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Breath Ammonia and Ethanol Increase in Response To a High Protein ChallengeLisa A Spacek1,2, Matthew L Mudalel1, Rafal Lewicki3, Frank K Tittel3, Terence H Risby2, Jill Stoltfuz1, Steven F Solga11- St. Luke’s University Hospital, Bethlehem, PA 180152- Johns Hopkins University, Baltimore, MD 212053- Rice University, Houston, TX 77251IntroductionAmmonia, a by-product of protein metabolism, and ethanol, a by-product of carbohydrate metabolism, are both relevant to human health. Ammonia is produced and metabolized by bacterial and mammalian cells, whereas ethanol is presumed to be produced only by bacteria. Hydrogen, which we used as a comparator, is a by-product of solely bacterial carbohydrate metabolism. Commercial hydrogen breath testing is recognized as a method to detect bacterial fermentation in the gastrointestinal tract ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.cgh.2013.09.055", "ISSN" : "1542-7714", "PMID" : "24095975", "abstract" : "The diagnosis of small intestinal bacterial overgrowth (SIBO) has increased considerably due to a growing recognition of its association with common bowel symptoms including chronic diarrhea, bloating, abdominal distention and the irritable bowel syndrome. Ideally, an accurate and objective diagnosis of SIBO should be established prior to initiating antibiotic treatment Unfortunately, no perfect test exists for the diagnosis of SIBO, The current \"gold standard\",. small bowel aspiration and quantitative culture is limited by its high cost, invasive nature, lack of standardization, sampling error, and need for dedicated infrastructure.. Though not without shortcomings, hydrogen breath testing provides the simplest, non-invasive and widely available diagnostic modality for suspected SIBO. Carbohydrates such as lactulose and glucose are the most widely used substrates in hydrogen breath testing with glucose arguably providing greater testing accuracy. Lactose, fructose and sorbitol should not be used as substrates in the assessment of suspected SIBO. The measurement of methane in addition to hydrogen can increase the sensitivity of breath testing for SIBO. Diagnostic accuracy of hydrogen breath testing in SIBO can be maximized by careful patient selection for testing, proper test preparation, and standardization of test performance as well as test interpretation.", "author" : [ { "dropping-particle" : "", "family" : "Saad", "given" : "Richard J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Chey", "given" : "William D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013", "10", "1" ] ] }, "title" : "Breath Testing for small intestinal bacterial overgrowth: Maximizing test accuracy.", "type" : "article-journal" }, "uris" : [ "", "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Saad & Chey, 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Saad & Chey, 2013). And, unabsorbed sugars, such as lactulose, serve to provoke an increase in gut bacteria hydrogen production ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1136/gut.2005.075127", "ISSN" : "0017-5749", "PMID" : "16474100", "abstract" : "Hydrogen breath tests are widely used to explore the pathophysiology of functional gastrointestinal disorders. Small intestinal bacterial overgrowth and carbohydrate malabsorption are disorders detected by these tests that have been proposed to be of great importance for symptoms in, for instance, irritable bowel syndrome. However, conclusions drawn from these studies are highly controversial and divergent results exist. There is also an extensive use of these tests in clinical practice with difficulties regarding interpretation of the tests and sometimes erroneous conclusions. The limitations and pitfalls of these tests will be reviewed in this article, and hopefully the occasional abuse of these tests can be turned into proper clinical and scientific use instead in the future.", "author" : [ { "dropping-particle" : "", "family" : "Simr\u00e9n", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stotzer", "given" : "P-O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Gut", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2006", "3" ] ] }, "page" : "297-303", "title" : "Use and abuse of hydrogen breath tests.", "type" : "article-journal", "volume" : "55" }, "uris" : [ "", "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Simr\u00e9n & Stotzer, 2006)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Simrén & Stotzer, 2006).Human ammonia physiology is complex due to multiple sources and sinks ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1016/j.metabol.2012.07.007", "ISSN" : "1532-8600", "PMID" : "22921946", "abstract" : "Free ammonium ions are produced and consumed during cell metabolism. Glutamine synthetase utilizes free ammonium ions to produce glutamine in the cytosol whereas glutaminase and glutamate dehydrogenase generate free ammonium ions in the mitochondria from glutamine and glutamate, respectively. Ammonia and bicarbonate are condensed in the liver mitochondria to yield carbamoylphosphate initiating the urea cycle, the major mechanism of ammonium removal in humans. Healthy kidney produces ammonium which may be released into the systemic circulation or excreted into the urine depending predominantly on acid-base status, so that metabolic acidosis increases urinary ammonium excretion while metabolic alkalosis induces the opposite effect. Brain and skeletal muscle neither remove nor produce ammonium in normal conditions, but they are able to seize ammonium during hyperammonemia, releasing glutamine. Ammonia in gas phase has been detected in exhaled breath and skin, denoting that these organs may participate in nitrogen elimination. Ammonium homeostasis is profoundly altered in liver failure resulting in hyperammonemia due to the deficient ammonium clearance by the diseased liver and to the development of portal collateral circulation that diverts portal blood with high ammonium content to the systemic blood stream. Although blood ammonium concentration is usually elevated in liver disease, a substantial role of ammonium causing hepatic encephalopathy has not been demonstrated in human clinical studies. Hyperammonemia is also produced in urea cycle disorders and other situations leading to either defective ammonium removal or overproduction of ammonium that overcomes liver clearance capacity. Most diseases resulting in hyperammonemia and cerebral edema are preceded by hyperventilation and respiratory alkalosis of unclear origin that may be caused by the intracellular acidosis occurring in these conditions.", "author" : [ { "dropping-particle" : "", "family" : "Adeva", "given" : "Maria M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Souto", "given" : "Gema", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Blanco", "given" : "Natalia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Donapetry", "given" : "Crist\u00f3bal", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Metabolism: clinical and experimental", "id" : "ITEM-1", "issue" : "11", "issued" : { "date-parts" : [ [ "2012", "11", "1" ] ] }, "page" : "1495-511", "publisher" : "Elsevier", "title" : "Ammonium metabolism in humans.", "type" : "article-journal", "volume" : "61" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Adeva, Souto, Blanco, & Donapetry, 2012)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Adeva, Souto, Blanco, & Donapetry, 2012). And, ammonia balance is influenced by numerous physiologic and pathophysiologic events, including food intake and composition, bowel function, muscle physiology, and kidney disease. Given its role in several pathophysiologic conditions, accurate, rapid, and non-invasive quantification of ammonia levels has clinically important applications ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0085-2538", "author" : [ { "dropping-particle" : "", "family" : "Davies", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Spanel", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Kidney international", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "1997", "7" ] ] }, "page" : "223-8", "title" : "Quantitative analysis of ammonia on the breath of patients in end-stage renal failure.", "type" : "article-journal", "volume" : "52" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Davies, Spanel, & Smith, 1997)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Davies, Spanel, & Smith, 1997). Ammonia physiology research is hindered by its volatility. It is a ‘sticky’ molecule. This makes reliable and reproducible ammonia measurement difficult by any method. In the past, most research utilized ammonia blood assays; these can be variable and vexed by technical errors. Moreover, phlebotomy generally occurs via limb venipuncture, and other body compartments are rarely evaluated. Perhaps more importantly, research relying on ammonia blood assays is inherently limited by episodic sampling and therefore cannot fluidly capture ammonia physiology. Breath researchers have, for many years, attempted to advance ammonia research using a variety of monitors and measurement protocols. Numerous pilot studies have been published on a range of topics related to ammonia physiology in normal ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1088/1752-7155/5/3/037101", "ISSN" : "1752-7163", "PMID" : "21654023", "abstract" : "Photoacoustic laser spectroscopy was used as a technique to measure real-time levels of ammonia in exhaled human breath in a small, locally recruited, normal healthy population (n = 30). This yielded an average level of breath ammonia of 265 ppb, ranging from 29 to 688 ppb. Although average levels were marginally higher in male volunteers, this was not statistically significant. In addition, no correlation could be found between age, body mass index, or breath carbon dioxide levels. Monitoring of the daily routine of two individuals showed a consistent decrease in oral breath ammonia concentrations by the early afternoon (post-prandial), but was followed by a gradual increase towards late afternoon. However, in a comparison of oral and nasal breath in two volunteers, nasal breath ammonia levels were found to be significantly lower than oral levels. In addition, the daily variation was only seen in oral rather than nasal measurements which may indicate that significant background levels are predominantly of oral origin and that nasal sampling is the preferred route to eradicate this background in future studies. These results provide a healthy human breath ammonia baseline upon which other studies may be compared.", "author" : [ { "dropping-particle" : "", "family" : "Hibbard", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Killard", "given" : "A J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of breath research", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2011", "9" ] ] }, "page" : "037101", "title" : "Breath ammonia levels in a normal human population study as determined by photoacoustic laser spectroscopy.", "type" : "article-journal", "volume" : "5" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISSN" : "0967-3334", "abstract" : "Selected ion flow tube mass spectrometry, SIFT-MS, has been used to monitor the volatile compounds in the exhaled breath of 30 volunteers (19 males, 11 females) over a 6 month period. Volunteers provided breath samples each week between 8:45 am and 1 pm (before lunch), and the concentrations of several trace compounds were obtained. In this paper the focus is on ammonia, acetone and propanol. It was found that the concentration distributions of these compounds in breath were close to log-normal. The median ammonia level estimated as a geometric mean for all samples was 833 parts per billion (ppb) with a multiplicative standard deviation of 1.62, the values ranging from 248 to 2935 ppb. Breath ammonia clearly increased with increasing age in this volunteer cohort. The geometric mean acetone level for all samples was 477 parts per billion (ppb) with a multiplicative standard deviation of 1.58, the values ranging from 148 to 2744 ppb. The median propanol level for all samples was 18 ppb, the values ranging from 0 to 135 ppb. A weak but significant correlation between breath propanol and acetone levels is apparent in the data. The findings indicate the potential value of SIFT-MS as a non-invasive breath analysis technique for investigating volatile compounds in human health and in the diseased state.", "author" : [ { "dropping-particle" : "", "family" : "Turner", "given" : "Claire", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Spanel", "given" : "Patrik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Physiological measurement", "id" : "ITEM-2", "issue" : "4", "issued" : { "date-parts" : [ [ "2006", "4" ] ] }, "page" : "321-37", "title" : "A longitudinal study of ammonia, acetone and propanol in the exhaled breath of 30 subjects using selected ion flow tube mass spectrometry, SIFT-MS.", "type" : "article-journal", "volume" : "27" }, "uris" : [ "" ] } ], "mendeley" : { "manualFormatting" : "(Hibbard & Killard, 2011)(Turner, Spanel, & Smith, 2006)", "previouslyFormattedCitation" : "(Hibbard & Killard, 2011a; Turner, Spanel, & Smith, 2006a)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Hibbard & Killard, 2011)(Turner, Spanel, & Smith, 2006) and disease states ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0163-2116", "abstract" : "Measurement of arterial ammonia has been used as a diagnostic test for hepatic encephalopathy, but obtaining an arterial specimen is an invasive procedure. The aim of this study was to evaluate the ability of a minimally invasive, highly sensitive optical sensing device to detect ammonia in the breath of patients with end-stage liver disease and to evaluate the correlation of breath ammonia levels, arterial ammonia levels, and psychometric testing. Fifteen subjects with liver cirrhosis and clinical evidence of hepatic encephalopathy underwent mini-mental status examination, number connection test, focused neurological examination, and arterial ammonia testing. On the same day, breath ammonia testing was performed using an apparatus that consists of a sensor (a thin membrane embedded with a pH-sensitive dye) attached to a fiberoptic apparatus that detects optical absorption. Helicobacter pylori testing was performed using the 14C urea breath test. A positive correlation was found between arterial ammonia level and time to complete the number connection test (r = 0.31, P = 0.03). However, a negative correlation was found between breath ammonia level and number connection testing (r = -0.55, P = 0.03). Furthermore, no correlation was found between breath and arterial ammonia levels (r = -0.005, P = 0.98). There is a significant correlation between the trailmaking test and arterial ammonia levels in patients with cirrhosis. However, no correlation was found between breath and arterial ammonia levels using the fiberoptic ammonia sensor apparatus in this small study.", "author" : [ { "dropping-particle" : "", "family" : "DuBois", "given" : "Suja", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Eng", "given" : "Sue", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bhattacharya", "given" : "Renuka", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rulyak", "given" : "Steve", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hubbard", "given" : "Todd", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Putnam", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kearney", "given" : "David J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Digestive diseases and sciences", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "2005", "10" ] ] }, "page" : "1780-4", "title" : "Breath ammonia testing for diagnosis of hepatic encephalopathy.", "type" : "article-journal", "volume" : "50" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(DuBois et al., 2005a)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(DuBois et al., 2005a)ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "1573-2568", "abstract" : "BACKGROUND: Hepatic encephalopathy (HE) is a serious neuropsychiatric complication in both acute and chronic liver disease.\n\nAIMS: To establish the utility of a portable noninvasive method to measure ammonia in the breath of healthy subjects and patients with HE.\n\nMETHODS: The study included 106 subjects: 44 women and 62 men, 51 healthy and 55 cirrhotic. The breath ammonia was measured with an electrochemical sensor and expressed in parts/billion (ppb).\n\nRESULTS: The breath ammonia in healthy subjects had an average value of 151.4 ppb (95% confidence interval [CI]: 149.4-153.4) and the average value in cirrhotic patients was 169.9 ppb (95% CI: 163.5-176.2) (P < 0.0001). In cirrhotic patients with and without HE, the corresponding values were 184.1 ppb (95% CI: 167.7-200.6) and 162.9 ppb (95% CI: 158.8-167.0), respectively (P = 0.0011). Ammonia levels \u2265 165 ppb permitted a differentiation between healthy and cirrhotic subjects; the area under the receiver operating characteristic (ROC) curve for the ammonia-level values in cirrhotic versus control patients was 0.86 (95% CI: 0.79-0.93). In cirrhotic patients, ammonia levels \u2265 175 ppb permitted the distinction between patients with and without HE; the area under the ROC curve in cirrhotic patients with versus without HE was 0.83 (95% CI: 0.73-0.94).\n\nCONCLUSION: A portable sensor for measuring breath ammonia can be developed. If the results of the present study are confirmed, breath-ammonia determinations could produce a significant impact on the care of patients with cirrhosis and could even include the possibility of self-monitoring.", "author" : [ { "dropping-particle" : "", "family" : "Adrover", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cocozzella", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ridruejo", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Garc\u00eda", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rome", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Podest\u00e1", "given" : "J J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Digestive diseases and sciences", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2012", "1" ] ] }, "page" : "189-95", "title" : "Breath-ammonia testing of healthy subjects and patients with cirrhosis.", "type" : "article-journal", "volume" : "57" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Adrover et al., 2012)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Adrover et al., 2012)ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0085-2538", "author" : [ { "dropping-particle" : "", "family" : "Davies", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Spanel", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Kidney international", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "1997", "7" ] ] }, "page" : "223-8", "title" : "Quantitative analysis of ammonia on the breath of patients in end-stage renal failure.", "type" : "article-journal", "volume" : "52" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Davies et al., 1997)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Davies et al., 1997). However, recent research suggests that exhaled breath ammonia may not reliably determine systemic ammonia; these investigators assert that its volatility and the multiple sources of contamination in oral-pharyngeal membranes cannot be overcome ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1088/1752-7155/7/1/017109", "ISSN" : "1752-7163", "PMID" : "23445955", "abstract" : "Ammonia concentrations in exhaled breath (eNH3) and skin gas of 20 healthy subjects were measured on-line with a commercial cavity ring-down spectrometer and compared to saliva pH and plasma ammonium ion (NH(+)4), urea and creatinine concentrations. Special attention was given to mouth, nose and skin sampling procedures and the accurate quantification of ammonia in humid gas samples. The obtained median concentrations were 688 parts per billion by volume (ppbv) for mouth-eNH3, 34 ppbv for nose-eNH3, and 21 ppbv for both mouth- and nose-eNH3 after an acidic mouth wash (MW). The median ammonia emission rate from the lower forearm was 0.3\u00a0ng cm(-2) min(-1). Statistically significant (p\u00a0<\u00a00.05) correlations between the breath, skin and plasma ammonia/ammonium concentrations were not found. However, mouth-eNH3 strongly (p\u00a0<\u00a00.001) correlated with saliva pH. This dependence was also observed in detailed measurements of the diurnal variation and the response of eNH3 to the acidic MW. It is concluded that eNH3 as such does not reflect plasma but saliva and airway mucus NH(+)4 concentrations and is affected by saliva and airway mucus pH. After normalization with saliva pH using the Henderson-Hasselbalch equation, mouth-eNH3 correlated with plasma NH(+)4, which points to saliva and plasma NH(+)4 being linked via hydrolysis of salivary urea.", "author" : [ { "dropping-particle" : "", "family" : "Schmidt", "given" : "F M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vaittinen", "given" : "O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mets\u00e4l\u00e4", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lehto", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forsblom", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Groop", "given" : "P-H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Halonen", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of breath research", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013", "3" ] ] }, "page" : "017109", "title" : "Ammonia in breath and emitted from skin.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Schmidt et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Schmidt et al., 2013). And, others have preferred nose-exhaled ammonia over mouth exhaled ammoniaADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1088/1752-7155/2/3/037013", "ISSN" : "1752-7155", "PMID" : "21386174", "abstract" : "Analyses have been performed, using on-line selected ion flow tube mass spectrometry (SIFT-MS), of the breath of three healthy volunteers, as exhaled via the mouth and the nose and also of the air in the oral cavity during breath hold, each morning over a period of one month. Nine trace compounds have been quantified and concentration distributions have been constructed. Of these compounds, the levels of acetone, methanol and isoprene are the same in the mouth-exhaled and the nose-exhaled breath; hence, we deduce that these compounds are totally systemic. The levels of ammonia, ethanol and hydrogen cyanide are much lower in the nose-exhaled breath than in the mouth-exhaled breath and highest in the oral cavity, indicating that these compounds are largely generated in the mouth with little being released at the alveolar interface. Using the same ideas, both the low levels of propanol and acetaldehyde in mouth-exhaled breath appear to have both oral and systemic components. Formaldehyde is at levels in mouth- and nose-exhaled breath and the oral cavity that are lower than that of the ambient air and so its origin is difficult to ascertain, but it appears to be partially systemic. These results indicate that serious contamination of alveolar breath exhaled via the mouth can occur and if breath analysis is to be used to diagnose metabolic disease then analyses should be carried out of both mouth- and nose-exhaled breath to identify the major sources of particular trace compounds.", "author" : [ { "dropping-particle" : "", "family" : "Wang", "given" : "Tianshu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pysanenko", "given" : "Andriy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dryahina", "given" : "Kseniya", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Span\u011bl", "given" : "Patrik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of breath research", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2008", "9" ] ] }, "page" : "037013", "title" : "Analysis of breath, exhaled via the mouth and nose, and the air in the oral cavity.", "type" : "article-journal", "volume" : "2" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "id" : "ITEM-2", "issued" : { "date-parts" : [ [ "0" ] ] }, "title" : "Volatile Biomarkers, 1st Edition | Anton Amann, David Smith | ISBN 9780444626134", "type" : "webpage" }, "uris" : [ "" ] } ], "mendeley" : { "manualFormatting" : " (Wang, Pysanenko, Dryahina, Span\u011bl, & Smith, 2008)", "previouslyFormattedCitation" : "(\u201cVolatile Biomarkers, 1st Edition | Anton Amann, David Smith | ISBN 9780444626134,\u201d n.d.; Wang, Pysanenko, Dryahina, Span\u011bl, & Smith, 2008a)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" } (Wang, Pysanenko, Dryahina, Spaněl, & Smith, 2008). Papers reporting the difference in nose-exhaled versus mouth-exhaled ammonia have consistently found lower ammonia levels in nose-exhaled samples.Ethanol is somewhat less volatile than ammonia and, since it is produced only by bacteria, has fewer potential sources. Interest in endogenous ethanol has been growing as it has been increasingly implicated in the pathophysiology of fatty liver and the metabolic syndrome ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "1471-2466", "abstract" : "BACKGROUND: Exhaled breath volatile organic compound (VOC) analysis for airway disease monitoring is promising. However, contrary to nitric oxide the method for exhaled breath collection has not yet been standardized and the effects of expiratory flow and breath-hold have not been sufficiently studied. These manoeuvres may also reveal the origin of exhaled compounds.\n\nMETHODS: 15 healthy volunteers (34 +/- 7 years) participated in the study. Subjects inhaled through their nose and exhaled immediately at two different flows (5 L/min and 10 L/min) into methylated polyethylene bags. In addition, the effect of a 20 s breath-hold following inhalation to total lung capacity was studied. The samples were analyzed for ethanol and acetone levels immediately using proton-transfer-reaction mass-spectrometer (PTR-MS, Logan Research, UK).\n\nRESULTS: Ethanol levels were negatively affected by expiratory flow rate (232.70 +/- 33.50 ppb vs. 202.30 +/- 27.28 ppb at 5 L/min and 10 L/min, respectively, p < 0.05), but remained unchanged following the breath hold (242.50 +/- 34.53 vs. 237.90 +/- 35.86 ppb, without and with breath hold, respectively, p = 0.11). On the contrary, acetone levels were increased following breath hold (1.50 +/- 0.18 ppm) compared to the baseline levels (1.38 +/- 0.15 ppm), but were not affected by expiratory flow (1.40 +/- 0.14 ppm vs. 1.49 +/- 0.14 ppm, 5 L/min vs. 10 L/min, respectively, p = 0.14). The diet had no significant effects on the gasses levels which showed good inter and intra session reproducibility.\n\nCONCLUSIONS: Exhalation parameters such as expiratory flow and breath-hold may affect VOC levels significantly; therefore standardisation of exhaled VOC measurements is mandatory. Our preliminary results suggest a different origin in the respiratory tract for these two gasses.", "author" : [ { "dropping-particle" : "", "family" : "Bikov", "given" : "Andras", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paschalaki", "given" : "Koralia", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Logan-Sinclair", "given" : "Ron", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Horv\u00e1th", "given" : "Ildiko", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kharitonov", "given" : "Sergei A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Barnes", "given" : "Peter J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Usmani", "given" : "Omar S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Paredi", "given" : "Paolo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "BMC pulmonary medicine", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013", "7", "9" ] ] }, "page" : "43", "title" : "Standardised exhaled breath collection for the measurement of exhaled volatile organic compounds by proton transfer reaction mass spectrometry.", "type" : "article-journal", "volume" : "13" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1088/1752-7155/2/3/037013", "ISSN" : "1752-7155", "PMID" : "21386174", "abstract" : "Analyses have been performed, using on-line selected ion flow tube mass spectrometry (SIFT-MS), of the breath of three healthy volunteers, as exhaled via the mouth and the nose and also of the air in the oral cavity during breath hold, each morning over a period of one month. Nine trace compounds have been quantified and concentration distributions have been constructed. Of these compounds, the levels of acetone, methanol and isoprene are the same in the mouth-exhaled and the nose-exhaled breath; hence, we deduce that these compounds are totally systemic. The levels of ammonia, ethanol and hydrogen cyanide are much lower in the nose-exhaled breath than in the mouth-exhaled breath and highest in the oral cavity, indicating that these compounds are largely generated in the mouth with little being released at the alveolar interface. Using the same ideas, both the low levels of propanol and acetaldehyde in mouth-exhaled breath appear to have both oral and systemic components. Formaldehyde is at levels in mouth- and nose-exhaled breath and the oral cavity that are lower than that of the ambient air and so its origin is difficult to ascertain, but it appears to be partially systemic. These results indicate that serious contamination of alveolar breath exhaled via the mouth can occur and if breath analysis is to be used to diagnose metabolic disease then analyses should be carried out of both mouth- and nose-exhaled breath to identify the major sources of particular trace compounds.", "author" : [ { "dropping-particle" : "", "family" : "Wang", "given" : "Tianshu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pysanenko", "given" : "Andriy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dryahina", "given" : "Kseniya", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Span\u011bl", "given" : "Patrik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of breath research", "id" : "ITEM-2", "issue" : "3", "issued" : { "date-parts" : [ [ "2008", "9" ] ] }, "page" : "037013", "title" : "Analysis of breath, exhaled via the mouth and nose, and the air in the oral cavity.", "type" : "article-journal", "volume" : "2" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "DOI" : "10.1152/japplphysiol.01034.2003", "ISSN" : "8750-7587", "PMID" : "14672964", "abstract" : "A computerized system has been developed to monitor tidal volume, respiration rate, mouth pressure, and carbon dioxide during breath collection. This system was used to investigate variability in the production of breath biomarkers over an 8-h period. Hyperventilation occurred when breath was collected from spontaneously breathing study subjects (n = 8). Therefore, breath samples were collected from study subjects whose breathing were paced at a respiration rate of 10 breaths/min and whose tidal volumes were gauged according to body mass. In this \"paced breathing\" group (n = 16), end-tidal concentrations of isoprene and ethane correlated with end-tidal carbon dioxide levels [Spearman's rank correlation test (r(s)) = 0.64, P = 0.008 and r(s) = 0.50, P = 0.05, respectively]. Ethane also correlated with heart rate (r(s) = 0.52, P < 0.05). There was an inverse correlation between transcutaneous pulse oximetry and exhaled carbon monoxide (r(s) = -0.64, P = 0.008). Significant differences were identified between men (n = 8) and women (n = 8) in the concentrations of carbon monoxide (4 parts per million in men vs. 3 parts per million in women; P = 0.01) and volatile sulfur-containing compounds (134 parts per billion in men vs. 95 parts per billion in women; P = 0.016). There was a peak in ethanol concentration directly after food consumption and a significant decrease in ethanol concentration 2 h later (P = 0.01; n = 16). Sulfur-containing molecules increased linearly throughout the study period (beta = 7.4, P < 0.003). Ventilation patterns strongly influence quantification of volatile analytes in exhaled breath and thus, accordingly, the breathing pattern should be controlled to ensure representative analyses.", "author" : [ { "dropping-particle" : "", "family" : "Cope", "given" : "Keary A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Watson", "given" : "Michael T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Foster", "given" : "W Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sehnert", "given" : "Shelley S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Risby", "given" : "Terence H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of applied physiology (Bethesda, Md. : 1985)", "id" : "ITEM-3", "issue" : "4", "issued" : { "date-parts" : [ [ "2004", "4" ] ] }, "page" : "1371-9", "title" : "Effects of ventilation on the collection of exhaled breath in humans.", "type" : "article-journal", "volume" : "96" }, "uris" : [ "" ] } ], "mendeley" : { "manualFormatting" : "(Bikov et al., 2013)(Cope, Watson, Foster, Sehnert, & Risby, 2004)(Wang, Pysanenko, Dryahina, Span\u011bl, & Smith, 2008b)", "previouslyFormattedCitation" : "(Bikov et al., 2013; K. A. Cope, Watson, Foster, Sehnert, & Risby, 2004; Wang, Pysanenko, Dryahina, Span\u011bl, & Smith, 2008b)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Bikov et al., 2013)(Cope, Watson, Foster, Sehnert, & Risby, 2004)(Wang, Pysanenko, Dryahina, Spaněl, & Smith, 2008b). Because the gut, specifically the distal small bowel and colon, hosts the largest bacterial community in humans, this compartment has generally been assumed to be the source of exhaled ethanol; however, this assertion has not been rigorously tested. In this study, we have evaluated the capacity of our breath collection apparatus and procedure to determine systemic ammonia. And, we also hypothesize that exhaled breath ethanol is gut-derived. Our aim was to measure the ammonia and ethanol response to a high protein oral challenge versus a negative control oral challenge. Further, we used breath hydrogen as the gold standard for gut-derived breath products, and also compared the concordance between peaks in ammonia, ethanol, and hydrogen. METHODSStudy ParticipantsParticipants were recruited via flyers and advertisements. All eligible participants provided informed consent as required by the St. Luke’s University Hospital Institutional Review Board. Thirty healthy volunteers, without periodontal, liver, or kidney disease or report of tobacco use, fasted 12 hours prior to presentation. Volunteers abstained from exercise the morning of the study and brushed their teeth at least an hour before arrival. Data CollectionWe measured the alveolar portion of the exhaled breath for NH3, EtOH, and H2 with three devices serially over 6 hours on 2 days in each subject. Each day began with 30 minutes of baseline breath collection; three NH3 measurements were taken 10 minutes apart and two samples were measured for EtOH and H2 each taken 15 minutes apart. This baseline breath measurement phase was followed by an oral intervention. On Day #1 (control trial), we mapped trends of NH3, EtOH, and H2 in response to the oral ingestion of Gatorade (32 fl oz containing: 200 calories, 52 g sugar, 0 g fiber, 0 g protein, and 0 g fat). On Day #2 (intervention trial), we measured breath NH3, EtOH, and H2 in response to the consumption of lactulose (10g) as well as a high protein challenge (Rockin Refuel Muscle Builder shakes containing: 380 calories, 12g sugar, 6g fiber, 60g protein, and 9g fat). The oral intervention was followed by a 30 second water rinse to flush any residue from the mouth. Breath samples for NH3, EtOH, and H2 were taken every 30 minutes for 5 hours following the rinse. Breath collection: The participants were required to exhale for at least 10 seconds in a defined manner via a restrictor and each exhalation constituted one sample. Each sample had its corresponding profiles for carbon dioxide and mouth pressure measured. Ideal mouth pressure for a sample is 10 cm of water maintained at least 10 seconds. This mouth pressure corresponds to a flow rate of 50 ml/s. Latex gloves were worn when inserting the disposable mouthpiece into the breath sampler in order to prevent contamination with ammonia from the skin. The mouthpiece was not touched for the remainder of the study. Determination of breath ammonia: NH3 was measured with a novel, sensitive, selective and fast quartz enhanced photoacoustic spectroscopy monitor ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISBN" : "9781557528698", "abstract" : "Quantum cascade laser based breath sensor platform for medical applications employing a quartz-enhanced photoacoustic spectroscopy technique is reported. The detection sensitivity for exhaled ammonia is at &amp;lt;10 ppbv level with 1 s time resolution.", "author" : [ { "dropping-particle" : "", "family" : "Lewicki", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kosterev", "given" : "A A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bakhirkin", "given" : "Y A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Thomazy", "given" : "D M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Doty", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dong", "given" : "Lei Dong Lei", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tittel", "given" : "F K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Risby", "given" : "T H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Solga", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kane", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Day", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "2009 Conference on Lasers and ElectroOptics and 2009 Conference on Quantum electronics and Laser Science Conference", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "2009-2010", "title" : "Real time ammonia detection in exhaled human breath with a quantum cascade laser based sensor", "type" : "bill", "volume" : "1" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Lewicki et al., 2009)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Lewicki et al., 2009) (Rice University, Houston, TX) as previously described ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1088/1752-7155/7/3/037101", "ISSN" : "17527163", "PMID" : "23774041", "abstract" : "Amongst volatile compounds (VCs) present in exhaled breath, ammonia has held great promise and yet it has confounded researchers due to its inherent reactivity. Herein we have evaluated various factors in both breath instrumentation and the breath collection process in an effort to reduce variability. We found that the temperature of breath sampler and breath sensor, mouth rinse pH, and mode of breathing to be important factors. The influence of the rinses is heavily dependent upon the pH of the rinse. The basic rinse (pH 8.0) caused a mean increase of the ammonia concentration by 410 221 ppb. The neutral rinse (pH 7.0), slightly acidic rinse (pH 5.8), and acidic rinse (pH 2.5) caused a mean decrease of the ammonia concentration by 498 355 ppb, 527 198 ppb, and 596 385 ppb, respectively. Mode of breathing (mouth-open versus mouth-closed) demonstrated itself to have a large impact on the rate of recovery of breath ammonia after a water rinse. Within 30min, breath ammonia returned to 98 16% that of the baseline with mouth open breathing, while mouth closed breathing allowed breath ammonia to return to 53 14% of baseline. These results contribute to a growing body of literature that will improve reproducibly in ammonia and other VCs.", "author" : [ { "dropping-particle" : "", "family" : "Solga", "given" : "Steven F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mudalel", "given" : "Matthew", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Spacek", "given" : "Lisa A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lewicki", "given" : "Rafal", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tittel", "given" : "Frank", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Loccioni", "given" : "Claudio", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Russo", "given" : "Adolfo", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Risby", "given" : "Terence H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of breath research", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "037101", "title" : "Factors influencing breath ammonia determination.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Steven F Solga et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Steven F Solga et al., 2013) (Solga, et al, JoVE 2014, in press). Since each study subject was his/her own control, consistent breath sampling technique was critical. Therefore, a specially designed breath sampler (Loccioni, Angeli di Rosora, Italy) was used to monitor breath exhalation in a manner similar to the American Thoracic Society/European Respiratory Society recommended breath collection protocol for analyzing breath nitric oxide (FeNO) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1164/rccm.200406-710ST", "ISSN" : "1073-449X", "PMID" : "15817806", "container-title" : "American journal of respiratory and critical care medicine", "id" : "ITEM-1", "issue" : "8", "issued" : { "date-parts" : [ [ "2005", "4" ] ] }, "page" : "912-30", "title" : "ATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005.", "type" : "article-journal", "volume" : "171" }, "uris" : [ "" ] } ], "mendeley" : { "manualFormatting" : "(ATS/ERS 2005)", "previouslyFormattedCitation" : "(\u201cATS/ERS recommendations for standardized procedures for the online and offline measurement of exhaled lower respiratory nitric oxide and nasal nitric oxide, 2005.,\u201d 2005)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(ATS/ERS 2005). This breath sampler monitors, displays, prompts and archives real-time measurements of mouth pressure and the concentration of carbon dioxide. Real-time ammonia concentrations determined by the ammonia sensor are also displayed on the breath sampler and archived. For all breath sampling, a disposable one-way in-line valve was used on the mouth port of the breath sampler. Single breaths were sampled continuously into the ammonia monitor via a 50 cm long inlet line (Teflon) heated to 55°C. Plateau breath ammonia concentrations measured during the phase III portions of the exhalation profiles were reported in parts per billion (ppb). Determination of breath ethanol: Ethanol was measured by a thermal desorption-capillary gas chromatograph (Fast GC)-differential mobility spectrometer (DMS) (microAnalyzer, Sionex Inc, Bedford, MA) capable of real-time measurement of ethanol, acetone, and isoprene. The sampled breath (10 mL) was adsorbed onto sequential adsorbent beds (Carbopack X (13 mm long, 60/80 mesh) and Carboxen 1003 (13 mm long, 80/100 mesh); Supelco, Bellefonte, PA) contained in a stainless steel tube (6.6 cm long, 1.59 mm od, 1.30 mm id) at 40°C. After breath had been sampled, the trap was purged for 15 seconds with dry air. After purging, the trap was switched to the head of the capillary column and the gas chromatographic separation was initiated. After a delay of 1 second, the adsorbent trap was heated to 300°C to thermally desorb the collected breath molecules. Separation was performed on a wall coated silicosteel capillary column (0.53mm od, 15 m MXT VMS crossbond diphenyldimethyl polysiloxane phase; Siltek, Restek, Bellefonte, PA). The column was maintained at 40°C for 150 seconds, temperature programmed from 40 to 140°C in 250 seconds and held isothermally at 140°C for 140 seconds. The column effluent was passed into the source of the differential mobility spectrometer and ionized with thermalized electrons. For the first 90 seconds, the radiofrequency (RF) voltage was set to 1200 volts and then to 1000 volts. The compensation voltage was scanned from -30 to 4.99 volts and the ion current was monitored continuously. The complete analysis took 540 seconds. Data were recorded as a function of gas chromatographic retention time and compensation voltage. Calibration curves were obtained for ethanol, acetone, and isoprene. Breath concentrations for isoprene, acetone and ethanol were reported in parts per billion (ppb).Normalization by correction CO2 factor: Both the ammonia and ethanol values were normalized by a CO2 correction factor in the same fashion as H2 is normalized in the MicroLyzer protocol as shown below. We used an approximated alveolar CO2 pressure (PACO2) of 40 mmHg: Corrected Breath Value = Raw Breath Value * (40/Sample CO2 Pressure).Determination of breath hydrogen: H2 was measured using a Quintron SC MicroLyzer (Milwaukee, WI). The protocol includes sample correction by normalizing each sample with a correction factor based on an alveolar CO2 pressure of approximately 40 mmHg (torr). Peak hydrogen > 20 ppm was deemed a positive test and provided evidence of gut activity. In addition to hydrogen, methane breath levels were quantified, as 5-10% of hydrogen testing may result in false-negative results due to methane rather than hydrogen production ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1088/1752-7155/7/2/024001", "ISBN" : "1752-7155", "ISSN" : "1752-7163", "PMID" : "23470880", "abstract" : "Sugar malabsorption in the bowel can lead to bloating, cramps, diarrhea and other symptoms of irritable bowel syndrome as well as affecting absorption of other nutrients. The hydrogen breath test is now a well established noninvasive test for assessing malabsorption of sugars in the small intestine. However, there are patients who can suffer from the same spectrum of malabsorption issues but who produce little or no hydrogen, instead producing relatively large amounts of methane. These patients will avoid detection with the traditional breath test for malabsorption based on hydrogen detection. Likewise the hydrogen breath test is an established method for small intestinal bacterial overgrowth (SIBO) diagnoses. Therefore, a number of false negatives would be expected for patients who solely produce methane. Usually patients produce either hydrogen or methane, and only rarely there are significant co-producers, as typically the methane is produced at the expense of hydrogen by microbial conversion of carbon dioxide. Various studies show that methanogens occur in about a third of all adult humans; therefore, there is significant potential for malabsorbers to remain undiagnosed if a simple hydrogen breath test is used. As an example, the hydrogen-based lactose malabsorption test is considered to result in about 5-15% false negatives mainly due to methane production. Until recently methane measurements were more in the domain of research laboratories, unlike hydrogen analyses which can now be undertaken at a relatively low cost mainly due to the invention of reliable electrochemical hydrogen sensors. More recently, simpler lower cost instrumentation has become commercially available which can directly measure both hydrogen and methane simultaneously on human breath. This makes more widespread clinical testing a realistic possibility. The production of small amounts of hydrogen and/or methane does not normally produce symptoms, whereas the production of higher levels can lead to a wide range of symptoms ranging from functional disorders of the bowel to low level depression. It is possible that excess methane levels may have more health consequences than excess hydrogen levels. This review describes the health consequences of methane production in humans and animals including a summary of the state of the art in detection methods. In conclusion, the combined measurement of hydrogen and methane should offer considerable improvement in the diagnosis of malabsorp\u2026", "author" : [ { "dropping-particle" : "", "family" : "Lacy Costello", "given" : "B P J", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ledochowski", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ratcliffe", "given" : "N M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of breath research", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "024001", "title" : "The importance of methane breath testing: a review.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "", "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(de Lacy Costello, Ledochowski, & Ratcliffe, 2013a)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(de Lacy Costello, Ledochowski, & Ratcliffe, 2013a). Statistical AnalysisWe compared baseline values versus post-rinse maximum ammonia, hydrogen, and ethanol values for each subject in each study trial. As the raw data approximated log normal distributions, all data was log transformed ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1371/journal.pone.0021403", "ISSN" : "1932-6203", "PMID" : "21779325", "abstract" : "BACKGROUND: The gaussian or normal distribution is the most established model to characterize quantitative variation of original data. Accordingly, data are summarized using the arithmetic mean and the standard deviation, by mean \u00b1 SD, or with the standard error of the mean, mean \u00b1 SEM. This, together with corresponding bars in graphical displays has become the standard to characterize variation.\n\nMETHODOLOGY/PRINCIPAL FINDINGS: Here we question the adequacy of this characterization, and of the model. The published literature provides numerous examples for which such descriptions appear inappropriate because, based on the \"95% range check\", their distributions are obviously skewed. In these cases, the symmetric characterization is a poor description and may trigger wrong conclusions. To solve the problem, it is enlightening to regard causes of variation. Multiplicative causes are by far more important than additive ones, in general, and benefit from a multiplicative (or log-) normal approach. Fortunately, quite similar to the normal, the log-normal distribution can now be handled easily and characterized at the level of the original data with the help of both, a new sign, x/, times-divide, and notation. Analogous to mean \u00b1 SD, it connects the multiplicative (or geometric) mean mean * and the multiplicative standard deviation s* in the form mean * x/s*, that is advantageous and recommended.\n\nCONCLUSIONS/SIGNIFICANCE: The corresponding shift from the symmetric to the asymmetric view will substantially increase both, recognition of data distributions, and interpretation quality. It will allow for savings in sample size that can be considerable. Moreover, this is in line with ethical responsibility. Adequate models will improve concepts and theories, and provide deeper insight into science and life.", "author" : [ { "dropping-particle" : "", "family" : "Limpert", "given" : "Eckhard", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Stahel", "given" : "Werner A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "PloS one", "id" : "ITEM-1", "issue" : "7", "issued" : { "date-parts" : [ [ "2011", "1" ] ] }, "page" : "e21403", "title" : "Problems with using the normal distribution--and ways to improve quality and efficiency of data analysis.", "type" : "article-journal", "volume" : "6" }, "uris" : [ "", "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Limpert & Stahel, 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Limpert & Stahel, 2011)ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.4161/fly.4.4.13260", "ISSN" : "1933-6942", "PMID" : "20855971", "abstract" : "While many quantifiable biological phenomena can be described by making use of an assumption of normality in the distribution of individual values, many biological phenomena are not accurately described by the normal distribution. An unquestioned assumption of normality of distribution of possible outcomes can lead to misinterpretation of data, which could have serious consequences. Thus it is extremely important to test the validity of an assumption of normality of possible outcomes. As it turns out, the logarithmic-normal (log-normal) distribution pattern is often far more accurate in describing statistical biological phenomena. Herein I examine large samples of values for circulating blood cell (hemocyte) concentration (CHC) among both wild-type and mutant Drosophila larvae, and demonstrate in both cases that the distribution of individual values does not conform to normality, but does conform to log-normality.", "author" : [ { "dropping-particle" : "", "family" : "Sorrentino", "given" : "Richard Paul", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Fly", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "0" ] ] }, "page" : "327-32", "title" : "Large standard deviations and logarithmic-normality: the truth about hemocyte counts in Drosophila.", "type" : "article-journal", "volume" : "4" }, "uris" : [ "", "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Sorrentino, n.d.)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Sorrentino, n.d.). Geometric means (?*) and multiplicative standard deviations (MSD) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1089/dia.2013.0295", "ISSN" : "1557-8593", "PMID" : "24261421", "author" : [ { "dropping-particle" : "", "family" : "Braithwaite", "given" : "Susan Shapiro", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Diabetes technology & therapeutics", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2014", "4" ] ] }, "page" : "195-7", "title" : "Multiplicative standard deviation for blood glucose.", "type" : "article-journal", "volume" : "16" }, "uris" : [ "", "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Braithwaite, 2014)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Braithwaite, 2014) were calculated. Reported results were back-transformed to the original scale after analysis. Two-way repeated measures analysis of variance (ANOVA) for treatment type (control versus challenge), change from baseline to maximum, and the interaction of treatment and change from baseline to maximum was performed. All statistical analyses were performed with SAS v9.2 (SAS Institute, Inc., Cary, NC). For all tests, a p-value of < 0.05 was considered significant.We also explored the potential diagnostic utility of exhaled breath ammonia. We identified thresholds by which diagnostically significant increases in ammonia levels could be recognized and interpreted as a positive result. Increase in breath ammonia (maximum ammonia minus baseline ammonia) for each participant was calculated and compared to the following thresholds: 300 ppb, 400 ppb, 500 ppb, 600 ppb, 1.5 x baseline, 1.8 x baseline, and 2.0 x baseline. We calculated the sensitivity, or true positive rate, by counting those participants with an increase in breath ammonia during the intervention trial that exceeded a pre-defined threshold (positive result) and by dividing that count by the total number of participants (N=30). And, we calculated the specificity, or true negative rate, by counting those participants with an increase in breath ammonia during the control trial that did not exceed a pre-defined threshold (negative result) and by dividing that count by the total number of participants (N=30).Results For 30 study participants, mean age was 24 years (SD, 7 yrs), 47% were men (14/30), and mean body mass index was 24.2 kg/m2 (SD, 4.0). Table 1 lists geometric means (?*) and multiplicative standard deviations (MSD) for NH3, EtOH, and H2. Figure 1 illustrates the baseline and maximum values for control and intervention treatment types for NH3 (1a), EtOH (1b), and H2 (1c). The interaction of treatment type and change from baseline to maximum was significant for NH3 (p<0.0001), EtOH (p=0.017), and H2 (p<0.0001).Figure 2a illustrates the mean ammonia and mean hydrogen calculated at each time point without consideration of subject-specific data, with maximum mean ammonia occurring at 300 minutes and maximum mean hydrogen at 240 minutes. The mean time difference between peak ammonia to peak hydrogen calculated for each participant was 45 minutes. Figure 2b shows the trends for ethanol and hydrogen calculated for each time point without consideration of subject-specific data; ethanol peaked 30 minutes after the oral challenge. And, when calculated for each participant, the peak ethanol occurred on average within one hour of the mouth rinse.We explored the utility of increased breath ammonia by comparing breath values for intervention and control trials (Table 3). Sensitivity to discern response to protein challenge was greatest (97%) when defined as an increase in breath NH3 of at least 300 ppb. When greater increases in breath NH3 were required, the sensitivity was lower. At a pre-defined threshold of 600 ppb increase, the specificity was 100%; however, sensitivity was 77%. We also evaluated multiplicative increases from baseline (x1.5, x1.8 and x2) to determine an “elevation” in breath ammonia after high protein challenge compared to control trials, but this did not generate sensitivity above 87%. Four participants did not contribute to the EtOH analysis due to malfunction of data collection equipment and missing data for control trial EtOH values. Of these four, two were also missing data for the intervention trial. Furthermore, an additional two participants were excluded from the EtOH analysis due to exceptionally high EtOH levels attributable to alcohol consumption within 12 hours prior to testing. Twenty-eight participants contributed to H2 measurements because two participants did not produce measureable hydrogen ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1088/1752-7155/7/2/024001", "ISBN" : "1752-7155", "ISSN" : "1752-7163", "PMID" : "23470880", "abstract" : "Sugar malabsorption in the bowel can lead to bloating, cramps, diarrhea and other symptoms of irritable bowel syndrome as well as affecting absorption of other nutrients. The hydrogen breath test is now a well established noninvasive test for assessing malabsorption of sugars in the small intestine. However, there are patients who can suffer from the same spectrum of malabsorption issues but who produce little or no hydrogen, instead producing relatively large amounts of methane. These patients will avoid detection with the traditional breath test for malabsorption based on hydrogen detection. Likewise the hydrogen breath test is an established method for small intestinal bacterial overgrowth (SIBO) diagnoses. Therefore, a number of false negatives would be expected for patients who solely produce methane. Usually patients produce either hydrogen or methane, and only rarely there are significant co-producers, as typically the methane is produced at the expense of hydrogen by microbial conversion of carbon dioxide. Various studies show that methanogens occur in about a third of all adult humans; therefore, there is significant potential for malabsorbers to remain undiagnosed if a simple hydrogen breath test is used. As an example, the hydrogen-based lactose malabsorption test is considered to result in about 5-15% false negatives mainly due to methane production. Until recently methane measurements were more in the domain of research laboratories, unlike hydrogen analyses which can now be undertaken at a relatively low cost mainly due to the invention of reliable electrochemical hydrogen sensors. More recently, simpler lower cost instrumentation has become commercially available which can directly measure both hydrogen and methane simultaneously on human breath. This makes more widespread clinical testing a realistic possibility. The production of small amounts of hydrogen and/or methane does not normally produce symptoms, whereas the production of higher levels can lead to a wide range of symptoms ranging from functional disorders of the bowel to low level depression. It is possible that excess methane levels may have more health consequences than excess hydrogen levels. This review describes the health consequences of methane production in humans and animals including a summary of the state of the art in detection methods. In conclusion, the combined measurement of hydrogen and methane should offer considerable improvement in the diagnosis of malabsorp\u2026", "author" : [ { "dropping-particle" : "", "family" : "Lacy Costello", "given" : "B P J", "non-dropping-particle" : "de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ledochowski", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ratcliffe", "given" : "N M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of breath research", "id" : "ITEM-1", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "024001", "title" : "The importance of methane breath testing: a review.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "", "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(de Lacy Costello, Ledochowski, & Ratcliffe, 2013b)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(de Lacy Costello, Ledochowski, & Ratcliffe, 2013b).ConclusionsOur results show that ammonia significantly increases over time in response to a high protein oral challenge compared to a negative control oral challenge, and we hypothesize that exhaled breath ammonia represents systemic ammonia. We also found that the ammonia peak following a high protein challenge is temporally related to the hydrogen peak (which identifies the time at which the food bolus encounters the major bacterial population of the distal small bowel and colon). This result is consistent with a gut-derived source of the systemic increase in ammonia. There are two putative mechanisms: increased activity of gut flora and/or activity of small bowel glutaminase. Notably, our interpretation of this temporally-associated increase in ammonia and hydrogen runs counter to the conclusions of others. However, we note that this temporal association does not prove the ammonia is gut-derived, and other mechanisms may contribute. For example, amino acid absorption in the proximal small bowel might result in ammonia release by inter-organ trafficking (e.g. from skeletal muscle) that could explain the temporal association. More research is needed to evaluate these possibilities.Our median ammonia value is comparable to those measured by other groups ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1088/1752-7155/7/1/017109", "ISSN" : "1752-7163", "PMID" : "23445955", "abstract" : "Ammonia concentrations in exhaled breath (eNH3) and skin gas of 20 healthy subjects were measured on-line with a commercial cavity ring-down spectrometer and compared to saliva pH and plasma ammonium ion (NH(+)4), urea and creatinine concentrations. Special attention was given to mouth, nose and skin sampling procedures and the accurate quantification of ammonia in humid gas samples. The obtained median concentrations were 688 parts per billion by volume (ppbv) for mouth-eNH3, 34 ppbv for nose-eNH3, and 21 ppbv for both mouth- and nose-eNH3 after an acidic mouth wash (MW). The median ammonia emission rate from the lower forearm was 0.3\u00a0ng cm(-2) min(-1). Statistically significant (p\u00a0<\u00a00.05) correlations between the breath, skin and plasma ammonia/ammonium concentrations were not found. However, mouth-eNH3 strongly (p\u00a0<\u00a00.001) correlated with saliva pH. This dependence was also observed in detailed measurements of the diurnal variation and the response of eNH3 to the acidic MW. It is concluded that eNH3 as such does not reflect plasma but saliva and airway mucus NH(+)4 concentrations and is affected by saliva and airway mucus pH. After normalization with saliva pH using the Henderson-Hasselbalch equation, mouth-eNH3 correlated with plasma NH(+)4, which points to saliva and plasma NH(+)4 being linked via hydrolysis of salivary urea.", "author" : [ { "dropping-particle" : "", "family" : "Schmidt", "given" : "F M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vaittinen", "given" : "O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mets\u00e4l\u00e4", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lehto", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forsblom", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Groop", "given" : "P-H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Halonen", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of breath research", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013", "3" ] ] }, "page" : "017109", "title" : "Ammonia in breath and emitted from skin.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "ISSN" : "8750-7587", "PMID" : "10562594", "abstract" : "The selected ion flow tube technique was used to quantify in breath the trace gases acetone, ammonia, ethanol, isoprene, and methanol during single exhalations while fasting and in response to feeding. Six normal volunteers were fasted for 12 h, and, after baseline breath samples were obtained, were fed a liquid protein-calorie meal to provide 0.47 g/kg of protein (Fortisip). Further breath samples were obtained at 20, 40, and 60 min, and then hourly for a further 5 h. Breath acetone concentrations fell from a maximum during fasting, reaching their nadir between 4 and 5 h. Breath ammonia concentrations fell immediately to one-half their fasting levels before a steady increase to two or three times baseline values at 5 h. There was a brief increase in breath ethanol concentrations after feeding, reflecting detectable ethanol contamination of the food. Subsequently, breath ethanol levels remained low throughout the experimental protocol. Isoprene concentrations did not change significantly, whereas changes in methanol concentrations reflected those in the ambient air. This preliminary study indicates that the selected ion flow tube technique may be used to detect changes in the trace gases present in breath and define their concentrations in the fasting and replete state. Of particular interest is the biphasic response of the breath ammonia concentration after feeding.", "author" : [ { "dropping-particle" : "", "family" : "Smith", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Spanel", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Davies", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of applied physiology (Bethesda, Md. : 1985)", "id" : "ITEM-2", "issue" : "5", "issued" : { "date-parts" : [ [ "1999", "11" ] ] }, "page" : "1584-8", "title" : "Trace gases in breath of healthy volunteers when fasting and after a protein-calorie meal: a preliminary study.", "type" : "article-journal", "volume" : "87" }, "uris" : [ "" ] }, { "id" : "ITEM-3", "itemData" : { "ISSN" : "0951-4198", "abstract" : "Selected ion flow tube mass spectrometry (SIFT-MS) has been used to carry out a pilot parallel study on five volunteers to determine changes occurring in several trace compounds present in exhaled breath and emitted from skin into a collection bag surrounding part of the arm, before and after ingesting 75 g of glucose in the fasting state. SIFT-MS enabled real-time quantification of ammonia, methanol, ethanol, propanol, formaldehyde, acetaldehyde, isoprene and acetone. Following glucose ingestion, blood glucose and trace compound levels were measured every 30 min for 2 h. All the above compounds, except formaldehyde, were detected at the expected levels in exhaled breath of all volunteers; all the above compounds, except isoprene, were detected in the collection bag. Ammonia, methanol and ethanol were present at lower levels in the bag than in the breath. The aldehydes were present at higher levels in the bag than in breath. The blood glucose increased to a peak about 1 h post-ingestion, but this change was not obviously correlated with temporal changes in any of the compounds in breath or emitted by skin, except for acetone. The decrease in breath acetone was closely mirrored by skin-emitted acetone in three volunteers. Breath and skin acetone also clearly change with blood glucose and further work may ultimately enable inferences to be drawn of the blood glucose concentration from skin or breath measurements in type 1 diabetes.", "author" : [ { "dropping-particle" : "", "family" : "Turner", "given" : "Claire", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Parekh", "given" : "Bhavin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Walton", "given" : "Christopher", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Spanel", "given" : "Patrik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Evans", "given" : "Mark", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Rapid communications in mass spectrometry : RCM", "id" : "ITEM-3", "issue" : "4", "issued" : { "date-parts" : [ [ "2008", "1" ] ] }, "page" : "526-32", "title" : "An exploratory comparative study of volatile compounds in exhaled breath and emitted by skin using selected ion flow tube mass spectrometry.", "type" : "article-journal", "volume" : "22" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Schmidt et al., 2013; Smith, Spanel, & Davies, 1999; Turner et al., 2008)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Schmidt et al., 2013; Smith, Spanel, & Davies, 1999; Turner et al., 2008) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1088/0967-3334/27/4/001", "ISSN" : "0967-3334", "PMID" : "16537976", "abstract" : "Selected ion flow tube mass spectrometry, SIFT-MS, has been used to monitor the volatile compounds in the exhaled breath of 30 volunteers (19 males, 11 females) over a 6 month period. Volunteers provided breath samples each week between 8:45 am and 1 pm (before lunch), and the concentrations of several trace compounds were obtained. In this paper the focus is on ammonia, acetone and propanol. It was found that the concentration distributions of these compounds in breath were close to log-normal. The median ammonia level estimated as a geometric mean for all samples was 833 parts per billion (ppb) with a multiplicative standard deviation of 1.62, the values ranging from 248 to 2935 ppb. Breath ammonia clearly increased with increasing age in this volunteer cohort. The geometric mean acetone level for all samples was 477 parts per billion (ppb) with a multiplicative standard deviation of 1.58, the values ranging from 148 to 2744 ppb. The median propanol level for all samples was 18 ppb, the values ranging from 0 to 135 ppb. A weak but significant correlation between breath propanol and acetone levels is apparent in the data. The findings indicate the potential value of SIFT-MS as a non-invasive breath analysis technique for investigating volatile compounds in human health and in the diseased state.", "author" : [ { "dropping-particle" : "", "family" : "Turner", "given" : "Claire", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Spanel", "given" : "Patrik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Physiological measurement", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2006", "4" ] ] }, "page" : "321-37", "title" : "A longitudinal study of ammonia, acetone and propanol in the exhaled breath of 30 subjects using selected ion flow tube mass spectrometry, SIFT-MS.", "type" : "article-journal", "volume" : "27" }, "uris" : [ "", "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Turner, Spanel, & Smith, 2006b)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Turner, Spanel, & Smith, 2006b). Some groups have concluded that exhaled breath ammonia measured via the mouth may be contaminated by oral bacterial products and exhaled breath ammonia does not reflect systemic or plasma ammonia ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1088/1752-7155/7/1/017109", "ISSN" : "1752-7163", "PMID" : "23445955", "abstract" : "Ammonia concentrations in exhaled breath (eNH3) and skin gas of 20 healthy subjects were measured on-line with a commercial cavity ring-down spectrometer and compared to saliva pH and plasma ammonium ion (NH(+)4), urea and creatinine concentrations. Special attention was given to mouth, nose and skin sampling procedures and the accurate quantification of ammonia in humid gas samples. The obtained median concentrations were 688 parts per billion by volume (ppbv) for mouth-eNH3, 34 ppbv for nose-eNH3, and 21 ppbv for both mouth- and nose-eNH3 after an acidic mouth wash (MW). The median ammonia emission rate from the lower forearm was 0.3\u00a0ng cm(-2) min(-1). Statistically significant (p\u00a0<\u00a00.05) correlations between the breath, skin and plasma ammonia/ammonium concentrations were not found. However, mouth-eNH3 strongly (p\u00a0<\u00a00.001) correlated with saliva pH. This dependence was also observed in detailed measurements of the diurnal variation and the response of eNH3 to the acidic MW. It is concluded that eNH3 as such does not reflect plasma but saliva and airway mucus NH(+)4 concentrations and is affected by saliva and airway mucus pH. After normalization with saliva pH using the Henderson-Hasselbalch equation, mouth-eNH3 correlated with plasma NH(+)4, which points to saliva and plasma NH(+)4 being linked via hydrolysis of salivary urea.", "author" : [ { "dropping-particle" : "", "family" : "Schmidt", "given" : "F M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Vaittinen", "given" : "O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Mets\u00e4l\u00e4", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lehto", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Forsblom", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Groop", "given" : "P-H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Halonen", "given" : "L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of breath research", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013", "3" ] ] }, "page" : "017109", "title" : "Ammonia in breath and emitted from skin.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Schmidt et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Schmidt et al., 2013)ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1088/1752-7155/7/1/017106", "ISSN" : "1752-7163", "PMID" : "23445832", "abstract" : "Throughout the development of breath analysis research, there has been interest in how the concentrations of trace compounds in exhaled breath are related to their concentrations in the ambient inhaled air. In considering this, Phillips introduced the concept of 'alveolar gradient' and judged that the measured exhaled concentrations of volatile organic compounds should be diminished by an amount equal to their concentrations in the inhaled ambient air. The objective of the work described in this paper was to investigate this relationship quantitatively. Thus, experiments have been carried out in which inhaled air was polluted by seven compounds of interest in breath research, as given below, and exhaled breath has been analysed by SIFT-MS as the concentrations of these compounds in the inhaled air were reduced. The interesting result obtained is that all the exogenous compounds are partially retained in the exhaled breath and there are close linear relationships between the exhaled and inhaled air concentrations for all seven compounds. Thus, retention coefficients, a, have been derived for the following compounds: pentane, 0.76 \u00b1 0.09; isoprene, 0.66 \u00b1 0.04; acetone, 0.17 \u00b1 0.03; ammonia, 0.70 \u00b1 0.13, methanol, 0.29 \u00b1 0.02; formaldehyde, 0.06 \u00b1 0.03; deuterated water (HDO), 0.09 \u00b1 0.02. From these data, correction to breath analyses for inhaled concentration can be described by coefficients specific to each compound, which can be close to 1 for hydrocarbons, as applied by Phillips, or around 0.1, meaning that inhaled concentrations of such compounds can essentially be neglected. A further deduction from the experimental data is that under conditions of the inhalation of clean air, the measured exhaled breath concentrations of those compounds should be increased by a factor of 1/(1\u00a0-\u00a0a) to correspond to gaseous equilibrium with the compounds dissolved in the mixed venous blood entering the alveoli. Thus, for isoprene, this is a factor of 3, which we have confirmed experimentally by re-breathing experiments.", "author" : [ { "dropping-particle" : "", "family" : "Span\u011bl", "given" : "Patrik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dryahina", "given" : "Kseniya", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of breath research", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2013", "3" ] ] }, "page" : "017106", "title" : "A quantitative study of the influence of inhaled compounds on their concentrations in exhaled breath.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Span\u011bl, Dryahina, & Smith, 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Spaněl, Dryahina, & Smith, 2013). The differences between groups may be due to protocols followed during breath collection, mouth- versus nose-exhaled breath, or difference in devices used to collect samples. Importantly, we measured the phase III portion of the breath and reported an immediate decrease in breath ammonia before a steady increase to above baseline seen in samples collected over 5 hours. We propose that a recovery period after rinsing is necessary. If measurements are recorded without adequate lag time or not followed for a long enough duration, recorded breath ammonia values may be relatively low as maximum levels have not yet been achieved. Some investigators may have recorded low breath ammonia levels due to this methodological difference. For example, Adrover et al. report that samples were collected 15 minutes after tooth brushing with results that are much lower than those reported in the literature ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "1573-2568", "abstract" : "BACKGROUND: Hepatic encephalopathy (HE) is a serious neuropsychiatric complication in both acute and chronic liver disease.\n\nAIMS: To establish the utility of a portable noninvasive method to measure ammonia in the breath of healthy subjects and patients with HE.\n\nMETHODS: The study included 106 subjects: 44 women and 62 men, 51 healthy and 55 cirrhotic. The breath ammonia was measured with an electrochemical sensor and expressed in parts/billion (ppb).\n\nRESULTS: The breath ammonia in healthy subjects had an average value of 151.4 ppb (95% confidence interval [CI]: 149.4-153.4) and the average value in cirrhotic patients was 169.9 ppb (95% CI: 163.5-176.2) (P < 0.0001). In cirrhotic patients with and without HE, the corresponding values were 184.1 ppb (95% CI: 167.7-200.6) and 162.9 ppb (95% CI: 158.8-167.0), respectively (P = 0.0011). Ammonia levels \u2265 165 ppb permitted a differentiation between healthy and cirrhotic subjects; the area under the receiver operating characteristic (ROC) curve for the ammonia-level values in cirrhotic versus control patients was 0.86 (95% CI: 0.79-0.93). In cirrhotic patients, ammonia levels \u2265 175 ppb permitted the distinction between patients with and without HE; the area under the ROC curve in cirrhotic patients with versus without HE was 0.83 (95% CI: 0.73-0.94).\n\nCONCLUSION: A portable sensor for measuring breath ammonia can be developed. If the results of the present study are confirmed, breath-ammonia determinations could produce a significant impact on the care of patients with cirrhosis and could even include the possibility of self-monitoring.", "author" : [ { "dropping-particle" : "", "family" : "Adrover", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cocozzella", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ridruejo", "given" : "E", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Garc\u00eda", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rome", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Podest\u00e1", "given" : "J J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Digestive diseases and sciences", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2012", "1" ] ] }, "page" : "189-95", "title" : "Breath-ammonia testing of healthy subjects and patients with cirrhosis.", "type" : "article-journal", "volume" : "57" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Adrover et al., 2012)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Adrover et al., 2012). As an element to explore diurnal variation, we compared intervention to control trials. During control trials, we measured a modest increase in ammonia. Hibbard and Killard noted “a consistent decrease in oral breath ammonia concentrations by the early afternoon (post-prandial)...followed by gradual increase towards late afternoon” in two individuals ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1088/1752-7155/5/3/037101", "ISSN" : "1752-7163", "PMID" : "21654023", "abstract" : "Photoacoustic laser spectroscopy was used as a technique to measure real-time levels of ammonia in exhaled human breath in a small, locally recruited, normal healthy population (n = 30). This yielded an average level of breath ammonia of 265 ppb, ranging from 29 to 688 ppb. Although average levels were marginally higher in male volunteers, this was not statistically significant. In addition, no correlation could be found between age, body mass index, or breath carbon dioxide levels. Monitoring of the daily routine of two individuals showed a consistent decrease in oral breath ammonia concentrations by the early afternoon (post-prandial), but was followed by a gradual increase towards late afternoon. However, in a comparison of oral and nasal breath in two volunteers, nasal breath ammonia levels were found to be significantly lower than oral levels. In addition, the daily variation was only seen in oral rather than nasal measurements which may indicate that significant background levels are predominantly of oral origin and that nasal sampling is the preferred route to eradicate this background in future studies. These results provide a healthy human breath ammonia baseline upon which other studies may be compared.", "author" : [ { "dropping-particle" : "", "family" : "Hibbard", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Killard", "given" : "A J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of breath research", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2011", "9" ] ] }, "page" : "037101", "title" : "Breath ammonia levels in a normal human population study as determined by photoacoustic laser spectroscopy.", "type" : "article-journal", "volume" : "5" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Hibbard & Killard, 2011a)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Hibbard & Killard, 2011a). As acknowledged by Hibbard and Killard, values they reported are lower on average than those reported here and in other studies ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1088/1752-7155/3/3/036001", "ISSN" : "1752-7155", "abstract" : "Using selected ion flow tube mass spectrometry (SIFT-MS), measurements have been made of the levels of several metabolites in the exhaled breath of 200 healthy school children. Thus, concentration distributions of each metabolite have been obtained for the first time in the paediatric age range. The median values (in parentheses) of the concentrations in parts per billion, ppb, were ammonia (628), acetone (297), methanol (193), ethanol (187), isoprene (37), propanol (16), acetaldehyde (23) and pentanol (15). Hydrogen cyanide was not present in the breath above the detection limit of 2 ppb in the majority of subjects. The water vapour level (humidity) of the breath samples was routinely measured as a check on the sample integrity. Such data are essential if SIFT-MS breath analyses are to be used as a clinical tool to aid diagnosis and/or as a monitor of disease in children. The levels of metabolites usually followed a log-normal distribution and the levels of some compounds were similar to those obtained previously in adults. Lower values were found in the levels of acetone, ammonia, methanol and isoprene. There were no major variations in relation to gender. Some metabolites showed significant variation in relation to age and body mass index. To our knowledge, these are the first measurements of exhaled mouth breath pentanol levels. The median ammonia levels in mouth-exhaled breath of these children decreased with age, whereas in older adults, ammonia has been shown to increase with age. Breath acetone levels were significantly increased for those who had not eaten for more than 6 h prior to providing the breath sample, although dietary control was not a mandatory aspect of the protocol.", "author" : [ { "dropping-particle" : "", "family" : "Enderby", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lenney", "given" : "W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brady", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Emmett", "given" : "C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Spanel", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of Breath Research", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2009" ] ] }, "page" : "36001", "publisher" : "IOP PUBLISHING LTD", "title" : "Concentrations of some metabolites in the breath of healthy children aged 7-18 years measured using selected ion flow tube mass spectrometry (SIFT-MS) RID B-6574-2008 RID A-3622-2010", "type" : "article-journal", "volume" : "3" }, "uris" : [ "", "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1088/0967-3334/27/4/001", "ISSN" : "0967-3334", "PMID" : "16537976", "abstract" : "Selected ion flow tube mass spectrometry, SIFT-MS, has been used to monitor the volatile compounds in the exhaled breath of 30 volunteers (19 males, 11 females) over a 6 month period. Volunteers provided breath samples each week between 8:45 am and 1 pm (before lunch), and the concentrations of several trace compounds were obtained. In this paper the focus is on ammonia, acetone and propanol. It was found that the concentration distributions of these compounds in breath were close to log-normal. The median ammonia level estimated as a geometric mean for all samples was 833 parts per billion (ppb) with a multiplicative standard deviation of 1.62, the values ranging from 248 to 2935 ppb. Breath ammonia clearly increased with increasing age in this volunteer cohort. The geometric mean acetone level for all samples was 477 parts per billion (ppb) with a multiplicative standard deviation of 1.58, the values ranging from 148 to 2744 ppb. The median propanol level for all samples was 18 ppb, the values ranging from 0 to 135 ppb. A weak but significant correlation between breath propanol and acetone levels is apparent in the data. The findings indicate the potential value of SIFT-MS as a non-invasive breath analysis technique for investigating volatile compounds in human health and in the diseased state.", "author" : [ { "dropping-particle" : "", "family" : "Turner", "given" : "Claire", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Spanel", "given" : "Patrik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Physiological measurement", "id" : "ITEM-2", "issue" : "4", "issued" : { "date-parts" : [ [ "2006", "4" ] ] }, "page" : "321-37", "title" : "A longitudinal study of ammonia, acetone and propanol in the exhaled breath of 30 subjects using selected ion flow tube mass spectrometry, SIFT-MS.", "type" : "article-journal", "volume" : "27" }, "uris" : [ "", "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Enderby et al., 2009; Turner et al., 2006b)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Enderby et al., 2009; Turner et al., 2006b). In our study, by comparing breath ammonia levels measured after oral intervention to levels after high protein intervention, each participant served as their own control. Breath ammonia was significantly increased after high protein intervention when compared to the control. Some investigators have recommended measurement of nose-exhaled breath indicating that it represents systemic ammonia and avoids oral contamination that occurs with mouth-exhaled samples ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1088/1752-7155/2/3/037013", "ISSN" : "1752-7155", "PMID" : "21386174", "abstract" : "Analyses have been performed, using on-line selected ion flow tube mass spectrometry (SIFT-MS), of the breath of three healthy volunteers, as exhaled via the mouth and the nose and also of the air in the oral cavity during breath hold, each morning over a period of one month. Nine trace compounds have been quantified and concentration distributions have been constructed. Of these compounds, the levels of acetone, methanol and isoprene are the same in the mouth-exhaled and the nose-exhaled breath; hence, we deduce that these compounds are totally systemic. The levels of ammonia, ethanol and hydrogen cyanide are much lower in the nose-exhaled breath than in the mouth-exhaled breath and highest in the oral cavity, indicating that these compounds are largely generated in the mouth with little being released at the alveolar interface. Using the same ideas, both the low levels of propanol and acetaldehyde in mouth-exhaled breath appear to have both oral and systemic components. Formaldehyde is at levels in mouth- and nose-exhaled breath and the oral cavity that are lower than that of the ambient air and so its origin is difficult to ascertain, but it appears to be partially systemic. These results indicate that serious contamination of alveolar breath exhaled via the mouth can occur and if breath analysis is to be used to diagnose metabolic disease then analyses should be carried out of both mouth- and nose-exhaled breath to identify the major sources of particular trace compounds.", "author" : [ { "dropping-particle" : "", "family" : "Wang", "given" : "Tianshu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pysanenko", "given" : "Andriy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dryahina", "given" : "Kseniya", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Span\u011bl", "given" : "Patrik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of breath research", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2008", "9" ] ] }, "page" : "037013", "title" : "Analysis of breath, exhaled via the mouth and nose, and the air in the oral cavity.", "type" : "article-journal", "volume" : "2" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Wang et al., 2008a)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Wang et al., 2008a). Wang et al. report geometric means (MSD) of ammonia: 1088 (1.3) ppb, 885 (1.3) ppb, and 855 (1.3) ppb for three volunteers using a protocol that sampled “direct exhaled breath via the mouth.” Additionally, they employed protocols for direct exhaled breath via the nose and static gas in the oral cavity during breath hold. Others incorporated a urea mouth wash to evaluate the potential for oral contamination and found supra-physiologic ammonia levels (4500 ppb) seen in mouth-exhaled breath of a single subject ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "author" : [ { "dropping-particle" : "", "family" : "Smith, D, Chippendale, TWE, Dryahina, K, Spanel", "given" : "", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Current Analytical Chemistry", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2013" ] ] }, "page" : "565-575", "title" : "SIFT-MS analysis of nose-exhaled breath; mouth contamination and the influence of exercise", "type" : "article-journal", "volume" : "9" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Smith, D, Chippendale, TWE, Dryahina, K, Spanel, 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Smith, D, Chippendale, TWE, Dryahina, K, Spanel, 2013). However, this maneuver does not rule out a gastrointestinal source of mouth-exhaled breath ammonia. In reviewing the literature, results for breath ammonia collected via nose-exhaled versus mouth-exhaled protocols are different ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1088/1752-7155/2/3/037013", "ISSN" : "1752-7155", "PMID" : "21386174", "abstract" : "Analyses have been performed, using on-line selected ion flow tube mass spectrometry (SIFT-MS), of the breath of three healthy volunteers, as exhaled via the mouth and the nose and also of the air in the oral cavity during breath hold, each morning over a period of one month. Nine trace compounds have been quantified and concentration distributions have been constructed. Of these compounds, the levels of acetone, methanol and isoprene are the same in the mouth-exhaled and the nose-exhaled breath; hence, we deduce that these compounds are totally systemic. The levels of ammonia, ethanol and hydrogen cyanide are much lower in the nose-exhaled breath than in the mouth-exhaled breath and highest in the oral cavity, indicating that these compounds are largely generated in the mouth with little being released at the alveolar interface. Using the same ideas, both the low levels of propanol and acetaldehyde in mouth-exhaled breath appear to have both oral and systemic components. Formaldehyde is at levels in mouth- and nose-exhaled breath and the oral cavity that are lower than that of the ambient air and so its origin is difficult to ascertain, but it appears to be partially systemic. These results indicate that serious contamination of alveolar breath exhaled via the mouth can occur and if breath analysis is to be used to diagnose metabolic disease then analyses should be carried out of both mouth- and nose-exhaled breath to identify the major sources of particular trace compounds.", "author" : [ { "dropping-particle" : "", "family" : "Wang", "given" : "Tianshu", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Pysanenko", "given" : "Andriy", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dryahina", "given" : "Kseniya", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Span\u011bl", "given" : "Patrik", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Smith", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of breath research", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2008", "9" ] ] }, "page" : "037013", "title" : "Analysis of breath, exhaled via the mouth and nose, and the air in the oral cavity.", "type" : "article-journal", "volume" : "2" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1088/1752-7155/5/3/037101", "ISSN" : "1752-7163", "PMID" : "21654023", "abstract" : "Photoacoustic laser spectroscopy was used as a technique to measure real-time levels of ammonia in exhaled human breath in a small, locally recruited, normal healthy population (n = 30). This yielded an average level of breath ammonia of 265 ppb, ranging from 29 to 688 ppb. Although average levels were marginally higher in male volunteers, this was not statistically significant. In addition, no correlation could be found between age, body mass index, or breath carbon dioxide levels. Monitoring of the daily routine of two individuals showed a consistent decrease in oral breath ammonia concentrations by the early afternoon (post-prandial), but was followed by a gradual increase towards late afternoon. However, in a comparison of oral and nasal breath in two volunteers, nasal breath ammonia levels were found to be significantly lower than oral levels. In addition, the daily variation was only seen in oral rather than nasal measurements which may indicate that significant background levels are predominantly of oral origin and that nasal sampling is the preferred route to eradicate this background in future studies. These results provide a healthy human breath ammonia baseline upon which other studies may be compared.", "author" : [ { "dropping-particle" : "", "family" : "Hibbard", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Killard", "given" : "A J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of breath research", "id" : "ITEM-2", "issue" : "3", "issued" : { "date-parts" : [ [ "2011", "9" ] ] }, "page" : "037101", "title" : "Breath ammonia levels in a normal human population study as determined by photoacoustic laser spectroscopy.", "type" : "article-journal", "volume" : "5" }, "uris" : [ "", "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Hibbard & Killard, 2011b; Wang, Pysanenko, Dryahina, Span\u011bl, & Smith, 2008c)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Hibbard & Killard, 2011b; Wang, Pysanenko, Dryahina, Spaněl, & Smith, 2008c). Future research must clearly report the method of breath exhalation: nose- or mouth-exhaled, especially since the evidence indicates that nose-exhaled ammonia values are consistently lower than mouth-exhaled samples. This may be due to the greater surface area of the nasal cavity compared to the oral cavity to act as an ammonia sink. In that reproducible ammonia levels have been published in the literature, we propose that consistent use of either method will allow for the study of gut-derived ammonia.Investigations have not definitively or reproducibly described the biological mechanisms that produce measurable ammonia in exhaled breath. Van de Poll et al. and Yang et al. have presented data supporting the thesis that gut-derived ammonia does not increase systemic ammonia in healthy persons without porto-systemic shunting ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0193-1857", "abstract" : "The gut is classically seen as the main source of circulating ammonia. However, the contribution of the intestines to systemic ammonia production may be limited by hepatic extraction of portal-derived ammonia. Recent data suggest that the kidney may be more important than the gut for systemic ammonia production. The aim of this study was to quantify the role of the kidney, intestines, and liver in interorgan ammonia trafficking in humans with normal liver function. In addition, we studied changes in interorgan nitrogen metabolism caused by major hepatectomy. From 21 patients undergoing surgery, blood was sampled from the portal, hepatic, and renal veins to assess intestinal, hepatic, and renal ammonia metabolism. In seven cases, blood sampling was repeated after major hepatectomy. At steady state during surgery, intestinal ammonia release was equaled by hepatic ammonia uptake, precluding significant systemic release of intestinal-derived ammonia. In contrast, the kidneys released ammonia to the systemic circulation. Major hepatectomy led to increased concentrations of ammonia and amino acids in the systemic circulation. However, transsplanchnic concentration gradients after major hepatectomy were similar to baseline values, indicating the rapid institution of a new metabolic equilibrium. In conclusion, since hepatic ammonia uptake exactly equals intestinal ammonia release, the splanchnic area, and hence the gut, probably does not contribute significantly to systemic ammonia release. After major hepatectomy, hepatic ammonia clearance is well preserved, probably related to higher circulating ammonia concentrations.", "author" : [ { "dropping-particle" : "", "family" : "Poll", "given" : "Marcel C G", "non-dropping-particle" : "van de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ligthart-Melis", "given" : "Gerdien C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Olde Damink", "given" : "Steven W M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Leeuwen", "given" : "Paul A M", "non-dropping-particle" : "van", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Beets-Tan", "given" : "Regina G H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Deutz", "given" : "Nicolaas E P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Wigmore", "given" : "Stephen J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Soeters", "given" : "Peter B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dejong", "given" : "Cornelis H C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American journal of physiology. Gastrointestinal and liver physiology", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2008", "10" ] ] }, "page" : "G760-5", "title" : "The gut does not contribute to systemic ammonia release in humans without portosystemic shunting.", "type" : "article-journal", "volume" : "295" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(van de Poll et al., 2008)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(van de Poll et al., 2008) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0193-1849", "PMID" : "10710501", "abstract" : "The substrates for hepatic ureagenesis are equimolar amounts of ammonium and aspartate. The study design mimics conditions in which the liver receives more NH(+)(4) than aspartate precursors (very low-protein diet). Fasted dogs, fitted acutely with transhepatic catheters, were infused with a tracer amount of (15)NH(4)Cl. From arteriovenous differences, the major NH(+)(4) precursor for hepatic ureagenesis was via deamidation of glutamine in the portal drainage system (rather than in the liver), because there was a 1:1 stoichiometry between glutamine disappearance and NH(+)(4) appearance, and the amide (but not the amine) nitrogen of glutamine supplied the (15)N added to the portal venous NH(+)(4) pool. The liver extracted all this NH(+)(4) from glutamine deamidation plus an additional amount in a single pass, suggesting that there was an activator of hepatic ureagenesis. The other major source of nitrogen extracted by the liver was [(14)N]alanine. Because alanine was not produced in the portal venous system, we speculate that it was derived ultimately from proteins in peripheral tissues.", "author" : [ { "dropping-particle" : "", "family" : "Yang", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hazey", "given" : "J W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "David", "given" : "F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Singh", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rivchum", "given" : "R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Streem", "given" : "J M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Halperin", "given" : "M L", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Brunengraber", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American journal of physiology. Endocrinology and metabolism", "id" : "ITEM-1", "issue" : "3", "issued" : { "date-parts" : [ [ "2000", "3" ] ] }, "page" : "E469-76", "title" : "Integrative physiology of splanchnic glutamine and ammonium metabolism.", "type" : "article-journal", "volume" : "278" }, "uris" : [ "", "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Yang et al., 2000)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Yang et al., 2000). The difference between our study results and these conclusions may be related to the methods used in the determination of ammonia levels. In our study, we collected exhaled breath, whereas van de Poll et al., for example, used phlebotomy from multiple body compartments during laparotomy. As well, the work of Olde Daminik et al. was exceptional, specifically because portal and hepatic vein phlebotomy occurred simultaneously ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1097/MEG.0b013e328346a7bd", "ISSN" : "1473-5687", "PMID" : "21537121", "abstract" : "Hepatic encephalopathy is a neuropsychiatric syndrome associated with liver failure. Its aetiology has been debated for the past 100 years. Nevertheless, elevated ammonia levels are still believed to play a central role in its pathogenesis. After intestinal production, ammonia is detoxified by the liver. In liver failure, skeletal muscle and brain have been proposed to be alternative, although temporary, ammonia detoxifying organs. However, there is an increasing body of evidence that the kidney, in addition to the gut, is a pivotal organ determining systemic ammonia levels. In the last 20 years, it has been shown that the kidney can switch from an organ of systemic net ammonia production to a net ammonia excretion organ. The kidney plays a central role in the determination of ammonia levels. It is at least as important as the gut and could therefore serve as a target for new treatments for hepatic encephalopathy.", "author" : [ { "dropping-particle" : "", "family" : "Mpabanzi", "given" : "Liliane", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Olde Damink", "given" : "Steven W M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Poll", "given" : "Marcel C G", "non-dropping-particle" : "van de", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Soeters", "given" : "Peter B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Jalan", "given" : "Rajiv", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dejong", "given" : "Cees H C", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "European journal of gastroenterology & hepatology", "id" : "ITEM-1", "issue" : "6", "issued" : { "date-parts" : [ [ "2011", "6" ] ] }, "page" : "449-54", "title" : "To pee or not to pee: ammonia hypothesis of hepatic encephalopathy revisited.", "type" : "article-journal", "volume" : "23" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Mpabanzi et al., 2011)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Mpabanzi et al., 2011).While our study lacks data from blood assays, we do not believe this is an important impediment for the study of ammonia or ethanol. To illustrate with ammonia only, our breath assays measure exhaled NH3 presumably derived from the lungs while venipuncture measures NH4+ derived from a limb. As already noted, both approaches have the potential for significant variability and error. In the case of blood assays, this concern has been repeatedly reviewed. Thus, while NH3 and NH4+ may have a precise stoichiometric relationship at a given pH in a chemistry lab, the same relationship may not be observed when this most volatile metabolite is measured from different compartments of a whole organism. In fact, DuBois et al. used fiberoptic sensors to detect breath ammonium and compared it to arterial ammonium in 15 cirrhotic individuals and found no correlation ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1007/s10620-005-2937-6", "ISSN" : "0163-2116", "PMID" : "16187173", "abstract" : "Measurement of arterial ammonia has been used as a diagnostic test for hepatic encephalopathy, but obtaining an arterial specimen is an invasive procedure. The aim of this study was to evaluate the ability of a minimally invasive, highly sensitive optical sensing device to detect ammonia in the breath of patients with end-stage liver disease and to evaluate the correlation of breath ammonia levels, arterial ammonia levels, and psychometric testing. Fifteen subjects with liver cirrhosis and clinical evidence of hepatic encephalopathy underwent mini-mental status examination, number connection test, focused neurological examination, and arterial ammonia testing. On the same day, breath ammonia testing was performed using an apparatus that consists of a sensor (a thin membrane embedded with a pH-sensitive dye) attached to a fiberoptic apparatus that detects optical absorption. Helicobacter pylori testing was performed using the 14C urea breath test. A positive correlation was found between arterial ammonia level and time to complete the number connection test (r = 0.31, P = 0.03). However, a negative correlation was found between breath ammonia level and number connection testing (r = -0.55, P = 0.03). Furthermore, no correlation was found between breath and arterial ammonia levels (r = -0.005, P = 0.98). There is a significant correlation between the trailmaking test and arterial ammonia levels in patients with cirrhosis. However, no correlation was found between breath and arterial ammonia levels using the fiberoptic ammonia sensor apparatus in this small study.", "author" : [ { "dropping-particle" : "", "family" : "DuBois", "given" : "Suja", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Eng", "given" : "Sue", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Bhattacharya", "given" : "Renuka", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Rulyak", "given" : "Steve", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Hubbard", "given" : "Todd", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Putnam", "given" : "David", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kearney", "given" : "David J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Digestive diseases and sciences", "id" : "ITEM-1", "issue" : "10", "issued" : { "date-parts" : [ [ "2005", "10" ] ] }, "page" : "1780-4", "title" : "Breath ammonia testing for diagnosis of hepatic encephalopathy.", "type" : "article-journal", "volume" : "50" }, "uris" : [ "", "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(DuBois et al., 2005b)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(DuBois et al., 2005b). Nevertheless, our own preliminary work on this comparison using a separate cohort suggests a fair correlation between breath and blood ammonia (unpublished data). And, our current study provides an internal control by comparing repeated levels of breath ammonia in participants after an oral control intervention followed by a treatment intervention.Our results also demonstrate significant increases in breath ethanol following a high protein challenge, compared to a negative control oral challenge that showed a similar yet less pronounced increase. This is consistent with the concept of gut-derived “endogenous ethanol”, which has previously been shown in several small studies using highly sensitive blood assays in response to food ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "1387-2273", "PMID" : "10360426", "abstract" : "We have established an ultra-sensitive method for determination of ethanol in whole blood by headspace capillary gas chromatography (GC) with cryogenic oven trapping. After heating a blood sample containing ethanol and isobutyl alcohol (internal standard, IS) in a 7.0-ml vial at 55 degrees C for 15 min, 5 ml of the headspace vapor was drawn into a glass syringe and injected into a GC port. All vapor was introduced into an Rtx-BAC2 wide-bore capillary column in the splitless mode at -60 degrees C oven temperature to trap entire analytes, and then the oven temperature was programmed up to 240 degrees C for GC measurements with flame ionization detection. The present method gave sharp peaks of ethanol and IS, and low background noise for whole blood samples. The mean partition into the gaseous phase for ethanol and IS was 3.06+/-0.733 and 8.33+/-2.19%, respectively. The calibration curves showed linearity in the range 0.02-5.0 microg/ml whole blood. The detection limit was estimated to be 0.01 microg/ml. The coefficients of intra-day and inter-day variation for spiked ethanol were 8.72 and 9.47%, respectively. Because of the extremely high sensitivity, we could measure low levels of endogenous ethanol in whole blood of subjects without drinking. The concentration of endogenous ethanol measured for 10 subjects under uncontrolled conditions varied from 0 to 0.377 microg/ml (mean, 0.180 microg/ml). Data on the diurnal changes of endogenous ethanol in whole blood of five subjects under strict food control are also presented; they are in accordance with the idea that endogenous blood ethanol is of enteric bacterial origin.", "author" : [ { "dropping-particle" : "", "family" : "Watanabe-Suzuki", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Seno", "given" : "H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Ishii", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Kumazawa", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Suzuki", "given" : "O", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of chromatography. B, Biomedical sciences and applications", "id" : "ITEM-1", "issue" : "1-2", "issued" : { "date-parts" : [ [ "1999", "4", "30" ] ] }, "page" : "89-94", "title" : "Ultra-sensitive method for determination of ethanol in whole blood by headspace capillary gas chromatography with cryogenic oven trapping.", "type" : "article-journal", "volume" : "727" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Watanabe-Suzuki, Seno, Ishii, Kumazawa, & Suzuki, 1999)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Watanabe-Suzuki, Seno, Ishii, Kumazawa, & Suzuki, 1999) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0145-6008", "PMID" : "11329490", "abstract" : "BACKGROUND: Endogenous methanol and ethanol levels are found in human blood. It is assumed that these compounds are derived mainly from microflora in the gastrointestinal tract and that the small amounts formed are consequently eliminated, mainly in the liver, by the alcohol dehydrogenase (ADH) pathway. The objective of the present study was to investigate the effect of 4-methylpyrazole (4-MP), a specific ADH inhibitor, on endogenous plasma methanol and ethanol levels in healthy women and men.\n\nMETHODS: A double-blind placebo-controlled interventional study was carried out.\n\nRESULTS: A significant elevation in plasma endogenous ethanol and methanol levels was observed after intake of 4-MP (10-15 mg/kg p.o.). For methanol levels, a linear increase from 20 +/- 14 micromol/l before intake to 39 +/- 22 micromol/l at 420 min from intake of 4-MP (levels 20 +/- 14 micromol/l and 14 +/- 9 micromol/l during the corresponding placebo time points) was found. For ethanol, concentrations increased from levels below detection limit (i.e., < 5 micromol/l, determined by headspace gas chromatography) before intake to 30 +/- 20 micromol/l at 195 min from intake of 4-MP. A small increase in ethanol levels, to 13 +/- 8 micromol/l, but not in methanol levels, was observed after the intake of lingonberry juice containing no ethanol or methanol. No sex differences in the ethanol and methanol levels before or after the intake of 4-MP were found.\n\nCONCLUSIONS: The present study provides conclusive evidence for a constant endogenous production as well as clearance of ethanol and methanol in humans. In addition, the study shows that the ethanol and methanol produced are, at least in part, eliminated by the ADH pathway.", "author" : [ { "dropping-particle" : "", "family" : "Sarkola", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Eriksson", "given" : "C J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Alcoholism, clinical and experimental research", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2001", "4" ] ] }, "page" : "513-6", "title" : "Effect of 4-methylpyrazole on endogenous plasma ethanol and methanol levels in humans.", "type" : "article-journal", "volume" : "25" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Sarkola & Eriksson, 2001)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Sarkola & Eriksson, 2001) as well as prior breath research using a murine model ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "0016-5085", "PMID" : "11054393", "abstract" : "BACKGROUND & AIMS: Similarities in the hepatic responses to obesity and ethanol exposure suggest that these conditions evoke common pathogenic mechanisms. Thus, it is possible that ethanol exposure is increased in obesity. Given that intestinal bacteria can produce ethanol, the aim of this study was to determine if the intestinal production of ethanol is increased in obesity.\n\nMETHODS: Breath was collected from genetically obese, ob/ob male C57BL/6 mice and lean male littermates at different ages (14, 20, and 24 weeks) and times of the day (9 AM, 3 PM, and 9 PM). Obese mice (24 weeks old) were then treated with neomycin (1 mg/mL) for 5 days, and sampling was repeated.\n\nRESULTS: Breath collected in the morning from 24-week-old obese mice had a higher ethanol content than breath from their lean littermates (271 vs. 78 pmol/mL CO(2); P < 0.0001). Subsequent studies in 14- and 20-week-old mice showed that exhaled ethanol increased with age in obese (from 26 to 107 pmol/mL CO(2); P < 0. 002) but not lean (29 and 12 pmol/mL CO(2)) mice and was greater in older obese mice than in older lean mice (P < 0.0006). Obese mice showed a diurnal increase in breath ethanol in the morning that decreased through the afternoon and evening (107 to 33 to 13 pmol/mL CO(2)). Neomycin treatment decreased morning breath ethanol levels by 50% (from 220 to 110 pmol/mL CO(2); P < 0.0003).\n\nCONCLUSIONS: Even in the absence of ethanol ingestion, ethanol can be detected in exhaled breath. In obesity, an age-related increase in breath ethanol content reflects increased production of ethanol by the intestinal microflora. Hence, intestinal production of ethanol may contribute to the genesis of obesity-related fatty liver.", "author" : [ { "dropping-particle" : "", "family" : "Cope", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Risby", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Diehl", "given" : "A M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Gastroenterology", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "2000", "11" ] ] }, "page" : "1340-7", "title" : "Increased gastrointestinal ethanol production in obese mice: implications for fatty liver disease pathogenesis.", "type" : "article-journal", "volume" : "119" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(K. Cope, Risby, & Diehl, 2000)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(K. Cope, Risby, & Diehl, 2000) and humans ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/j.1572-0241.2001.03702.x", "ISSN" : "0002-9270", "PMID" : "11316170", "abstract" : "OBJECTIVES: Similarities between histological features of alcoholic hepatitis and obesity-related liver disease suggest a common pathogenic mechanism. Because intestinal bacteria can produce ethanol, it is conceivable that intestinally derived alcohol may contribute to fatty liver disease. An indirect way of measuring endogenous ethanol is to measure the breath ethanol concentration. In a previous study in ob/ob mice, breath ethanol decreased with a course of non-absorbable antibiotics, suggesting that the ethanol is derived from intestinal bacterial flora. The aims of this study were 1) to determine whether alcohol can be detected in the breath of human subjects, and 2) to assess whether there is any correlation between ethanol and obesity in patients with nonalcoholic steatohepatits (NASH) and control subjects without known liver disease.\n\nMETHODS: Breath ethanol concentration was determined in 21 patients with biopsy-proven NASH and in 10 control subjects by gas chromatography. An abnormal breath ethanol level was defined as two standard deviations above the mean value of the breath ethanol of lean controls.\n\nRESULTS: Minute quantities of ethanol were detected in the breath of human subjects who had not consumed alcohol in the recent past. Patients who were obese were more likely to have higher breath ethanol concentrations. Women also had higher breath alcohol than men. However, there was no difference between patients with NASH and controls. Severity of liver disease, as evidenced by cirrhosis, did not influence the breath ethanol concentration.\n\nCONCLUSIONS: Higher breath ethanol concentrations are observed in obese subjects than in leaner ones. It is possible that intestinally derived ethanol may contribute to the pathogenesis of NASH.", "author" : [ { "dropping-particle" : "", "family" : "Nair", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cope", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Risby", "given" : "T H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Diehl", "given" : "A M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Terence", "given" : "R H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "The American journal of gastroenterology", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2001", "4" ] ] }, "page" : "1200-4", "title" : "Obesity and female gender increase breath ethanol concentration: potential implications for the pathogenesis of nonalcoholic steatohepatitis.", "type" : "article-journal", "volume" : "96" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Nair, Cope, Risby, Diehl, & Terence, 2001)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Nair, Cope, Risby, Diehl, & Terence, 2001) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1080/13547500500421070", "ISSN" : "1354-750X", "PMID" : "16766393", "abstract" : "Breath biomarkers have the potential to offer information that is similar to conventional clinical tests or they are entirely unique. Preliminary data support the use of breath biomarkers in the study of liver disease, in particular non-alcoholic fatty liver disease (NAFLD). It was evaluated whether breath ethanol, ethane, sulfur compounds and acetone would be associated with hepatic histopathology amongst morbidly obese patients presenting for bariatric surgery. Breath samples were collected during a preoperative visit and compared with liver biopsies obtained during the surgery. A Student's two-tailed t-test was used to compare differences between the two groups. Linear regression was used to analyse associations between the concentrations of breath molecules and independent predictor variables. It was found that breath ethanol, ethane and acetone can be useful biomarkers in patients with NAFLD. In particular, breath ethanol can be associated with hepatic steatosis, and breath acetone can be associated with non-alcoholic steatohepatitis.", "author" : [ { "dropping-particle" : "", "family" : "Solga", "given" : "S F", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alkhuraishe", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Cope", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Tabesh", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clark", "given" : "J M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Torbenson", "given" : "M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Schwartz", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Magnuson", "given" : "T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Diehl", "given" : "A M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Risby", "given" : "T H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "0" ] ] }, "page" : "174-83", "title" : "Breath biomarkers and non-alcoholic fatty liver disease: preliminary observations.", "type" : "article-journal", "volume" : "11" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(S F Solga et al., n.d.)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(S F Solga et al., n.d.). Endogenous ethanol is postulated to contribute to the pathogenesis of non-alcoholic fatty liver and perhaps the metabolic syndrome ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1111/1469-0691.12140", "ISSN" : "1469-0691", "PMID" : "23452163", "abstract" : "Non-alcoholic fatty liver disease (NAFLD) is a severe liver disease that is increasing in prevalence with the worldwide epidemic of obesity and its related insulin-resistance state. A 'two-hit' mechanism has been proposed; however, the complete physiopathogenesis remains incompletely understood. Evidence for the role of the gut microbiota in energy storage and the subsequent development of obesity and some of its related diseases is now well established. More recently, a new role of gut microbiota has emerged in NAFLD. The gut microbiota is involved in gut permeability, low-grade inflammation and immune balance, it modulates dietary choline metabolism, regulates bile acid metabolism and produces endogenous ethanol. All of these factors are molecular mechanisms by which the microbiota can induce NAFLD or its progression toward overt non-alcoholic steatohepatitis.", "author" : [ { "dropping-particle" : "", "family" : "Aron-Wisnewsky", "given" : "J", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gaborit", "given" : "B", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Dutour", "given" : "A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Clement", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases", "id" : "ITEM-1", "issue" : "4", "issued" : { "date-parts" : [ [ "2013", "4" ] ] }, "page" : "338-48", "title" : "Gut microbiota and non-alcoholic fatty liver disease: new insights.", "type" : "article-journal", "volume" : "19" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Aron-Wisnewsky, Gaborit, Dutour, & Clement, 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Aron-Wisnewsky, Gaborit, Dutour, & Clement, 2013) ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1038/nrgastro.2010.172", "ISSN" : "1759-5053", "PMID" : "21045794", "abstract" : "Important metabolic functions have been identified for the gut microbiota in health and disease. Several lines of evidence suggest a role for the gut microbiota in both the etiology of nonalcoholic fatty liver disease (NAFLD) and progression to its more advanced state, nonalcoholic steatohepatitis (NASH). Both NAFLD and NASH are strongly linked to obesity, type 2 diabetes mellitus and the metabolic syndrome and, accordingly, have become common worldwide problems. Small intestinal bacterial overgrowth of Gram-negative organisms could promote insulin resistance, increase endogenous ethanol production and induce choline deficiency, all factors implicated in NAFLD. Among the potential mediators of this association, lipopolysaccharide (a component of Gram-negative bacterial cell walls) exerts relevant metabolic and proinflammatory effects. Although the best evidence to support a role for the gut microbiota in NAFLD and NASH comes largely from animal models, data from studies in humans (albeit at times contradictory) is accumulating and could lead to new therapeutic avenues for these highly prevalent conditions.", "author" : [ { "dropping-particle" : "", "family" : "Abu-Shanab", "given" : "Ahmed", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Quigley", "given" : "Eamonn M M", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Nature reviews. Gastroenterology & hepatology", "id" : "ITEM-1", "issue" : "12", "issued" : { "date-parts" : [ [ "2010", "12", "2" ] ] }, "page" : "691-701", "publisher" : "Nature Publishing Group", "title" : "The role of the gut microbiota in nonalcoholic fatty liver disease.", "type" : "article-journal", "volume" : "7" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Abu-Shanab & Quigley, 2010)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Abu-Shanab & Quigley, 2010). However, a unique aspect of this study, especially in regards to the interpretation of the ethanol data, is the use of breath hydrogen. In contrast to ammonia and ethanol, hydrogen is easy to measure, inert, and its source is relatively non-controversial: it is produced when the food bolus residue encounters the bulk of bacteria in the distal small bowel and, to a greater degree, colon. It therefore serves as a distinctive and essential timing marker. This is important to the consideration of serial data after an oral challenge because gut transit time is variable and unpredictable ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1152/ajpgi.90380.2008", "ISSN" : "0193-1857", "PMID" : "18988693", "abstract" : "Peristaltic motor activity of the gut is an essential activity to sustain life. In each gut organ, a multitude of overlapping mechanisms has developed to acquire the ability of coordinated contractile activity under a variety of circumstances and in response to a variety of stimuli. The presence of several simultaneously operating control systems is a challenge for investigators who focus on the role of one particular control activity since it is often not possible to decipher which control systems are operating or dominant in a particular situation. A crucial advantage of multiple control systems is that gut motility control can withstand injury to one or more of its components. Our efforts to increase understanding of control mechanism are not helped by recent attempts to eliminate proven control systems such as interstitial cells of Cajal (ICC) as pacemaker cells, or intrinsic sensory neurons, nor does it help to view peristalsis as a simple reflex. This review focuses on the role of ICC as slow-wave pacemaker cells and places ICC into the context of other control mechanisms, including control systems intrinsic to smooth muscle cells. It also addresses some areas of controversy related to the origin and propagation of pacemaker activity. The urge to simplify may have its roots in the wish to see the gut as a consequence of a single perfect design experiment whereas in reality the control mechanisms of the gut are the messy result of adaptive changes over millions of years that have created complementary and overlapping control systems. All these systems together reliably perform the task of moving and mixing gut content to provide us with essential nutrients.", "author" : [ { "dropping-particle" : "", "family" : "Huizinga", "given" : "Jan D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Lammers", "given" : "Wim J E P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "American journal of physiology. Gastrointestinal and liver physiology", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "2009", "1" ] ] }, "page" : "G1-8", "title" : "Gut peristalsis is governed by a multitude of cooperating mechanisms.", "type" : "article-journal", "volume" : "296" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Huizinga & Lammers, 2009)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Huizinga & Lammers, 2009). Since “endogenous ethanol” has been postulated to be derived from this same microbial community ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1002/hep.26093", "ISSN" : "1527-3350", "PMID" : "23055155", "abstract" : "UNLABELLED: Nonalcoholic steatohepatitis (NASH) is a serious liver disease associated with obesity. Characterized by metabolic syndrome, hepatic steatosis, and liver inflammation, NASH is believed to be under the influence of the gut microflora. Here, the composition of gut bacterial communities of NASH, obese, and healthy children was determined by 16S ribosomal RNA pyrosequencing. In addition, peripheral blood ethanol was analyzed to monitor endogenous ethanol production of patients and healthy controls. UniFrac-based principle coordinates analysis indicated that most of the microbiome samples clustered by disease status. Each group was associated with a unique pattern of enterotypes. Differences were abundant at phylum, family, and genus levels between healthy subjects and obese patients (with or without NASH), and relatively fewer differences were observed between obese and the NASH microbiomes. Among those taxa with greater than 1% representation in any of the disease groups, Proteobacteria, Enterobacteriaceae, and Escherichia were the only phylum, family and genus types exhibiting significant difference between obese and NASH microbiomes. Similar blood-ethanol concentrations were observed between healthy subjects and obese non-NASH patients, but NASH patients exhibited significantly elevated blood ethanol levels.\n\nCONCLUSIONS: The increased abundance of alcohol-producing bacteria in NASH microbiomes, elevated blood-ethanol concentration in NASH patients, and the well-established role of alcohol metabolism in oxidative stress and, consequently, liver inflammation suggest a role for alcohol-producing microbiota in the pathogenesis of NASH. We postulate that the distinct composition of the gut microbiome among NASH, obese, and healthy controls could offer a target for intervention or a marker for disease.", "author" : [ { "dropping-particle" : "", "family" : "Zhu", "given" : "Lixin", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Baker", "given" : "Susan S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gill", "given" : "Chelsea", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Liu", "given" : "Wensheng", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Alkhouri", "given" : "Razan", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Baker", "given" : "Robert D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Gill", "given" : "Steven R", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Hepatology (Baltimore, Md.)", "id" : "ITEM-1", "issue" : "2", "issued" : { "date-parts" : [ [ "2013", "2" ] ] }, "page" : "601-9", "title" : "Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH.", "type" : "article-journal", "volume" : "57" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Zhu et al., 2013)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Zhu et al., 2013), then these peaks should be approximate temporally.Notably, though, our ethanol peak, on both days, was consistently and considerably earlier than the hydrogen peak, suggesting that the source of the ethanol peak is unrelated to the direct impact of the food bolus residue entering the distal small bowel or colon. Both the source of this early peak and the absence of a later peak coinciding with the hydrogen peak were unexpected and not easily explained. However, the presence of an early peak has been appreciated by other breath researchers ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "ISSN" : "8750-7587", "PMID" : "10562594", "abstract" : "The selected ion flow tube technique was used to quantify in breath the trace gases acetone, ammonia, ethanol, isoprene, and methanol during single exhalations while fasting and in response to feeding. Six normal volunteers were fasted for 12 h, and, after baseline breath samples were obtained, were fed a liquid protein-calorie meal to provide 0.47 g/kg of protein (Fortisip). Further breath samples were obtained at 20, 40, and 60 min, and then hourly for a further 5 h. Breath acetone concentrations fell from a maximum during fasting, reaching their nadir between 4 and 5 h. Breath ammonia concentrations fell immediately to one-half their fasting levels before a steady increase to two or three times baseline values at 5 h. There was a brief increase in breath ethanol concentrations after feeding, reflecting detectable ethanol contamination of the food. Subsequently, breath ethanol levels remained low throughout the experimental protocol. Isoprene concentrations did not change significantly, whereas changes in methanol concentrations reflected those in the ambient air. This preliminary study indicates that the selected ion flow tube technique may be used to detect changes in the trace gases present in breath and define their concentrations in the fasting and replete state. Of particular interest is the biphasic response of the breath ammonia concentration after feeding.", "author" : [ { "dropping-particle" : "", "family" : "Smith", "given" : "D", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Spanel", "given" : "P", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Davies", "given" : "S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of applied physiology (Bethesda, Md. : 1985)", "id" : "ITEM-1", "issue" : "5", "issued" : { "date-parts" : [ [ "1999", "11" ] ] }, "page" : "1584-8", "title" : "Trace gases in breath of healthy volunteers when fasting and after a protein-calorie meal: a preliminary study.", "type" : "article-journal", "volume" : "87" }, "uris" : [ "" ] }, { "id" : "ITEM-2", "itemData" : { "DOI" : "10.1152/japplphysiol.01034.2003", "ISSN" : "8750-7587", "PMID" : "14672964", "abstract" : "A computerized system has been developed to monitor tidal volume, respiration rate, mouth pressure, and carbon dioxide during breath collection. This system was used to investigate variability in the production of breath biomarkers over an 8-h period. Hyperventilation occurred when breath was collected from spontaneously breathing study subjects (n = 8). Therefore, breath samples were collected from study subjects whose breathing were paced at a respiration rate of 10 breaths/min and whose tidal volumes were gauged according to body mass. In this \"paced breathing\" group (n = 16), end-tidal concentrations of isoprene and ethane correlated with end-tidal carbon dioxide levels [Spearman's rank correlation test (r(s)) = 0.64, P = 0.008 and r(s) = 0.50, P = 0.05, respectively]. Ethane also correlated with heart rate (r(s) = 0.52, P < 0.05). There was an inverse correlation between transcutaneous pulse oximetry and exhaled carbon monoxide (r(s) = -0.64, P = 0.008). Significant differences were identified between men (n = 8) and women (n = 8) in the concentrations of carbon monoxide (4 parts per million in men vs. 3 parts per million in women; P = 0.01) and volatile sulfur-containing compounds (134 parts per billion in men vs. 95 parts per billion in women; P = 0.016). There was a peak in ethanol concentration directly after food consumption and a significant decrease in ethanol concentration 2 h later (P = 0.01; n = 16). Sulfur-containing molecules increased linearly throughout the study period (beta = 7.4, P < 0.003). Ventilation patterns strongly influence quantification of volatile analytes in exhaled breath and thus, accordingly, the breathing pattern should be controlled to ensure representative analyses.", "author" : [ { "dropping-particle" : "", "family" : "Cope", "given" : "Keary A", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Watson", "given" : "Michael T", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Foster", "given" : "W Michael", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Sehnert", "given" : "Shelley S", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Risby", "given" : "Terence H", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Journal of applied physiology (Bethesda, Md. : 1985)", "id" : "ITEM-2", "issue" : "4", "issued" : { "date-parts" : [ [ "2004", "4" ] ] }, "page" : "1371-9", "title" : "Effects of ventilation on the collection of exhaled breath in humans.", "type" : "article-journal", "volume" : "96" }, "uris" : [ "" ] } ], "mendeley" : { "manualFormatting" : "(Cope, Watson, Foster, Sehnert, & Risby, 2004b)(Smith, Spanel, & Davies, 1999)", "previouslyFormattedCitation" : "(K. A. Cope et al., 2004; Smith et al., 1999)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Cope, Watson, Foster, Sehnert, & Risby, 2004b)(Smith, Spanel, & Davies, 1999). It is possible, therefore, that “gut derived” endogenous ethanol is actually from the relatively sterile stomach or proximal small bowel. Finally, we note more variability in ethanol response compared to ammonia. Since alcohol dehydrogenase is inducible and differentially expressed in various tissue beds including the gastrointestinal tract and liver ADDIN CSL_CITATION { "citationItems" : [ { "id" : "ITEM-1", "itemData" : { "DOI" : "10.1006/bbrc.1993.1588", "ISSN" : "0006-291X", "PMID" : "8503936", "abstract" : "The amounts of mRNA expressed for different alcohol dehydrogenase (ADH) classes were determined in human tissues by Northern hybridization. ADH classes I, II, and III were expressed in all tissues. The mRNAs were highest for class I ADHs, with particularly strong signals in liver, lung, ileum, colon, and uterus. For class II ADH, such a wide tissue distribution had not been recognized previously. Expression of class III ADH was highest in testis, followed by uterus, colon, and ileum. The amounts of class I and III ADH mRNAs varied significantly, indicating that tissue-specific factors modulate the expression of these enzymes above a basal level. Class V ADH (ADH6) was not detected in any of the tissues, including stomach. This suggests that class V ADH is not identical with human stomach sigma-ADH (class IV). The results support the general proposition that ADHs are not restricted to liver and have functions other than those in ethanol oxidation.", "author" : [ { "dropping-particle" : "", "family" : "Engeland", "given" : "K", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" }, { "dropping-particle" : "", "family" : "Maret", "given" : "W", "non-dropping-particle" : "", "parse-names" : false, "suffix" : "" } ], "container-title" : "Biochemical and biophysical research communications", "id" : "ITEM-1", "issue" : "1", "issued" : { "date-parts" : [ [ "1993", "5", "28" ] ] }, "page" : "47-53", "title" : "Extrahepatic, differential expression of four classes of human alcohol dehydrogenase.", "type" : "article-journal", "volume" : "193" }, "uris" : [ "" ] } ], "mendeley" : { "previouslyFormattedCitation" : "(Engeland & Maret, 1993)" }, "properties" : { "noteIndex" : 0 }, "schema" : "" }(Engeland & Maret, 1993), increased variability may be expected. It is also possible, therefore, that endogenous ethanol produced in the distal small bowel and colon are not measurable in breath due to rapid clearance and first pass metabolism in the liver. Our ethanol results are generally consistent with recent work that has explored the use of breath ethanol (often coupled with acetone) to determine blood glucose amongst diabetes (Table 3).Our study also has various limitations, including small sample size and single-center experience. As our monitors are unique prototypes, our results may not be generalizable. Unfortunately, this is a common problem for trace breath analysis research. Furthermore, we are not able to verify the exact source of either ammonia or ethanol in our study. Perhaps the most important limitation, though, is that neither exhaled breath ammonia nor ethanol has yet been linked to a clinical outcome of interest. However, our study also highlights a key strength of breath analysis: the ability to non-invasively evaluate the individual’s response to a physiologic challenge. Each individual may therefore serve as his or her own control, and multiple data points can be easily obtained over several hours and testing days. Another important strength of both our work and breath analysis in general is the capability to evaluate gut flora activity in real time through a combination of biomarkers. Naturally, each metabolite offers distinct information, but when combined they offer insights into digestion and metabolism not matched by other methods. In this instance, ammonia and ethanol represent by-products of protein and carbohydrate metabolism, respectively, while hydrogen serves as a reliable marker to time the passage of bolus through the gut. To our knowledge, no previous human breath study has measured these metabolites together in response to a physiologic challenge compared to a negative control day. We believe this approach; however, holds great promise and is timely given the worldwide effort to evaluate the impact of the gut microbiome on health and metabolism (Owyang and Wu 2014). Ongoing work will evaluate the differential response of breath ammonia to various kinds of proteins. AcknowledgmentsThe assistance of Claudio Loccioni, Adolfo Russo, and Alessandro Ragnoni is gratefully acknowledged. The authors acknowledge financial support from a National Science Foundation (NSF) grant EEC-0540832 entitled ‘Mid-Infrared Technologies for Health and the Environment (MIRTHE)’. The Rice University group acknowledges financial support from an NSF-ANR award for international collaboration in chemistry ‘Next generation of Compact Infrared Laser based Sensor for environmental monitoring (NexCILAS)’ and grant C-0586 from the Robert Welch Foundation. ReferencesADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY Abu-Shanab, A., & Quigley, E. M. M. (2010). The role of the gut microbiota in nonalcoholic fatty liver disease. Nature Reviews. Gastroenterology & Hepatology, 7(12), 691–701. doi:10.1038/nrgastro.2010.172Adeva, M. M., Souto, G., Blanco, N., & Donapetry, C. (2012). Ammonium metabolism in humans. Metabolism: Clinical and Experimental, 61(11), 1495–511. doi:10.1016/j.metabol.2012.07.007Adrover, R., Cocozzella, D., Ridruejo, E., García, A., Rome, J., & Podestá, J. J. (2012). Breath-ammonia testing of healthy subjects and patients with cirrhosis. Digestive Diseases and Sciences, 57(1), 189–95. Retrieved from , J., Gaborit, B., Dutour, A., & Clement, K. (2013). 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S., Gill, C., Liu, W., Alkhouri, R., Baker, R. D., & Gill, S. R. (2013). Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology (Baltimore, Md.), 57(2), 601–9. doi:10.1002/hep.26093Table 1. Geometric mean (?*) times and divide (÷/x) multiplicative standard deviation (MSD). 95.5% confidence interval (95.5% CI) is calculated as ?* ÷/x MSD. Ammonia (NH3) and ethanol (EtOH) are expressed in ppb. Hydrogen (H2) is expressed in ppm. Interaction of treatment and change from baseline to maximum was significant for NH3 (p<0.0001), H2 (P<0.0001), and EtOH (p=0.017). Calculation of hydrogen values excludes 2 participants (#1 and #2). Calculation of ethanol values excludes 6 participants (#4, #5, #21, #22, #28, #29).Figure 1a. Breath ammonia (ppb) in control versus intervention groups. Interaction of treatment type and change from baseline to maximum was significant for NH3 (p<0.0001).323850091439900091440000 Figure 1b. Breath ethanol (ppb) in control versus intervention groups. Interaction of treatment type and change from baseline to maximum was significant for ethanol (p=0.017). Figure 1c. Breath hydrogen (ppm) in control versus intervention groups. Interaction of treatment type and change from baseline to maximum was significant for hydrogen (p<0.0001).Figure 2a. Breath ammonia (NH3) in ppb and hydrogen (H2) in ppm for control and intervention trials. N=30 for all NH3 measurements, N=28 for all H2 measurements. Open circle designates control trial NH3; closed circle, intervention trial NH3; open square, control trial H2; closed square, intervention trial H2. Arrow designates the time of intervention.Figure 2b. Breath ethanol (EtOH) in ppb and hydrogen (H2) in ppm for control and intervention trials. N=24 for EtOH control measurements, N=26 for EtOH intervention trial measurements, N=28 for all H2 measurements. Open triangle designates control trial EtOH; closed triangle, intervention trial EtOH; open square, control trial H2; closed square, intervention trial H2. Arrow designates the time of intervention.-7239000 ?Intervention Trial DataControl Trial DataSensitivity SpecificityTrue positive rateFalse negative rateTrue negative rateFalse positive rate?n%95%CIn%95%CIn%95%CIn%95%CI300 ppb299783-100130.1-17258365-945176-35%400 ppb279073-983102-27%289378-99271-22%500 ppb268769-964134-31%289378-99271-22%600 ppb237758-9072310-42%3010088-100000-12%1.5 x baseline268769-964134-31%268769-964134-31%1.8 x baseline237758-9072310-42%299783-100130.1-17%2.0 x baseline227354-8882712-36%3010083-100000-12% Table 2. Table 2. Exploratory diagnostic application of breath ammonia levels (ppb). True positive (sensitivity) and false negative rates were calculated based on the intervention trial data, by counting those participants with increase in breath ammonia (maximum – baseline ammonia) that exceeded a pre-set threshold (positive result) and dividing by total number of participants (N=30). True negative (specificity) and false positive rates were calculated based on the control trial data by counting those participants with increase in breath ammonia (maximum – baseline ammonia) that did not exceed a pre-set threshold (negative result) and dividing by the total number of participants (N=30).95% CI, 95% confidence interval. ................
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