Appropriateness of colonoscopy in Europe (EPAGE II). Iron-deficiency anemia and hematochezia.

BACKGROUND AND STUDY AIMS: To summarize the published literature on assessment of appropriateness of colonoscopy for the investigation of iron-deficiency anemia (IDA) and hematochezia, and report appropriateness criteria developed by an expert panel, the 2008 European Panel on the Appropriateness of Gastrointestinal Endoscopy, EPAGE II. METHODS: A systematic search of guidelines, systematic reviews and primary studies regarding the evaluation and management of IDA and hematochezia was performed. The RAND/UCLA Appropriateness Method was applied to develop appropriateness criteria for colonoscopy for these conditions. RESULTS: IDA occurs in 2 %-5 % of adult men and postmenopausal women. Examination of both the upper and lower gastrointestinal tract is recommended in patients with iron deficiency. Colonoscopy for IDA yields one colorectal cancer (CRC) in every 9-13 colonoscopies. Hematochezia is a well-recognized alarm symptom and such patients are likely to be referred for colonoscopy. Colonoscopy is unanimously recommended in patients aged > or = 50. Diverticulosis, vascular ectasias, and ischemic colitis are common causes of acute lower gastrointestinal bleeding (LGIB); CRC is found in 0.2 %-11 % of the colonoscopies performed for LGIB. Most patients with scant hematochezia have an anorectal or a distal source of bleeding. The expert panel considered most clinical indications for colonoscopy as appropriate in the presence of IDA (58 %) or hematochezia (83 %). CONCLUSION: Despite the limitations of the published studies, guidelines unanimously recommend colonoscopy for the investigation of IDA and hematochezia in patients aged > or = 50 years. These indications were also considered appropriate by EPAGE II, as were indications in patients at low risk for CRC with no obvious cause of bleeding found during adequate previous investigations.

Risk factors for complication following ERCP; results of a large-scale, prospective multicenter study.

BACKGROUND AND STUDY AIMS: Analyses of endoscopic retrograde cholangiopancreatography (ERCP) complication are often constrained by the number of endpoints observed. This large-scale study aimed to identify the principal risk factors for ERCP complication. PATIENTS AND METHODS: This was a prospective multicenter study of ERCP complications, based in five English regions. An exploratory univariable analysis of patients' first recorded procedures identified potentially important patient- and procedure-related factors. For overall complications and pancreatitis, variables significant in univariable analysis were included in multiple regression. RESULTS: A total of 66 centers collected data on 5264 ERCPs, performed on 4561 patients. A therapeutic intervention was attempted in 3447/4561 (76%) of patients as part of their first recorded ERCP. Following first recorded ERCP, 230 patients (5.0%) suffered > or = 1 complication: pancreatitis in 74 (1.6%), cholangitis in 48 (1.0 %), hemorrhage in 40 (0.9%), perforation in 20 (0.4%), and miscellaneous in 54 (1.2%). Significant factors from multiple regression were included in a multi-level analysis, which incorporated variables measured at the level of the endoscopist and hospital. For overall complication, risk factors ( P value, odds ratio [OR], 95% confidence interval [CI]) were: cannulation attempts > 1 ( P = 0.094, OR 1.32, 95% CI 0.95-1.83), precut ( P = 0.033, OR 1.55, 95 % CI 1.04-2.32), and suspected sphincter of Oddi dysfunction ( P = 0.121, OR 1.97, 95 % CI 0.84-4.64). For pancreatitis, risk factors ( Pvalue, OR, and 95 % CI) were: cannulation attempts > 1 ( P = 0.0001, OR 3.14, 95% CI 1.74-5.67), female sex ( P < 0.001, OR 2.22, 95% CI 1.43-3.45), age ( P < 0.002, OR 1.09 per 5 year decrease, 95% CI 1.03-1.15), and performance in a district (as opposed to university) hospital ( P = 0.034, OR 2.41, 95% CI 1.08-5.41). CONCLUSION: Careful patient selection combined with skilled cannulation minimizes complications. Higher-risk procedures should be performed in specialist centers.

Reconstitution into liposomes of glucose active transport from the rabbit renal proximal tubule. Characteristics of the system.

This paper describes the characteristics of Na+ -dependent D-glucose transport into liposomes made from soybean phospholipids into which have been reconstituted detergent-solubilized components from the rabbit renal proximal tubular brush border membrane. Conditions for optimal and quantitative reconstitution of glucose carriers are defined. Na+ -dependent D-glucose uptake occurs via a saturable system with a Km of 0.125--0.135 mM, is responsive to the volume of the internal liposomal space, and shows 'overshoot' as seen in natural membranes. The rate of Na+-dependent D-glucose uptake and the magnitude of the 'overshoot" are proportional to the concentration of protein used in reconstitution.

A rapid method for the isolation of kidney brush border membranes.

A simple rapid method for the preparation of purified brush border membranes from rabbit kidney proximal tubules is described. The method is based on hypotonic lysis, Ca2+ aggregation of contaminants and differential centrifugation. In contrast to most other published methods, the brush border membranes are free of contamination by basolateral membranes.

Characterisation of penicillin-G uptake in rabbit small-intestinal brush-border membrane vesicles.

Uptake of penicillin-G has been studied in rabbit intestinal brush-border membrane vesicles (BBMV). Penicillin-G was transported into the lumen of BBMV via an H+-dependent, Na+-independent uptake system. This was a saturable carrier-mediated process, which adhered to Michaelis-Menten kinetics, having a pH optimum of 4.5 and resulting in a net-negative charge transfer. Vmax was 59 nmol penicillin-G (mg protein)-1 (30s)-1 and Km 22.7 mM. Ampicillin, penicillin-V, cefadroxil, cephalexin, cephalothin, cephradine, L-carnosine, glycyl-L-alanine, glycyl-L-tyrosine and glycylglycylglycine inhibited the uptake of penicillin-G. However, glycylsarcosine stimulated uptake by 92%. Countertransport experiments suggested that this effect took place at the active site of the transporter. Penicillin-G uptake appeared to be mediated via a common transport system shared by penicillins, cephalosporins and peptides.

Endoscopic ultrasound in the localisation of pancreatic islet cell tumours.

The role of endoscopic ultrasound (EUS) in the evaluation of entero-pancreatic endocrine tumours has evolved in conjunction with advances in other imaging methods. The high spatial resolution of this technique allows the detection of very small lesions and their precise anatomical localisation. In patients with biochemically proven insulinoma, EUS can be effectively used as a first line investigation, with a sensitivity of 94%. Combined with thin section CT, the sensitivity rises to 100%. There is also high sensitivity in diagnosing intrapancreatic gastrinomas but lower for those arising in the duodenal wall which require detailed duodenal evaluation at surgery. EUS in conjunction with Somatostatin Receptor Scanning (SRS) has a combined sensitivity of 93% for gastrinomas. EUS is recommended for screening of asymptomatic patients with genetically proven MEN1. There is a limited role for EUS guided biopsy in pancreatic endocrine tumours.

An evaluation of patient performance of and their satisfaction with various rapid blood glucose measurement systems.

We evaluated the performance of 50 insulin-dependent diabetic patients in the measurement of their own capillary blood glucose concentrations using Chemstrip bG, Dextrostix-Dextrometer, and Stat Tek systems. With all systems, patient performance was suboptimal when compared with the accuracy of paramedical personnel. The percentage of patient determinations that differed from the laboratory value by more than 20% was 37%, 30%, and 14% for the Chemstrip bG, Dextrostix-Dextrometer, and Stat Tek systems, respectively. Only 39 of the patients (78%) could perform accurately with any system. Youth, lack of a higher education, and lower income status contributed significantly to the patients' inaccuracy with the Chemstrip bG technique, whereas these factors had no effect on patient performance with the reflectance meter techniques. Nearly all of the patients were enthusiastic about the value of home glucose monitoring as a means to assess their glycemic control. However, only 30% of the patients selected for home use a technique at which they were suitably adept. In part, this selection error appeared to be due to the greater cost and inconvenience of the reflectance meter techniques compared with the Chemstrip bG technique. These data indicate that unless proper instruction is provided, home glucose monitoring should only be used by a fraction of insulin-requiring diabetic patients and the choice of a particular system for use by an individual patient should be predicated upon his or her demonstrated proficiency with that system.

Insulin-like growth factor I and the development of colorectal neoplasia in acromegaly.

Patients with acromegaly are at increased risk of colorectal neoplasia and, by analogy with high-risk nonacromegalic patients, may require regular colonoscopic screening. However, it is unknown whether the risk is equal in all patients or whether some should be regarded as carrying a particularly high risk. The aims of this study were: 1) to establish the natural history of colorectal neoplasia in acromegaly; 2) to establish which patients are at increased risk of developing neoplasia; and 3) to elucidate the influence of insulin-like growth factor I (IGF-I) in adenoma formation. A prospective colonoscopic evaluation of the development of new premalignant adenomas in the colon was performed in 66 patients with biochemically proven acromegaly who had previously undergone colonoscopic screening and removal of all visible polyps. Twenty-five patients (38%) had a total of 37 polyps detected at the second colonoscopy: nine (14%) had at least one adenoma, and 18 (27%) had one or more hyperplastic polyps (2 patients had both). The development of new adenomas, but not hyperplastic polyps, was associated both with elevated serum IGF-I (P < 0.005) and, to a lesser extent, with a previous adenoma at the original colonoscopy (P < 0.07). In summary, patients with acromegaly and in whom serum IGF-I remains elevated and/or who have had a previous adenoma should be regarded as having an especially high risk for the development of subsequent colorectal neoplasia. Serum IGF-I seems to be implicated in the development of colorectal neoplasia in acromegaly, although the exact mechanisms remain uncertain.

Effect of insulin therapy on lipoproteins in non-insulin dependent diabetes mellitus (NIDDM).

Thirty patients with NIDDM and severe hyperglycemia (fasting plasma glucose greater than 200 mg/dl) were initiated on insulin therapy. Lipoprotein concentrations were measured by the Vertical Autoprofile procedure before insulin therapy and 1, 3, 6 and 26 weeks after insulin initiation. Patients were divided into 4 phenotypes based on their pretreatment lipoprotein profile: HyperVLDL (elevated VLDL), HyperLDL (elevated LDL), HyperVLDL-LDL (elevated VLDL and LDL), and non-hyperlipidemic. There were no differences in the initial fasting plasma glucose, Hgb Alc, or fasting free insulin concentrations between the groups. Both the HyperVLDL and HyperLDL groups had significantly lower HDL-C concentrations that the non-hyperlipidemic group and the HyperVLDL-LDL group had significantly higher IDL-C than any of the other groups. Insulin therapy resulted in similar decreases in fasting plasma glucose and increases in fasting free insulin concentrations in all 4 groups. HDL-C increased in all 4 groups. The most marked improvements in HDL-C were seen in the non-hyperlipidemic (+37%) and HyperLDL (+42%) groups while the HyperVLDL group had only an 18% increase. VLDL-C fell in all groups but in the HyperVLDL group it fell dramatically to almost normal levels within the first week, whereas it took 6 weeks for the HyperVLDL-LDL group to reach its VLDL-C nadir and this was still significantly higher than normal. LDL-C improved modestly in only the HyperLDL patients after 6 weeks of insulin therapy. There were no statistically significant changes in either the IDL-C or Lp(a)-C in any of the groups during insulin therapy. The changes in HDL-C and IDL-C were negatively correlated with the fasting plasma glucose and Hgb Alc but not with the free insulin concentration. We conclude that: 1) Insulin therapy can cause dramatic improvements in HDL-C and VLDL-C while it has only a mild suppressive effect on LDL-C and no statistically significant effect on IDL-C or Lp(a)-C. The degree of improvement in the lipid profiles varied considerably between the different lipid phenotypes. 2) The hyperlipidemic phenotypes seen in these patients appear to be determined primarily by factors other than the degree of hyperglycemia and hypoinsulinemia.

Selective COX-2 inhibitors and human inflammatory bowel disease.

BACKGROUND: Much recent effort has been made to produce selective inhibitors of cyclo-oxygenase-2 (COX-2) in the belief that these will lack the gastrointestinal damaging effects of traditional non-steroidal anti-inflammatory drugs (NSAIDs). Inflammatory bowel disease is associated with increased local production of prostanoids. These prostanoids, particularly PGE2 and PGI2, may well be protective as inflammatory bowel disease is aggravated by NSAID use. AIM: To examine the effects of a traditional NSAID and a highly selective COX-2 inhibitor on the production of these prostanoids in human inflammatory bowel disease. METHODS: Colonic mucosal biopsies were obtained from patients undergoing routine colonoscopy and biopsy for diagnostic or surveillance purposes. Biopsies were incubated in culture medium containing 10% foetal calf serum and antibiotics, plus test drugs or vehicle for 24 h, after which time the medium was removed and the content of PGE2, PGI2 (measured as 6 keto-PGF1alpha) and thromboxane (Tx) A2 (measured as TxB2) determined. RESULTS: Biopsies obtained from diseased colonic mucosa produced significantly more PGE2, PGI2 and thromboxane A2 than did controls (for example, PGE2: ulcerative colitis, 4.17+/-1.06; Crohn's disease, 3.97+/-1.66; control, 0.12 +/-0.13 ng/mL, n = 8-12). These increases were inhibited to a similar extent by either a highly selective COX-2 inhibitor (L-745,337) or a traditional non-selective NSAID (indomethacin). CONCLUSIONS: Until selective COX-2 inhibitors have been assessed adequately in human inflammatory bowel disease, these compounds should not be assumed to be safe for the gastrointestinal tract in inflammatory bowel disease.

Dose-dependent stimulation of gallbladder contraction by intravenous erythromycin in man.

We have previously shown that a single oral dose of 500 mg erythromycin causes gallbladder contraction. The effect of intravenous erythromycin on antroduodenal motility is dose-dependent; < 3 mg/kg body weight stimulates propagated contractions in a fashion similar to motilin while doses > 7 mg/kg cause giant non-propagated antral contractions not seen with motilin. Using ultrasound, we have examined the effect of differing doses of intravenous erythromycin on gallbladder motility in man. Erythromycin (1 mg/kg) caused fasting gallbladder contraction to 52% of basal gallbladder volume (P < 0.001), and increased gallbladder emptying following a liquid meal (maximal percentage emptied 75 +/- 6.8% vs. 58 +/- 9.0% following saline, P < 0.05). Erythromycin (7 mg/kg) however, had no effect on gallbladder fasting or post-prandial motor activity. We conclude that the effect of erythromycin on gallbladder motility is dose-dependent, with higher doses having no effect. It is possible that at higher doses erythromycin stimulates other receptors in addition to the motilin receptor, and that the combined effect is different to the stimulation of the motilin receptor alone.

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.

Early experience with intrasphincteric botulinum toxin in the treatment of achalasia.

BACKGROUND: Recent reports have suggested that intrasphincteric injection of botulinum toxin is effective and long-lasting in the treatment of achalasia. AIM: To report our experience of botulinum toxin injection in a prospective series of consecutive patients with achalasia. METHODS: Eleven consecutive patients with achalasia (eight male, mean age 55 years, range 20-87) were treated with 60 units of botulinum toxin (Dysport; Speywood Pharmaceuticals Ltd, UK) into each of four quadrants at the lower oesophageal sphincter. Patients were assessed pre-treatment and 1 month after treatment using a symptom score and oesophageal manometry. Median follow-up was 12 months (range 6-28). RESULTS: The injection procedure was simple to perform and free of adverse effects. Although treatment had a beneficial effect on dysphagia (median pre-treatment score 3 [interquartile range 3-3]; post-treatment score 2 [0-3]: P=0.03) 1 month following therapy, there was no significant improvement in chest pain or regurgitation scores. Similarly, no significant reduction in median lower oesophageal sphincter pressure was observed (29.5 mmHg [21-42] pre-treatment, 28.5 [17.5-55.5] post-treatment P=0.67). Four patients (36%) required further therapy within 3 months and the overall relapse rate was 73% (eight of 11) within 2 years. CONCLUSION: Although botulinum toxin injection was well tolerated, these results using Dysport at a dose of 240 mouse units question its efficacy as a treatment for achalasia.

Changing patterns of sedation use for routine out-patient diagnostic gastroscopy between 1989 and 1998.

BACKGROUND: Knowledge of sedation trends for upper gastrointestinal endoscopy is important for health service planning, particularly in view of rapidly increasing demands on endoscopy services. However, no data are available on sedation trends in Britain over the past 10 years. AIM: To determine sedation use for routine gastroscopy in a single endoscopy unit between 1989 and 1998. METHODS: This was a retrospective study of 9795 consecutive adults (mean age 56 years, range 18-100 years; 4512 females) who had undergone a gastroscopy between 1989 and 1998. Clinical, pharmacological and endoscopic data were retrieved from a computerized database. RESULTS: Over the 10-year study period, the sedation rate remained constant for patients undergoing therapeutic endoscopy (P=0.99) and those undergoing in-patient diagnostic examinations (P=0.63). In contrast, the sedation rate for out-patient diagnostic endoscopy decreased by 54%, from a high of 70% in 1990 to 32% in 1998 (P < 0.0001). Logistic regression analysis showed that the decline in sedation use was greater in females (P < 0.0001) than males and in procedures performed by non-consultant compared to consultant staff (P=0.01). CONCLUSIONS: If our results form part of a national trend, they will have important implications for cardiopulmonary monitoring strategies, recovery room practices and for complication rates due to the use of sedation for upper gastrointestinal endoscopy.

A new model of human secretory diarrhoea using cholera toxin.

Secretory diarrhoea is a major cause of morbidity and mortality worldwide. However, there is no biologically relevant test system in man for assessing new anti-diarrhoeal therapies prior to clinical trial. We have used highly purified cholera toxin in combination with the triple lumen jejunal perfusion technique to establish a subclinical model of cholera in man. Cholera toxin was administered either by mouth with sodium bicarbonate or directly into a 30 cm 'open' or 'closed' (isolated between two inflated balloons) jejunal segment in healthy adult volunteers. Both oral dosing and direct delivery into an 'open' jejunal segment failed to produce consistent secretion of water and electrolytes. In contrast 15 micrograms or 25 micrograms of cholera toxin elicited secretion of water and sodium 3 h after instillation into the balloon occluded 'closed' jejunal segment (P less than 0.05 vs. controls). The rate of secretion was constant over the maximal period studied (4.5 h) and was similar to that reported in human cholera. None of the subjects experienced troublesome diarrhoea. We believe this model offers a relevant test system for assessing anti-diarrhoeal therapy in man.

The nature of gastric secretions in a patient with Zollinger-Ellison syndrome without peptic ulceration.

A study has been made of the gastric secretions from a patient with Zollinger-Ellison syndrome without peptic ulceration, before and after treatment with cimetidine. The amount of non-diffusable glycoconjugates was measured as an index of mucin output, and found to be within normal limits. Cimetidine, which greatly reduced the volume of secretions, had no effect on the non-diffusable glycoconjugates. These results may explain the absence of peptic ulceration in certain patients with this syndrome.

Dilutional diarrhoea: under-diagnosed and over-investigated.

We report two cases of factitious diarrhoea caused by stool dilution. In the first report stools from a patient with chronic diarrhoea were found to have been diluted with urine, and the diarrhoea further compounded by surreptitious laxative misuse. In the second report, after prolonged investigation of high output ileostomy, the patient's ileal effluent was found to have been diluted with water. We conclude that factitious diarrhoea, in particular dilutional diarrhoea, is over-investigated and underdiagnosed. Stool weights, complete input/output measurement, analysis of stool osmolality and electrolytes, and laxative screening are essential in the investigation of chronic watery diarrhoea.

Behavioural psychotherapy in the treatment of irritable bowel syndrome.

The irritable bowel syndrome is a highly prevalent condition whose underlying aetiology is not understood. While many patients respond to a combination of gastrointestinal antispasmodics, bulking agents and dietary manipulation, controlled clinical trials have suggested that the benefit is only marginal and is due mainly to the large placebo effect found in this condition, which has been calculated to range between 54 and 81%. Associations between the syndrome and psychological and social stresses suggest, however, that treatment involving a systematic approach to the management of symptoms may hold out real therapeutic possibilities. In the current study, 42 IBS patients were randomly allocated to either medical treatment or to behavioural psychotherapy with a nurse therapist. They were assessed initially and at 4 and 9 months. There was a general improvement over the 9 months on a number of physical and psychological symptoms measured. However, no differences were found between treatment groups except for changes in two avoidance scores. A significant correlation was found, however, between improvement in the bowel symptoms of IBS (stomach pain and diarrhoea) and improvement in the psychological symptoms measured by the Clinical Interview Schedule, suggesting a close interrelationship between the two.

Use of a peptide rather than free amino acid nitrogen source in chemically defined "elemental" diets.

Previous studies have shown that amino acid (AA) residues are absorbed more rapidly from di- tripeptides than from free AA. In the present study, an intestinal perfusion technique has been used in normal human subjects to compare absorption of AA residues and total alpha-amino nitrogen (N) from 4 partial enzymic hydrolysates of protein (50--80% of the N contents present as small peptides) and their respective equimolar free AA mixtures. alpha-Amino N absorption was greater from 2 casein hydrolytes and a lactalbumin hydrolysate than from the respective free AA mixtures but similar to that from a fish protein hydrolysate and its AA mixture. The considerable variation in absorption of individual AA residues from the AA mixtures was much reduced when the protein hydrolysates were perfused, as a number of AA which were poorly absorbed from the AA mixtures were absorbed to a greater extent from the protein hydrolysates. The casein and lactalbumin hydrolysates had a stimulatory effect on jejunal absorption of water and electrolytes. In contrast, the fish protein hydrolysate appeared to cause a mean net secretion of fluid and electrolytes. The findings indicate that when absorption is limited by diminished luminal hydrolysis or absorptive capacity, serious consideration might be given to using partial enzymic hydrolysates of whole protein rather than free AA mixtures as the N source in "elemental" diets. Care should be taken, however, in ensuring that the preparation of choice does not promote a net secretion of fluid and electrolytes for such a property could have a deleterious effect in the clinical setting.

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.