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The monoclonal antibody RL23/36 has been shown to discriminate normal from malignant hepatocytes in man. In frozen sections of liver tissue from 25 Thai patients without hepatocellular carcinomas, the antibody reacted strongly and preferentially with hepatocytes. Reactivity with 7 hepatocellular carcinomas was invariably abnormal, being totally absent in 5 and partially lost in 2. This discrimination was superior to that achieved with Ca1 and 791T/36 monoclonal antibodies. In 2 cases of hepatocellular carcinoma, binding of RL23/36 to associated apparently non-malignant hepatocytes was abnormal, being absent in one and partially lost in the other. These data show that RL23/36 detects an antigenic determinant which is lost during malignant transformation of human hepatocytes, sometimes before the development of frank malignancy.

1. We evaluated injury to the human gastric mucosa caused by low doses of aspirin and its prophylaxis by ranitidine. On two separate occasions, 30 subjects took aspirin 300 mg daily for 12 days either with or without ranitidine 150 mg, 30 min before aspirin. This dose of aspirin caused more than a 5 fold increase in gastric bleeding, from control values of 0.5 microliters 10 min-1 (95% confidence limits 0.3-0.8 microliters 10 min-1) to 2.8 microliters 10 min-1 (1.9-4.1 microliters 10 min-1, P less than 0.01) after 5 days of aspirin. Adaptation did not occur and the gastric bleeding rates remained elevated at 3.4 microliters 10 min-1 (1.9-6.1 microliters 10 min-1) after 12 days of aspirin consumption (P less than 0.01). 2. Coadministration of ranitidine significantly raised intragastric pH and reduced aspirin induced bleeding to 1.5 microliters 10 min-1 (1.0-2.3 microliters 10 min-1) after 5 days and 1.6 (1.0-2.5 microliters 10 min-1) after 12 days (P less than 0.05). 3. Although these values were higher than control levels our results raise the possibility that coadministration of ranitidine may reduce the incidence of peptic ulceration and gastrointestinal haemorrhage which is increasingly reported in some subjects taking low dose aspirin for vascular prophylaxis.

1. We investigated the effect of the haemostatic agent ethamsylate on aspirin-induced gastric mucosal bleeding. 2. Eighteen healthy subjects were studied three times: at the end of 48 h periods of treatment with (a) placebo, (b) aspirin 600 mg four times daily, (9 doses) and (c) aspirin 600 mg four times daily with each dose preceded by ethamsylate 500 mg. 3. At the end of each treatment period gastric mucosal bleeding into timed gastric washings was quantified using the orthotolidine reaction. 4. Aspirin increased bleeding from a rate on placebo of 1.2 microliters 10 min-1 geometric mean (95% confidence limits) (0.7-1.8) microliters 10 min-1 to 20.0 (11.6-34.2) microliters 10 min-1, (P less than 0.01). The rate of bleeding after aspirin preceded by ethamsylate [14.1 (8.5-23.4) microliters 10 min-1] was not significantly different from that after aspirin alone. 5. We conclude that ethamsylate does not reduce acute aspirin-induced gastric mucosal bleeding in healthy humans.

A case, diagnosed clinically as the Prader-Willi syndrome, was shown by Giemsa banding, to have a 15/15 chromosome translocation. A review of the literature indicates that such a translocation has only been described once before, in a normal woman, but that chromosme abnormalities in the Prader-Willi syndrome most commonly involve the D group. The significance of this would be clarified by specific chromosome identification in these patients.

Pleomorphic T-cell leukaemia occurring in an adult Caucasian patient is described. The leukaemia cells expressed both antigenic determinants (T4 and T8) normally detected separately on either helper or suppressor cells. They functioned as helper cells and there was evidence of unbridled antibody production. It is possible that a distinctive subtype of pleomorphic T-cell leukaemia occurs in Caucasian patients.

A trial of subcutaneous low-dose heparin in the prevention of deep-vein thrombosis was carried out in elderly patients admitted to hospital after an acute stroke. A statistically significant reduction was observed in deep-vein thrombosis as assessed by isotope leg scanning.

1. We have compared acute gastric bleeding caused by a new slow release preparation of indomethacin (indomethacin Continus) with that caused by aspirin and other indomethacin preparations. 2. In a randomized crossover study, blood loss into timed gastric aspirates was determined in 20 healthy volunteers after receiving, over 96 h, either placebo, aspirin (600 mg four times daily; 17 doses) indomethacin BP (50 mg three times daily; 13 doses), Indocid-R (75 mg twice daily; 9 doses) or indomethacin Continus (75 mg twice daily; 9 doses). A venous blood sample was also taken during each treatment period for subsequent determination of alpha 1-glycoprotein, and for drug assay. 3. Gastric bleeding on placebo was 1.4 (0.7-2.8) microliters 10 min-1 (mean, 95% confidence interval). Both aspirin and the indomethacin preparations caused significantly more bleeding (P less than 0.05). Rates of bleeding after aspirin, indomethacin BP, Indocid-R, and indomethacin Continus were respectively 22.0 (10.7-47.2) microliters 10 min-1, 4.4 (2.2-9.1) microliters 10 min-1, 10.8 (5.3-22.3) microliters 10 min-1, and 5.1 (3.0-10.6) microliters 10 min-1. 4. Rates of bleeding after indomethacin BP and indomethacin Continus, but not Indocid-R, were significantly less than after aspirin (P less than 0.01). 5. Salicylate or indomethacin was detectable in the plasma of all subjects after the active treatment periods, except for one instance involving a subject allocated indomethacin BP. Indomethacin levels were significantly higher 2 h after Indocid-R than with indomethacin BP or indomethacin Continus. 6. alpha 1-acid glycoprotein levels were not significantly affected by prior treatment with aspirin or indomethacin.

Prostaglandins protect the gastric mucosa in animals, but the evidence of an effect independent of pH changes in man is not overwhelming. Gastrointestinal bleeding because of non-steroidal anti-inflammatory drugs is a major clinical problem, which we have investigated in a model system measuring bleeding rates caused by short-term administration of aspirin. Of the various strategies tested, only those that elevated intra-gastric pH reduced aspirin-induced bleeding.

We have investigated whether plasma exchange in myasthenia gravis synergises with additional immunosuppressive drug therapy (azathioprine, cyclophosphamide or cytosine arabinoside). Serum anti-acetylcholine receptor (AChR) antibody titres were followed over 28 days after a course of PE in 20 patients, of whom 17 were taking 20-80 mg prednisone on alternate days. No significant difference was observed in mean anti-AChR antibody recovery following plasma exchange with and without additional immunosuppressive therapy. In paired studies where patients served as their own controls, mean anti-AChR recovery with and without azathioprine or cytosine arabinoside showed no significant differences. Anti-AChR recovery rates after large and small plasma exchange courses also did not differ significantly. Prolonged administration of azathioprine reduced antibody titres independently of plasma exchange. These results fail to demonstrate significant synergy between plasma exchange and the additional immunosuppressive drugs used, and suggest that the effects of plasma exchange were transient.

A rotating disc apparatus was used to study the dissolution of cholesterol in sodium cholate solutions and ox bile. Drugs with structures that render them capable of lowering interfacial resistance were tested and shown to increase cholesterol dissolution rates in both systems. In sodium cholate solutions, loperamide (3 X 10(-4)M) increased the rate of dissolution by over six times, and a similar effect was observed with amitriptyline (3 X 10(-3)M), diphenhydramine (3 X 10(-3)M), dicyclomine (3 X 10(-3)M) and propantheline (3 X 10(-3)M). These drugs are as effective as benzalkonium chloride at these concentrations. Amitriptyline, propantheline, dicyclomine and diphenhydramine also increased cholesterol dissolution rates into ox bile. If these drugs are excreted into human bile in sufficient quantities and in an active form they may be able to enhance the speed of cholesterol gallstone dissolution therapy.

Prostaglandins have numerous mucosal protective properties, impairment of which contribute to NSAID injury. It is not clear which is the most important injurious factor affecting patients taking NSAIDs. Is it the NSAID itself, either by topical toxicity and/or production of toxic mediators or does the patient become more sensitive to NSAIDs as a result of some other luminal component, such as acid or bile acids, food (by physical or chemical mechanisms) or accompanying alcohol? Intrinsic irritancy/toxicity probably accounts for the greater mucosal toxicity of aspirin, although it is not clear whether this is due to a direct (non-prostaglandin-dependent) effect on mucus or bicarbonate secretion, membrane integrity, interference with intermediary metabolism or the production of toxic products. Similarly, the relationship of irritancy to the symptom of dyspepsia, to which patients on aspirin are prone, is as yet not well understood. While strategies for short-term protection of experimental animals and humans are well established, protection against important, but relatively rare clinical events, is more difficult to study and much less well understood. In particular, the importance of the ability of NSAIDs to exacerbate bleeding, independent of injury, has been largely neglected in the context of presentation with haematemesis and melaena.

Objective: To investigate the suitability of treatment with low dose aspirin or warfarin, or both, as possible prophylaxis against cardiovascular disease by determining the effect on gastric mucosal bleeding., Design: Randomised crossover trial., Setting: Academic department of therapeutics., Subjects: Twenty healthy male volunteers aged 19-22., Interventions: On separate occasions and in randomised order all subjects received aspirin 75 mg, warfarin, or aspirin 75 mg combined with warfarin. Each treatment was given for 12 days or (when warfarin was used) for longer if necessary until the international normalised ratio of the prothrombin time was stable at 1.4-1.6., End Point: Loss of blood over 10 minutes into gastric washings., Measurements and Main Results: Bleeding over 10 minutes into gastric washings under baseline conditions and after five days, and at end of each regimen of treatment. Aspirin 75 mg increased bleeding from 0.60 (95% confidence interval 0.36 to 0.99) microliters/10 minutes to 1.26 (0.71 to 2.25) microliters/10 minutes at five days, with no evidence of either progressive change or adaptation thereafter. Warfarin had no effect on bleeding either alone or when combined with aspirin., Conclusions: Aspirin 75 mg causes gastric mucosal bleeding. Low dose warfarin neither induces gastric mucosal bleeding nor enhances that caused by aspirin.

Forty-four patients with symptomatic endoscopically proven mild to moderate reflux oesophagitis were enrolled in a single-centre, double-blind, clinical trial comparing trimoprostil 750 micrograms taken 4 times daily with placebo. Patients treated with trimoprostil but not placebo experienced a significant reduction in the frequency (p less than 0.005) and duration (p less than 0.02) of heartburn. Both groups reported a reduction in the severity of heartburn and resulting sleep disturbance during the trial, but differences between them in these respects at the end of the trial did not reach statistical significance. There was a significant reduction in the severity of oesophagitis seen at endoscopy after treatment with trimoprostil (p less than 0.01) but not placebo. Trimoprostil was well tolerated and appears to be more effective than placebo in the treatment of mild to moderate symptomatic reflux oesophagitis. Although this agent's mode of action was not investigated, we speculate that it may be protective to human squamous oesophageal mucosa.

Twenty four hour intragastric acidity was measured in five duodenal ulcer patients studied at least three times. The effects of different dosage regimens of intravenous omeprazole was compared with placebo. Mean intragastric acidity from 1000 to 0800 was 34.3 +/- 4.3 mmol/l on placebo. After omeprazole 80 mg at 0900 and 40 mg at 1700 mean acidity was 2.1 +/- 0.9 mmol/l and after omeprazole 80 mg at 0900 and 80 mg at 1700 it was 0.7 +/- 0.2 mmol/l. pH remained above 4.0 for about 80% of recordings with these regimens and for only 5% with placebo. Three of the five patients also received omeprazole 80 mg at 0900, 40 mg at 1700 and 40 mg at 0100 when pH remained above 4.0 for 90% of recordings with 99% inhibition of acidity. Omeprazole rapidly raised intragastric pH in all patients and maintained a gastric pH of greater than 4.0 for most of the time. Large doses of IV omeprazole were required compared with studies using the oral compound.

We have conducted an open pilot trial to assess the therapeutic effect of the lipoxygenase inhibitor, benoxaprofen, in 10 patients with active ulcerative proctocolitis. After 18 days treatment with benoxaprofen (600 mg daily) there was no significant change in bowel habit, rectal bleeding, constitutional upset, sigmoidoscopic appearance, mucosal histology, haemoglobin, ESR, serum albumin or serum orosomucoid. Benoxaprofen itself seems unlikely to prove useful in ulcerative colitis, but evaluation of the therapeutic potential of other lipoxygenase inhibitors in inflammatory bowel disease may be worthwhile.

A 57 year old man developed theophylline toxicity in association with acute pulmonary artery thrombosis. The plasma half life of theophylline was prolonged suggesting impaired metabolism secondary to acute right heart failure.

The use of acute human models of gastric mucosal injury has been stimulated by a need to understand more fully the problems of non-steroidal anti-inflammatory drugs but such models have other applications. None is ideal and they all share certain drawbacks. For none of them has a precise relationship to clinical events been established and they have all tended to be employed on a population of young healthy subjects who are not those at greatest clinical risk. Of individual methods mucosal potential difference is an indirect measure which is too often affected by other influences to be acceptable as a measure of mucosal injury when used alone, although it has some value as an adjunct to other measurements. Assay of DNA in gastric washings is a suitable technique for quantifying desquamation of gastric epithelial cells occurring in response to acute injury; on present evidence its significance is much more difficult to assess in the context of continuing challenge over several days. By contrast, measurement of microbleeding is more suitable for quantifying injury over several days of NSAID ingestion; little bleeding is recorded with a single acute challenge. Endoscopy can demonstrate macroscopic lesions which result from mucosal injury--injury which is quantified more easily and sensitively by measurements of cellular exfoliation or bleeding. Paradoxically, endoscopy's strength has been to underline the scientific weakness of acute models because it shows that it is rare for ulcers, which are the lesions of clinical concern to develop in these studies.

Because endogenous prostaglandins may protect the gastric mucosa a study was conducted to determine factors influencing the synthesis of immunoreactive prostaglandin (iPG) E2 and thromboxane (iTx) B2 as measured by radioimmunoassay and prostaglandin catabolism measured radiometrically, in human gastric mucosa. Gastric mucosa was obtained at endoscopy. Synthesis of iPE2 and iTxB2 was inhibited in vitro by indomethacin; iTxB2 synthesis was also selectively inhibited by the thromboxane synthesis inhibitor dazmegrel. Prostaglandin catabolism was inhibited by carbenoxolone. Multivariate analysis showed that synthesis of iPGE2 from endogenous precursor during homogenisation was decreased in patients on non-steroidal anti-inflammatory drugs. Mucosal inflammation was associated with significantly increased synthesis of iPGE2 and decreased prostaglandin catabolism. There were no differences between the mucosa of patients with or without gastric ulcers, nor between the ulcer rim and mucosa 5 cm away. Age, sex, smoking history and ingestion of antisecretory drugs appeared to exert no influence. In this study gastritis was the major influence on prostaglandin synthesis. It seems unlikely that prostaglandin deficiency is a strong predisposing factor for gastric ulceration.

The balance between thromboxane A2 (a vasoconstrictor) and prostacyclin (a vasodilator) may be important in the pathogenesis of Raynaud's phenomenon. Dazoxiben is a selective inhibitor of thromboxane synthetase, with no effect on prostacyclin synthetase. It has been shown to abolish cold induced forearm vasoconstriction in normal volunteers. We have compared its effect with that of placebo in a double blind crossover study in eight patients with severe Raynaud's phenomenon. No consistently clinically useful benefit was demonstrated from three weeks' treatment with dazoxiben, and there were no significant changes in finger temperature or finger blood flow. We conclude that dazoxiben at this dosage is unlikely to be of practical clinical benefit in Raynaud's phenomenon.

Endogenous and exogenous prostaglandins mobilize gastroduodenal mucosal defenses which are compromised by inhibition of prostaglandin synthesis with non-steroidal anti-inflammatory drugs (NSAIDS). There is some evidence, conversely, that stimulation of endogenous prostaglandin synthesis by increasing precursor availability by dietary enrichment or by provoking its release may increase mucosal integrity. However, there are also non-prostaglandin defense mechanisms which can be elicited even when prostaglandin synthesis is profoundly depressed. Most (but not all) evidence suggests that gastric ulcer patients have deficient prostaglandin synthesis, though it is not clear whether this is a primary or secondary defect and the evidence on duodenal ulcer patients is incoherent. Prostaglandin analogues heal both gastric ulcers and duodenal ulcers, mainly as a result of acid inhibition. There is suggestive, but not conclusive, evidence that subsequent relapse may be retarded. Misoprostol has obtained a licensed indication for the prevention of NSAID-induced peptic ulcer on the basis of studies showing a reduced development of peptic ulcers and erosions over 4-8 weeks, implying that deficient endogenous prostaglandin levels can be replaced by exogenous administration.

We have developed an ultrathin endoscope for repeated endoscopy in unsedated subjects and used it with assessment of bleeding rates to investigate aspirin-induced gastric mucosal injury and its prevention by famotidine. Compared with placebo, 900 mg of aspirin b.i.d. taken for 48 h caused significant endoscopic injury (median grade 3.5, interquartile range 2-4, modified Lanza scale, p less than 0.01), with an increase in mucosal bleeding from 2.0 (geometric mean; 95% confidence limits, 1.1-3.9) microliters/12 min, to 8.3 (2.4-28.8) microliters/12 min (p less than 0.05). Famotidine (20 mg b.i.d.) raised intragastric pH and reduced endoscopic antral injury (median 1.5, interquartile range 0.5-2, p less than 0.05) and bleeding [3.1 (1.2-8.3) microliters/12 min, p less than 0.01] to levels not significantly different from placebo [1 (0-1) and 2.0 (1.1-3.9) microliters/12 min, respectively]. By contrast, 2 mg of famotidine b.i.d. had no significant effect on intragastric pH endoscopic injury or bleeding rates. The two assessments of gastric mucosal injury correlated strongly (r = 0.71, p less than 0.01). The reduction in bleeding with famotidine tended to be higher, the greater the intragastric pH (r = 0.66, p = 0.057). Ultrathin endoscopy is a simple technique that validates gastric mucosal bleeding as a measure of acute gastric mucosal injury in humans. Acid suppression is an effective method of ameliorating this injury.

Miniaturised methods have been used to construct dose-response curves for the effects of inhibitory drugs on prostaglandin synthesis using individual rectal biopsies obtained from patients with ulcerative colitis. The potency of different drugs has been compared. Sulphasalazine, 5 amino salicylic acid (5-ASA) and N-acetyl 5-ASA inhibited prostaglandin synthesis at high concentration, but sulphapyridine and prednisolone did not. Indomethacin and flurbiprofen were considerably more potent inhibitors. These data imply that sulphasalazine does not act by simple inhibition of prostaglandin synthesis but leave open the possibility that sulphasalazine or 5-ASA may be inhibitors of the synthesis of related lipoxygenase products.

Spirochetes resembling Brachyspira aalborgi were found in the feces and rectal biopsies of a patient with persistent diarrhea. Although the organism failed to grow on bacteriologic media, it was found attached to the surfaces of the epithelial cells on the rectal lumen. Blunting and destruction of the cellular microvilli was evident. These induced pathologic cell surface changes, together with the presence of intracellular bacteria in the cells of the rectal colon, suggest a pathogenic mechanism for the persistent diarrhea often associated with this condition. Both the spirochetosis and clinical symptoms disappeared on treatment with metronidazole.

During 2 years, 6 out of 34 patients presenting with newly diagnosed non-Hodgkin's lymphoma developed central nervous system (CNS) complications. All were male and had diffuse, undifferentiated lymphomas. In all 6 patients, CNS disease developed during, or shortly after, treatment. We suggest that a group at high risk from these complications can be identified and should be considered for a trial of prophylaxis.