Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis in irritable bowel syndrome.

Enhanced stress responsiveness has been implicated as a potential mechanism contributing to the pathophysiology of irritable bowel syndrome (IBS), and should be reflected in altered function of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. Both of these systems can modulate mucosal immune function. The aims of this study were: (i) to characterize the basal circadian rhythm of adrenocorticotropin hormone (ACTH) and cortisol in IBS vs healthy controls; (ii) to compare stimulated ACTH, cortisol and noradrenaline responses to a pelvic visceral stressor (sigmoidoscopy) in IBS and controls; and (iii) to correlate neuroendocrine responses with colonic mucosal cytokine expression and symptoms in IBS. Two separate studies were conducted in women. In Study 1, basal cortisol levels were analysed in 41 IBS and 25 controls using 24-h collections of plasma ACTH and cortisol (q10 min sampling). In Study 2, 10 IBS patients with diarrhoea (IBS-D) and 10 controls underwent sigmoidoscopy with measurements of stimulated neuroendocrine responses and cytokine mRNA expression in colonic tissue. Basal ACTH levels were significantly blunted (P < 0.05), while basal and stimulated plasma cortisol levels were higher in patients. Basal cortisol levels prior to an experimental visceral stressor positively correlated with anxiety symptoms (P < 0.004), but not IBS symptoms. Irritable bowel syndrome patients with diarrhoea had significantly decreased mRNA expression of mucosal cytokines [interleukin (IL)-2, IL-6] in the sigmoid colon vs controls (P < 0.05). Although dysregulations in stress-responsive systems such as the HPA axis and mucosal immune function are demonstrated in IBS, they do not appear to have a primary role in modulating IBS severity and abdominal pain.

Neural and psychological predictors of treatment response in irritable bowel syndrome patients with a 5-HT3 receptor antagonist: a pilot study.

BACKGROUND: Symptom improvement in irritable bowel syndrome (IBS) treatment trials varies widely, with only 50-70% of patients qualifying as responders. Factors predicting treatment responsiveness are not known, although we have demonstrated that symptom improvement with the 5-HT3R antagonist alosetron is correlated with reduced amygdala activity. AIM: To determine whether neural activity during rectal discomfort or psychological distress predicts symptom improvement following treatment with alosetron. METHODS: Basal psychological distress and neural activity (15O PET) during uncomfortable rectal stimulation were measured in 17 nonconstipated IBS patients who then received 3 weeks of alosetron treatment. RESULTS: Greater symptom improvement was predicted by less activity in bilateral orbitofrontal cortex (OFC) and medial temporal gyrus during pre-treatment scans. Lower levels of interpersonal sensitivity predicted greater symptom improvement and were positively related to activity in left OFC. Connectivity analysis revealed a positive relationship between activity in the left OFC and right amygdala. CONCLUSIONS: Irritable bowel disease symptom improvement with 5-HT3R antagonist alosetron is related to pre-treatment reactivity of the left OFC, which may be partially captured by subjective measures of interpersonal sensitivity. The left OFC may fail to modulate amygdala response to visceral stimulation, thereby diminishing effectiveness of treatment. Psychological factors and their neurobiological correlates are plausible predictors of IBS treatment outcome.

Abnormalities in normal appearing tissues in early primary progressive multiple sclerosis and their relation to disability: a tissue specific magnetisation transfer study.

BACKGROUND: Patients with primary progressive multiple sclerosis (PPMS) often develop severe disability despite low levels of abnormality on conventional magnetic resonance imaging (MRI). This may relate to diffuse pathological processes occurring in normal appearing brain tissue (NABT) involving both white matter (NAWM) and grey matter (NAGM). Magnetisation transfer imaging (MTI) is capable of identifying these processes and may be particularly informative when applied to patients with early PPMS. AIM: To assess the relationship between abnormalities in NABT identified by MTI and disability and other radiological data in patients with early PPMS. METHODS: We studied 43 patients within 5 years of disease onset and 43 controls. The Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC) were scored. Magnetisation transfer ratios (MTR) of NABT, NAWM, and NAGM were calculated and the following MTR parameters were measured: mean, peak height, peak location, and MTR value at the 25th, 50th, and 75th percentiles. Proton density, T2, T1, and gadolinium enhancing lesion loads were also calculated. RESULTS: Differences were found between patients and controls in mean, peak height, and peak location of NAWM and NAGM (p < or = 0.001). Weak to moderate correlations were found between MTR parameters and disability in both NAWM and NAGM. Strong correlations between MTR parameters and lesion loads were found, particularly in NAWM. CONCLUSION: MTR abnormalities are seen in NAWM and NAGM in early PPMS and both are associated with disability. NAWM MTR abnormalities are more closely related to conventional MRI measures than those seen in NAGM.

Prevalence and demographics of irritable bowel syndrome: results from a large web-based survey.

BACKGROUND: Irritable bowel syndrome is a common gastrointestinal disorder, and its prevalence and demographics have been evaluated by different methodologies with varying results. AIM: To evaluate irritable bowel syndrome demographic and prevalence characteristics utilizing a web-enabled panel. METHODS: From an existing 150 000-member panel, 31 829 individuals were randomly selected and sent screening questionnaires to evaluate irritable bowel syndrome symptoms. Individuals who agreed to participate and completed the screening questionnaire received a second questionnaire related to a diagnosis of irritable bowel syndrome, a more detailed symptom description, and additional burden of illness data. RESULTS: Irritable bowel syndrome prevalence was 7%. Prevalence was higher in women vs. men, unmarried individuals vs. married individuals and unemployed individuals vs. employed individuals. Of those completing the second questionnaire, 51% had seen their physicians for irritable bowel syndrome symptoms in the past year and most had an episode within the past 3 months. During the past year, approximately half of the participants had used a prescription medication, and over 90% had used an over-the-counter medication for irritable bowel syndrome. Participants with irritable bowel syndrome demonstrated quality-of-life reductions relative to norms of the United States population. CONCLUSIONS: Web-enabled data collection represents a novel tool for rapidly surveying a large population of individuals with irritable bowel syndrome symptoms.

A metabolic balance study in term infants fed lactose-containing or lactose-free formula.

Lactose-free (L-) formulas are recommended for infants with conditions affecting lactose digestion. Cows' milk protein-based formulas containing other carbohydrate sources are most often used for such infants. This study compared fat absorption and absorption and retention of nitrogen, calcium, phosphorus, and magnesium in term infants fed either a L- or standard lactose-containing (L+) bovine milk protein-based formula. Data from three single-centre, double-blind, randomized, parallel-group metabolic balance studies were combined. After a 4-7-d equilibration period on either L- or L+ formula, a 72-h balance study was performed. Twenty infants received L- and 21 received L+ formula. Besides the L- group having a higher percentage of males (65%) and the L+ group a higher percentage of females (52.4%), other baseline measurements were similar. The majority of nutrient balance data was similar between the two groups. Exceptions were relative nitrogen absorption, calcium intake and calcium retention, magnesium retention, and faecal phosphorus excretion, all of which were significantly higher in the L- group. Vitamin D supplementation did not significantly affect either calcium or phosphorus data. This new L- formula provided similar nutrients and is a suitable alternative to a L+ formula in term infants requiring L- feedings.

Transdermal nicotine patches do not cause clinically significant gastroesophageal reflux or esophageal motor disorders.

Transdermal nicotine delivery systems are widely used in smoking cessation. The purpose of this study was to determine whether common symptoms of pyrosis and dyspepsia associated with these patches are related to gastroesophageal reflux or esophageal dysmotility. Twenty-seven paid volunteer cigarette smokers (> 15 cigarettes/day) without symptomatic gastroesophageal reflux disease participated in this single-blinded, placebo-controlled study. Twenty subjects completed the study. Subjects underwent three sequential 24-h intraesophageal pH/motor studies (Synectics model T32342084, Shore View, MN). The pH/motility probe was positioned 5 cm above the manometrically determined LES. A placebo patch was applied for the first 24-h study and a 15-mg nicotine patch (Nicotrol) was applied for the initial 16 h (removed for remaining 8 h) of the second 24-h period. A 21-mg nicotine patch (Nicoderm) was applied for another 24-h study period. All subjects consumed an identical, defined diet documented by meal receipts, and refrained from smoking and tobacco use throughout the study periods (CO breath test confirmation). The Wilcoxon, paired t-test, exact McNemar statistical methods were used. The results showed that there were no significant differences in reflux symptoms (pyrosis, chest pain, nausea, dysphagia), supine gastroesophageal reflux (number of episodes, duration, or cumulative acid exposure), or the total number of reflux episodes between placebo and nicotine patch treatment periods. The number of post-prandial upright acid reflux episodes (p = 004) and number of upright acid reflux episodes lasting more than 5 min (p = 0.007) were statistically higher with the placebo patch compared to the active nicotine patches. No differences in intraesophageal pH or motility indices were noted between the two transdermal nicotine patches (Nicotrol, Nicoderm). It was concluded that dyspeptic symptoms in subjects utilizing transdermal nicotine patches are not related to gastroesophageal reflux or to esophageal motor abnormalities.

Quantitative fecal carbohydrate excretion in premature infants.

Despite relative lactase deficiency and pancreatic insufficiency, premature infants are fed formulas containing 50% lactose plus 50% glucose polymers. We measured total fecal carbohydrate excretion in six healthy 32-wk gestation premature infants who had been fed two 0.784-kcal/g formulas that were similar except for the carbohydrate source (100% lactose vs 50% lactose plus 50% glucose polymers). Using a cross-over design with the first formula randomly assigned, two 72-h balance studies were performed with carmine red, an intermittent external marker, and polyethylene glycol (PEG), a continuous internal marker. Formula and stools were analyzed for total carbohydrate (anthrone method) and PEG. There were no significant differences between the two formula periods for carbohydrate intake, mean daily stool output, or fecal carbohydrate excretion. Mean fecal carbohydrate excretion was less than 0.2 g/d, or less than 1% of carbohydrate intake. Thus, older (32-wk gestation) premature infants fed either 100% lactose or 50% lactose plus 50% glucose polymers have minimal fecal losses of intact carbohydrate.

Liver transplantation.

A multidisciplinary approach is necessary in addressing the needs of a patient with end-stage liver disease. The development of the liver transplant program at MHI was a natural extension of the transplant and critical care programs already in place. The case report described exemplifies that valuable input from ancillary support groups is necessary for a successful liver transplant program. Experience gained in the area of liver transplantation not only benefits liver transplant patients but also extends to other areas of clinical medicine. One year ago, an Indiana resident had to travel out of state to receive this specialized form of care. Today this is no longer the case.

Quantitation of fecal carbohydrate excretion in patients with short bowel syndrome.

We performed inpatient balance studies in 11 patients to evaluate the role of carbohydrate malabsorption in the pathogenesis of the diarrhea seen in short bowel syndrome. Stool weight, total reducing substance as measured by Clinitest, and total fecal carbohydrate as measured by anthrone were determined. Patients had markedly increased fecal carbohydrate excretion, up to 65% of dietary carbohydrate intake. When the diet contained oligosaccharides, measures of total reducing substance greatly underestimated fecal carbohydrate excretion and were unreliable for quantitation. Stool weight correlated with total fecal carbohydrate excretion and with total reducing substance (r = 0.79, p less than 0.001). Multiple balance studies in 2 patients suggested a relationship between both the amount and type of dietary carbohydrate and fecal carbohydrate excretion. These studies suggest that carbohydrate malabsorption is a major cause of the watery diarrhea and subsequent fluid, electrolyte, and acid-base imbalance seen in patients with short bowel syndrome.

A simple spectrophotometric method for quantitative fecal carbohydrate measurement.

A simple quantitative assay was developed for measuring total fecal carbohydrate (CHO) excretion using stools obtained during balance studies performed for fecal fat determination. This spectrophotometric method utilizes Dreywood's anthrone reagent which reacts with equal weights of CHO whether monosaccharide or polysaccharide. Analysis of known dietary CHO solutions yielded greater than 90% of the known theoretical concentration. Recovery of CHO (Polycose) added to fresh stool was greater than 95%, inter-assay coefficient of variation (CV) 6.2%. Stool specimens stored frozen and analyzed over a 21-month period yielded stable results. Fecal CHO excretion/day determined in 32 normal patients, ages 1 month to 13 years, on diets with varying CHO sources, ranged from 0.04 to 0.85 g, average 0.33 g, SD +/- 0.24. Three patients with diseases known to be associated with CHO malabsorption studied showed markedly increased total fecal CHO excretion, up to 53% of their CHO intake. Quantitative fecal CHO excretion in these patients allowed for assessment of the severity of their disease and provided a means for evaluating the use of different dietary CHO sources in their management.