Dealing with research misconduct in the United Kingdom. An editor's response to fraudsters.
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Biomedical Research↗
Biomedical subjects
M J Farthing
Publications and source records attributed to M J Farthing.
High adult mortality in Lusaka.
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Adolescent↗
Does sucrase deficiency in black South Africans protect against colonic disease?
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Black People↗
Crucial role for 5-HT in cholera toxin but not Escherichia coli heat-labile enterotoxin-intestinal secretion in rats.
BACKGROUND & AIMS: Many consider cholera toxin (CT) and Escherichia coli heat-labile enterotoxin (LT) to be functionally identical. Both increase intracellular adenosine 3',5'-cyclic monophosphate concentration; however, differences between the two and the severity of the diseases they cause have been reported. The secretagogue 5-hydroxytryptamine (5-HT) is implicated in CT-induced secretion, but its role in LT-induced secretion is unclear. We tested the hypothesis that LT fails to recruit 5-HT in its secretory processes. METHODS: In vivo small intestinal perfusions were undertaken in adult male Wistar rats after incubation with equipotent doses of CT or LT, or saline. Small intestinal 5-HT release and the effect on net small intestinal water and electrolyte transport of (1) pharmacological depletion of 5-HT; (2) blockade of 5-HT type 2, 3, and 4 receptors; and (3) pretreatment with lidocaine, hexamethonium, and atropine were determined. RESULTS: CT- but not LT-induced secretion was accompanied by 5-HT release, reduced by 5-HT depletion, and inhibited by each 5-HT antagonist. By contrast, lidocaine and hexamethonium inhibited secretion induced by both toxins. CONCLUSIONS: LT induces secretion without recruiting a 5-HT-dependent cascade. This may account for differences in clinical severity of the diseases CT and LT cause and has implications for the development of antisecretory therapies.
Animals↗
Enhancing clinical efficacy of oral rehydration therapy: is low osmolality the key?
Many empirical clinical trials have used complex carbohydrate as substrate in oral rehydration solutions (ORSs) instead of glucose and have shown a number of important clinical benefits. Foremost among these are reduced stool volumes, shorter duration of diarrheal illness, and lower ORS intake. The underlying mechanisms to explain this clinical advantage have not been fully established, but a number of possible factors have been proposed: (1) increased substrate availability, (2) a "kinetic advantage" for glucose absorption by glucose polymer, (3) differential handling of glucose monomer and polymer by the small intestine, (4) low osmolality, (5) a separate effect of peptides and amino acids on solute-linked sodium absorption, (6) an antisecretory moiety in rice, and (6) enhanced mucosal repair and regeneration by luminal nutrients. In this report, we assess the relative contribution of these factors using evidence from laboratory-based studies, mainly in disease-related intestinal perfusion systems in animals and humans, and the relevant clinical studies available to date. We advance the hypothesis that of all the possible mechanisms proposed to underlie the enhanced clinical efficacy of complex carbohydrate ORSs, their hypotonicity plays the dominant role. If confirmed, this concept could guide future development of glucose and complex carbohydrate-based ORSs.
Diarrhea↗
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.
Adult↗
Helicobacter pylori infection: an overview.
For many decades the dictum 'no acid, no ulcer' dominated thinking on the pathogenesis of peptic ulcer. When I was a medical student, not surprisingly, the standard therapy for a peptic ulcer was an antacid possibly combined with carbenoxolone. As a medical registrar, I was involved in the early studies with H2-receptor antagonists which, at the time, many of us believed would lead to the removal of peptic ulceration as a clinically important disease. It was soon evident, however, that ulcers returned rapidly when the H2-receptor antagonist was withdrawn and the concept of maintenance therapy was born. Within about 5 years of the launch of the first H2-receptor antagonist, cimetidine, two major developments occurred namely the discovery of Helicobacter pylori and the characterisation of the proton pump with the development of drugs to inhibit its action. The discovery of H. pylori not only turned the aetiopathogenesis of peptic ulceration on its head but soon emerged as a major factor in the causation of gastric cancer and mucosa associated lymphocytic tissue (MALT) gastric lymphoma. The potential clinical impact of this organism continues to expand, with suggestions that it might be involved in growth retardation in children and possibly a factor in the development of ischaemic heart disease. The high prevalence of this organism worldwide presents clinicians and other healthcare workers with a formidable challenge with regard to its control at a population level.
Gastric Mucosa↗
Bacterial infections of the gut (excluding enteric fever).
Bacterial enteric infections are still a major cause of morbidity and mortality, and many challenges lie ahead in understanding and managing these conditions. Clostridium difficile remains the most important nosocomial infection. Antibiotic resistance makes the treatment of shigella infections increasingly difficult. Molecular and cellular techniques are, however, rapidly expanding our understanding of the complexity of the pathogenesis of established and newly recognized pathogens.
Journal Article↗
Variable distribution of Cryptosporidium parvum in the intestine of AIDS patients revealed by polymerase chain reaction.
OBJECTIVE: Cryptosporidium parvum is associated with persistent diarrhoea and malnutrition in children, with large waterborne outbreaks and with the diarrhoea-wasting syndrome in AIDS. However, pathophysiology of infection remains to be defined and the reasons for the variability of clinical features are uncertain. The polymerase chain reaction (PCR) is valuable for the analysis of infections with non-culturable organisms because of its high sensitivity, so we compared PCR and microscopy as tools for the analysis of the distribution of infection. DESIGN: PCR was compared with light microscopy (LM) and electron microscopy (EM) in duodenal biopsies from a well characterized series of 75 Zambian AIDS patients. PCR and LM were then used to define the distribution of infection in biopsies from duodenum, ileum, right colon and left colon in eight South African patients with persistent AIDS-related cryptosporidiosis. RESULTS: PCR specifically detected 10 fg of genomic C. parvum DNA. When applied to duodenal biopsies from 75 Zambian AIDS patients, infection was detected in all seven cases of duodenal cryptosporidiosis that were identified by LM or EM and in six additional cases which appeared to be negative by microscopy. Distribution of infection was defined in six of eight South African AIDS patients. Two had pan-enteric infection, three had small bowel infection and one had purely ileo-colonic infection. In two cases infection could not be localized despite using PCR, suggesting that infection was confined to the inaccessible mid-small intestine. CONCLUSIONS: PCR detection of C. parvum DNA demonstrated that infection is highly variable in distribution, which must be taken into account when designing and interpreting studies of pathophysiology.
Acquired Immunodeficiency Syndrome↗
Postprandial plasma 5-hydroxytryptamine in diarrhoea predominant irritable bowel syndrome: a pilot study.
BACKGROUND: Increased concentrations of 5-hydroxytryptamine (5-HT) can be detected in the systemic circulation after a meal and may be involved in the physiological control of gastrointestinal motility. Abnormalities of 5-HT release after a meal might explain some of the postprandial symptoms associated with the irritable bowel syndrome (IBS). AIM: To investigate the effect of a standard meal on plasma 5-HT and urinary 5-hydroxyindole acetic acid (5-HIAA) concentrations in patients with diarrhoea predominant IBS and in healthy volunteers. METHODS: After an overnight fast, six volunteers and five patients with IBS were given a carbohydrate-rich meal. Blood and urine samples were taken before and for four hours after the meal. Platelet-poor plasma 5-HT and urinary 5-HIAA were analysed by reversed phase high performance liquid chromatography with fluorometric detection. 5-HIAA was expressed as a ratio with urinary creatinine concentration, which was measured by spectrophotometry. RESULTS: During the four hour postprandial period, 5-HT concentrations were significantly higher in patients with IBS than in healthy volunteers at 0.5 hours (p < 0.05), 2 hours (p < 0.05) and 2.5 hours (p < 0.05). 5-HT was not detected in the plasma in the fasting state in patients or volunteers. Median peak 5-HT in patients with IBS (359 (198-796) nmol/l) was significantly greater than volunteers (83 (7-190)) (p < 0.05). "Area under the curve" for 5-HT detection was greater for patients with IBS (317 (138-771)) than for healthy volunteers (51 (4-129); p < 0.05). The duration of the 5-HT peak was significantly longer in patients with IBS (3 (1-3) hours) than in the healthy volunteers (1 (1-1) hours; p < 0.01). Postprandial urinary median 5-HIAA values in controls (5.6 (5.5-5.8) mumol/mmol creatinine) and patients with IBS (3.0 (2.5-6.8) mumol/mmol creatinine) were not significantly different from preprandial values (controls: 5.9 (5.5-6.6) mumol/mmol creatinine; patients with IBS: (6.2 (2.4-9.3) mumol/mmol creatinine). CONCLUSION: These findings indicate that there may be a difference in the way that 5-HT is released in patients with diarrhoea predominant IBS, and could suggest a possible role for 5-HT in the postprandial symptoms of these patients.
Adolescent↗
Effect of the nitric oxide donor, glyceryl trinitrate, on human gall bladder motility.
BACKGROUND: Nitric oxide is a major neurotransmitter in non-adrenergic, non-cholinergic (NANC) pathways. NANC inhibitory innervation has been shown in human gall bladder muscle in vitro; the role of nitric oxide in human gall bladder emptying however is undefined. AIMS: To study the effect of glyceryl trinitrate, a nitric oxide donor, on gall bladder emptying in healthy subjects using a randomised, double blind, cross-over, placebo controlled design. METHODS: Ultrasonographic gall bladder volume was measured in the fasting state in eight healthy volunteers after randomised administration of either glyceryl trinitrate 1200 micrograms buccal spray or placebo spray. On two further occasions, after randomised administration of either glyceryl trinitrate 1200 micrograms buccal spray or placebo spray, gall bladder volumes were also measured after a liquid test meal. RESULTS: Glyceryl trinitrate significantly increased fasting gall bladder volume to a mean of 114% (SEM 5%) of pretreatment volume (p = 0.039). Glyceryl trinitrate also significantly impaired gall bladder emptying between five and 40 minutes postprandially. Gall bladder ejection fraction was also reduced after glyceryl trinitrate compared with placebo (43 (6.9)% versus 68.4 (6.5)%, p = 0.016). CONCLUSIONS: This study shows that glyceryl trinitrate produces gall bladder dilatation in the fasting state and reduces postprandial gall bladder emptying, suggesting that nitric oxide mechanisms may be operative in the human gall bladder in vivo.
Adult↗
Persistent systemic inflammatory response after stent insertion in patients with malignant bile duct obstruction.
BACKGROUND: Surgery in patients with malignant bile duct obstruction is associated with high postoperative morbidity and mortality. Tumour necrosis factor alpha (TNF-alpha) plays a key role in the pathogenesis of these complications. AIMS: To determine the effect of biliary drainage on plasma concentrations of TNF-alpha, its soluble circulating receptors (sTNFr), and other proinflammatory cytokines. METHODS: Plasma concentrations of TNF-alpha, sTNFr-P75, interleukin 6 (IL-6), and IL-1 alpha were measured in 25 patients with malignant bile duct obstruction before and after endoscopic stent insertion. RESULTS: Mean serum bilirubin was 157 mumol/l before stent insertion and 35.2 mumol/l one week post stent insertion. There was complete relief of jaundice in 77% of patients by four weeks. Plasma concentrations of TNF-alpha and IL-1 alpha were below the detection limit of the assays in all samples. Median plasma sTNFr-P75 in the cancer patients was 960 ng/l (range 400-6600), before stent insertion and remained unchanged at one and four weeks after stenting. Plasma sTNFr-P75 in cancer patients was significantly higher (p < 0.01) than in healthy controls (250 (200-650) ng/l). Before stent insertion, plasma IL-6 concentrations were detectable (above 5 ng/l) in 17 (68%) patients. After relief of biliary obstruction IL-6 levels fell from a prestent median of 13.2 to less than 5 ng/l at one week after stent insertion. Plasma concentrations of IL-6 were undetectable in 76% of patients at this time. CONCLUSION: Activation of the TNF/sTNFr complex is unchanged after biliary drainage in patients with malignant bile duct obstruction. This may explain why preoperative drainage does not influence the high morbidity and mortality associated with surgery in these patients.
Cholestasis↗
The relation between gastric vitamin C concentrations, mucosal histology, and CagA seropositivity in the human stomach.
BACKGROUND: Vitamin C may be protective against gastric cancer though infection with Helicobacter pylori is associated with a reduction in intragastric concentrations of vitamin C. AIMS: To examine the effects of H pylori infection, gastric juice pH, the severity and extent of gastric inflammation, and CagA antibody status of the individual on gastric juice and mucosal vitamin C concentrations. PATIENTS: One hundred and fifteen patients undergoing routine gastroscopy for investigation of dyspepsia. METHODS: High performance liquid chromatography was used to determine vitamin C concentrations. CagA antibody was detected by western blot analysis. RESULTS: Gastric juice ascorbic acid concentration was significantly lower in patients infected with H pylori compared with those uninfected (19.3 mumol/l (interquartile range (IQR) 10.7-44.5) versus 66.9 mumol/l (IQR 24.4-94.2), p = 0.003). The reduction in gastric juice ascorbic acid concentration was inversely related to the severity of gastritis (p = 0.01). CagA positive patients had significantly lower gastric juice ascorbic acid concentrations than CagA negative ones (14.8 mumol/1 (IQR 7.9-52.2) versus 39 mumol/l (IQR 19.9-142.2), p = 0.05). Decreased gastric juice dehydroascorbic acid concentrations were observed in patients with gastric atrophy and intestinal metaplasia. Mucosal ascorbic acid concentrations were also significantly lower in infected patients than uninfected patients (p = 0.04). CONCLUSIONS: The reduction in gastric vitamin C concentrations is related to gastric juice pH, the severity and extent of gastritis, the presence of H pylori, and the CagA antibody status of the individual. These findings may have implications in H pylori associated carcinogenesis.
Adult↗
Impaired splenic function and tuftsin deficiency in patients with intestinal failure on long term intravenous nutrition.
BACKGROUND: Reticuloendothelial system function is impaired in humans receiving lipid regimens. AIMS: To evaluate the effects of long term administration of long chain triglyceride emulsions on reticuloendothelial system function. METHODS: Splenic function and tuftsin activity were measured in 20 patients on intravenous nutrition for intestinal failure, 20 patients with Crohn's disease who were not receiving intravenous nutrition, and 50 healthy controls. RESULTS: Pitted red cells counts in patients on intravenous nutrition (8.0%) were significantly higher (p<0.001) than in healthy controls (0.6%) and in patients with Crohn's disease (0.9%). No difference was found between healthy controls and patients with Crohn's disease. There was a correlation (r=0.50; p<0.03) between percentage of pitted red cells and duration of intravenous nutrition. Tuftsin activity was significantly reduced in the intravenous nutrition patient group (6%) compared with both disease controls (16.5%, p<0.01) and healthy volunteers (17.8%, p<0.001). An inverse correlation between tuftsin activity and pitted red cell percentage was found in the patients on intravenous nutrition (r(s) =-0.44, p<0.05). No relation was found in the patients on intravenous nutrition between pitted red cell percentage or tuftsin activity and type of disease, percentage of ideal body weight, residual length of small intestine, or administration (quantity and frequency) of lipid emulsion. Eight patients on intravenous nutrition had serious infections within the previous 12 months. CONCLUSIONS: Patients with a short bowel treated with long term intravenous nutrition have impaired splenic function, reduced tuftsin activity, and an increased risk of infection.
Adult↗
New drugs in the management of the irritable bowel syndrome.
Irritable bowel syndrome (IBS) continues to provide a major therapeutic challenge to clinicians and those involved in drug development. It seems unlikely from the data before us that this multisymptom syndrome with peripheral and central components is likely to respond reliably in all patients to the same single agent. There is still a lack of well designed, appropriately powered, randomised clinical trials and the problems of dealing with the high placebo response rate in this group of patients remains a dilemma for trial designers. There are, however, some new ideas, particularly those relating to the role of hyperalgesia in IBS. For many patients, abdominal pain and bloating are the most distressing symptoms of this disease and the new drugs targeted at pain control, such as kappa agonists and serotonin antagonists (5-HT3) and possibly 5-HT4), may eventually find a place in the clinical management of this syndrome. Other candidates include somatostatin analogues and antidepressants, the latter predominantly for their effects on increasing pain threshold. More speculative new drugs for IBS include cholecystokinin antagonists such as loxiglumide and the gonadotrophin-releasing hormone analogue, leuprorelin (leuprolide). The results of on-going randomised clinical trials are still awaited for some of these newer agents. The irritable bowel syndrome (IBS) is the most common gastrointestinal condition encountered by general practitioners and is reported to account for up to 50% of the work of gastroenterologists in secondary care. However, most people with the symptoms of IBS (60 to 75%) do not consult a doctor. Its cause is unknown, its development is poorly understand and, perhaps not surprisingly, no universally agreed approach to treatment exists.
Adult↗
A prospective study of K-ras mutations in the plasma of pancreatic cancer patients.
K-ras mutations are frequently found in primary pancreatic adenocarcinomas. In this prospective study, we looked for K-ras mutations in the plasma of patients with pancreatic cancer. We isolated plasma DNA from 21 pancreatic cancer patients using a simple and rapid extraction technique and detected K-ras alterations with a PCR assay and subsequent product sequencing. Patients were followed up to determine their clinical outcome. We found K-ras mutations in the plasma of 17 patients (81%). In cases in which both plasma and pancreatic tissue were available, DNA mutations were similar in corresponding plasma and tissue samples. Plasma DNA alterations were found 5-14 months before clinical diagnosis in four patients. Mutant DNA was not found in the plasma of two patients with chronic pancreatitis or in five healthy controls. Our results indicate that K-ras mutations are often found in DNA isolated from the plasma of pancreatic cancer patients and that a noninvasive plasma-based assay may provide qualitative diagnostic information to clinicians in the future. Larger studies are required to further assess the relevance of our findings to clinical practice.
Adult↗
General practitioner access to gastroscopy: is 'censorship' valuable?
An audit was carried out on the activities of a one stop clinic where patients referred by GPs for endoscopy are first interviewed by a gastroenterologist, directly before the procedure. Such a barrier to open access endoscopy did not seem to reduce the workload or the rate of normal examinations.
Adult↗
Octreotide in the treatment of intestinal lymphangiectasia.
Primary intestinal lymphangiectasia is characterized by dilated small bowel lymphatics and loss of lymph into the bowel lumen resulting in hypoproteinaemia and oedema. Some patients have a more generalized lymphatic abnormality associated with lymphoedema of the limbs and chylous pleural effusions. There is no specific treatment although enteric protein loss may decrease with a low-fat diet. This report describes a patient with severe primary intestinal lymphangiectasia, associated with limb oedema and recurrent pleural effusions, who responded to treatment with octreotide. Before starting octreotide she required weekly intravenous albumin infusions to maintain the serum albumin above 20 g/l. Bilateral pleural effusions repeatedly reaccumulated despite pleurectomy and subsequently tetracycline pleurodesis. Treatment with octreotide, 200 microg twice daily, resulted in a reduction in enteric protein loss from 16 to 4.1% in 5 days (normal less than 1%) and the serum albumin was maintained between 22 and 26 g/l without the need for albumin infusion. Oedema in the arms resolved completely and the pleural effusions did not reaccumulate. The mechanism of action of octreotide in this condition appears to be due to a reduction in gut protein loss and another, as yet unidentified, action.
Adolescent↗