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Biomedical subjects

R E Pounder

Publications and source records attributed to R E Pounder.

At least 91 records · Page 5Linked to original sources
PubMed1995

Gastric persorption of bismuth from ranitidine bismuth citrate.

AIM: To determine whether bismuth penetrates the gastric mucosa after dosing with ranitidine bismuth citrate. METHODS: Twelve patients presenting with dyspepsia were randomized to receive either ranitidine bismuth citrate or placebo, 20-40 min prior to endoscopy. Biopsies were taken from four sites during endoscopy: the first and second parts of the duodenum, the antrum, and the body of the stomach. Biopsies were analysed by electron microscopy and X-ray microanalysis. RESULTS: Bismuth particles were found to be interposed between epithelial cells in the antral mucosa of three of eight patients who were dosed with ranitidine bismuth citrate. Columns of bismuth particles could be tracked down the lamina propria and were seen to be surrounding blood vessels. Bismuth particles were observed in the inter- and intra-cellular channels of the endothelial cells of the blood vessels in the lamina propria and also close to the luminal surface of the endothelial cell. This process of persorption was similar to that described in a previous report of electron microscopy appearances of the gastric antrum after dosing with tripotassium dicitrato bismuthate, but was quantifiably smaller and not observed in all the patients dosed with ranitidine bismuth citrate. No penetration of the mucosa by bismuth particles was seen in the body of the stomach or the duodenum. CONCLUSION: Penetration of bismuth particles into the gastric mucosa may occur after oral dosing with ranitidine bismuth citrate.

Adult↗
PubMed1995

Pre-ulcerative villous contraction and microvascular occlusion induced by indomethacin in the rat jejunum: a detailed morphological study.

BACKGROUND: In indomethacin-induced jejunal ulceration in the rat, villi undergo both early microvascular injury and shortening that may involve activation of villous smooth muscle. AIM: This study sought to substantiate light microscopic observations using three-dimensional imaging of early villous architectural changes in response to indomethacin. METHODS: At both 2 and 6 h after oral indomethacin 15 mg/kg or vehicle to groups of rats, the vasculature of the small intestine was visualised by both carbon-ink perfusion/confocal microscopy and injection casting. The mucosa was also examined for lesions by dissection microscopy and scanning electron microscopy. RESULTS: In indomethacin-dosed rats examined by scanning electron microscopy and histology, the mucosa at 2 h showed villous shortening and wrinkling of the surface epithelium without epithelial loss; at 6 h, the mucosa was flattened, often with epithelial loss to expose a 'contracted' villous core. Examination of the 'vasculature in carbon-injected tissues indicated significant reductions of both mucosal height and inter-capillary distance at both 2 and 6 h post-indomethacin. Scanning electron microscopy of injection casts at 2 and 6 h indicated similar changes. These changes were not seen in control tissues. CONCLUSION: Histology, confocal microscopy and scanning electron microscopy support the proposal that villous shortening with disruption of surface capillary architecture are early changes in the ulcerative enteropathy induced by nonsteroidal anti-inflammatory drugs.

Animals↗
PubMed1995

Inter-individual and intra-individual variability of ethanol concentration-time profiles: comparison of ethanol ingestion before or after an evening meal.

1. The magnitude of the variability of ethanol absorption is an important factor for studies that seek to determine the significance of potential interactions between ethanol and drugs. The aim of this study was to determine the extent of inter- and intra-individual variability of ethanol concentration-time profiles in fasted and fed subjects. 2. Twenty-four healthy male subjects were randomized to receive ethanol 0.3 g kg-1 before an evening meal on two study days and ethanol 0.3 g kg-1 after an evening meal on two study days. Plasma ethanol concentrations were measured at intervals from 0-240 min. 3. There were significant differences in the mean area under the ethanol concentration-time curve (AUC), the mean peak ethanol concentration (Cmax), the mean ethanol elimination slope and the time to peak ethanol concentration between the fed and fasted subjects. There were no significant differences between the first and second study days for either fed or fasting subjects for all parameters. 4. There was no statistically significant difference in inter- or intra-subject variance between fed and fasted studies although the coefficients of variation (standard deviation expressed as a percentage of the mean) for the differences between the first and second study day were higher for fed studies. 5. The large inter- and intra-individual variability of alcohol absorption for both fasted and fed subjects must be considered in the design of alcohol-drug interaction studies.

Adult↗
PubMed1995

Autoimmunity in ulcerative colitis: tropomyosin is not the major antigenic determinant of the Das monoclonal antibody, 7E12H12.

Ulcerative colitis (UC) has a proposed autoimmune pathogenesis. A 40-kD antigen (P40) has been isolated from UC colon, bound to immunoglobulin. Tropomyosin has been reported as the target antigen of a MoAb (7E12H12) raised against P40. We set out to investigate whether tropomyosin is the major antigenic determinant for 7E12H12. Formalin-fixed, paraffin-processed and cryostat sections of fresh frozen colon from patients with UC, Crohn's disease and normals, were immunostained with 7E12H12 and commercial anti-tropomyosin antibodies. In addition, the immunoreactivity of 7E12H12 with cytoskeletal components was examined on human endothelial cells (HUVEC) using anti-tropomyosin as a positive control. Con-focal microscopy was used to determine the subcellular localization of signal. An extract of total colonic protein from UC colon was prepared. Using a combination of Western and immunoblotting (dot-blots), the immunoreactivities of both tropomyosin (porcine and chicken) and colon protein extract with either 7E12H12 or commercial anti-tropomyosin were examined. Immunocytochemically, 7E12H12 localized to the apical and basolateral regions of plasma membrane, and to the supranuclear cytoplasm in colonic epithelium. Using anti-tropomyosin antibody it was not possible to identify the cytoskeleton in colonic epithelium. Cytoskeletal components were identifiable in HUVEC cultures with anti-tropomyosin antibody but not with 7E12H12. P40 antigen was identified in the colon protein extract by immunoblotting with 7E12H12. There was clear immunoreactivity between anti-tropomyosin antibody and both chicken and porcine tropomyosin, and the colon protein extract. 7E12H12 did not bind to either chicken or porcine tropomyosin in appropriately controlled systems. We conclude that the pattern of immunostaining with 7E12H12 is not cytoskeletal, and there is no reactivity in immunoblots, between tropomyosin and 7E12H12. Tropomyosin is not the major target antigen of this antibody in ulcerative colitis.

Antibodies, Monoclonal↗
PubMed1995

Persistent measles virus infection of the intestine: confirmation by immunogold electron microscopy.

This study sought to investigate persistent measles virus infection of the intestine: a novel protocol for immunogold electron microscopy was developed using a polyclonal anti-measles nucleoprotein antibody on reprocessed, formalin fixed paraffin wax embedded tissue sections. Antibody binding was detected using both immunoperoxidase and light microscopy on tissue sections, and 10 nm gold conjugated secondary antibody and electron microscopy on ultrathin sections. The techniques were validated using both measles infected vero cells and human tissues with established measles infection: these included brain affected by subacute sclerosing panencephalitis and acute measles appendicitis. The technique was applied subsequently to six untreated cases of granulomatous Crohn's disease, and two cases of ileocaecal tuberculosis, a granulomatous control. Mumps primary antibody--applied to both mumps infected vero cells, and measles infected vero cells and tissues studied by immunoperoxidase, and measles antibody on mumps infected cells studied by immunoperoxidase and immunogold--were used as specificity controls: the primary antibodies identified their respective target antigen and there was no antibody cross reactivity. Measles virus nucleocapsids labelled with gold conjugated antibody in both infected cells and tissues, including foci of granulomatous inflammation in five of six cases of Crohn's disease: in the fifth case, the granuloma could not be identified in ultrathin section. In one of the tuberculosis cases, a low level of signal was noted while the second case was negative. Labelling adopted a characteristic pattern in all infected tissues, strengthening the specificity of these findings. This study provides the first direct confirmation of persistent measles virus infection of the intestine.

Animals↗
PubMed1995

Procoagulant and prothrombotic responses of human endothelium to indomethacin and endotoxin in vitro. Relevance to non-steroidal anti-inflammatory drug enteropathy.

BACKGROUND: In view of the association between non-steroidal anti-inflammatory drugs (NSAIDs) and microvascular injury in the intestine, this study investigated the procoagulant changes in cultured human umbilical vein endothelial cells (HUVEC) when exposed to indomethacin either alone or in the presence of bacterial lipopolysaccharide (LPS). METHODS: Confluent HUVEC cultures were cultured for 1, 6, 12, and 24 h in the presence of LPS (10 micrograms/ml) with or without indomethacin (1-100 microM). After incubation, supernatants were analysed for 6-keto-prostaglandin (PG) F1 alpha and PGE2 content, whereas cells were freeze-fractured and assayed in a one-stage clotting assay for the expression of procoagulant activity (PCA). RESULTS: LPS induced a significant expression of PCA at 6, 12, and 24 h, with a significantly increased production of 6-keto-PGF1 alpha, whereas the increased PGE2 production was much less pronounced. Indomethacin alone induced a time-dependent PCA response; when coincubated with LPS the PCA response was greater than that produced by either indomethacin or LPS alone. Indomethacin totally abolished the synthesis of antithrombotic eicosanoids. CONCLUSION: Indomethacin induces PCA in HUVEC and augments LPS-induced PCA, while it abolishes the antithrombotic prostanoid response in these cells. These observations may be relevant to the microvascular injury and thrombosis observed in NSAID enteropathy.

6-Ketoprostaglandin F1 alpha↗
PubMed1995

Intestinal disaccharidase activity in human immunodeficiency virus disease.

BACKGROUND: The relationship between disaccharidase activity, progression of human immunodeficiency virus (HIV) disease, and diarrhoea and weight loss was investigated. METHODS: Forty-six HIV-positive patients ingested a solution of lactose, palatinose, sucrose, and lactulose after 24 h of dietary exclusion and overnight fasting, after which urine was collected for 10 h. Urinary disaccharide (activity) ratios-lactose/lactulose (L/LL), palatinose/lactulose (P/LL), and sucrose/lactulose (S/LL)-were measured by thin-layer chromatography. RESULTS: There was a significant decrease in disaccharidase activity (L/LL, P/LL, and S/LL) with advancing clinical stage of HIV disease (p < 0.05, Wilcoxon rank sum test) as well as decreasing CD4 count (p < 0.05, Spearman correlation). Patients with weight loss/diarrhoea also had significantly (p < 0.05) decreased disaccharidase activity compared with control but not as compared with AIDS patients. Anti-retroviral therapy did not influence disaccharidase activity. CONCLUSION: Impairment of disaccharidase activity occurs with advancing HIV disease, but its role in HIV patients with weight loss and diarrhoea remains to be determined.

Adult↗
PubMed1995

Detection of herpesvirus DNA in cottontop tamarins: no association with colitis.

Colitis occurs spontaneously in the cottontop tamarin; it shares similar clinical, endoscopic and histological features with, and has a similar response to treatment as, human ulcerative colitis. An association between human ulcerative colitis and the presence of DNA from multiple herpesviruses (human herpesvirus 6 (HHV-6), cytomegalovirus (CMV) and Epstein-Barr virus (EBV) in the colon has been described. Intestinal herpesvirus infection may be involved in the pathogenesis of this condition. In a pilot study, coded full thickness colonic specimens from 27 cottontop tamarins were examined for the presence of HHV-6, CMV and EBV DNA using the nested polymerase chain reaction. The sections represented a spectrum of disease activity ranging from histologically normal bowel to severe colitis. A low prevalence of DNA from these viruses was found, which bore no relation to the presence of inflammation. Although these herpesviruses may have a pathogenetic role in human ulcerative colitis, they are not associated with colitis in this animal model.

Animals↗
PubMed1995

Perinatal and childhood risk factors for inflammatory bowel disease: a case-control study.

OBJECTIVE: To determine whether exposure to a measles epidemic in utero or in infancy is a risk factor for the development of Crohn's disease, and to determine whether such an association can be found in individuals with subacute sclerosing panencephalitis (SSPE), a condition in which early infection with measles is known to be of aetiological importance. METHODS: A postal questionnaire was sent to 16,875 members of two national inflammatory bowel disease patient support groups. A control group was composed of friends or neighbours. Birth data were compared with the dates of measles epidemics and six possible periods of susceptibility were examined. Birth data from a national register of patients with SSPE were analysed similarly. Previously identified risk factors were also examined. RESULTS: The answers from 2522 members and 2379 controls were analysed. We found no evidence of an association between the development of Crohn's disease and exposure to a measles epidemic. The birth dates of both groups were distributed normally throughout the year. No other early risk factor for the development of inflammatory bowel disease was detected. Exposure to a measles epidemic before the age of 1 year did not emerge as a risk factor for SSPE. CONCLUSION: These data contradict reports from a recent study in central Sweden, but relatively early exposure to measles in childhood may still be a risk factor for the development of Crohn's disease.

Adult↗
PubMed1995

Mycobacterial granulomatous inflammation in the ulcerated caecum of indomethacin-treated rats.

We report mycobacterial granulomatous inflammation in the ulcerated caecum of rats that received indomethacin. Two groups of male rats were treated with dietary indomethacin 3 mg/kg/day or untreated diet for 3 weeks. Six out of 8 indomethacin treated rats showed both ulceration and inflammation of the caecal mucosa. Two of the rats showing caecal ulceration also showed distinct granulomatous inflammation of the caecal mucosa and acid-fast bacilli were identified within granulomata. None of the other indomethacin treated or control rats contained acid-fast bacilli within caecal tissue sections but they were present, in the same sections, within the lumen of most rats in both groups. Polymerase chain reaction analysis identified the mycobacterial 65 kDa GroEL gene within control and granulomatous caecal tissue. In a repeat of indomethacin administration to a third group of rats, culture of both non-granulomatous caecal tissue (containing histologically identified luminal acid-fast bacilli) and faecal samples for mycobacteria was negative.

Animals↗
PubMed1995

The prevalence of Helicobacter pylori infection in different countries.

The prevalence of Helicobacter pylori infection in a community is related to three factors: firstly, the rate of acquisition of infection with H. pylori--that is, incidence; secondly, the rate of loss of the infection; thirdly, the prolonged persistence of the bacterium in the gastroduodenal mucosa between infection and eradication. Variation in the prevalence of H. pylori is dominated by the great differences between communities in the incidence of H. pylori infection during childhood. The countries of the world form two groups: Group One is made up of those where the majority of children become infected with H. pylori during childhood and chronic infection continues during adult life; in Group Two only a minority of children are infected during childhood, but the prevalence of infection rises in proportion to age during adult life. Understanding the ages at which people acquire infection with H. pylori is crucial to the interpretation of H. pylori prevalence data.

Adult↗
PubMed1995

Measles virus and Crohn's disease: research from the Royal Free Hospital in London.

This paper provides a summary of a 6-year program of research by the Inflammatory Bowel Disease Study Group at the Royal Free Hospital and School of Medicine, London. Research has demonstrated: 1. That Crohn's disease is associated with profound damage to the mesenteric vascular blood supply, even in areas where tissue or bowel appear macroscopically normal; 2. That Crohn's disease is a granulomatous vasculitis; 3. That aphthous ulceration is due to damage to underlying blood vessels; 4. That Crohn's disease is associated with a hypercoagulable state, and that patients with hemophilia rarely develop Crohn's disease; 5. That measles virus genome is localized to foci of granulomatous vasculitis and lymphoid follicles in the bowel of patients with Crohn's disease. In conclusion, we have not proved that measles virus is the cause of Crohn's disease. Proof may be difficult until there is a specific anti-viral drug that is able to eradicate this RNA virus.

Animals↗
PubMed1994

Serum immunoglobulin G reactive with endothelial cells in inflammatory bowel disease.

Evidence of a humoral immune response to endothelium was sought in the sera of patients with inflammatory bowel disease. In an ELISA, IgG binding to human umbilical vein endothelial cells was found in 21% of Crohn's disease sera, 10% of ulcerative colitis sera, 6% of sera from patients with acute infective diarrhea, and 8% of normal control sera. The increased prevalence in Crohn's disease sera was significant (P < 0.05). IgG-endothelial cell binding was cell specific, was not Fc-mediated, and did not mediate complement-dependent cell lysis. It was not increased by pretreatment of cells with interleukin-1 or tumor necrosis factor. Endothelial cell binding was retained by IgG F(ab')2 fragments from one of three reactive Crohn's sera, but none of three nonreactive sera. The low prevalence of this interaction, even in patients with immunohistochemically confirmed vasculitis, makes it unlikely that Crohn's disease is determined by a humoral autoimmune response to endothelium.

Adult↗
PubMed1994

A vascular hypersensitivity model of acute multifocal gastrointestinal infarction.

We have investigated the hypothesis that submucosal vasculitis may account for the patchy transmural inflammation observed in Crohn's disease. Test ferrets (N = 11) were sensitized to human albumin. Five days after the last sensitization injection, human albumin microspheres (15-150 microns diameter) were injected intraarterially into the mesenteric circulation of a defined loop of mid-gut. Six control ferrets showed no histological abnormality at either 48 hr or two weeks after intraarterial injection. At 48 hr, five of six presensitized ferrets demonstrated submucosal vasculitis with fibrinoid necrosis. In two cases there was transmural inflammation and mucosal ulceration. A further five presensitized ferrets received weekly subcutaneous human albumin injections following the mesenteric intraarterial injection of albumin microspheres: after two weeks one animal demonstrated mild perivascular inflammatory changes and another demonstrated vasculitis. One of the two animals with transmural inflammation and mucosal ulceration at 48 hr, and the animal with vasculitis at two weeks, had precipitating antibodies to human serum albumin. This model demonstrates that an immune-mediated submucosal vasculitis can sometimes result in discontinuous transmural inflammation of the intestinal wall.

Animals↗
PubMed1994

Effects of ranitidine 150 mg four times a day on 24-hour intragastric acidity and 24-hour plasma gastrin concentration.

Twenty-four-hour integrated intragastric acidity and 24-hr integrated plasma gastrin concentration was measured twice in 23 healthy male volunteers on the seventh day of oral dosing with placebo or ranitidine 150 mg four times a day. The study was a randomized, double-blind, placebo-controlled, two-way crossover investigation. The mean integrated 24-hr intragastric acidity during dosing with ranitidine 150 mg four times a day decreased to 32% of the placebo value (placebo 825 mmol/hr/liter; ranitidine 265 mmol/hr/liter). The mean integrated 24-hr plasma gastrin concentration during dosing with ranitidine 150 mg four times a day was 904 pmol/hr/liter compared with placebo (410 pmol/hr/liter)--an increase of 122%. The median number of hours of pH > 3 during dosing with placebo and with ranitidine 150 mg four times a day were 5 and 11 hr, respectively. Ranitidine 150 mg four times a day caused a significant decrease of mean integrated intragastric acidity for each meal-related interval and also during the night.

Adult↗
PubMed1994

Acute indomethacin-induced jejunal injury in the rat: early morphological and biochemical changes.

BACKGROUND/AIMS: Gastrointestinal injury induced by nonsteroidal anti-inflammatory drugs includes smooth muscle contraction, endothelial cell injury, and neutrophil infiltration. The aim of this study was to correlate early morphological changes with those in the metabolism of arachidonic acid. METHODS: Rats administered a single oral dose of indomethacin (15 mg/kg) or vehicle were killed and their intestines perfusion-fixed at 1, 2, 3, 6, and 48 hours after dosage. Serial sections of affected small intestine were immunostained for neutrophils, macrophages, actin, and fibrinogen. In addition, rats receiving either indomethacin (15 mg/kg) or vehicle were killed at 1 and 6 hours after dosage; blood and small intestinal tissue were assayed for blood thromboxane B2, intestinal tissue prostaglandin E2, and the intestinal production of leukotriene B4. RESULTS: At 2-6 hours, both intravascular and extravascular fibrin deposition were evident at the villus tip, and vertical alignment of villus smooth muscle cells was prominent. Significant neutrophil infiltration associated with a significant increase in leukotriene production was observed 6 hours after dosage. The extracted prostaglandin E2 content that was suppressed at 1 hour had recovered by 6 hours, whereas the blood thromboxane B2 levels were suppressed throughout the experiment. CONCLUSIONS: This study identifies an early neutrophil-independent phase of indomethacin-induced enteropathy that involves rapid cyclooxygenase inhibition and both microvascular and smooth muscle changes.

Animals↗
PubMed1994

Treatment of peptic ulcers from now to the millennium.

The present strategies for the management of peptic ulceration are well tolerated and clinically effective. Histamine H2-receptor antagonists can be used for mild to moderate disease, and proton pump inhibitors are of particular benefit for patients with severe peptic ulceration and the Zollinger-Ellison syndrome. However, none of these treatments provides protection against recurrent ulceration, except when taken as long-term continuous treatment. Long-term exposure to pharmacological agents raises problems of safety, particularly relating to a lack of intragastric acidity. In addition, the accelerated development of atrophic gastritis in patients receiving omeprazole requires investigation and assessment. It is unlikely that there will be any major development in the area of control of gastric acid secretion, except perhaps the introduction of specific immunization against gastrin. However, the clinical benefit of this strategy awaits assessment. The main area for development must be the introduction of convenient and effective regimens for the eradication of Helicobacter pylori infection. Existing regimens are either simpler and relatively ineffective, or too complicated for widespread application. Bearing in mind the long gestation period of any new drug, it seems likely that the only innovative drug that will be introduced for the management of peptic ulceration before the millennium will be ranitidine bismuth citrate, an antisecretory anti-H. pylori drug that will usually be used in combination with an antibiotic.

Anti-Ulcer Agents↗