Review article: intestinal serotonin signalling in irritable bowel syndrome.

Alterations in motility, secretion and visceral sensation are hallmarks of irritable bowel syndrome. As all of these aspects of gastrointestinal function involve serotonin signalling between enterochromaffin cells and sensory nerve fibres in the mucosal layer of the gut, potential alterations in mucosal serotonin signalling have been explored as a possible mechanism of altered function and sensation in irritable bowel syndrome. Literature related to intestinal serotonin signalling in normal and pathophysiological conditions has been searched and summarized. Elements of serotonin signalling that are altered in irritable bowel syndrome include: enterochromaffin cell numbers, serotonin content, tryptophan hydroxylase message levels, 5-hydroxyindoleacedic acid levels, serum serotonin levels and expression of the serotonin-selective reuptake transporter. Both genetic and epigenetic factors could contribute to decreased serotonin-selective reuptake transporter in irritable bowel syndrome. A serotonin-selective reuptake transporter gene promoter polymorphism may cause a genetic predisposition, and inflammatory mediators can induce serotonin-selective reuptake transporter downregulation. While a psychiatric co-morbidity exists with IBS, changes in mucosal serotonin handling support the concept that there is a gastrointestinal component to the aetiology of irritable bowel syndrome. Additional studies will be required to gain a more complete understanding of changes in serotonin signalling that are occurring, their cause and effect relationship, and which of these changes have pathophysiological consequences.

Antineuronal antibodies in idiopathic achalasia and gastro-oesophageal reflux disease.

BACKGROUND AND AIMS: The precise aetiology of achalasia is unknown although autoimmunity has been implicated and is supported by several studies. We screened sera from patients with achalasia or gastro-oesophageal reflux disease (GORD) to test for circulating antimyenteric neuronal antibodies. METHODS: Serum was obtained from 45 individuals with achalasia, 16 with GORD, and 22 normal controls. Serum was used in immunohistochemistry to label whole mount preparations of ileum and oesophagus of the guinea pig and mouse. Also, sections of superior cervical and dorsal root ganglia, and spinal cord were examined. RESULTS: Positive immunostaining of the myenteric plexus was detected in significantly more achalasia and GORD samples than control samples (achalasia, p<0.001; GORD, p<0.01), and immunoreactivity was significantly more intense with achalasia and GORD serum samples than controls (achalasia, p<0.01; GORD, p<0.05). There was no correlation between intensity of immunoreactivity and duration of achalasia symptoms. In most cases, achalasia and GORD sera stained all ileal submucosal and myenteric neurones, and oesophageal neurones. Immunostaining was not species specific; however, immunostaining was largely specific for enteric neurones. Western blot analysis failed to reveal specific myenteric neuronal proteins that were labelled by antibodies in achalasia or GORD serum. CONCLUSIONS: These data suggest that antineuronal antibodies are generated in response to tissue damage or some other secondary phenomenon in achalasia and GORD. We conclude that antineuronal antibodies found in the serum of patients with achalasia represent an epiphenomenon and not a causative factor.

Mycotic arch aneurysm and aortoesophageal fistula in a patient with melioidosis.

Aortoesophageal fistula due to an aortic arch aneurysm is a rare entity with an extremely high mortality. There are few reports of successfully managed cases and even fewer of long term survival. We report a case of an aortoesophageal fistula resulting from a mycotic pseudoaneurysm of the distal aortic arch in a patient with melioidosis, its surgical management, and outcome.

Severe hepatotoxicity associated with bromfenac sodium.

Subacute hepatitis and liver failure occurred in a 40-yr-old woman following a 1-month course of treatment with the nonsteroidal anti-inflammatory drug bromfenac. Serologies for hepatitis A, B, and C were negative, as were antinuclear antibodies and ceruloplasmin. A transjugular liver biopsy demonstrated submassive hepatic necrosis. The clinical course was complicated by encephalopathy, fluid retention, and spontaneous bacterial peritonitis, prompting consideration for liver transplantation. With supportive measures, jaundice and fluid retention resolved over a 3-month period. We conclude that prolonged use of bromfenac was the etiological agent in this case, and that this drug can cause severe hepatotoxicity resulting in liver failure.

Inflammatory bowel disease. 1. Origins, presentation, and course.

The exact cause of inflammatory bowel disease remains undiscovered, but its destructive nature is clearly recognized. In this article, the authors summarize what is known about the pathogenesis and epidemiology of ulcerative colitis and Crohn's disease and how to distinguish between the two, both clinically and pathologically. They also describe disorders that may mimic inflammatory bowel disease. In part 2 of this article, beginning on page 86, the authors discuss some of the therapeutic options that are the commonly used as well as some that are investigational but show promise for patients with this chronic and relapsing disease.

Inflammatory bowel disease. 2. Current and future therapeutic options.

The exact source of interference with the normal protective immune response in patients with inflammatory bowel disease remains unclear. Infectious causes have been proposed, and the increased incidence among family members indicates genetic predisposition. No matter what the pathogenesis may be, the disease is chronic, recurrent, and destructive in many cases. Conventional therapy with 5-ASAs, corticosteroids, immunomodulating agents, methotrexate, and antibiotics often offers relief. However, adverse effects accompany long-term use of many of these agents, so follow-up is important. Much investigation of alternative methods is under way, and anecdotal as well as published experience suggests benefits in at least some patients. Because of the chronic nature of their condition, patients with inflammatory bowel disease often become quite sophisticated in their understanding of treatment methods. Therefore, they should be told of updates regarding new options for disease control. We recommend that patients be seen periodically by a gastroenterologist who has expertise in inflammatory bowel disease, even when the disease is quiescent. Our experience in observing these patients over time strongly supports use of some of the agents discussed in this article for prophylaxis against flares and chronic inflammation.

Renal failure associated with hepatitis C virus infection. Improvement in renal function after treatment with interferon-alpha.

Hepatitis C virus infection can result in mixed cryoglobulinemia and associated clinical syndromes including membranoproliferative glomerulonephritis. Reports regarding the efficacy of interferon-alpha (IFN-alpha) in the treatment of patients with membranoproliferative glomerulonephritis and chronic hepatitis C infection have been inconclusive regarding improvement of renal function. We describe two patients with chronic hepatitis secondary to hepatitis C virus complicated by mixed cryoglobulinemia and membranoproliferative glomerulonephritis who developed severe renal failure which resolved after treatment with standard doses of IFN-alpha 2b.

Efficacy of tele-endoscopy in a rural capitated market.

PURPOSE: To attempt to quantify the potential for success of tele-endoscopy as a component of the VTMEDNET Plus telemedicine implementation, a multi-part prospective study was undertaken by faculty of the Vermont Initiative for Rural Health Informatics and Telemedicine. METHOD: The study was comprised of three separate parts, evaluation of image quality, cost analysis, and identification of referring providers needs and attitudes regarding tele-endoscopy. FINDINGS: The image quality was satisfactory to support remote diagnosis in most cases; there was significant cost savings in a managed care environment; referring providers were generally positive about the attributes of tele-endoscopy. CONCLUSION: Tele-endoscopy is a viable and cost-effective component within a telemedicine system.

Endoscopic evaluation of iron deficiency anemia. A guide to diagnostic strategy in older patients.

Gastrointestinal blood loss is the primary cause of iron deficiency anemia in older adults. Bidirectional endoscopy (combined colonoscopy and esophagogastroduodenoscopy) is highly sensitive and specific in its ability to locate gastro-intestinal lesions resulting in iron deficiency anemia. Although the diagnostic yield of esophagogastroduodenoscopy is higher than that of colonoscopy, the possibility of malignant disease dictates that initial colonoscopy be performed in all but a few cases involving distinct upper gastrointestinal risk factors and symptoms. If neither colonoscopy nor esophagogastroduodenoscopy identifies a source of blood loss, a safe course is to observe the patient and provide supplemental iron. Patients who fail to respond to supplemental iron or who become transfusion-dependent require further evaluation. Small-bowel evaluation has a role in selected patients.

The ability of certain anorexic drugs to suppress food consumption depends on the nutrient composition of the test diet.

The effects of five anorexic agents on food consumption were tested in rats offered single, isocaloric, isonitrogenous diets differing in carbohydrate content. Three of the test agents, d-amphetamine, benzphetamine and chlorphentermine, are sympathomimetic and cause CNS stimulation; the others, MK-212 and d-fenfluramine, are thought to facilitate serotonin-mediated neurotransmission. At ED50 doses, the sympathomimetic drugs reduced food consumption whether the test diet was rich (75% dextrin) or poor (25% dextrin) in carbohydrate. In contrast, MK-212 and d-fenfluramine failed to reduce consumption of the 25% dextrin test diet. These observations suggest that anorexic drugs like d-amphetamine and d-fenfluramine do not act via a common "amphetamine receptor," and are compatible with earlier observations, made on rats given diet pairs simultaneously, that enhanced serotoninergic neurotransmission selectively suppresses appetite for carbohydrates.

Tyrosine's vasoactive effect in the dog shock model depends on the animal's starting blood pressure.

We examined the effect of tyrosine (10-200 mg/kg given intravenously) or placebo on blood pressure (BP) in dogs made hypotensive (systolic BP = 50 mm Hg) by bleeding one hour previously. Animals which, prior to induction of hypotension, had been normotensive (mean arterial pressures, [MAP] less than or equal to 145 mm Hg) subsequently exhibited a dose-related increase in BP after tyrosine administration. In contrast, dogs which had been hypertensive prior to bleeding exhibited a fall in BP after tyrosine. These observations indicated that prior cardiovascular status may be an important factor influencing responses to exogenous tyrosine, and to endogenous catecholamines produced from the tyrosine.

Prior carbohydrate consumption affects the amount of carbohydrate that rats choose to eat.

Consumption of protein-rich, carbohydrate-restricted reducing diets has been associated anecdotally with an increased appetite for carbohydrate. We have tested the effect of such a diet on carbohydrate intake by rats. Rats were given either a calorie-restricted ketogenic diet containing protein and fat or a control diet containing carbohydrate along with the protein and fat. When allowed to choose from a pair of isocaloric, isonitrogenous diets containing 25 or 75% dextrin, ketotic rats ate significantly more carbohydrate and total food than control animals during the first 30 minutes of feeding, apparently requiring more of the carbohydrate to obtain an increase in brain tryptophan similar to controls. Ketotic rats ate a significantly higher proportion of total calories as carbohydrate. Similar results were obtained when sucrose replaced dextrin. When ketotic and control rats chose between two diets differing in proportions of fat or protein, no differences were observed between the groups in total food intake nor in the amounts or proportions of fat or protein eaten. We also compared the effects of a small, isocaloric premeal containing only carbohydrate (1.4 g dextrose) or mixed nutrients on subsequent carbohydrate consumption in otherwise untreated rats allowed to choose from 25 and 75% dextrin diets. Rats eating the carbohydrate premeal subsequently ate as much total food as the mixed-nutrient controls, but significantly less carbohydrate. These observations suggest that carbohydrate intake is influenced by prior nutrient consumption and that prolonged deprivation of carbohydrate can lead to overconsumption of this nutrient when it is reintroduced into the diet.