus, biochemical changes and jaw muscle pain.</IDText><MDL Ref_Type="Thesis/Dissertation"><Ref_Type>Thesis/Dissertation</Ref_Type><Ref_ID>19307</Ref_ID><Title_Primary>An investigation of the association between toxin-producing staphylococcus, biochemical changes and jaw muscle pain.</Title_Primary><Authors_Primary>McGregor,N.R.</Authors_Primary><Date_Primary>2000</Date_Primary><Keywords>Jaw</Keywords><Keywords>Pain</Keywords><Keywords>Staphylococcus</Keywords><Keywords>Temporomandibular Joint Disorders</Keywords><Reprint>Not in File</Reprint><Start_Page>1</Start_Page><End_Page>150</End_Page><Publisher>University of Sydney</Publisher><Misc_1>PhD</Misc_1><Misc_2>Thesis</Misc_2><Address>Parramatta Road, Sydney</Address><ZZ_WorkformID>29</ZZ_WorkformID></MDL></Cite></Refman>6. This study also identified that these changes were greater with the increasing duration of the illness PFJlZm1hbj48Q2l0ZT48QXV0aG9yPk1jR3JlZ29yPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48

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ADDIN EN.CITE.DATA 7. An inflammatory related change in renal function appeared to be associated with the development of the widespread pain and facial pain. Thus these interesting observations need to be assessed in a better designed study in an attempt to delineate the biochemical relationships.The objective of this paper is to assess pain severity and frequency of multiple body areas including the face, and the related biochemistry (Blood and urine) in MECFS patients and controls. This will be assessed as severity responses within the last 7-days and their frequency over a 12-month period. These will be assessed for their association with inflammation and the previously observed alterations in renal function. Subjects were assessed using standard serum biochemistry, a 24-hour urine assessment and a blood and urine metabolome.Methods.Forty-six patients with MECFS and twenty-six, fatigue free, age and sex-matched healthy individuals were recruited. Obtaining an age and sex matched control was undertaken by placing advertisements on University billboards and selecting from those patient of the same sex and age (±5 years) and these patients were than assessed using the same clinical examinations. The MECFS group comprised patients that are currently symptomatic and diagnosed as having MECFS in accordance to the Canadian guidelines and its exclusionary criteria PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkNhcnJ1dGhlcnM8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFy

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ADDIN EN.CITE.DATA 8. A Depression Anxiety Stress assessment (DASS) was used to assess their psychiatric comorbidity. Only those MECFS subjects who complied with the criteria were included in the study. All subjects were asked to list their drugs and oral supplements. None of the subjects were related to one another nor were they ever living together. All subjects signed consent forms. This study was approved by the University of Melbourne human research ethics committee (HREC# 0723086).Clinical measuresThe patients had a full clinical examination and were questioned about their illness, onset, family histories to determine whether they complied with the Canadian ME/CFS guidelines. All subjects completed several questionnaires, including a large symptom questionnaire developed for chronic pain research ADDIN REFMGR.CITE <Refman><Cite><Author>McGregor</Author><Year>2000</Year><RecNum>19307</RecNum><IDText>An investigation of the association between toxin-producing staphylococcus, biochemical changes and jaw muscle pain.</IDText><MDL Ref_Type="Thesis/Dissertation"><Ref_Type>Thesis/Dissertation</Ref_Type><Ref_ID>19307</Ref_ID><Title_Primary>An investigation of the association between toxin-producing staphylococcus, biochemical changes and jaw muscle pain.</Title_Primary><Authors_Primary>McGregor,N.R.</Authors_Primary><Date_Primary>2000</Date_Primary><Keywords>Jaw</Keywords><Keywords>Pain</Keywords><Keywords>Staphylococcus</Keywords><Keywords>Temporomandibular Joint Disorders</Keywords><Reprint>Not in File</Reprint><Start_Page>1</Start_Page><End_Page>150</End_Page><Publisher>University of Sydney</Publisher><Misc_1>PhD</Misc_1><Misc_2>Thesis</Misc_2><Address>Parramatta Road, Sydney</Address><ZZ_WorkformID>29</ZZ_WorkformID></MDL></Cite></Refman>6. It asked patients to score how severe a symptom was in the last 7 days (0-4 scalar response) and how frequently the symptom occurred over the last 12-month period (0-4 scalar response), as previously published PFJlZm1hbj48Q2l0ZT48QXV0aG9yPk5pYmxldHQ8L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 9. The 7-day severity and 12-month frequency scores were designed to differentiate between acute and chronic responses. These 7 day and 12 month assessments have been assessed against the biochemistry and found to differentiate between an acute response and a chronic event (unpublished data). These questionnaires were checked by the reception staff and the medical clinician (DL).Biochemistry assessments.The sample collection and processing has previously been published ADDIN REFMGR.CITE <Refman><Cite><Author>Armstrong</Author><Year>2015</Year><RecNum>43643</RecNum><IDText>Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in chronic fatigue syndrome.</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>43643</Ref_ID><Title_Primary>Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in chronic fatigue syndrome.</Title_Primary><Authors_Primary>Armstrong,C.W.</Authors_Primary><Authors_Primary>McGregor,N.R.</Authors_Primary><Authors_Primary>Lewis,D.P.</Authors_Primary><Authors_Primary>Butt,H.L.</Authors_Primary><Authors_Primary>Gooley,P.R.</Authors_Primary><Date_Primary>2015/5/30</Date_Primary><Keywords>Energy Metabolism</Keywords><Keywords>metabolism</Keywords><Keywords>Oxidative Stress</Keywords><Keywords>Stress</Keywords><Keywords>Fatigue</Keywords><Keywords>Syndrome</Keywords><Reprint>In File</Reprint><Start_Page>1626</Start_Page><Periodical>Metabolomics</Periodical><Volume>11</Volume><Issue>6</Issue><ZZ_JournalFull><f name="System">Metabolomics</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>10 and are given in summary. Subjects had a phlebotomy for serum chemistry, a 24-hour urine collection, a glucose tolerance test and all performed a standing test during which blood pressure and transcutaneous PO2 was measured. Only 9 controls had a 24-hour urine. Standard serum biochemistry was performed at a commercial (NATA accredited) laboratory. Serum osmolality was calculated using the formula ((Sodium x 2) + Glucose + Urea). Urine osmolality was calculated by a publish formula PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkltYW11cmE8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 11. A second urine sample was collected upon rising by each subject at their home and stored at 4?C and within 6 hours a blood sample was then taken by venipuncture into BD Vacutainer? blood collection tubes. All samples were stored at -80 ?C prior to performing an NMR analysis using a liquid-liquid extraction technique in a Bruker Avance US 2 spectrometer. The compound libraries in the Chenomx software were used to identify and quantitate the metabolites. Metabolite identities were confirmed using 2D TOCSY experiments with TOPSPIN 1.3 software. Twenty-nine metabolites per blood serum sample and thirty metabolites per urine sample were identified. The level of creatinine in the blood is a useful guide to kidney function, and can be used to estimate the Glomerular filtration rate (eGFR). This is a validated assessment and the criteria from the Kidney Disease Outcomes Quality Initiative guidelines () was used in this study. They are: >90 mL/min/1.73m2?- normal GFR.60 - 89 mL/min/1.73m2?- mild reduction in GFR.30 - 59 mL/min/1.73m2?- moderate reduction in GFR.Data AnalysisThe metabolome data were prepared as raw data (?M) and as relatively distributed data (%) by dividing each metabolite concentration by the total concentration of metabolites quantified in each sample. The parametric data prior to statistical analysis was assessed for normality and log converted if not normally distributed. All percentage data were arcsine converted for analysis. The dataset was evaluated using Statistica for Windows Ver. 12.0 (StatSoft Inc., Tulsa, USA) using statistical calculations, including t-tests and Pearson correlation coefficients, ANOVA and multivariate analysis. The nonparametric data was assessed using Spearman rank correlations, Mann-Whitney U-tests or Kruskal-Wallis ANOVA. Small sample frequency data were assessed with Fisher exact Chi square analysis (χ2). Multiplicity correction was carried out on the data based upon the number of variables assessed in each statistical test.Results.Demographics.In the whole group (N=72) the following pain distribution was noted. Headache 49 (C=44% v MECFS=83%), Face Pain 22 (C=0% v MECFS=48%), Neck pain 38 (C=20% v MECFS=78%), Shoulder 46 (C=28% v MECFS=85%), Chest Pain 31 (C=8% v MECFS=63%), Arm Pain 39 (C=4% v MECFS=83%), Low back Pain 40 (C=16% v MECFS=78%), Leg Pain 42 (C=16% v MECFS=83%). Eight controls (11.3% of total group) but no MECFS patients were pain free, 22 (C=60% v MECFS=13%) had 1 to 3 pain locations, 19 (C=8% v MECFS=41%) had 4 -5 pain locations, and 22 (C=0 v MECFS=28%) had pain in ≥6 locations. Face pain was only found in the MECFS patients in this sample so to examine the pain biochemistry we chose to divide the MECFS group on this basis for the analysis as it had less potential confounders and face pain had a relatively unique pain associated biochemistry. The other analyses are available as supplementary data.Table 1 shows the patient demographics for the MECFS patients divided on the basis of presence or absence of face pain (FP and NoFP) and the control group. No differences were found for sudden v gradual onset or triggers at onset, such as infections or trauma.Symptoms.Table 1 also shows the distribution of body pain symptoms across the groups. Whilst the widespread pain distribution and the cumulative severity scores were increased in the FP group compared with both the NoFP and control groups this only related to increases in only five areas of pain (headaches, face, neck/shoulder and low back). Table 2 shows the distribution of potential inflammatory or exacerbating symptoms for each group. Table 3 shows the correlation analysis of the various potentially inflammatory or exacerbating symptoms associated with face pain scores, body distribution scores and the cumulative pain scores within the MECFS patients. The 7-Day febrile score was associated with pain symptom expression but not the 12-month frequency score. Food intolerance, including cases of gluten intolerance, were associated with widespread pain. Interestingly irritable bowel symptom scores did not correlate with widespread pain within the MECFS patients even though it did if the controls were included in the correlation analysis.Assessment of renal function (Estimated Glomerular Filtration Rate - eGFR). Only one NoFP patient had an eGFR of 59 and 31 of the 43 MECFS patients (72.1%) had an eGFR between 60 and 89 suggestive of mild changes in renal function (74% abnormal). Table 4 shows the eGFR for each group. Table 5 shows the eGFR was positively correlated with the pain scores, showing that a reduction in renal function was not related to the pain scores. No association was found between the Body Mass index (BMI), the drugs being taken and the eGFR.Biochemistry.Table 4 shows a summary of the renal function measure differences between the groups. A pattern of increased glucose and 24-hour urine volume, and reduced urea, lysine and, phenylalanine were observed to relate to increased pain scores. None of these factors correlated with the subjects BMI. Three subjects (all FP) had a serum urea below the normal two standard deviation range for Caucasians in the US (Males 3.46-11.86 mmol/L; females 3.21-10.33 mmol/L) ADDIN REFMGR.CITE <Refman><Cite><Author>Estrada</Author><Year>2001</Year><RecNum>21</RecNum><IDText>Racial variation in fasting and random homocysteine levels</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>21</Ref_ID><Title_Primary>Racial variation in fasting and random homocysteine levels</Title_Primary><Authors_Primary>Estrada,D.A.</Authors_Primary><Authors_Primary>Billett,H.H.</Authors_Primary><Date_Primary>2001/4</Date_Primary><Keywords>African Continental Ancestry Group</Keywords><Keywords>genetics</Keywords><Keywords>Blood Urea Nitrogen</Keywords><Keywords>Body Mass Index</Keywords><Keywords>Creatinine</Keywords><Keywords>blood</Keywords><Keywords>European Continental Ancestry Group</Keywords><Keywords>Fasting</Keywords><Keywords>Female</Keywords><Keywords>Folic Acid</Keywords><Keywords>Genetic Predisposition to Disease</Keywords><Keywords>Homocysteine</Keywords><Keywords>Humans</Keywords><Keywords>Hyperhomocysteinemia</Keywords><Keywords>ethnology</Keywords><Keywords>Lipids</Keywords><Keywords>Male</Keywords><Keywords>New York City</Keywords><Keywords>epidemiology</Keywords><Keywords>Personnel,Hospital</Keywords><Keywords>Random Allocation</Keywords><Keywords>Reference Values</Keywords><Keywords>Time Factors</Keywords><Keywords>Vitamin B 12</Keywords><Reprint>Not in File</Reprint><Start_Page>252</Start_Page><End_Page>256</End_Page><Periodical>Am.J.Hematol.</Periodical><Volume>66</Volume><Issue>4</Issue><Misc_3>10.1002/ajh.1053 [doi]</Misc_3><Address>Division of Hematology, Department of Medicine, Montefiore Medical Center of the Albert Einstein College of Medicine, Bronx, New York 10467, USA</Address><Web_URL>PM:11279635</Web_URL><ZZ_JournalStdAbbrev><f name="System">Am.J.Hematol.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>12. Multiple regression modelling was used to identify the metabolites of significance for pain development and they were predominately a fall in acetate and an increase in betaine (supplemental data available). However, the increasing pain body distribution was also associated with increases in glucose and falls in acetate, lysine and phenylalanine.Table 5 (a heat map) shows the correlation analysis of the metabolites against the pain scores. For the whole study group, the 7-Day severity scores strongly negatively correlated with serum phenylalanine, acetate and osmolality, and urine urea and acetate. For the 12-month frequency scores serum phenylalanine and urine urea were the strongest correlates followed by both serum and urine acetate (all negative). For the MECFS patients no metabolite reached statistical significance at p<.01. The 24-hour urine volume correlated positively with 7-day face pain severity.Table 6 (a heat map) shows the changes in the metabolite associations within the 3 study groups and the assessment of their statistical differences between the groups. The patterns of metabolite correlations were significantly different between the groups. Discriminant Function analysis models using the variables within table 5 revealed significant models for: FP v Control (Wilk’s Lambda= .353, F(11,35) =5.83 p<.0000) with 3 variables identified: Betaine (p<.001), Phenylalanine (p<.03) and Glucose (p<.04).NoFP v Control (Wilk’s Lambda= .611, F(11,38) =2.19 p<.04) with 1 variable identified: Glucose (p<.04).NoFP v FP (Wilk’s Lambda= .524, F(11,35) =2.88 p<.008) with 2 variables identified: 24-hour urine volume (p<.008) and Betaine (p<.02). These analyses identify glucose, phenylalanine, betaine and 24-hour urine volume as the best predictors of the group differences.Discussion.This paper has confirmed many of the associations identified in other studies, namely the associations with: face pain and widespread pain; MECFS; irritable bowel syndrome; and inflammatory/infective events (the subjective feelings of infection) PFJlZm1hbj48Q2l0ZT48QXV0aG9yPk1jR3JlZ29yPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48

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ADDIN EN.CITE.DATA 5. Assessment of the findings within the MECFS cohort did not confirm the association between irritable bowel and face or widespread pain. However, it did identify a potential association with food intolerance, possibly gluten intolerance, which some may report as irritable bowel.This paper has confirmed our earlier finding of a change in renal function, urea and amino acids being associated with face and widespread pain PFJlZm1hbj48Q2l0ZT48QXV0aG9yPk1jR3JlZ29yPC9BdXRob3I+PFllYXI+MjAwMDwvWWVhcj48

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ADDIN EN.CITE.DATA 6;7. The fall in urea was associated with a reduction in serum essential amino acids, in particular phenylalanine and lysine, and the non-essential amino acids, which facilitate urea production within the urea cycle. It was not associated with changes in the BMI or eGFR. These data are consistent with the observations of urea cycle associated amino acid differences in fibromyalgia and MECFS PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkFybXN0cm9uZzwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+

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ADDIN EN.CITE.DATA 7.These changes are very similar to the renal changes seen in Central Diabetes Insipidus ADDIN REFMGR.CITE <Refman><Cite><Author>Comtois</Author><Year>1988</Year><RecNum>2933</RecNum><IDText>Low serum urea level in dehydrated patients with central diabetes insipidus</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2933</Ref_ID><Title_Primary>Low serum urea level in dehydrated patients with central diabetes insipidus</Title_Primary><Authors_Primary>Comtois,R.</Authors_Primary><Authors_Primary>Bertrand,S.</Authors_Primary><Authors_Primary>Beauregard,H.</Authors_Primary><Authors_Primary>Vinay,P.</Authors_Primary><Date_Primary>1988/11/15</Date_Primary><Keywords>Adult</Keywords><Keywords>Creatinine</Keywords><Keywords>blood</Keywords><Keywords>urine</Keywords><Keywords>Dehydration</Keywords><Keywords>Diabetes Insipidus</Keywords><Keywords>Female</Keywords><Keywords>Fluid Therapy</Keywords><Keywords>Humans</Keywords><Keywords>Hypernatremia</Keywords><Keywords>Male</Keywords><Keywords>Middle Aged</Keywords><Keywords>Osmolar Concentration</Keywords><Keywords>Prospective Studies</Keywords><Keywords>Retrospective Studies</Keywords><Keywords>Urea</Keywords><Keywords>Vasopressins</Keywords><Keywords>pharmacology</Keywords><Reprint>Not in File</Reprint><Start_Page>965</Start_Page><End_Page>969</End_Page><Periodical>CMAJ.</Periodical><Volume>139</Volume><Issue>10</Issue><User_Def_5>PMC1268390</User_Def_5><Address>Department of Medicine, Notre-Dame Hospital, University of Montreal, PQ</Address><Web_URL>PM:3179869</Web_URL><ZZ_JournalStdAbbrev><f name="System">CMAJ.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>15, protein-calorie restriction PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkNoYXV2ZWF1PC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48

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ADDIN EN.CITE.DATA 17-19. However, no subjects had Diabetes Insipidus or were protein calorie restricted, and all had average BMI’s, which supports an inflammatory origin. The FP and widespread pain group had a higher level of reporting of infectious events and scalar responses (table 2) as previously reported PFJlZm1hbj48Q2l0ZT48QXV0aG9yPk1jR3JlZ29yPC9BdXRob3I+PFllYXI+MTk5NjwvWWVhcj48

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ADDIN EN.CITE.DATA 19. In support of this, urea is produced in the kidney by arginase 2 and deprivation of protein will induce a fall in urea and arginase activity ADDIN REFMGR.CITE <Refman><Cite><Author>Aperia</Author><Year>1979</Year><RecNum>1664</RecNum><IDText>Studies of renal urea cycle enzymes. I. Renal concentrating ability and urea cycle enzymes in the rat during protein deprivation</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>1664</Ref_ID><Title_Primary>Studies of renal urea cycle enzymes. I. Renal concentrating ability and urea cycle enzymes in the rat during protein deprivation</Title_Primary><Authors_Primary>Aperia,A.</Authors_Primary><Authors_Primary>Broberger,O.</Authors_Primary><Authors_Primary>Larsson,A.</Authors_Primary><Authors_Primary>Snellman,K.</Authors_Primary><Date_Primary>1979/6</Date_Primary><Keywords>Animals</Keywords><Keywords>Arginase</Keywords><Keywords>Arginine</Keywords><Keywords>Argininosuccinate Lyase</Keywords><Keywords>Argininosuccinate Synthase</Keywords><Keywords>Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)</Keywords><Keywords>Chromatography,Thin Layer</Keywords><Keywords>complications</Keywords><Keywords>deficiency</Keywords><Keywords>Diet</Keywords><Keywords>Enzymes</Keywords><Keywords>enzymology</Keywords><Keywords>etiology</Keywords><Keywords>Growth</Keywords><Keywords>Growth Disorders</Keywords><Keywords>Kidney</Keywords><Keywords>Kidney Concentrating Ability</Keywords><Keywords>Liver</Keywords><Keywords>Male</Keywords><Keywords>Malnutrition</Keywords><Keywords>metabolism</Keywords><Keywords>Ornithine</Keywords><Keywords>Ornithine Carbamoyltransferase</Keywords><Keywords>physiopathology</Keywords><Keywords>Protein Deficiency</Keywords><Keywords>Rats</Keywords><Keywords>Serum</Keywords><Keywords>Urea</Keywords><Keywords>urine</Keywords><Keywords>Water-Electrolyte Balance</Keywords><Reprint>Not in File</Reprint><Start_Page>329</Start_Page><End_Page>336</End_Page><Periodical>Scand.J.Clin.Lab Invest</Periodical><Volume>39</Volume><Issue>4</Issue><Web_URL>PM:523984</Web_URL><ZZ_JournalStdAbbrev><f name="System">Scand.J.Clin.Lab Invest</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>21. The Arginase II gene (ARG2) has NF-Kappa-β binding sites in the promoter region and is altered by inhibition of NF-Kappa-β PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkVzcGFub2w8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 23 and its levels have been reported to be elevated in MECFS patients PFJlZm1hbj48Q2l0ZT48QXV0aG9yPk1hZXM8L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFyPjxSZWNO

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ADDIN REFMGR.CITE PFJlZm1hbj48Q2l0ZT48QXV0aG9yPk1hZXM8L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA 24. In that study there were significant positive correlations between the production of NF-Kappa-β and the severity of illness as measured with the FibroFatigue scale and with symptoms, such as aches and pain, muscular tension, fatigue, irritability, sadness, and the subjective feeling of infection PFJlZm1hbj48Q2l0ZT48QXV0aG9yPk1hZXM8L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA 24. The action of upregulation of kidney arginase during inflammation is to remove excess nitrogen from the system after its release from muscle and tissue stores. Based upon these observations we originally proposed a model of repeated inflammatory stimuli initiating an aminoaciduria and electrolyte loss which resulted in the development of an amino acid deficiency and a change in electrolyte balance and the subsequent development of widespread pain ADDIN REFMGR.CITE <Refman><Cite><Author>McGregor</Author><Year>2000</Year><RecNum>19307</RecNum><IDText>An investigation of the association between toxin-producing staphylococcus, biochemical changes and jaw muscle pain.</IDText><MDL Ref_Type="Thesis/Dissertation"><Ref_Type>Thesis/Dissertation</Ref_Type><Ref_ID>19307</Ref_ID><Title_Primary>An investigation of the association between toxin-producing staphylococcus, biochemical changes and jaw muscle pain.</Title_Primary><Authors_Primary>McGregor,N.R.</Authors_Primary><Date_Primary>2000</Date_Primary><Keywords>Jaw</Keywords><Keywords>Pain</Keywords><Keywords>Staphylococcus</Keywords><Keywords>Temporomandibular Joint Disorders</Keywords><Reprint>Not in File</Reprint><Start_Page>1</Start_Page><End_Page>150</End_Page><Publisher>University of Sydney</Publisher><Misc_1>PhD</Misc_1><Misc_2>Thesis</Misc_2><Address>Parramatta Road, Sydney</Address><ZZ_WorkformID>29</ZZ_WorkformID></MDL></Cite></Refman>6. This study supports that hypothesis. A fall in the essential amino acids, phenylalanine and lysine, would interfere with intracellular protein synthesis and DNA translation through a Eukaryotic initiation factor kinase 2 (EIF2) mechanism ADDIN REFMGR.CITE <Refman><Cite><Author>Kimball</Author><Year>2001</Year><RecNum>1855</RecNum><IDText>Regulation of translation initiation by amino acids in eukaryotic cells</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>1855</Ref_ID><Title_Primary>Regulation of translation initiation by amino acids in eukaryotic cells</Title_Primary><Authors_Primary>Kimball,S.R.</Authors_Primary><Date_Primary>2001</Date_Primary><Keywords>Adaptor Proteins,Signal Transducing</Keywords><Keywords>Amino Acids,Essential</Keywords><Keywords>metabolism</Keywords><Keywords>Animals</Keywords><Keywords>Carrier Proteins</Keywords><Keywords>DNA-Binding Proteins</Keywords><Keywords>Eukaryotic Initiation Factor-2</Keywords><Keywords>Eukaryotic Initiation Factor-2B</Keywords><Keywords>Fungal Proteins</Keywords><Keywords>genetics</Keywords><Keywords>Humans</Keywords><Keywords>Models,Biological</Keywords><Keywords>Peptide Chain Initiation,Translational</Keywords><Keywords>physiology</Keywords><Keywords>Phosphoproteins</Keywords><Keywords>Phosphorylation</Keywords><Keywords>Protein Kinases</Keywords><Keywords>Protein-Serine-Threonine Kinases</Keywords><Keywords>RNA,Fungal</Keywords><Keywords>RNA,Messenger</Keywords><Keywords>RNA,Transfer,Met</Keywords><Keywords>Ribosomal Protein S6 Kinases</Keywords><Keywords>Ribosomes</Keywords><Keywords>Saccharomyces cerevisiae</Keywords><Keywords>Saccharomyces cerevisiae Proteins</Keywords><Keywords>Signal Transduction</Keywords><Keywords>eIF-2 Kinase</Keywords><Reprint>Not in File</Reprint><Start_Page>155</Start_Page><End_Page>184</End_Page><Periodical>Prog.Mol.Subcell.Biol.</Periodical><Volume>26</Volume><Address>Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA</Address><Web_URL>PM:11575165</Web_URL><ZZ_JournalStdAbbrev><f name="System">Prog.Mol.Subcell.Biol.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>25. Possibly also involved would be insulin resistance mediated amino acid uptake as evidenced by the association with increasing blood glucose PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkJpb2xvPC9BdXRob3I+PFllYXI+MTk5NTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA 26;27. The MECFS patients do have an anomaly in insulin excretion in this study (Data to be published separately) which supports this conclusion. Also involved in the wide pain development is the fall in acetate, which indicates a disturbance of acetylation, and the increase in betaine, which may indicate a disturbance in methylation PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkFsYW1kYXJpPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

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ADDIN EN.CITE.DATA 28;29. The reduction in lysine observed, only in the pain subjects, may be of critical importance, as acetate binding to lysine residues within enzymatic proteins regulates many enzyme activities ADDIN REFMGR.CITE <Refman><Cite><Author>Glozak</Author><Year>2005</Year><RecNum>14982</RecNum><IDText>Acetylation and deacetylation of non-histone proteins</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>14982</Ref_ID><Title_Primary>Acetylation and deacetylation of non-histone proteins</Title_Primary><Authors_Primary>Glozak,M.A.</Authors_Primary><Authors_Primary>Sengupta,N.</Authors_Primary><Authors_Primary>Zhang,X.</Authors_Primary><Authors_Primary>Seto,E.</Authors_Primary><Date_Primary>2005/12/19</Date_Primary><Keywords>Acetylation</Keywords><Keywords>Chromosomal Proteins,Non-Histone</Keywords><Keywords>Cytoskeletal Proteins</Keywords><Keywords>Histone Deacetylases</Keywords><Keywords>metabolism</Keywords><Keywords>Molecular Chaperones</Keywords><Keywords>Proteins</Keywords><Keywords>Research</Keywords><Keywords>Transcription Factors</Keywords><Keywords>Viral Proteins</Keywords><Reprint>Not in File</Reprint><Start_Page>15</Start_Page><End_Page>23</End_Page><Periodical>Gene</Periodical><Volume>363</Volume><Address>H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, SRB 23011, Tampa, FL 33612, USA</Address><Web_URL>PM:16289629</Web_URL><ZZ_JournalStdAbbrev><f name="System">Gene</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>30 including inflammation ADDIN REFMGR.CITE <Refman><Cite><Author>Wieczorek</Author><Year>2012</Year><RecNum>2832</RecNum><IDText>Acetylation modulates the STAT signaling code</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2832</Ref_ID><Title_Primary>Acetylation modulates the STAT signaling code</Title_Primary><Authors_Primary>Wieczorek,M.</Authors_Primary><Authors_Primary>Ginter,T.</Authors_Primary><Authors_Primary>Brand,P.</Authors_Primary><Authors_Primary>Heinzel,T.</Authors_Primary><Authors_Primary>Kramer,O.H.</Authors_Primary><Date_Primary>2012/12</Date_Primary><Keywords>Acetylation</Keywords><Keywords>Animals</Keywords><Keywords>Apoptosis</Keywords><Keywords>Biochemistry</Keywords><Keywords>Gene Expression</Keywords><Keywords>Histone Code</Keywords><Keywords>Humans</Keywords><Keywords>Immunity</Keywords><Keywords>Inflammation</Keywords><Keywords>Lysine</Keywords><Keywords>metabolism</Keywords><Keywords>Phosphorylation</Keywords><Keywords>Proteins</Keywords><Keywords>Serine</Keywords><Keywords>Signal Transduction</Keywords><Keywords>STAT Transcription Factors</Keywords><Keywords>Transcription Factors</Keywords><Keywords>Tyrosine</Keywords><Reprint>Not in File</Reprint><Start_Page>293</Start_Page><End_Page>305</End_Page><Periodical>Cytokine Growth Factor Rev.</Periodical><Volume>23</Volume><Issue>6</Issue><Address>Center for Molecular Biomedicine, Institute for Biochemistry and Biophysics, Department of Biochemistry, Friedrich Schiller University of Jena, Jena, Germany</Address><Web_URL>PM:22795479</Web_URL><ZZ_JournalStdAbbrev><f name="System">Cytokine Growth Factor Rev.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>31. The increase in betaine has been observed in an animal model of allergic encephalitis along with a fall in acetate ADDIN REFMGR.CITE <Refman><Cite><Author>Preece</Author><Year>1993</Year><RecNum>10579</RecNum><IDText>Experimental allergic encephalomyelitis raises betaine levels in the spinal cord of strain 13 guinea-pigs</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>10579</Ref_ID><Title_Primary>Experimental allergic encephalomyelitis raises betaine levels in the spinal cord of strain 13 guinea-pigs</Title_Primary><Authors_Primary>Preece,N.E.</Authors_Primary><Authors_Primary>Baker,D.</Authors_Primary><Authors_Primary>Butter,C.</Authors_Primary><Authors_Primary>Gadian,D.G.</Authors_Primary><Authors_Primary>Urenjak,J.</Authors_Primary><Date_Primary>1993/5</Date_Primary><Keywords>Acetylation</Keywords><Keywords>analogs &amp; derivatives</Keywords><Keywords>Animals</Keywords><Keywords>Aspartic Acid</Keywords><Keywords>Betaine</Keywords><Keywords>Biophysics</Keywords><Keywords>Brain</Keywords><Keywords>Cerebrospinal Fluid</Keywords><Keywords>Choline</Keywords><Keywords>Dipeptides</Keywords><Keywords>Disease</Keywords><Keywords>Encephalomyelitis,Autoimmune,Experimental</Keywords><Keywords>England</Keywords><Keywords>Guinea Pigs</Keywords><Keywords>Humans</Keywords><Keywords>London</Keywords><Keywords>Magnetic Resonance Spectroscopy</Keywords><Keywords>metabolism</Keywords><Keywords>Multiple Sclerosis</Keywords><Keywords>Mycobacterium</Keywords><Keywords>Mycobacterium tuberculosis</Keywords><Keywords>Recurrence</Keywords><Keywords>Research</Keywords><Keywords>Spinal Cord</Keywords><Keywords>Tissue Extracts</Keywords><Keywords>Tuberculosis</Keywords><Reprint>Not in File</Reprint><Start_Page>194</Start_Page><End_Page>200</End_Page><Periodical>NMR Biomed.</Periodical><Volume>6</Volume><Issue>3</Issue><Address>Department of Biophysics, Hunterian Institute, Royal College of Surgeons of England, London, UK</Address><Web_URL>PM:8347453</Web_URL><ZZ_JournalStdAbbrev><f name="System">NMR Biomed.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>32. Betaine may be important in the development of the widespread pain through a central sensitization mechanism as it inhibits gamma-amino butyric acid (GABA) transport ADDIN REFMGR.CITE <Refman><Cite><Author>Beart</Author><Year>1973</Year><RecNum>14313</RecNum><IDText>GABA uptake in rat brain slices: inhibition by GABA analogues and by various drugs</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>14313</Ref_ID><Title_Primary>GABA uptake in rat brain slices: inhibition by GABA analogues and by various drugs</Title_Primary><Authors_Primary>Beart,P.M.</Authors_Primary><Authors_Primary>Johnston,G.A.</Authors_Primary><Date_Primary>1973/2</Date_Primary><Keywords>Acetylation</Keywords><Keywords>Acids</Keywords><Keywords>Acylation</Keywords><Keywords>Aminobutyrates</Keywords><Keywords>Animals</Keywords><Keywords>antagonists &amp; inhibitors</Keywords><Keywords>Aspartic Acid</Keywords><Keywords>Betaine</Keywords><Keywords>Brain</Keywords><Keywords>Brain Chemistry</Keywords><Keywords>Chlorine</Keywords><Keywords>Choline</Keywords><Keywords>drug effects</Keywords><Keywords>Esters</Keywords><Keywords>Fatty Acids</Keywords><Keywords>Fluorine</Keywords><Keywords>Glutamates</Keywords><Keywords>Glycine</Keywords><Keywords>Hydroxylation</Keywords><Keywords>Imidazoles</Keywords><Keywords>metabolism</Keywords><Keywords>Methylation</Keywords><Keywords>pharmacology</Keywords><Keywords>Rats</Keywords><Keywords>Sulfur</Keywords><Keywords>Tritium</Keywords><Keywords>Valerates</Keywords><Reprint>Not in File</Reprint><Start_Page>319</Start_Page><End_Page>324</End_Page><Periodical>J Neurochem.</Periodical><Volume>20</Volume><Issue>2</Issue><Web_URL>PM:4698282</Web_URL><ZZ_JournalStdAbbrev><f name="System">J Neurochem.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>33. 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ADDIN EN.CITE.DATA 37;38. Studies are required to confirm these interesting findings.In our original study we found that the serum sodium level was inversely correlated with the face pain scores in females but not correlated with widespread pain ADDIN REFMGR.CITE <Refman><Cite><Author>McGregor</Author><Year>2000</Year><RecNum>19307</RecNum><IDText>An investigation of the association between toxin-producing staphylococcus, biochemical changes and jaw muscle pain.</IDText><MDL Ref_Type="Thesis/Dissertation"><Ref_Type>Thesis/Dissertation</Ref_Type><Ref_ID>19307</Ref_ID><Title_Primary>An investigation of the association between toxin-producing staphylococcus, biochemical changes and jaw muscle pain.</Title_Primary><Authors_Primary>McGregor,N.R.</Authors_Primary><Date_Primary>2000</Date_Primary><Keywords>Jaw</Keywords><Keywords>Pain</Keywords><Keywords>Staphylococcus</Keywords><Keywords>Temporomandibular Joint Disorders</Keywords><Reprint>Not in File</Reprint><Start_Page>1</Start_Page><End_Page>150</End_Page><Publisher>University of Sydney</Publisher><Misc_1>PhD</Misc_1><Misc_2>Thesis</Misc_2><Address>Parramatta Road, Sydney</Address><ZZ_WorkformID>29</ZZ_WorkformID></MDL></Cite></Refman>6. In this study we found the same relationship between serum sodium and face pain scores and also no relationship with widespread pain. A fall in arginase II expression in the kidney has been linked to variation in salt tolerance in Dahl salt sensitive rats ADDIN REFMGR.CITE <Refman><Cite><Author>Iwata</Author><Year>2002</Year><RecNum>687</RecNum><IDText>Decreased expression of arginase II in the kidneys of Dahl salt-sensitive rats</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>687</Ref_ID><Title_Primary>Decreased expression of arginase II in the kidneys of Dahl salt-sensitive rats</Title_Primary><Authors_Primary>Iwata,S.</Authors_Primary><Authors_Primary>Tsujino,T.</Authors_Primary><Authors_Primary>Ikeda,Y.</Authors_Primary><Authors_Primary>Ishida,T.</Authors_Primary><Authors_Primary>Ueyama,T.</Authors_Primary><Authors_Primary>Gotoh,T.</Authors_Primary><Authors_Primary>Mori,M.</Authors_Primary><Authors_Primary>Yokoyama,M.</Authors_Primary><Date_Primary>2002/5</Date_Primary><Keywords>analysis</Keywords><Keywords>Animals</Keywords><Keywords>Arginase</Keywords><Keywords>Arginine</Keywords><Keywords>biosynthesis</Keywords><Keywords>blood</Keywords><Keywords>Cerebellum</Keywords><Keywords>Diet</Keywords><Keywords>enzymology</Keywords><Keywords>etiology</Keywords><Keywords>genetics</Keywords><Keywords>Hydrolysis</Keywords><Keywords>Hypertension</Keywords><Keywords>Kidney</Keywords><Keywords>Liver</Keywords><Keywords>Male</Keywords><Keywords>metabolism</Keywords><Keywords>Nitric Oxide</Keywords><Keywords>Ornithine</Keywords><Keywords>pharmacology</Keywords><Keywords>Rats</Keywords><Keywords>Rats,Inbred Dahl</Keywords><Keywords>Research Support,Non-U.&apos;t</Keywords><Keywords>Rna</Keywords><Keywords>RNA,Messenger</Keywords><Keywords>Sodium</Keywords><Keywords>Sodium Chloride</Keywords><Keywords>Urea</Keywords><Keywords>urine</Keywords><Reprint>Not in File</Reprint><Start_Page>411</Start_Page><End_Page>418</End_Page><Periodical>Hypertens.Res.</Periodical><Volume>25</Volume><Issue>3</Issue><Address>Department of Internal Medicine, Kobe University Graduate School of Medical Science, Japan</Address><Web_URL>PM:12135320</Web_URL><ZZ_JournalStdAbbrev><f name="System">Hypertens.Res.</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>39 and alteration in sodium channel Nav1.6 has been linked to the development of neuropathic pain in diabetes PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlJlbjwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJlY051

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ADDIN EN.CITE.DATA 40. In this study a fall in serum osmolality, a measure of electrolyte balance, was a major predictor of 7-day pain responses, but it was not as strong for the 12-month frequency scores. Two important studies have associated urea, sodium and/or betaine with regulation of water channel (aquaporin 1-3) expression within the kidney PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlVtZW5pc2hpPC9BdXRob3I+PFllYXI+MjAwNTwvWWVhcj48

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ADDIN EN.CITE.DATA 41;42 suggesting the relationship between urine volume, sodium and betaine observed in this study is of importance. In further support of this, changes in expression of aquaporin 1 have been associated with central sensitization within the spinal column PFJlZm1hbj48Q2l0ZT48QXV0aG9yPk5lc2ljPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA 42. Changes in Betaine may also be associated with polymorphic variation in the methylation/one carbon pool enzymes PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkhvZmZtYW5uPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

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bj5=

ADDIN REFMGR.CITE PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkhvZmZtYW5uPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

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bj5=

ADDIN EN.CITE.DATA 43. How these changes in sodium, urea and aquaporin may relate to pain is not known but aquaporins are expressed within various tissues including the temporomandibular joint and vary with arthritis PFJlZm1hbj48Q2l0ZT48QXV0aG9yPk1lbmc8L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA 44.This study was designed to investigate metabolic changes in MECFS subjects using a discovery hypothesis and not a specific hypothesis driven method to assess specific biochemical events. This study with these limitations has resulted in the development of a hypothesis which now requires to be assessed by a typical hypothesis driven process. Whilst the study size is small it reproduced the earlier findings but should be reproduced with a larger sample to reconfirm the findings. The use of self-reported symptoms may introduce a recall bias within the patient and in a larger study each of the variables found to be associated with the pain severity and distribution need to be evaluated by other means. Studies investigating the genetic polymorphic variation and their association with the biochemical events should allow the development of the understanding of the mechanisms of pain development and the development of appropriate therapies based upon the underlying biochemistry.Conclusions.This study has confirmed and extended the findings of our previous studies showing an association between altered amino acid excretion, urine volume, serum sodium, osmolality and increases in facial and widespread pain expression in MECFS patients. The falls in serum essential amino acids appeared involved in the development of the changes in urea, urine volume and sodium. The changes noted appear consistent with alterations in kidney function induced by an inflammatory process and/or sepsis. Widespread pain appears to be a consequence of the repeated inflammatory driven changes in renal concentrating activity leading to essential amino acid depletion. Well-designed studies evaluating these important factors are warranted.Acknowledgements: The authors of this work would like to thank the nursing and administrative staff at the CFS Discovery clinic for their important help throughout this study. The work was supported by grants from the Judith Jane Mason & Harold Stannett Williams memorial foundation (The Mason Foundation) and equipment grants from the Rowen White Foundation and the State of Victoria.Conflicts of Interest: There are no conflicts of pliance with ethics: The study was approved by the University of Melbourne human research ethics committee (HREC# 0723086). ADDIN REFMGR.REFLIST Reference List(1) Aaron LA, Burke MM, Buchwald D. Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder. Arch Intern Med 2000; 160(2):221-227.(2) Goldenberg DL, Simms RW, Geiger A, Komaroff AL. 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