Impaired bioavailability of vitamin A in adults and children with persistent diarrhoea in Zambia.

BACKGROUND: We have previously demonstrated a strong relationship between low serum retinol concentration and mortality in Zambian AIDS patients with diarrhoea, but were unable to detect any benefit from oral micronutrient supplementation. AIM: To test the hypothesis that this is related to impaired availability of vitamin A, we analysed serum retinol concentration changes over 6 h following oral mega-dose therapy (60, 120 or 180 mg retinol). METHODS: Twenty-four men without diarrhoea, 15 adults with persistent diarrhoea and 11 children (six girls, five boys) with persistent diarrhoea were studied. RESULTS: Men with persistent diarrhoea had lower baseline serum retinol concentrations (median 0.39 micromol/L, interquartile range 0.21-0.56) than controls (median 1.16 micromol/L, interquartile range 0.84-1.47; P=0.0003). After 60 mg retinol, the rise in serum retinol in HIV seropositive controls (median 0.63 micromol/L, interquartile range 0.35-0.77) did not differ significantly from that observed in HIV seronegative controls (median 0.35 micromol/L, interquartile range - 0.04-0.56; P=0.20). Increasing the dose to 120 mg or 180 mg retinol did not enhance the increase in serum retinol concentration. The increase in serum retinol was less in adults with persistent diarrhoea (median 0.25 micromol/L, interquartile range 0.04-0.35) and in children (median 0.11 micromol/L, interquartile range 0.04-0.46) than in men without diarrhoea (median 0.44 micromol/L, interquartile range 0.26-0.74; P=0.03). Adults and children with diarrhoea had greater losses of retinol in urine over a 24-h period than controls, but less than 1% of the ingested dose was excreted. CONCLUSIONS: These results suggest that persistent diarrhoea in this population is associated with reduced bioavailability of retinol. Further work is required to determine the metabolic fate of therapeutic doses of retinol and to determine appropriate replacement strategies for HIV infected individuals.

Role of hypothalamic neuropeptide Y and orexigenic peptides in anorexia associated with experimental colitis in the rat.

Neuropeptide Y (NPY) is thought to play a crucial role in the normal hypothalamic response to starvation. After a period of food restriction, increased release of NPY induces hunger and hyperphagia, and helps to restore body weight to its set point. Persistent anorexia in rats with experimental colitis implies failure of this adaptive feeding response. In vivo NPY release and regional hypothalamic NPY concentrations were measured in rats with trinitrobenzenesulphonic acid (TNBS)-induced colitis, healthy controls and animals pair-fed to match the food intake of the colitic group. Food intake in the colitic group was assessed after administration of NPY and two other potent orexigenic peptides: melanin-concentrating hormone (MCH) and hypocretin (orexin-A). Food intake was decreased by 30-80% below control values for 5 days in the colitic rats. In both the pair-fed and colitic groups, release of NPY in the paraventricular nucleus was significantly increased compared with free-feeding controls. Intraventricular or intrahypothalamic administration of NPY, MCH or hypocretin elicited a feeding response in healthy controls, but not in the colitic group. In summary, animals with TNBS-colitis and anorexia show an appropriate increase in hypothalamic NPYergic activity. However, the failure of NPY and other orexigenic peptides to increase feeding in the colitic group indicates suppression of feeding, either by inhibition of a common downstream hypothalamic neuronal pathway or by induction of one or more potent anorexigenic agents.

Growth failure occurs through a decrease in insulin-like growth factor 1 which is independent of undernutrition in a rat model of colitis.

BACKGROUND: Linear growth retardation is a frequent complication of inflammatory bowel disease in children. The precise mechanisms causing growth failure are not known. AIMS: To determine the relative contribution of reduced calorie intake and inflammation to linear growth delay and to determine the effect of inflammation on the hypothalamic-pituitary-growth axis. METHODS: Linear growth was assessed in prepubertal rats with trinitrobenzenesulphonic acid (TNBS) induced colitis, in healthy free feeding controls, and in a pair-fed group (i.e. healthy animals whose daily food intake was matched to the colitic group thereby distinguishing between the effects of undernutrition and inflammation). RESULTS: Changes in length over five days in the TNBS colitis and pair-fed groups were 30% and 56%, respectively, of healthy free feeding controls. Linear growth was significantly reduced in the colitic group compared with the pair-fed group. Nutritional supplementation in the colitic group increased weight gain to control values but did not completely reverse the growth deficit. Plasma interleukin 6 (IL-6) concentrations were sixfold higher in the colitic group compared with controls. Plasma concentrations of insulin-like growth factor 1 (IGF-1) but not growth hormone (GH) were significantly lower in the colitic compared with the pair-fed group. Administration of IGF-1 to the colitic group increased plasma IGF-1 concentrations and linear growth by approximately 44-60%. CONCLUSIONS: It seems likely that approximately 30-40% of linear growth impairment in experimental colitis occurs as a direct result of the inflammatory process which is independent of undernutrition. Inflammation acts principally at the hepatocyte/IGF-1 level to impair linear growth. Optimal growth in intestinal inflammation may only be achieved by a combination of nutritional intervention and anticytokine treatment.

The role of medial hypothalamic serotonin in the suppression of feeding in a rat model of colitis.

BACKGROUND & AIMS: Experimental colitis is associated with anorexia that is attenuated by treatment with an interleukin (IL)-1 receptor antagonist. Serotonin (5-hydroxytryptamine [5-HT]) is a potent inhibitor of feeding, and its release from the hypothalamus is stimulated by IL-1. We have tested the hypotheses that anorexia associated with experimental colitis results from increased activity of hypothalamic 5-HT neurons and that the increase in activity occurs secondary to an increase in availability of tryptophan, the precursor of 5-HT. METHODS: In vivo 5-HT release and regional hypothalamic 5-HT and tryptophan concentrations were measured in rats with 2,4,6,-trinitrobenzene sulfonic acid (TNBS)-induced colitis, healthy controls, and animals pair-fed to match the food intake of the colitic group. Food intake in the colitic group was assessed after depletion of brain 5-HT by p-chlorophenylalanine (PCPA). RESULTS: In the colitic group, release of 5-HT from the hypothalamic paraventricular nucleus (PVN) was 3-fold (P = 0.01) and 14-fold (P < 0.001) higher than in control and pair-fed groups, respectively. Concentrations of tryptophan were similar in each group in all hypothalamic regions. Food intake was significantly increased in the colitic group after PCPA treatment but was not restored to control values. CONCLUSIONS: In animals with TNBS-induced colitis, 5-HT release from the PVN is increased. The increase in food intake after depletion of brain 5-HT suggests that hypothalamic 5-HT contributes to anorexia but is not the only mediator. Increased 5-HT release in the colitic group was not driven by increased precursor availability.

Micronutrient supplementation in the AIDS diarrhoea-wasting syndrome in Zambia: a randomized controlled trial.

OBJECTIVE: As HIV has spread through sub-Saharan Africa, persistent diarrhoea has emerged as a major problem in hospitals and in the community in severely affected areas. We have previously demonstrated that antiprotozoal therapy with albendazole reduces diarrhoea in AIDS patients in urban Zambia. This trial was designed to test the hypothesis that the clinical response to albendazole might be improved by oral micronutrient supplementation. DESIGN: Randomized, placebo-controlled trial. SETTING: Home care service of Ndola Central Hospital, Zambia. PATIENTS: HIV-seropositive patients with persistent diarrhoea. INTERVENTION: Patients were randomized to albendazole plus vitamins A, C and E, selenium and zinc orally or albendazole plus placebo, for 2 weeks. MAIN OUTCOME MEASURES: Time with diarrhoea following completion of treatment; mortality; adverse events. RESULTS: Serum vitamin A and E concentrations before treatment were powerful predictors of early mortality, but supplementation did not reduce time with diarrhoea or mortality during the first month, even after taking into account initial vitamin A or E concentrations, CD4 cell count or clinical markers of illness severity. Serum concentrations of vitamins A and E did not increase significantly in supplemented patients compared with those given placebo, and there were no changes in CD4 cell count or haematological parameters. No adverse events were detected except those attributable to underlying disease. CONCLUSIONS: Although micronutrient deficiency is predictive of early death in Zambian patients with the diarrhoea-wasting syndrome, short-term oral supplementation does not overcome it nor influence morbidity or mortality.

Local understandings of adult diarrhoeal disease and its treatment in an area of high HIV-seroprevalence in Zambia.

We set out to investigate the extent to which cultural constructs might determine treatment-seeking for diarrhoea in the poorer populations of Lusaka, Zambia. This paper describes these concepts and perceptions and outlines a classification of such illnesses, together with an analysis of its implications for understanding treatment choice. Data were derived from focus group discussions, a household survey, a survey of practitioners of traditional medicine and interviews with local residents attending an urban health centre with persistent diarrhoea. The classification is based on symptoms and perceptions of aetiology. While resulting categories convey imperatives for treatment choice, it is clear that individuals with diarrhoeal illnesses seek treatment from multiple sources. This may be because any single illness may fit more than once category, or because unrelenting ill-health engenders desperate behaviour. The cultural constructs do not fully explain treatment choice and attitudes to prevention, but could be used to improve communication regarding public health and treatment strategies.

A double-blind randomized trial of low-dose versus high-dose topical anaesthesia in unsedated upper gastrointestinal endoscopy.

BACKGROUND: Upper gastrointestinal endoscopy is frequently performed on unsedated subjects. Pharyngeal anaesthesia is thought to improve patient tolerance to the procedure but the optimum dose of anaesthesia is not known. The aim of this study was to assess the benefits of low-dose vs. high-dose topical anaesthesia in unsedated gastroscopy. METHODS: One hundred and fourteen subjects attending for diagnostic gastroscopy were studied. Patients were randomized to receive either 30 mg or 100 mg of topical pharyngeal lidocaine spray prior to endoscopy in a double-blind fashion. Subjects completed a questionnaire before and after endoscopy. RESULTS: A similar proportion of patients in each group required intravenous sedation because of discomfort or anxiety during the procedure (P = 0.48). The high-dose group experienced less discomfort during endoscope insertion (P = 0.002) and throughout the examination (P = 0.01). Overall satisfaction was almost identical in the two groups (P = 0.85) and a similar percentage of the high-dose and low-dose groups stated that they would request sedation prior to future endoscopy (37 vs. 44%; P = 0.48). Further analysis showed that apprehensive patients and younger patients reported relatively high levels of discomfort, and that female subjects were more likely to express a preference for sedation at any future gastroscopy. CONCLUSION: High-dose pharyngeal anaesthesia reduces patient discomfort during unsedated upper gastrointestinal endoscopy. However, patient tolerance is also influenced by clinical features, which might be useful in deciding which patients are suitable for this procedure.

Glucose polymer in the fluid therapy of acute diarrhoea: studies in a model of rotavirus infection in neonatal rats.

1. Unlike standard glucose-electrolyte oral rehydration solutions, solutions containing polymeric glucose as substrate can significantly reduce stool output, duration of diarrhoea and total oral rehydration solution requirements. However, neither the underlying mechanisms nor the optimal size and concentration of glucose polymer has been defined. 2. We have used a model of rotavirus diarrhoea in neonatal rats to compare the effects on water and solute absorption of varying the concentration of a glucose polymer (mean chain length five glucose residues) in experimental oral rehydration solutions. Three polymer (P) solutions were compared with solutions of identical electrolyte content (mmol/l: sodium, 60; potassium, 20; chloride, 60; citrate, 10) containing equivalent amounts of free glucose (G) as substrate by perfusion of the entire small intestine in situ. The polymer (9, 18, 36 mmol/l; 159, 168, 186 mosmol/kg, respectively) and the monomer (45, 90, 180 mmol/l; 195, 240 320 mosmol/kg) solutions were perfused in normal and rotavirus-infected neonatal rats. 3. In normal intestine polymer solutions promoted greater water absorption [P9, mean 291.4 (SEM 16.4); P18, 331.9 (13.1); P36, 284.3 (11.8) microliters min-1 g-1] than their equivalent monomer solutions [G45, 220.8 (8.4); G90, 240 (21); G180,79.4 (14.5) microliters min-1 g-1; P < 0.02]. In rotavirus-infected intestine, water absorption from all solutions declined, but the fall was much less pronounced from the polymer solutions [P9, 232.8 (6); P18, 277.2 (20.5); P36, 166 (18.2) microliters min-1 G-1] than from their monomeric counterparts [G45, 116.7 (25.5); G90, 68.7 (12.4); G180, 21 (11.6) microliters min-1 g-1; P < 0.005].(ABSTRACT TRUNCATED AT 250 WORDS)

Double blind, controlled trial of 4-aminosalicylic acid and prednisolone enemas in distal ulcerative colitis.

Corticosteroid or 5-aminosalicylic acid enemas are the treatment of choice for distal ulcerative colitis but up to one third of patients may be unresponsive. As an alternative therapy might be advantageous, the efficacy of six weeks' treatment with 2 g 4-aminosalicylic acid (4-ASA) (n = 24) and 20 mg prednisolone enemas (n = 21) were compared in a double blind, randomised trial in patients with acute distal (less than 30 cm from the anus) ulcerative colitis. Baseline demography and clinical severity were similar in both groups. Five of 24 patients receiving 4-ASA and 4 of 21 receiving prednisolone did not complete the trial because of deteriorating symptoms, failure to improve, or side effects. At the time of leaving the trial, 24 hour stool frequency, the presence of blood in the stools, and histological and sigmoidoscopic appearances were similar in both groups. Symptomatic improvement occurred in 17 of 24 patients receiving 4-ASA compared with 11 of 21 receiving prednisolone (chi 2 = 1.62, NS). Complete symptomatic improvement occurred in 9 of 24 patients receiving 4-ASA compared with 5 of 21 receiving prednisolone (chi 2 = 0.98, NS). Histological improvement was seen in 9 of 24 patients on 4-ASA compared with 7 of 21 on prednisolone (chi 2 = 0.08, NS). One patient receiving 4-ASA was considered to have an idiosyncratic reaction to the drug but other side effects were not considered to be drug related. Thus, 4-ASA, previously used in the treatment of tuberculosis (para-aminosalicyclic acid), is as good as prednisolone in the treatment of distal ulcerative colitis and should be considered in patients unresponsive to steroids or in whom steroid treatment is undesirable.

Search for the ideal oral rehydration solution: studies in a model of secretory diarrhoea.

In situ perfusion of whole rat small intestine was used to compare the efficacy of five oral rehydration solutions in promoting water and sodium absorption in normal intestine and secreting intestine after exposure to cholera toxin. Solutions varied in their sodium (35-90 mmol/l) and glucose (111-200 mmol/l) concentrations, molar ratio of glucose:sodium (1.2-5.8), and osmolality (281-331 mOsmol/kg), and contained either bicarbonate (18-30 mmol/l) or citrate (10 mmol/l). In normal intestine all solutions promoted net water absorption. Cholera toxin induced reproducible water secretion but all solutions reversed this to absorption. Water absorption was greatest with solutions containing sodium 60 mmol/l and glucose 111 or 140 mmol/l, and with a glucose:sodium ratio approximately 2, in both normal and secreting intestine. All solutions promoted net glucose absorption in both normal and secreting intestine. Net sodium absorption occurred with solutions containing greater than or equal to 60 mmol/l sodium in normal intestine but sodium secretion occurred from all solutions in secreting intestine. Sodium movement was directly related to the sodium concentration of the solution and sodium secretion occurred despite net water and glucose absorption. We consider that these studies may guide future development of oral rehydration solutions.

The effects of octreotide, soy polysaccharide, codeine and loperamide on nutrient, fluid and electrolyte absorption in the short-bowel syndrome.

Four agents, which could delay intestinal transit, were tested in six short-bowel patients (jejunal length 30-120 cm) on long-term nutritional/electrolyte replacement therapy. Intestinal transit time of a liquid test meal and nutrient, water and sodium absorption were measured during a control study and with each test agent on separate days. Soy polysaccharide tended to increase transit time, but decreased the absorption of water, sodium and nutrients. Codeine phosphate and loperamide caused inconsistent and clinically unimportant changes. Octreotide, a long-acting analogue of somatostatin, delayed transit and increased water, sodium and calorie absorption from the meal. Octreotide appears to have the potential to reduce the need for electrolyte and nutritional supplements in patients with the short-bowel syndrome.

4-Aminosalicylic acid retention enemas in treatment of distal colitis.

Forty-five of 47 patients with distal ulcerative colitis completed a two-week double-blind, randomized, controlled trial to determine if 4-aminosalicylic acid (4-ASA) enemas, 1 g bid or 2 g bid, were therapeutically effective compared to placebo. Forty-one patients enrolled because they were refractory to or had side effects during conventional therapy with sulfasalazine or corticosteroids. Proctoscopic examination was done before and after two weeks of treatment. Patients kept daily diaries assessing: blood in stools, mucus in stools, tenesmus, abdominal pain, loss of appetite, fatigue, weight loss, and malaise. Severity of each symptom ranged from 0 (absent) to 3 (severe). A total severity score was calculated from the above for each patient. At the end of the two-week study, 35 patients elected to take 4-ASA in an open-label trial for one year. 4-ASA enemas in the 1-g bid but not the 2-g bid dosage were significantly more effective in improving symptoms than placebo: P less than or equal to 0.05. Neither dose of 4-ASA enema was better than placebo in improving the sigmoidoscopic appearance at the end of two-weeks. Forty-six percent of patients had complete resolution of all signs and symptoms in the open-label trial and 31% were better but still had sigmoidoscopic evidence of disease, a total response rate of 77%. Side effects were similar in the placebo and 4-ASA groups. We conclude that 4-ASA enemas in a dose of 1 g bid are safe and effective in the treatment of distal ulcerative colitis.

The use of rats associated with a human faecal flora as a model for studying the effects of diet on the human gut microflora.

The activities of four bacterial biotransformation enzymes (beta-glucosidase, beta-glucuronidase, nitrate reductase and nitroreductase) were measured in the caecal contents of conventional flora rats or germ-free rats contaminated with a mixed, human faecal flora and compared with activities present in a fresh human stool preparation. Both the conventional flora rats and the rats inoculated with a human flora exhibited an enzyme profile generally similar to that of human faeces, although the conventional rat flora exhibited negligible nitrate reductase activity. The enzyme profile remained essentially unaltered in both human flora preparations following supplementation of the diet with pectin, whereas the conventional rat flora responded to this plant cell wall carbohydrate with a significant increase in nitrate reductase activity. The results demonstrate that enzymic activities of the human faecal microflora can be simulated in rats associated with a mixed population of human intestinal bacteria.

Dietary modification of intestinal bacterial enzyme activities--potential formation of toxic agents in the gut.

The bacterial population colonising the large intestine is able to metabolise a variety of ingested or endogenously produced substances to products, some of which possess toxic, mutagenic or carcinogenic properties. Dietary components, resistant to digestion and absorption in the upper alimentary tract, may influence these reactions by altering the environment of the gut or through the provision of nutrients to the flora. Evidence for the involvement of bacterial enzymes in the formation of toxic products in vivo has come largely from animal studies, particularly where fermentable plant cell-wall components are present in the diet. The role of diet in the modification of toxicologically important bacterial biotransformation processes will be discussed. Preliminary data will also be presented from a study demonstrating changes in the enzymic activity of the human faecal flora induced by pectin and bran. The significance of these changes to the disposition of chemicals in the gut will be discussed.

Effects of bile and bile salts on growth and membrane lipid uptake by Giardia lamblia. Possible implications for pathogenesis of intestinal disease.

We have shown previously that ox and pig bile accelerate in vitro growth of Giardia lamblia. We have now investigated the possible mechanisms by which mammalian biles promote parasite growth. Growth effects of (a) ox, pig, guinea pig, and human biles, (b) pure bile salts, and (c) egg and soybean lecithins were studied in the presence of a lecithin-containing growth medium. Individually, dilute native bile and pure sodium taurocholate (TC), glycocholate (GC), and taurodeoxycholate (TDC) promoted parasite growth; growth was most marked with biles of high phospholipid content, with biles enriched in more hydrophobic bile salts (ox approximately equal to human greater than pig greater than guinea pig) and with micellar concentrations of GC and submicellar concentrations of TC and TDC. By measuring uptake of radiolabeled biliary lipids from bile and bile salt-supplemented growth medium, we showed that the parasite consumed bile lipids, with the rank order lecithin greater than bile salts. Apparent net uptake of cholesterol was considered to be due to exchange, since net loss of cholesterol from the growth medium was not detected. Although bile and bile salt-stimulated parasite growth was associated with enhanced lecithin uptake, reduction in generation time was observed at low bile and bile salt concentrations when lecithin uptake was similar to bile free controls. Thus, bile salts may stimulate Giardia growth initially by a mechanism independent of enhanced membrane phospholipid uptake. However, since Giardia has no capacity to synthesize membrane lipid, biliary lecithin may be a major source of phospholipid for growth of this parasite.

Retrograde spread of hydrocortisone containing foam given intrarectally in ulcerative colitis.

A method is described of estimating retrograde spread through the colon of a 10% hydrocortisone acetate foam by labelling the foam with technetium-99m sulphur colloid and observing spread after intrarectal administration by serial gamma-camera pictures. The recommended 51 ml dose of foam reached the mid-sigmoid colon in all of the nine patients who had active ulcerative colitis. Furthermore, in seven the foam reached the proximal sigmoid colon. Foam spread less extensively in five patients with quiescent disease than in those with active disease. Increasing the volume of enema to 50 ml did not improve retrograde spread through the colon. These results suggest that 10% hydrocortisone foam may be useful in treating patients with distal ulcerative colitis that is not necessarily limited to the rectum.