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Sulphasalazine and other 5-aminosalicylic acid (5-ASA)-containing drugs are used in the treatment of acute inflammatory bowel disease and in the maintenance of clinical remission. Despite their use for over 50 years, the mechanism of action of this class of drugs remains uncertain, although a number of possibilities are discussed in this review. It seems likely that the aminosalicylates are important free radical scavengers, can reduce leukotriene production and can inhibit the cellular release of interleukin-1, all of which are likely to be important in reducing the acute inflammatory response in inflammatory bowel disease. The effects of these drugs on prostaglandin production are more contentious, but it appears that 10(-5) to 10(-4) M concentrations stimulate production of prostaglandins which may be cytoprotective, while higher doses of these drugs inhibit prostaglandin production. The aminosalicylates may maintain remission in inflammatory bowel disease by preventing leucocyte recruitment into the bowel wall. The drugs inhibit the chemotactic response to leukotriene B4, reduce the synthesis of platelet activating factor and also inhibit leucocyte adhesion molecule upregulation.

In a placebo-controlled study, 43 patients with stable ulcerative colitis were randomized to receive either MaxEPA (n = 16), super evening primrose oil (n = 19), or olive oil as placebo (n = 8) for 6 months, in addition to their usual treatment. Treatment with MaxEPA increased red-cell membrane concentrations of eicosapentaenoic acid (EPA) at 3 months by three-fold and at 6 months by four-fold (both P < 0.01), and doubled docosahexaenoic acid (DHA) levels at 6 months (P < 0.05). Treatment with super evening primrose oil increased red-cell membrane concentrations of dihomogamma-linolenic acid (DGLA) by 40% at 6 months (P < 0.05), whilst treatment with placebo reduced levels of DGLA and DHA at 6 months (both P < 0.05). Clinical outcome was assessed by patient diary cards, sigmoidoscopy and histology of rectal biopsy specimens. Super evening primrose oil significantly improved stool consistency compared to MaxEPA and placebo at 6 months, and this difference was maintained 3 months after treatment was discontinued (P < 0.05). There was however, no difference in stool frequency, rectal bleeding, disease relapse, sigmoidoscopic appearance or rectal histology in the three treatment groups. Despite manipulation of cell-membrane fatty acids, fish oils do not exert a therapeutic effect in ulcerative colitis, while evening primrose oil may be of some benefit.

In parallel studies, the effects of 5-aminosalicylic acid (5-ASA) and acetyl-5-aminosalicylic acid (acetyl-5-ASA) on peroxidation of red-cell membrane lipids and production of prostaglandins by peripheral blood mononuclear cells were assessed. 5-ASA at concentrations of 10(-5), 10(-4) and 10(-3) M significantly inhibited erythrocyte lipid peroxidation, measured as malondialdehyde production, by 20%, 56% and 63%, respectively, (P < 0.05, P < 0.002, P < 0.001, respectively) while acetyl-5-ASA had no effect. 10(-5) and 10(-4) M 5-ASA significantly increased production by stimulated peripheral blood mononuclear cells of PGE2 (by 31% and 30%, P < 0.01, P < 0.05, respectively) and PGF2 alpha (by 30% and 25%, P < 0.05, P < 0.01, respectively). 10(-4) M 5-ASA also significantly stimulated prostacyclin production measured as 6KF1 alpha by 10% (P < 0.05). At 10(-3) M 5-ASA there were significant falls in 6KF1 alpha (by 37%) PGE2 (by 45%) and PGF2 alpha (by 47%) (P < 0.01, P < 0.001, P < 0.001, respectively) although this was accompanied by a decrease in cell viability. Acetyl-5-ASA had little effect upon prostaglandin production. 5-ASA scavenges free radicals and stimulates production of cytoprotective prostaglandins.

Objective:The use of ELISA techniques to measure cytokine levels in clinical samples has chiefly replaced more labour intensive bioassays. ELISA measurements, however, do not reflect the functional activity of a cytokine within a sample; interleukin-1 (IL-1), for example, has two agonist isoforms (IL-1α and IL-1β) and a competitive receptor antagonist (IL-1ra), and can be regulated by transforming growth factor β1 (TGF-β1). The net effect of these cytokines, rather than IL-1 levels, are frequently suggested to regulate tissue inflammation, but confirming this has been difficult. Methods:We used the ELA4.NOB-1/CTLL co-culture IL-1 bioassay to investigate whether IL-1 activity was inhibited by IL-1ra and TGF-β1 in a predictable manner. Results:Thymidine incorporation into CTLL cells, induced by IL-1, was reduced dose dependently by IL-1ra and TGF-β1. With optimal levels of IL-1 CTLL responsiveness was reduced by 90% by 1 ng/ml TGF-β1 and completely abolished by 100 ng/ml IL-1ra. As expected, TGF-β1 and IL-1ra had independent mechanisms of action on the bioassay cell lines, and, in combination, they caused an additive, but not synergistic, effect. Importantly, the effect of these cytokines could be completely abolished in the presence of neutralising antibodies. Conclusions:Bioassay should provide specific functional information on the net IL-1 activity of clinical samples, while the use of specific antibodies could ascertain the contribution of individual cytokines within such samples.

Objectives: To study the pharmacokinetics of lithium chloride administered intravenously to patients who had undergone cardiac surgery within the previous 12 h and to normal volunteers, since lithium is used in a new indicator dilution method for measuring cardiac output. Methods: A prospective study was carried out in a London teaching hospital. Lithium chloride was administered intravenously and blood samples taken at intervals for up to one hour. Plasma lithium levels were measured by inductively coupled plasma optical emission spectrometry and standard pharmacokinetic parameters were calculated. Results: Two groups of patients were investigated; the first (n = 10) received five doses of 0.6 mmol LiCl at 2 min intervals, the second (n = 10) a single dose of 0.6 mmol LiCl. A further group of six normal volunteers also received a single dose of 0.6 mmol LiCl. Biexponential curves were fitted to the data. For the three groups the half-lives of the first exponentials (T1/2α) were 3.3, 4.2 and 3.9 min, resp...

Aim : To compare lansoprazole 30 mg once daily, lansoprazole 15 mg once daily and ranitidine 150 mg once nightly in the prevention of duodenal ulcer relapse in patients whose duodenal ulcers had been previously healed with lansoprazole 30 mg once daily or ranitidine 300 mg nightly. Methods : A double-blind, parallel group, randomized multicentre study conducted in 33 centres in the UK, Eire, Sweden and Australia. Two hundred and nineteen patients with a duodenal ulcer were randomized to receive lansoprazole 30 mg and 217 to receive ranitidine 300 mg for 8 weeks. Patients were then re-randomized to receive lansoprazole 30 mg (122 patients), lansoprazole 15 mg (121 patients) or ranitidine 150 mg (116 patients) for 12 months. All patients had an endoscopically-proven duodenal ulcer at baseline and were considered suitable for long-term maintenance therapy to prevent relapse. Results : Significantly more patients were healed on lansoprazole (98%) compared to ranitidine (89%) (P

Background: Oral iron supplements, which are usually in the form of ferrous (Fe2+) salts, are toxic to the gastrointestinal mucosa, and so intolerance is common, resulting in poor compliance and failure of treatment. The sugar derivative maltol strongly chelates iron, rendering it available for absorption and stabilized in the less toxic ferric (Fe3+) form. Aim: To test whether ferric trimaltol could correct iron deficiency anaemia in patients intolerant of ferrous sulphate. Methods: Twenty-three patients were recruited from gastroenterology clinics, of whom 15 had inflammatory bowel disease, a group often difficult to treat with oral iron. Patients with iron deficiency anaemia and documented intolerance to ferrous sulphate were given 3 months of treatment with ferric trimaltol. Results: Nineteen of 23 patients completed the treatment and anaemia was fully corrected in 14 of these, mean haemoglobin increased from 106 ± 15 to 126 ± 16 g/L, and there was a particularly low incidence of side-effects. Of 11 patients with inflammatory bowel disease who completed the study, nine fully corrected their anaemia. Conclusion: The results demonstrate that in patients intolerant of ferrous compounds, ferric trimaltol corrects iron deficiency and has a low incidence of side-effects.

New blood tests in inflammatory bowel disease Idiopathic inflammatory bowel disease (IBD) collectively describes ulcerative colitis (UC) and Crohn’s disease (CD). UC is characterised by inflammation limited to the colonic mucosa and collagen deposition only in the submucosa,1 whereas CD is characterised by transmural, granulomatous inflammation and thickening of the bowel wall as a result of thickening of the muscularis layers and transmural fibrosis. CD can affect any part of the gastrointestinal tract but most commonly affects the distal small intestine and proximal colon. In diseased bowel in CD there is excessive deposition of collagen, especially collagen types V, III, and I, throughout the mucosa, submucosa, and serosa. The resultant bowel strictures may require surgical resection.1–2 It has been suggested that fragments of collagen arising during its synthesis and breakdown and released into blood may be markers of tissue fibrosis and response to non-surgical treatment in CD.3 Disease activity is usually assessed from a combination of symptoms, endoscopy, radiology, isotope scanning, and laboratory findings, including C reactive protein (CRP) and albumin. Increasing interest is being shown in the extracellular matrix (ECM) and the gut epithelial basement membrane, which is a specialised form of ECM, in IBD, but there are so far only sparse data relating the serum concentrations of basement membrane components or other ECM serum markers to IBD. This is partially addressed in last month’s issue by Koutroubakis et al .4 In IBD, intestinal inflammation leads to mucosal ulceration and subsequent tissue repair with smooth muscle cell (SMC) proliferation and remodelling of the ECM. A major component of ECM is collagen, which, when present in excess, leads to tissue fibrosis. ECM undergoes constant turnover, with a balance between synthesis and breakdown of its components. The matrix metalloproteinase (MMP) enzymes, of which there are at …

Aims: To investigate the concentrations of bilirubin, bilirubin conjugates, phospholipid, and cholesterol in the gall bladder bile obtained at surgery from patients with and without cholesterol gallstones. Methods: Gall bladder bile was collected during surgery, by puncture, from 20 patients with gallstones undergoing routine cholecystectomy and from eight patients with normal liver blood tests. Concentrations of bilirubin, bilirubin conjugates, phospholipid, and cholesterol were measured using standard procedures. Results: The proportion of total bilirubin that was unconjugated was significantly higher in the bile from patients with stones than in bile from control patients, whether or not the bile from either group was saturated with cholesterol or not. Indeed, the mean concentration of cholesterol was significantly higher in control bile samples. Conclusion: The presence of stones was more closely related to the proportion of unconjugated bilirubin than to the degree of saturation of bile with cholesterol. Bilirubin and its metabolites probably play an important part in the formation of cholesterol gallstones.

The ability of erythrocytes to resist lipid peroxidation may be a useful marker of antioxidant status in alcoholic patients, in whom depletion of dietary antioxidants may combine with increased production of free radicals to produce liver damage. There are conflicting reports, however, on the resistance of erythrocytes from alcoholic patients to lipid peroxidation. This study examined the relation between the degree of alcohol induced liver disease and the resistance of erythrocytes to chemically induced lipid peroxidation, measuring lipid peroxidation as malondialdehyde production. Erythrocytes from alcoholic patients with Child's C cirrhosis had significantly increased resistance to lipid peroxidation compared with both controls (p < 0.001) and alcoholic patients with moderate liver disease (p < 0.001). There was no difference between alcoholic patients with moderate liver disease and controls. Increased resistance to free radical initiated lipid peroxidation in alcoholic patients is related to liver damage rather than to alcohol abuse alone. This could arise from changes in the lipid composition of the erythrocyte membranes resulting from abnormal liver function. Tests of antioxidant status based upon the resistance of erythrocytes to free radical stress in vitro may therefore be flawed when such changes in membrane lipid composition can occur.

Chronic alcohol consumption induces cytochrome P450IIE1, enabling habitual abusers to consume far greater quantities of alcohol than normal subjects. This pathway of metabolism leads to the production of free radical species, which cause tissue damage through peroxidation of cell membranes. Groups of Wistar rats of equal male: female ratio (n = 24) were fed alcohol by gavage twice daily to achieve a dosage of 15 g/kg body weight. Mean peak blood alcohol concentrations of 186 mg% were produced in males and 156 mg% in females. The animals were allowed free access to standard laboratory chow and water. Control animals were pair-fed to the alcoholic group and fed isocaloric glucose by gavage. Groups of animals were killed between 9 and 11 am on consecutive mornings, after nocturnal feeding, since it has previously been shown that fasting rapidly depletes hepatic glutathione concentrations. Hepatic glutathione was measured by a spectrophotometric enzymatic recycling procedure. As a marker of lipid peroxidation hepatic malonaldehyde (MDA) was measured by high performance liquid chromatography. Hepatic MDA was increased in the alcoholic group (p < 0.001), as was total hepatic glutathione (p < 0.0001). Plasma concentrations of alpha-tocopherol were increased in the alcoholic group, but ascorbic acid and superoxide dismutase values were not affected. No sex differences were detected. The increased MDA production in the alcohol group is strong evidence that lipid peroxidation is a mechanism of alcoholic tissue damage. The rise in hepatic glutathione may be an adaptive response to free radical production that protects the rat against tissue damage.

An aluminium (93 microM) sulphate solution freshly adjusted to pH 7.0 was perfused through the rat small bowel to mimic the reported physiological conditions that follow dietary aluminium ingestion. One third of this aluminium was taken up from the perfusate, but > 90% of this was then recovered from the intestinal mucus/mucosa and most (> 70%) from the distal third of the small bowel. The fresh perfusate was shown by ultrafiltration to contain largely particulate/colloidal aluminium-hydroxide, and this probably adhered to intestinal mucus which may be an important barrier to the gastrointestinal absorption of aluminium.

In the absence of exogenous (dietary) factors, there are five major determinants of mineral absorption: (a) degree of solubilisation in the stomach, (b) extent of hydrolysis/endogenous ligand interaction in the small bowel and lability of this new metal species; (c) transport through the mucus layer; (d) efficiency and mode of mucosal uptake which is partly dependent on (b), although some metals may be facilitated with active processes; (e) transport into blood which, for some minerals, is regulated by intra-mucosal and systemic factors. Addition of exogenous factors may either alter the luminal complex presented to the mucus/mucosa, or directly affect the permeability of the mucosa. Whether these effects increase or decrease absorption of the mineral depends on its normal mode and efficiency of uptake. Thus citrate increases the absorption of aluminium (normally poorly absorbed) but reduces the absorption of calcium (normally well absorbed). Finally, assessment of such effects requires the use of a validated model and should be considered in the context of real dietary situations.

In early hepatic fibrosis, increased amounts of type III collagen are deposited. Persistently high serum concentrations of aminoterminal type III procollagen propeptide (PIIIP) correlate with the activity of the fibrogenic process. Another index for the detection of fibrosis, the PGA index, combines the prothrombin time, gamma-glutamyl transpeptidase activity, and serum apolipoprotein A1 concentration (the latter falls with progressive fibrosis). We compared PIIIP measurements and PGA index in patients with various histological forms of alcoholic liver disease (104), primary biliary cirrhosis (38), and chronic B virus hepatitis (27), and in healthy age-matched controls (30). The ability of each test to identify correctly patients with fibrosis or cirrhosis was assessed with receiver operating curves. The PGA index was much higher in all groups of patients with alcoholic liver disease than in controls (p < 0.0001). PIIIP concentrations were also substantially higher than in controls (p < 0.05 for fatty liver, p < 0.0001 for all other groups), especially in the group with alcoholic hepatitis and cirrhosis. For the detection of cirrhosis the PGA was 91% sensitive and 81% specific and the PIIIP concentration was 94% sensitive and 81% specific. The two tests combined had 85% sensitivity, but 93% specificity. Among patients with primary biliary cirrhosis, both PGA index and PIIIP concentration correlated well with the severity of the disease, determined by the Mayo score (r = 0.72 and 0.66 respectively). The combined tests were 96% sensitive for the detection of fibrosis. All patients with chronic B virus hepatitis had raised PGA and PIIIP values in comparison with controls (p < 0.0001) but there were no differences between subgroups. Substantially raised PIIIP concentrations thus identify the subgroup of alcoholic patients with both hepatitis and cirrhosis. The combination of PGA index and PIIIP concentration may be useful for targeting treatment with antifibrotic drugs and to reduce the need for liver biopsy.

At low concentrations ethanol is metabolized largely by alcohol dehydrogenase to acetaldehyde, while at higher concentrations a microsomal ethanol oxidising system (MEOS) is involved, namely cytochrome P450 IIE1, which also probably generates free radical species. In hyperthyroidism hepatic glutathione stores are depleted and net superoxide anion production occurs. In contrast, in hypothyroidism hepatic glutathione may be increased and thus renders the liver less sensitive to alcohol generated free radical production. Steroid hormones inhibit lipid peroxidation. Sixty male Wistar rats either underwent thyroidectomy, adrenalectomy, or sham procedures. Twenty control animals were pair fed with thyroidectomized animals, whilst another twenty fed ad libitum. An intraperitoneal injection of alcohol (75 mmol/kg) was given 2.5 h prior to sacrifice to half the animals in each group, the remainder receiving saline. The total hepatic glutathione contents of the pair fed and the ad libitum groups were not different, but were significantly increased by thyroidectomy (p = < 0.001). This effect was significantly reduced by alcohol (p < 0.01). The sham procedures and dietary restrictions had no effect. The ethanol alone reduced total hepatic glutathione, but this only reached statistical significance in the thyroidectomized and sham-adrenalectomized groups. Hepatic malonaldehyde (MDA) levels were significantly reduced in the thyroidectomy group but alcohol had no effect on them. We conclude that hypothyroidism increased hepatic glutathione status, presumably by reducing radical production by enzyme systems, which would otherwise consume this important scavenger. Long term exposure to ethanol with induction of MEOS is probably required for it to generate toxic levels of free radical species.

To investigate the enterotrophic effects of bolus doses of long chain triglycerides, two groups of eight female Wistar rats were fed identical diets with 48.2% total calories as the essential fatty acid rich oil Efamol. To one group the oil was given in twice daily bolus doses by gavage, while for the other group the oil was mixed with the remainder of the feed and thus consumed over 24 hours. The animals were killed after 20 to 22 days. Bolus dosing significantly increased parameters of mucosal mass along the length of the small intestine in association with an increase in two hour accumulation of vincristine arrested metaphases in small intestinal crypts. In a second experiment, four replicate studies were carried out, each involving two groups of 12 rats respectively fed as described above. After 21 days one animal from each group was killed every two hours, providing regular plasma samples over 24 hours for measurement of gastrin, cholecystokinin, peptide tyrosine-tyrosine and enteroglucagon. Bolus dosing markedly enhanced release of peptide tyrosine-tyrosine and enteroglucagon, but not of gastrin or cholecystokinin. Thus, the enhanced enterotrophic effects of bolus doses of long chain triglycerides could be mediated by release of a distally located gut peptide, perhaps enteroglucagon.

Enprostil is a synthetic prostaglandin E2 analogue with gastric antisecretory and mucosal protective properties. We compared the effects of enprostil and ranitidine on the healing of gastric ulcers and the subsequent relapse rates over 6 months. Patients (N = 156) were recruited for a double-blind study from 12 centers in Europe; 71 were randomly assigned to oral treatment with 35 micrograms enprostil twice daily and 85 to 150 mg ranitidine twice daily for up to 8 weeks. Both groups were of similar demography; their healing rates were also similar. Cumulative intent-to-treat healing rates were at 4 weeks enprostil 48%, ranitidine 41%: at 6 weeks enprostil 65%, ranitidine 68%; and at 8 weeks enprostil 72%, ranitidine 80%. Of those patients who met all protocol criteria and completed treatment, and were endoscoped at the prescribed times, healing rates were at 4 weeks enprostil 55%, ranitidine 54%, at 6 weeks enprostil 75%, ranitidine 84%; and at 8 weeks enprostil 80%, ranitidine 90%. Relief of pain was rapid and similar in both groups. The incidence of adverse events was low and similar in the two groups. The treatment-free relapse rate at 6 months was enprostil 64%, ranitidine 49%; the median times to relapse were 169 and 203 days, respectively. Enprostil and ranitidine appear to be equally effective in healing gastric ulcers.

Pigmented cells, that contain inert, submicron-sized dietary particles, are a consistent feature of the base of human Peyer's patches (PP). We aimed (i) to phenotype these intestinal pigment cells (PC) in archival tissue specimens and (ii) to establish whether PC phenotype is altered in inflammatory conditions, especially Crohn's disease (CD).PCs contained within PP were identified by routine haematoxylin and eosin (HE) staining and dark field microscopy of archival ileal sections for: adenocarcinoma (n=16), colonic CD (n=23), non-CD colitis (n=10). Paraffin-embedded serial sections were graded for microscopic inflammation and then investigated immunohistochemically with antibodies against CD68, MAC387, CD14, CD11b, CD15, CD1a, S100, HLA-DR, CD86 and Cathepsin D. Analyses were by light and confocal microscopies.The majority of PCs were CD68 positive (circa 80%) with a minority (circa 20%) staining for MAC387. Microparticles were mainly identified within cathepsin D negative lysosomal compartments. Histological inflammatory grade and disease type had no influence on cell phenotype.The microparticle-containing PCs of the PP base are mainly mature macrophages (CD68) of low metabolic and immunological activity. There is no evidence of differential PC phenotype or activation in differing disease states, including CD.

The aims of this study were to determine, in peripheral blood mononuclear cells (PBMC), whether particulate antigen triggers (i) an amplified cell proliferative response compared to soluble antigen and (ii) a dysfunctional response in cells derived from patients with chronic inflammation and specifically in those with inflammatory bowel disease (IBD).Healthy volunteers (n = 17), inflammatory controls (n = 8) and patients with IBD (n = 17) were recruited from St Thomas' and Guys' Hospital, London, UK.Following optimisation of experimental conditions (0.1-10.0 mug/ml antigen), PBMC were stimulated with (i) 10.0 mug/ml recombinant soluble heat shock protein 65 (hsp 65) and (ii) 1.0 and 10.0 mug/ml hsp 65 conjugated to microparticles (0.5 mum diameter). PBMC proliferative responses were measured by (3)H-Thymidine incorporation at day 5 and results compared between groups using unpaired t-test.Conjugation to microparticles of low dose hsp 65 significantly increased overall proliferative responses by 2-11 fold compared to soluble antigen alone (p0.05). However, no specific PBMC proliferative dysregulation was noted in cells from subjects with IBD.Low dose antigen, in microparticulate form, leads to amplified cell proliferation in primary human cells, as showed previously in cell lines and animal studies. However there is no abnormal proliferative response in cells from subjects with IBD.

Studies aiming to define key cytokines in inflammatory bowel disease have been restricted to gene expression or protein quantitation but lack functional information on cytokine interactions. Some of the major cytokines that govern the extent and duration of the inflammatory process in ulcerative colitis (UC), appear to be interleukin 1 (IL-1), its natural inhibitor IL-1 receptor antagonist (IL-1ra) and transforming growth factor beta1 (TGF-beta 1). Indeed, as a predictor of inflammation, the mucosal status of IL-1, depicted as a ratio of IL-1ra/IL-1, has often been used.Using an IL-1 bioassay and specific anti-cytokine antibodies we have identified the functional role of these cytokines and their interactions in mucosal biopsy samples taken from patients with UC.Compared with control specimens, the secreted and tissue levels of IL-1 were consistently raised in UC samples. Levels of IL-1, rather than IL-1ra or the ratio of IL-1ra/IL-1, most closely mirrored the severity of inflammation. Using specific antibodies we showed that IL-1ra and TGF-beta 1 appear to modulate the degree of inflammation at different stages of the inflammatory process. Only in severely inflamed tissue, when IL-1 levels were high did IL-1ra inhibit IL-1-induced activity. In contrast, the levels of TGF-beta 1, and its effect in controlling inflammation, was most marked in mild but not severe UC.The functional roles of these cytokines in the inflammatory process can now be more carefully elucidated using a bioassay and specific neutralising antibodies.

Summary A 46 year old woman presented with the CREST variety of systemic sclerosis and occult gastrointestinal bleeding due to vascular malformations of her stomach. Partial gastrectomy cured her anaemia. In systemic sclerosis, visceral angiography should be performed early when initial investigations have been negative.

Castleman's lymphoma, a benign localized lymphoid hyperplasia, has been reported in association with POEMS syndrome, a multisystem reactive disorder that includes several skin manifestations. Benign reactive angioendotheliomatosis is a rare skin disorder that is associated with various systemic disorders. A patient with long-standing Castleman's lymphoma and POEMS syndrome also developed benign reactive angioendotheliomatosis.

BACKGROUND—Extracorporeal shockwave lithotripsy (ESWL) has been used since the mid-1980s to fragment bile duct stones which cannot be removed endoscopically. Early machines required general anaesthesia and immersion in a waterbath. AIMS—To investigate the effectiveness of the third generation Storz Modulith SL20 lithotriptor in fragmenting bile duct stones that could not be cleared by mechanical lithotripsy. METHODS—Eighty three patients with retained bile duct stones were treated. All patients received intravenous benzodiazepine sedation and pethidine analgesia. Stones were targeted by fluoroscopy following injection of contrast via a nasobiliary drain or T tube. Residual fragments were cleared at endoscopic retrograde cholangiopancreatography. RESULTS—Complete stone clearance was achieved in 69 (83%) patients and in 18 of 24 patients (75%) who required more than one ESWL treatment. Stone clearance was achieved in all nine patients (100%) with intrahepatic stones and also in nine patients (100%) referred following surgical exploration of the bile duct. Complications included six cases of cholangitis and one perinephric haematoma which resolved spontaneously. CONCLUSION—Using the Storz Modulith, 83% of refractory bile duct calculi were cleared with a low rate of complications. These results confirm that ESWL is an excellent alternative to surgery in those patients in whom endoscopic techniques have failed. Keywords: lithotripsy; bile duct calculi; extracorporeal lithotripsy

Background Soluble silica, a ubiquitous component of the diet, may be the natural ligand for dietary aluminum and may prevent its accumulation and toxicity in animals. However, previous studies on the inhibition of aluminum absorption and toxicity by soluble silica have produced conflicting results. We recently identified a soluble silica polymer, oligomeric silica, that has a much higher affinity for aluminum than does monomeric silica and that may be involved in the sequestration of aluminum. Objective By using (26)Al as a tracer, we investigated the effects of oligomeric and monomeric silica on the bioavailability of aluminum (study 1) and compared the availability of silicon from oligomeric and monomeric silica in the human gastrointestinal tract (study 2). Design In study 1, three healthy volunteers each ingested aluminum alone (control), aluminum with oligomeric silica (17 mg), and aluminum with monomeric silica (17 mg). In study 2, five healthy volunteers ingested both the oligomeric and monomeric forms of silica (34 mg). Serum and urine samples were analyzed for aluminum and silicon. Results Oligomeric silica reduced the availability of aluminum by 67% (P = 0.01) compared with the control, whereas monomeric silica had no effect (P = 0.40). Monomeric silica was readily taken up from the gastrointestinal tract and then excreted in urine (53%), whereas oligomeric silica was not detectably absorbed or excreted. Conclusions The oligomeric, high-aluminum-affinity form of soluble silica reduces aluminum availability from the human gastrointestinal tract. Its potential role in the amelioration of aluminum toxicity in other biological systems requires attention.

Various specific and non-specific environmental factors have been associated with the induction and/or exacerbation of disease activity in patients with Crohn's disease and ulcerative colitis. One such factor is the potential role of ingested ultrafine particles. In fact, based on a Western diet, recent data suggest that more than 10(12)ultrafine particles are ingested per person every day. These microparticles have been considered inert although they adsorb endogenous constituents of the intestinal lumen and are taken up by human intestinal lymphoid aggregates. Based on these observations, we determined whether one such dietary microparticle, titanium dioxide (TiO(2)), alters intestinal cell responsiveness to lipopolysaccharide (LPS) using colonic biopsy specimens from 28 patients with ulcerative colitis, 21 with Crohn's disease, and 36 healthy controls. These samples, as well as peripheral blood mononuclear cells when available, were incubated alone (control), or with either (a) LPS (1-2,000 ng/ml), (b) TiO(2)(5 microg/ml) or (c) LPS (1 ng/ml) adsorbed to TiO(2)(5 microg/ml). In each case, the levels of interleukin 1 (IL-1) produced in these assays were quantitated by bioassay and by ELISA. Interestingly, there was dramatic stimulation of peripheral blood mononuclear cells using the TiO(2)-LPS conjugate, with values 30-60-fold above controls and only minor stimulation with LPS or TiO(2)alone. In intestinal organ cultures there was no increase in IL-1 secretion when challenged with TiO(2)alone or with up to 2,000 ng/ml LPS. However, the TiO(2)-LPS conjugate produced a two-to-three-fold, significant increase in the intestinal secretion of IL-1. Our data demonstrate that ultrafine dietary particles are not immunologically inert and may be important adjuncts in overcoming normal gut cell hyporesponsiveness to endogenous luminal molecules. This may be particularly relevant to patients with inflammatory bowel disease where there is abnormal intestinal permeability.

The absorption and competition kinetics of the essential fatty acids (EFAs), linoleic acid (LA), alpha-linolenic acid (alphaLnA) and arachidonic acid (AA) in vivo were studied in the perfused rat jejunum. Uptake of each EFA on its own followed saturable kinetics at low luminal concentrations, suggesting a facilitative transport process, the affinity of which increased with chain length and degree of unsaturation. Absorption of one EFA was enhanced by low, whilst competitively inhibited by high, concentrations of a second EFA. Whereas LA and alphaLnA each interfered with the absorption of one another, both had little effect on AA. There was a strong inverse correlation between the relative unsaturation of an EFA and the change in Km of its absorption observed upon inhibition with another EFA. Overall, the results indicated a specific absorptive mechanism, probably involving a transport protein, the affinity of which increased with the degree of unsaturation of the EFA.

Winged scapula Not all shoulder pain arises from the shoulder joint. A meticulous history and thorough clinical examination is necessary to avoid missing an otherwise obvious diagnosis.

Urinary analysis of trace metals forms a significant role in clinical chemistry, but the optimal preparation and analysis of urine samples has not been investigated. Human urine is generally supersaturated with dissolved solids. Therefore, samples often precipitate following collection. X-ray microanalysis showed that this precipitate was predominantly rich in calcium and phosphorus but could include some trace metals from urine, potentially lowering their concentrations in solution. Hence, the precipitate must be fully redissolved for accurate analysis of trace metals in urine. Methods are emphasized for the best collection and preparation of urine samples for subsequent trace metal analysis; in this work inductively coupled plasma optical emission spectrometry (ICPOES) was used for the analysis of aluminium. For optimal accuracy, peak profiles were collected over 396.147 nm-396.157 nm. Urinary aluminium levels were investigated from 10 healthy volunteers and concentrations were obtained using either aqueous, pooled or individual urine-based standard curves. Since urine has a highly variable matrix, individual sample-based standards, which are unique to that particular sample, gave the most accurate results. However, where sample size is small or sample numbers are unfeasibly large, pooled sample-based standards give good approximations to within 15% and, with appropriate validation, other elements as internal standards could also be used for approximations. Aqueous standards should be avoided. Spike-recovery experiments confirmed these data since individual sample based standards showed optimal recovery [99.3 (4.4)%], while pooled sample-based standards were a close proxy [101.6 (9.2)%] but aqueous standards were inappropriate [137.4 (12.8)%]. Postprandial urinary aluminium levels of the 10 volunteers were [7.2 (3.7)μg/L] after analysis using individual sample-based standard curves.

Aluminum has become a dietary toxin in modern times but its mechanism of absorption is poorly understood. After ingestion, the systemic transfer of aluminum is small but it is greatly affected by the coingestion of certain dietary agents, such as citrate, that complex with the metal in the intestinal lumen or transiently alter the permeability of the mucosa. Here, mechanisms of aluminum absorption were studied by using freshly prepared aluminum hydroxide and aluminum citrate. Everted sacs of rat gut were used to investigate the site of absorption, effect of chemical charge on absorption of aluminum citrate, and presence of active or passive absorption with use of the metabolic inhibitor ouabain. Absorption was biphasic with a large tissue uptake that was consistent with adhesion to mucus-mucosal surface but little tissue transport, which was consistent with passive paracellular permeation. Citrate reduced the uptake-transport ratio both by competing with the mucosal uptake and by increasing mucus-mucosal permeation but not by affecting the charge of the luminal aluminum species. Despite the potential for hydroxypolymerization of aluminum at intestinal pH, the small bowel and colon absorbed aluminum passively and paracellularly but the stomach did not. The predominantly proximal absorption of aluminum observed in vivo is a reflection of the proximal absorption, and therefore removal, of dietary constituents (eg, citrate) that enhance mucosal permeation of aluminum. The colon should be investigated further as a site of significant paracellular permeability.

A 71 year old lady with Sezary syndrome presented with chronic diarrhoea and cramping abdominal pains. A small bowel meal x ray examination showed two mid-ileal strictures. At laparotomy the small intestine was found to be sub-acutely obstructed and resection of a 15 cm ileal stricture and stricturoplasty of a second, 10 cm stricture were performed. Histological examination of the stricture revealed a mesenteric vasculitis with secondary ischaemic changes in the small bowel wall. Mesenteric vasculitis causing small bowel stricture may be associated with Sezary syndrome.

Macrophages at the base of human gut associated lymphoid tissue (GALT), become loaded early in life with dark granular pigment that is rich in aluminium, silicon, and titanium. The molecular characteristics, intracellular distribution, and source of this pigment is described. Laser scanning and electron microscopy showed that pigmented macrophages were often closely related to collagen fibres and plasma cells in GALT of both small and large intestine and contained numerous phagolysosomes, previously described as granules, that are rich in electron dense submicron sized particles. Morphological assessment, x ray microanalysis, and image electron energy loss spectroscopy showed three distinct types of microparticle: type I - spheres of titanium dioxide, 100-200 nm diameter, characterised as the synthetic food-additive polymorph anatase; type II - aluminosilicates, < 100-400 nm in length, generally of flaky appearance, often with adsorbed surface iron, and mostly characteristic of the natural clay mineral kaolinite; and type III - mixed environmental silicates without aluminium, 100-700 nm in length and of variable morphology. Thus, this cellular pigment that is partly derived from food additives and partly from the environment is composed of inert inorganic microparticles and loaded into phagolysosomes of macrophages within the GALT of all human subjects. These observations suggest that the pathogenicity of this pigment should be further investigated since, in susceptible individuals, the same intracellular distribution of these three types of submicron particle causes chronic latent granulomatous inflammation.

Omeprazole causes irreversible inhibition of the hydrogen/potassium adenosine triphosphatase enzyme, leading to a marked reduction in both acid secretion and volume of gastric juice. Reported side-effects include nausea, vomiting, diarrhoea, constipation, and headache. We report the development of dry mouth during omeprazole therapy.We have identified six patients taking omeprazole for more than 6 weeks who complained of a dry mouth. Salivary production was measured as whole salivary flow produced over a 10-min period spat into a collecting vessel and as 5% citric acid-stimulated parotid salivary flow collected with a Lashley cup device placed over the parotid duct. Flow rates were evaluated both during and after cessation of treatment. Saliva produced was then cultured for microbes.Four of the six had subnormal parotid or whole salivary flow rates on treatment that recovered after stopping treatment. The increase after treatment was marked in four. Significant amounts of Candida albicans grew from the saliva of the three patients with the lowest salivary flows; one saliva also grew Staphylococcus aureus.Salivary flow is reduced in some patients treated with omeprazole, returning to normal after cessation of treatment. This reduction may predispose to opportunistic infection, particularly in the edentulous.

A 52 year old man with chronic pancreatitis presented with recurrent upper gastrointestinal bleeding. Gastroscopy was normal, but visceral angiography suggested that there were gastric varices. Despite treatment with propranolol he had further episodes of bleeding and so underwent splenectomy to decompress the gastric varices. When the spleen was removed, however, an inflammatory mass in the head of the pancreas adherent to the posterior gastric wall was noted. Within it the splenic artery was visible and communicated with the gastric lumen through a small opening in the gastric wall. The artery was ligated and the patient has since had no further bleeding. Thus, chronic pancreatitis should be considered as a cause of recurrent upper gastro-intestinal bleeding, especially when gastroscopy is normal.

The in vitro speciation of aluminium (Al) in black tea infusion (pH 4.8) was assessed using 3000, 10,000 and 30,000 Da cut-off ultrafilters, and the effect of adding human gastric juice (pH 2.3) and then raising the pH to 6.5 were also studied. 78% Al in the tea infusion passed through the 3000-Da ultrafilter; this percentage increased to more than 90% with the addition of gastric juice at pH 2.3, but then reduced to approximately 5% when the incubate was adjusted to pH 6.5. The breakdown of tea-derived polyphenols to low molecular weight phenols in vivo was measured using high-resolution 1H nuclear magnetic resonance spectroscopic analysis of ileostomy effluent, but there was no evidence of low molecular weight breakdown products from the polyphenols of ingested tea in this effluent. These results suggest that only a small proportion of Al in tea is potentially available for absorption throughout the small bowel. It may be misleading to estimate systemic Al absorption from tea drinking simply from total urinary aluminium excretion as has been done previously.

To compare the enterotrophic effects of different triglycerides, five groups of eight rats were fed mixed diets giving 50% of calories as oils rich in either essential fatty acids (EFA), alpha-linolenic acid, fully saturated fatty acids, oleic acid, or medium chain fatty acids. After 21-24 days there were no significant differences between the groups in overall small intestinal whole gut weight, mucosal weight, or mucosal DNA; overall mucosal protein showed slight variation (p < 0.05) that was compatible with differences in food intake between the groups. However, long chain triglycerides (LCT) and medium chain triglycerides (MCT) differed in their regional effects on cell proliferation; all four LCT rich diets increased mucosal mass and cell proliferation maximally in the mid small intestine, while MCT had their greatest effect proximally. Subsequently, two groups of eight rats were fed diets in which EFA or MCT were given as twice daily boluses (29% of dietary calories) for 20 to 23 days and compared with a third group of eight rats receiving a glucose rich, low fat diet. EFA and MCT boluses increased the overall parameters of small intestinal mucosal mass and for both oils the effects were now maximal in the mid small intestine. Thus different triglycerides have similar effects on overall small intestinal mucosal mass, but MCT differ from LCT in their regional effects on mucosal cell proliferation when they are given in mixed diets, although not when given as boluses.

The effects of the cytokine tumour necrosis factor alpha and the calcium ionophore A23187 upon CD11a, CD11b, CD11c and CD18 leucocyte membrane expression was analysed in whole blood using monoclonal antibodies and flow cytometry. Both agents significantly increased the density of CD11b/CD18 membrane expression on monocytes and granulocytes, but had no effects on adhesion molecule expression on lymphocytes. The effects of sulphasalazine, 5-aminosalicylic acid (5-ASA) and sulphapyridine upon adhesion molecule upregulation were then examined; 10(-3) and 10(-4) M sulphasalazine and 5-ASA significantly reduced tumour necrosis factor alpha induced CD11b/CD18 upregulation on monocytes and granulocytes but had no effects upon A23187 mediated upregulation. Sulphapyridine was inactive. These results suggest that sulphasalazine and 5-ASA may interfere with mechanisms of leucocyte recruitment in inflammatory bowel disease.

The concentrations of essential metal cations in gastric juice, collected at endoscopy from 17 normal patients and 11 with peptic ulcer disease, were determined by inductively coupled plasma emission spectrometry. Mean fasting levels in normal gastric juice were as follows: sodium 47.7 mM, potassium 14.6 mM, calcium 0.8 mM, magnesium 0.36 mM, zinc 13 microM, and copper 1.2 microM: these did not differ significantly in health or disease. Because samples were contaminated with iron, the concentration of this metal was only estimated (ca 3.5 microM in normal subjects), and this secretion could represent a significant proportion of the daily loss of endogenous iron. The pH of gastric juice predicted the concentrations of magnesium and calcium, but not copper or zinc, in the juice. It is concluded that previously reported values for trace metals in gastric juice have been incorrect and that the very low amounts secreted in the gastric juice will not interfere with the absorption of other trace metals from the diet. In contrast, the concentrations of macroelements in gastric juice may be sufficient to stimulate the absorption of trace metals from the gut.

1. The expression of leucocyte antigens CD11/CD18 and complement receptor 1 was studied on the circulating leucocytes of 13 patients with inflammatory bowel disease and 13 age- and sex-matched healthy control subjects. 2. Monoclonal antibodies against CD11/CD18 and complement receptor 1 were added to leucocyte suspensions from patients and control subjects. Antibody binding was detected using a fluorescein-conjugated rabbit anti-mouse antibody and flow cytometry. The proportions of lymphocytes, monocytes and granulocytes expressing these molecules and the density of antigen expression, measured as mean fluorescence intensity, were determined. 3. There were no differences between patients and control subjects in the mean fluorescence intensity of antibody staining of surface molecules or in the proportion of cells expressing each molecule for any cell type. Analysis of subgroups of patients according to disease type, severity or treatment also showed no difference compared with control subjects. 4. We conclude that failure to identify a population of circulating leucocytes whose adhesion molecules or complement receptors are upregulated may arise because cells are only activated locally within the gut vasculature. Alternatively, structural changes in these molecules, rather than an increase in their number or the expression of other surface glycoproteins, may be more important in mediating adhesive interactions in inflammatory bowel disease.

This study investigated how substitution of long chain triglycerides for glucose in a mixed diet affects the overall small intestinal mucosal mass and the distribution of mucosal mass and cell proliferation along the small intestine. Four groups of eight female Wistar rats (180-200 g) were isocalorically fed mixed diets containing the essential fatty acid rich oil Efamol substituted for glucose at concentrations of 1.2%, 10%, 25%, and 50% total calories for 20 to 23 days. The small intestine was divided into three equal length segments and whole gut weights, mucosal weights, protein and DNA determined. Cell proliferation was estimated from the two hour accumulation of vincristine arrested metaphases in microdissected crypts at points 0%, 17%, 33%, 50%, 66%, and 100% small intestinal length. There were no differences between groups in parameters of overall small intestinal or distal segment mucosal mass. With increasing levels of fat, however, there was a significant trend for the mucosal mass of the proximal segment to fall and that of the middle segment to rise. The pattern of two hour metaphase accumulation reflected these changes. These regional changes in mucosal mass and cell proliferation may reflect differences in the sites of absorption of fat and glucose.

The effects of sulphasalazine, 5-aminosalicylic acid (5-ASA), and sulphapyridine on peroxidation of red cell membrane lipids, measured as malondialdehyde production, were assessed. Sulphasalazine and 5-ASA, at concentrations of 10(-5)-10(-3) M significantly inhibit lipid peroxidation, suggesting an antioxidant action that may explain the efficacy of these drugs in treating inflammatory bowel disease. Sulphapyridine, which is not effective in inflammatory bowel disease inhibited malondialdehyde production at a concentration of 10(-3) M only.

Breast-fed infants in Bangladeshi villages were weighed at 1, 2, 6, 9 and 12 months. The concentrations of zinc and copper in the breast milk were measured and the daily intake of these elements calculated. Breast milk Zn concentration decreased over the year but was comparable with that found in developed countries. The calculated daily intake decreased from 17·7 to 8·0 μmol (10–30% of recommended dietary allowances (RDA); National Academy of Sciences, 1980). Breast milk Cu concentration also fell over the year and was lower than that reported from developed countries. Calculated daily Cu intake was 1·95–2·63 μmol (RDA 7·81–15·63 μmol). Deficiencies of trace elements may therefore be a problem in poorly nourished communities where breast feeding is continued for several years with only small amounts of additional food. Breast milk may not be adequate as the only source of infant nutrition after the first few months of life in Bangladesh.