Proof-of-principle that infection contributes to idiopathic parkinsonism (IP) was confirmed, in a randomised placebo-controlled efficacy study: successful Helicobacter pylori (Hp) eradication had a disease modifying effect. We propose that, in the presence of a genetically determined, intense innate inflammatory response, progression to and within parkinsonism would be accelerated. Presence of antibody against the pathogenicity island marker, cytotoxicity-associated-gene-product (CagA) is a bad prognostic sign in IP. An analogy may be found in the pathogenesis of non-cardia gastric carcinoma. Certain pro-inflammatory gene polymorphisms increase the risk. Having more than one of these escalates it. Seropositivity for Helicobacter escalates it further, having CagA antibodies further still. What, then, might distinguish between the pathogenic pathways to these very distinct conditions? In contrast to gastric cancer, even moderate gastric atrophy is rarely seen with Helicobacter-associated gastritis in IP. This is compatible with truncation of the natural history of the infection. Moreover in IP, mitochondrial function is impaired, different risk factors are associated, and other genetic characteristics may determine basal ganglia vulnerability.

BACKGROUND:The pathogenesis of NSAID-induced gastrointestinal damage is believed to involve a nonprostaglandin dependent effect as well as prostaglandin dependent effects. One suggestion is that the nonprostaglandin mechanism involves uncoupling of mitochondrial oxidative phosphorylation.AIMS:To assess the role of uncoupling of mitochondrial oxidative phosphorylation in the pathogenesis of small intestinal damage in the rat.METHODS:We compared key pathophysiologic events in the small bowel following (i) dinitrophenol, an uncoupling agent (ii) parenteral aspirin, to inhibit cyclooxygenase without causing a 'topical' effect and (iii) the two together, using (iv) indomethacin as a positive control.RESULTS:Dinitrophenol altered intestinal mitochondrial morphology, increased intestinal permeability and caused inflammation without affecting gastric permeability or intestinal prostanoid levels. Parenteral aspirin decreased mucosal prostanoids without affecting intestinal mitochondria in vivo, gastric or intestinal permeability. Aspirin caused no inflammation or ulcers. When dinitrophenol and aspirin were given together the changes in intestinal mitochondrial morphology, permeability, inflammation and prostanoid levels and the macro- and microscopic appearances of intestinal ulcers were similar to indomethacin.CONCLUSIONS:These studies allow dissociation of the contribution and consequences of uncoupling of mitochondrial oxidative phosphorylation and cyclooxygenase inhibition in the pathophysiology of NSAID enteropathy. While uncoupling of enterocyte mitochondrial oxidative phosphorylation leads to increased intestinal permeability and low grade inflammation, concurrent decreases in mucosal prostanoids appear to be important in the development of ulcers.

BACKGROUND:The "topical" effect of non-steroidal anti-inflammatory drugs (NSAIDs) seems to be an important cause of NSAID induced gastrointestinal damage. AIM:To examine the possible mechanism of the "topical" phase of damage in the small intestine. METHODS:Electron microscopy and subcellular organelle marker enzyme studies were done in rat small intestine after oral administration of indomethacin (doses varied between 5 and 30 mg/kg). The effect of conventional and non-acidic NSAIDs on rat liver mitochondrial respiration was measured in vitro in a Clarke-type oxygen electrode. RESULTS:The subcellular organelle marker enzymes showed mitochondrial and brush border involvement within an hour of indomethacin administration. Electron microscopy showed dose dependent mitochondrial changes following indomethacin administration consistent with uncoupling of oxidative phosphorylation (or inhibition of electron transport) which were indistinguishable from those seen with the uncoupler dinitrophenol. Parenteral indomethacin caused similar changes, but not in rats with ligated bile ducts. A range of NSAIDs, but not paracetamol or non-acidic NSAIDs which have a favourable gastrointestinal tolerability profile, uncoupled oxidative phosphorylation in vitro at micromolar concentrations and inhibited respiration at higher concentrations. In vivo studies with nabumetone and aspirin further suggested that uncoupling or inhibition of electron transport underlies the "topical" phase of NSAID induced damage. CONCLUSION:Collectively, these studies suggest that NSAID induced changes in mitochondrial energy production may be an important component of the "topical" phase of damage induction.

BACKGROUND:Nitric oxide derivatives of non-steroidal anti-inflammatory drugs (NSAIDs) are thought to be much less ulcerogenic than their parent compounds. AIM:To compare the effect and potency of flurbiprofen and nitroxybutyl-flurbiprofen to uncouple mitochondrial oxidative phosphorylation (an early pathogenic event in NSAID enteropathy), increase intestinal permeability (transitional stage), and cause macroscopic small intestinal damage. METHODS:In vitro uncoupling potency was assessed using isolated coupled rat liver mitochondria and in vivo by electron microscopy of rat small intestinal mucosa (two hours after the drugs). A dose-response study with flurbiprofen (single doses of 5, 10, 20, and 40 mg/kg) and equimolar doses of nitroxybutyl-flurbiprofen was performed; assessing their effect on intestinal permeability (at 18-20 hours), with 51Cr EDTA, and the number of pointed (< 5 mm) and longitudinal (> 5 mm) small intestinal ulcers at 24 hours. RESULTS:Flurbiprofen, but not nitroxybutyl-flurbiprofen, stimulated coupled respiration in vitro. Both drugs, however, uncoupled in vivo; in the case of nitroxybutyl-flurbiprofen possibly because hydrolysis of its ester bond released free flurbiprofen. Intestinal permeability was uniformly and equally increased with both drugs compared with controls. The number of small intestinal ulcers, pointed and longitudinal, was significantly reduced with nitroxybutyl-flurbiprofen apart from the number of longitudinal ulcers with the highest dose. CONCLUSIONS:These studies show that nitroxybutyl-flurbiprofen is associated with significantly less macroscopic damage in the small intestine than flurbiprofen but was associated with mitochondrial damage in vivo and caused similar increases in permeability of the small intestine, suggesting that its beneficial effect is on the later pathogenic stages of the damage.

Intestinal function is poorly defined in patients with HIV infection. Absorptive capacity and intestinal permeability were assessed using 3-O-methyl-D-glucose, D-xylose, L-rhamnose, and lactulose in 88 HIV infected patients and the findings were correlated with the degree of immunosuppression (CD4 counts), diarrhoea, wasting, intestinal pathogen status, and histomorphometric analysis of jejunal biopsy samples. Malabsorption of 3-O-methyl-D-glucose and D-xylose was prevalent in all groups of patients with AIDS but not in asymptomatic, well patients with HIV. Malabsorption correlated significantly (r = 0.34-0.56, p < 0.005) with the degree of immune suppression and with body mass index. Increased intestinal permeability was found in all subgroups of patients. The changes in absorption-permeability were of comparable severity to those found in patients with untreated coeliac disease. Jejunal histology, however, showed only mild changes in the villus height/crypt depth ratio as compared with subtotal villus atrophy in coeliac disease. Malabsorption and increased intestinal permeability are common in AIDS patients. Malabsorption, which has nutritional implications, relates more to immune suppression than jejunal morphological changes.

OBJECTIVE:To identify the source of intestinal blood loss in rheumatoid arthritis patients being treated with nonsteroidal antiinflammatory drugs (NSAIDs) and assess the response to sulfasalazine and other disease-modifying antirheumatic drugs (DMARDs).METHODS:Intestinal inflammation, blood loss, and gastroduodenal damage, and the response to treatment with DMARDs, were assessed in 46 patients taking NSAIDs.RESULTS:Intestinal inflammation and blood loss correlated significantly with one another (r = 0.43, P < 0.003), but not with the macroscopic or microscopic appearance of the gastroduodenal mucosa. Sulfasalazine reduced both intestinal inflammation and blood loss, whereas the other DMARDs did not.CONCLUSION:The small intestine is the main site of mild chronic blood loss in patients receiving NSAIDs, and this blood loss can be reduced with sulfasalazine treatment.

This study investigated the spectrum of gastric mucosal pathology, including the prevalence of reactive gastritis in patients on non-steroidal anti-inflammatory drugs (NSAIDs). The histological findings were correlated with upper gastrointestinal symptom status and endoscopic findings and were also compared with the histological appearances of the gastric mucosa in a corresponding age-matched control group of 75 patients not receiving NSAIDs or any other drug therapy. Reactive gastritis of the gastric antrum was more common in the NSAID group and was observed in 34 patients (45.3%), as an isolated phenomenon in 24 patients (32%) and with evidence of coexistent chronic gastritis in 10 patients (13.3%). In the control group reactive gastritis of the antrum was seen in 10 patients (13.3%), as an isolated finding in eight cases (10.7%) and with accompanying chronic gastritis in two cases. Chronic antral gastritis of usual type was observed in 36 patients on NSAIDs (48%) and Helicobacter-like organisms were identified histologically in 18 of these (50% carriage rate). These organisms were not seen in any of the patients in whom the picture of reactive gastritis was present. In the control group chronic antral gastritis was seen in 51 patients (68%) with organisms in 34 (66.6% carriage rate). No correlation was found between the presence or absence of upper gastrointestinal symptoms, endoscopic findings and the histological appearances of the gastric mucosa. We conclude that NSAIDs are an independent cause of reactive gastritis in the antrum and do not appear to alter gastric mucosal colonization by Helicobacter-like organisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Journal of Gastroenterology and HepatologyVolume 6, Issue 3 p. 209-222 The Sydney System: Histological division ASHLEY B PRICE, Corresponding Author ASHLEY B PRICE Department of Histopathology, Clinical Research Centre, Northwick Park Hospital, Harrow, Middlesex, UKDr. A. B. Price, Consultant Histopathologist, Department of Histopathology, Clinical Research Centre, Northwick Park Hospital, Harrow, Middlesex HAI 3UJ, UK.Search for more papers by this author ASHLEY B PRICE, Corresponding Author ASHLEY B PRICE Department of Histopathology, Clinical Research Centre, Northwick Park Hospital, Harrow, Middlesex, UKDr. A. B. Price, Consultant Histopathologist, Department of Histopathology, Clinical Research Centre, Northwick Park Hospital, Harrow, Middlesex HAI 3UJ, UK.Search for more papers by this author First published: June 1991 https://doi.org/10.1111/j.1440-1746.1991.tb01468.xCitations: 676AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL References 1 Marshall B. J. & Warren J. R. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984; i: 1311– 5. 2 Marshall B. J., Armstrong J. A., McGechie D. B. & Glancy R. J. 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Citing Literature Volume6, Issue3June 1991Pages 209-222 ReferencesRelatedInformation

The Workshop covered a wide range of gastric inflammatory pathology. The reports published here represent but a selection, and this summary simply draws attention to particular aspects of interest or contention. The emphasis was on Helicobacter pylori, its associated gastritis, the natural history of gastritis, and any impact these have on the current classification of gastric inflammatory disease.

The Journal of PathologyVolume 154, Issue 4 p. 378-378 Book Review Histogenesis and precursors of human gastric cancer. T. Nagayo. Springer-Verlag, Berlin, 1986. No. of pages: xi + 190. Price: DM165.00 (hard cover). ISBN: 3 540 15314 4 A. B. Price, A. B. Price Northwick Park Hospital, LondonSearch for more papers by this author A. B. Price, A. B. Price Northwick Park Hospital, LondonSearch for more papers by this author First published: April 1988 https://doi.org/10.1002/path.1711540422AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume154, Issue4April 1988Pages 378-378 RelatedInformation

The main features of the histopathology of Campylobacter pylori-associated gastritis are reviewed. The organism is strongly associated with the Type B pattern of chronic gastritis. It colonizes the abnormal antrum and is not usually seen on the normal mucosa. However it fails to colonize the abnormal antrum in the Type A gastritis of pernicious anaemia. When present in the duodenum it is in conjunction with severe duodenitis and gastric metaplasia. Although the organisms are present in over 70% of patients with peptic ulcer disease care must still be taken with identification, as other gastric spiral organisms can be present that are not Campylobacters.

138 Indian patients with megaloblastic haemopoiesis were studied. All were lifelong vegetarians. The diagnosis was nutritional cobalamin deficiency in 95 and pernicious anaemia in 20; only 4 patients had folate deficiency. A third had intestinal malabsorption, 20 had features of osteomalacia, and 87 were iron deficient. Tuberculosis was diagnosed in 17. Cobalamin deficiency may have contributed to these complications via intestinal malabsorption and impaired bacterial killing of phagocytosed bacilli by cobalamin-deficient macrophages. The frequency of pernicious anaemia was the same in Indian subjects as in Caucasians.