(Gut 1998;42:42-46)

Because cytomegalovirus (CMV) is an important opportunistic infection after liver transplant, we conducted a prospective study to see if the same applied to human herpesviruses (HHV)-6 and -7. We used polymerase chain reaction (PCR) methods optimised to detect active, not latent, infection and studied patients not receiving antiviral prophylaxis for CMV. Post-transplant, 536 blood samples were tested by PCR (median 7; range 4-50). Active infection with CMV was detected in 28/60 (47%), HHV-6 in 19/60 (32%), and HHV-7 in 29/60 (48%) of patients. The PCR-positive samples were tested by quantitative-competitive PCR to measure the virus load of each betaherpesvirus. The median peak virus load for CMV was significantly greater than that for HHV-6 or HHV-7. Detailed clinicopathological analyses for the whole population showed that CMV and HHV-6 were each significantly associated with biopsy-proven graft rejection. Individual case histories suggested that HHV-6 and HHV-7 may be the cause of some episodes of hepatitis and pyrexia. It is concluded that HHV-6 is a previously unrecognized contributor to the morbidity of liver transplantation, that HHV-7 may also be important and that both viruses should be included in the differential diagnosis of graft dysfunction.

Background-L-Arginine has been shown to induce fluid secretion in human jejunum. Nitric oxide, a derivative of L-arginne is thought to have an important role as an intestinal secretagogue. Aim-To determine the effect of Larginine and the nitric oxide synthase inhibitor, nitro L-arginine methyl ester (L-NAME), on fluid and electrolyte movement in rat jejunum. Methods-A 25 cm segment ofrat jejunum was perfused in situ with iso-osmotic solutions containing either (1) saline, (2) D-arginine 20, (3) L-arginine 20, (4) L-NAME 0-1, 1, or 20 mmol/l, or (5) a combination of L-arginine 20 and L-NAME 0.1, 1, or 20 mmol/l. In further groups the effect of a subcutaneous injection of L-NAME 100 mglkg was examined in rats pretreated with either Dor L-arginine 500 mg/kg. Results-L-Arginine, unlike D-arginine, induced fluid secretion despite being better absorbed (mean -7 3 v 17-0 ,l/min/ g; p<001). L-NAME at 0.1 mmol/l had no effect on basal fluid movement but reversed L-arginine induced secretion (7.8; p<005). L-NAME at 1 and 20 mmol/l induced fluid secretion (-15.4 and -28-4, respectively), which was enhanced by the addition of L-argilnlne (-30.0 and -41-0, respectively; both p<005). A subcutaneous injection of L-NAME resulted in marked fluid secretion (-39.9) and histological evidence of intestinal ischaemia. These changes were attenuated or reversed by pretreatment with subcutaneous L-but not D-arginine. Conclusions-L-Arginine induces intestinal fluid secretion through production of nitric oxide. There is a delicate balance between the effect of nitric oxide as a secretagogue and its effect on maintaining blood flow and thus preventing intestinal ischaemia. (Gut 1996; 39: 539-544) Keywords: arginine, nitric oxide, L-NAME, intestinal transport, bowel ischaemia.Actively transported sugars and most amino acids enhance small intestinal absorption of water and electrolytes.l`However, L-arginine (L-Arg), unlike other amino acids, has been shown by us and others to induce water secretion when perfused in human jejunum.' 5 A satisfactory explanation has never been put forward to explain this phenomenon, though it has been suggested that L-Arg induced secretion by a local effect that could be inhibited by the calmodulin antagonist chlorpromazine.5Over the past few years L-Arg has been found to be the precursor of the free radical nitric oxide (NO), which has an important role as a mediator of neural, cardiovascular, and gastrointestinal function.`8 Nitric oxide is derived from the guanidino terminal of L-Arg by the action of the stereospecific enzyme nitric oxide synthase (NOS) which, in the gut, is present in the myenteric plexus9 10 and submucosal arterioles and venules."' 12 In addition, it has been shown that NO could be produced by enterocytes through both the constitutive and the inducible NOS." In vitro studies have unveiled a role for NO as a secretagogue in the ileum14 '5 and colon, [16][17][18] and in vivo studies have suggested a possible role for NO in the laxative action of castor oil,"9 magnesium sulphat...

Background:5‐hydroxytryptamine type 3 receptor antagonists have been shown to reduce fluid and electrolyte secretion or promote absorption in experimental models of small intestinal secretion. The aim of this study was to compare the effects of a single dose (4 mg) of the 5‐hydroxytryptamine type 3 receptor antagonist alosetron and placebo on jejunal fluid and electrolyte movement in humans under basal conditions (n=7) and following cholera toxin‐induced secretion (n=5) in a randomized, double‐blind, crossover design over two separate study periods.Methods:One hour after oral alosetron or placebo, jejunal intubation was performed. A 30 cm segment of jejunum, isolated by two occluding balloons, was exposed to 15 μg of purified cholera toxin for 2 h prior to triple lumen perfusion with a plasma electrolyte solution containing []> 14C]‐polyethylene glycol as a non‐absorbable volume marker. In the basal study, intestinal perfusion was performed without exposure to cholera toxin. Collection and analysis of the effluent from the jejunal segment allowed fluid and electrolyte movement to be calculated.Results:Alosetron treatment increased basal jejunal fluid absorption (median 5.1 mL/cm/h [interquartile range 4.2 to 7.1] compared with placebo (3.8 [3.6 to 4.3] P=0.028, two sided Wilcoxon matched pairs signed rank test)). However, following establishment of a secretory state by cholera toxin, alosetron failed to significantly promote absorption or reduce secretion (0.3 [−1.2 to 1.2] compared to placebo (−4.3 [−7.7 to −1.3] P=0.14)). Adverse events during the study, which included anorexia, nausea, dizziness and loose bowel movements, were not considered to be clinically important. There were no clinically significant changes in laboratory parameters.Conclusion:The 5‐hydroxytyptamine type 3 receptor antagonist, alosetron increased basal fluid absorption in normal human small intestine but failed to have a beneficial effect in cholera toxin‐induced secretion.

Background-Cholera toxin produces intestinal secretion by activation of the adenylate cyclase complex. However animal studies have shown 5-hydroxytryptamine may be released after exposure to cholera toxin, and thereby contribute to the secretory state.

Using native fluorescence detection, 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA) and tryptophan were resolved from themselves and other naturally occurring compounds using reversed-phase HPLC within 5 min. Deproteinated platelet-poor plasma (PPP) and crude diluted urine were injected directly into the chromatograph. Careful selection of the HPLC column is important and various octadecyl silica (ODS) and base deactivated silic (BDS) columns were evaluated. Pre-treatment of an ODS column with tetrabutylammonium ions gave good selectivity. Between pH 5 and 6 the compounds were well resolved from each other. The limit of quantitative detection of 5-HT and 5-HIAA was 3.5 nmol/L. The overall chromatogram obtained using native fluorescence is cleaner than that obtained with the more commonly employed electrochemical (EC) systems although the chromatography is effectively the same. For analysis of 5-HT in plasma, collection in EDTA was more efficient than lithium heparin. Plasma 5-HT in healthy volunteers was mean 61 (SD = +/- 73) nmol/L, n = 20; urine 5-HIAA gave mean 28.95 (SD = +/- 0.98) mumol/L, (n = 12). Whole blood 5-HT analysis is unreliable in comparison with platelet-poor plasma.

Background-The antineoplastic drug cisplatin has been widely used for the treatment of cancer in humans but its use has been limited by vomiting and diarrhoea. Cisplatin releases 5-hydroxytryptamine into the gut which is thought to be the major mediator of cisplatin induced vomiting. Aim-To determine whether cisplatin affects fluid and electrolyte transport in rat jejunum and whether this change can be modulated by the 5-hydroxytryptamine 3 receptor antagonist, ondansetron. Methods-Jejunal perfusion in rats in vivo was performed one hour after intraperitoneal cisplatin (5 and 10 mg/kg) administration. The eVect of pretreatment with subcutaneous ondansetron 300 µg/kg was investigated. Results-Median net fluid absorption after cisplatin 10 mg/kg (67 µl/min/g dry intestinal weight (interquartile range 46 to 100); n = 15) was reduced compared with controls (120 (107 to 151) µl/min/g; n = 13; p<0.001). Ondansetron reversed the impairment of jejunal fluid absorption produced by cisplatin to normal (161 (130 to 176) µl/min/g; n = 11; p<0.001). Electrolyte movement paralleled fluid movement. Jejunal histological examination of sections from cisplatin treated animals showed villus damage, which was not prevented by pretreatment with ondansetron. Conclusion-These findings suggest that diarrhoea during cisplatin therapy may be due to altered fluid transport in the small bowel. The reversal of fluid transport to normal in the presence of a 5-hydroxytryptamine 3 receptor antagonist suggests that 5-hydroxytryptamine is a local mediator in the small intestine. (Gut 1999;44:174-179) Keywords: cisplatin; 5-hydroxytryptamine; rat; ondansetron; small intestine; fluid transportThe antineoplastic drug cisplatin (cisdiammine dichloroplatinum II) has been shown to be highly eVective against a wide variety of cancers. Its use was initially limited by severe nausea and emesis, and 67% of patients also suVered from diarrhoea.1 Emesis was partially controlled by high dose metoclopramide when its eVect was attributed to 5-hydroxytryptamine 3 (5-HT 3 ) receptor antagonism.2 Since then other more selective 5-HT 3 receptor antagonists have been developed, such as ondansetron and granisetron, which have been shown to reduce early cisplatin induced emesis considerably. [3][4][5] 5-HT has been implicated as a cause of diarrhoea in patients with carcinoid syndrome, and treatment with the 5-HT 3 receptor antagonist tropisetron has been shown to reduce the diarrhoea.6 Triple lumen perfusion in such patients has shown jejunal secretion of fluid, which could also be reduced by the 5-HT 1 receptor antagonist methysergide. 7 In addition, 5-HT has been shown to be released during cholera toxin induced secretion in man and rats, 8 9 and 5-HT 2 and 5-HT 3 receptor antagonism reverses cholera toxin induced secretion in rats and humans.10-12 5-HT is also released in morphine withdrawal induced intestinal secretion.13 After treatment with high dose cisplatin, increased 5-hydroxyindoleacetic acid (5-HIAA) was found in the urine of cancer patients 4...

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