Are there differences between patients with and without the homozygous--13910CC genetic variant in the MCM-6 gene upstream from the lactase gene?--A non-randomised, two armed intervention study without control group.

BACKGROUND: Patients with chronic abdominal complaints are a diagnostic challenge for general practitioners (GP). Lactose intolerance (LI) often remains undiagnosed in these patients. Genetic testing for the homozygous -13910CC variant of the MCM-6 gene (LI+) combined with a lactose-restricted diet (LRD) seems to be an acceptable approach. The primary aim of the study was to determine the effect of a LRD in patients with chronic abdominal complaints without a definite diagnosis, with or without the homozygous -13910CC variant. The secondary aim was to determine in family practices the prevalence of undiagnosed LI in these patients. METHODS: In 25 practices around Düsseldorf (Germany) all patients presenting with chronic abdominal complaints for at least 12 months without definite diagnosis were identified by their GPs. Patients participating underwent a MCM-6 gene test and all, including those not genetically predisposed, were asked to keep a LRD for eight weeks. Symptoms were evaluated three times over two months using a standardized gastrointestinal Questionnaire (GIQLI, max. score 144). RESULTS: 210 patients were included. The gene test revealed 29.5% genetically positive for the homozygous T-13910-C mutation (LI+). All patients showed a significant increase in GIQLI scores (improvement) during the observation period, i.e. after four and eight weeks on the diet (p = 0.001, two-way repeated measures ANOVA). There was no significant difference between both groups (LI+/LI-) at any point of symptom measurement. CONCLUSIONS: A lactose-restricted diet showed an unspecific positive effect for patients with chronic abdominal pain without a defined diagnosis. For the LI-group, this could be explained by an unspecific effect of a diet in general, e.g., getting special attention. This can be important for a group of patients probably having psychosomatic complaints focussed on the abdomen.

An e-learning platform for guideline implementation--evidence- and case-based knowledge translation via the Internet.

OBJECTIVES: Effective knowledge translation in medicine is an essential element of a modern health care system. Evidence-based clinical practice guidelines (CPGs) are considered relevant instruments for the transfer of knowledge into clinical practice. To improve this transfer we have created Internet-based continuing medical education (CME) modules and online case-based learning objects. METHODS: Building upon existing CPGs, an e-learning platform including a multi-step review process was developed to generate CME modules. These CME modules were presented through a modified content management system (CMS) that fulfils specific requirements of CME. An online questionnaire using a four-point Likert scale was designed to receive mandatory feedback from participating physicians. In the second step of development, case-based learning objects were added to the CMS. RESULTS: Existing clinical practice guidelines allowed a rapid development of CME modules specific to individual clinical indications. The modified CMS proved to be technically stable but also resource-intensive. 3105 physicians registered and used the platform between June 2003 and April 2005. 95% of the physicians expressed positive feedback in an evaluation questionnaire; only 35% of physicians actually used the corresponding CPGs in practice. Suggestions from the CME users led to the development of interactive medical case-based learning objects related to the main topics of the CPGs. CONCLUSIONS: To support the implementation of CPGs, an Internet platform for CME including case-based learning objects and examination tests was developed. An interactive online CME platform can support active learning and may establish an additional stimulus for knowledge translation into daily medical practice.

[Online continuing medical education based on national disease management guidelines. The e-learning platform leitlinien-wissen.de]. / Online-Fortbildung auf der Basis nationaler Versorgungsleitlinien : Die Fortbildungsplattform leitlinien-wissen.de.

Effective translation of relevant knowledge into clinical practice is essential for modern health care systems. National Disease Management Guidelines (NDMG) are considered relevant instruments to support this transfer. To implement NDMG Internet-based continuing medical education (CME), modules and online case-based learning objects were designed and published. To ensure high quality the contents are based on NDMG and subjected to multi-step review processes. Presentation on the web was realized through a modified content management system. To obtain a CME certificate, completing an online questionnaire using a four-point Likert scale was mandatory. Between June 2003 and April 2005, 3,105 physicians were registered and used the platform: 95% of the physicians expressed positive feedback in the evaluation questionnaire, and 35% actually used the corresponding NDMG in practice. This prompted the development of interactive medical case-based learning objects as a second learning pathway. An Internet platform for CME including case-based learning objects can be a helpful tool to assure the provision of scientific knowledge for patient care.

Lipopolysaccharide activation of human endothelial and epithelial cells is mediated by lipopolysaccharide-binding protein and soluble CD14.

Myeloid cell activation by lipopolysaccharides (LPS) involves two proteins, plasma LPS-binding protein (LBP) and cell-membrane CD14. Cell membrane CD14, anchored by a glycerophosphatidylinositol tail, is the cellular receptor for LPS-LBP complexes. Another form of CD14, without the lipid tail, circulates as a soluble plasma protein. In this work we show that soluble CD14 (sCD14) is required for activation of endothelial and epithelial cells by LPS. We propose that LPS-LBP complexes transfer LPS to sCD14, and the LPS-sCD14 complexes then bind to a cellular receptor. Support for this pathway comes from experiments in which LBP and CD14 in normal human serum are blocked by specific antibodies, experiments in which serum is replaced by purified LBP and sCD14, and experiments in which specific binding of [3H]LPS to epithelial cells is quantitated.

Interaction of liquid aluminium phosphate and aluminium hydroxide with the gastric acid profile. Influence of food components and timing of meals.

AlPO4 is generally perceived as a particularly weak antacid. Its neutralizing capacity, when evaluated with the classical Fordtran test at the pH 3 standard, is several times smaller than that of Al(OH)3, which is considered a particularly potent antacid. This difference of in vitro reactivity of the two antacids is largely due to the fact that the pKa value is considerably lower for AlPO4 than for Al(OH)3. The object of this study was to evaluate in vivo and in vitro the impact of the pKa value of these antacids on their efficacy at low pH values and the modulation of their neutralizing capacity through proteins. Since both preparations display a much closer antacid activity at pH 2, we felt it appropriate to reevaluate the comparative in vivo neutralizing capacity of the two antacids at doses matched with their in vitro reactivity at pH 2. In vivo antacid effects were measured by ambulant pH-metry in 18 healthy volunteers after randomized ingestion of carbohydrate or protein meals. Antacid or placebo medication was given 1 and 3 h after meals. At pH 3.0, the standard milieu of the Fordtran test, preparation A, composed of Al(OH)3 and a small fraction of Mg(OH)2, displayed in vitro a neutralizing capacity of 4.4 mmol/ml, whereas this was 0.18 mmol/ml for preparation B, composed solely of AlPO4 (p less than 0.001). When tested at pH 1, 1.5, and 2, however, the ratio between A and B was below 2.(ABSTRACT TRUNCATED AT 250 WORDS)

Aspects of the role of prostaglandins in gastrin histamine regulation of gastric acid secretion.

There is convincing evidence from in vitro studies that prostaglandins interfere with the gastrin histamine regulation of gastric acid secretion in an opposing manner. They can inhibit the action of histamine on the parietal cell when given as single-dose treatment. Conversely, when given at high doses, they liberate endogenous histamine, probably from nonparietal cells. In in vivo experiments prostaglandins are potent inhibitors of acid secretion when studied with single-dose treatment but are capable of stimulating basal acid secretion when chronically applied to rats. Studies performed in whole animal preparations on the effect of cyclooxygenase inhibitors have not fully clarified which of these two histamine-modulating effects of prostaglandins is of prime physiologic significance but favour suppression of histamine activity with subsequent acid inhibition. It appears that somatostatin release is the mechanism through which prostaglandin can simultaneously inhibit acid secretion and release plasma gastrin. At least in the rat, the pattern of plasma gastrin and somatostatin release is, similarly to acid secretion, partly reversed during prolonged prostaglandin treatment.

Effect of 16.16 dimethyl prostaglandin E2, N-acetyl-cysteine and the proton pump inhibitor BY 831-78 on hydrogen peroxide-induced mucosal damage in the rat stomach.

Reactive oxygen species are noxious to gastrointestinal mucosa and contribute to a variety of gastrointestinal diseases. We examined whether 16.16 dimethyl prostaglandin E2 (PG) is protective against the oxidizing action of 6% H2O2 causing gross hemorrhagic lesions in rat gastric mucosa. Male Wistar rats were treated with PG, 0.005-5 micrograms/kg, either intragastrically (i.g.) or subcutaneously, 30 min prior to i.g. administration of 6% H2O2, 0.5 ml/100 g. Further animals received 25 mg of the mucus dissolvent N-acetyl-cystein (NAC) following oral PG treatment or 30 mumol/kg of the H+K(+)-ATPase inhibitor BY 831-78 (BY), 4 h before onset of the experiments. Volume, pH and beta-N-acetyl-glucosaminidase and lactate dehydrogenase as parameters of cell damage were determined in the gastric juice. i.g. PG treatment achieved 60 and 55% reduction of the mucosal lesions in doses between 5 and 0.05 micrograms/kg, respectively. i.p. PG administration was effective in all doses tested. Gastric juice volume was only slightly and enzymes were not significantly affected by PG treatment. NAC did not diminish PG efficacy or aggravate mucosal lesions. Gastric acid suppression did not increase PG-induced protection but was strongly protective by itself, reducing damage by 75%. Low-dose PG treatment achieves an effective protection against oxidative damage in gastric mucosa, which is not the result of dilution or enhanced mucus production.

Smoking and pH response to H2-receptor antagonists.

Smoking has been shown to impair the therapeutic effect of H2-receptor antagonists. To evaluate the acid-reducing capacity of H2-receptor antagonists in relation to smoking habits, we tested the effect of ranitidine (Ran) and famotidine (Fam) under physiologic conditions, using ambulatory pH-metry. Intragastric pH was measured over 20 h. Each of 18 healthy volunteers, 9 smokers and 9 nonsmokers, received 40 mg Fam, 300 mg Ran, or placebo in a double-blind, randomized study as a single evening dose. With both drugs 20-h acidity was markedly suppressed. After Fam treatment mean inhibition was 61% in smokers and 76% in nonsmokers and after Ran 51% and 67%, respectively. When areas under the pH curves for each individual were calculated and treatment compared with placebo (= 100%), the response was smaller in smokers than in nonsmokers with either drug (Fam, 153 +/- 21% versus 214 +/- 19%, p less than 0.01; Ran, 176 +/- 21% versus 232 +/- 29%, p less than 0.05) during the first 4 h after drug intake. A similar effect was observed in the morning period from 0600 to 1000 h (Fam, 118 +/- 19% versus 206 +/- 19%, p less than 0.001; Ran, 133 +/- 21% versus 207 +/- 31%, p less than 0.02). During the nighttime there were no significant differences. These findings indicate that smoking impairs the response to both drugs tested.

Enprostil reduces the increase of gastric corpus mucosal mass induced by the hydrogen-potassium-stimulated adenosine triphosphatase inhibitor BY 831-78 in the rat.

We studied whether enprostil, a synthetic prostaglandin E2 derivative, might inhibit gastrin release and the trophic effects on gastric oxyntic mucosa induced by prolonged treatment with an inhibitor of hydrogen-potassium-stimulated adenosine triphosphatase, the substituted benzimidazole BY 831-78. Rats were treated intragastrically with enprostil (1 or 15 micrograms/kg b.i.d.), BY 831-78 (15 mumol/kg once daily), the combination of enprostil and BY 831-78, ranitidine (300 mumol/kg b.i.d.), and placebo. Plasma gastrin and somatostatin levels and gastric acid secretion were measured during a 1-day treatment in animals fitted with chronic gastric fistulas and repeatedly during 9 wk of treatment in intact rats. Despite inhibiting acid secretion, enprostil did not increase plasma gastrin. When combined with BY 831-78, enprostil transiently reduced the BY 831-78-induced increase of integrated plasma gastrin (1375 +/- 206 vs. 2137 +/- 256 pmol/L.12 h, p less than 0.05) in fasted rats with fistulas, but failed to prevent the marked hypergastrinemia following 9 wk of treatment with BY 831-78 (717 +/- 80 vs. 731 +/- 56 pmol/L) in intact rats. However, enprostil reduced the BY 831-78-induced increase of oxyntic mucosal volume (458 +/- 31 vs. 567 +/- 33 mm3, p less than 0.01), whereas BY 831-78 prevented the enprostil-induced increase of antral mucosal volume (42 +/- 3 vs. 56 +/- 3 mm3, p less than 0.01). These results demonstrate that some of the trophic effects induced by a hydrogen-potassium-stimulated adenosine triphosphatase inhibitor are not exclusively governed by gastrin.

Influence of prostaglandins, omeprazole, and indomethacin on healing of experimental gastric ulcers in the rat.

We investigated whether the trophic actions of prostaglandins, omeprazole, and indomethacin on gastric mucosa lead to accelerated healing of gastric ulcers in the rat. Cryoulcers were produced in the corpus area and treated with 16,16-dimethyl prostaglandin E2 (5 or 100 micrograms/kg b.i.d., intragastrically), omeprazole (40 mumol/kg once daily, subcutaneously), indomethacin (2 mg/kg b.i.d., subcutaneously), or placebo. At the end of the treatment, plasma gastrin, cell labeling index (autoradiography with [3H]thymidine), and the size and depth of mucosal defects were measured. Compared with placebo, omeprazole accelerated ulcer healing as indicated by a smaller ulcer area [1.1 +/- 0.2 vs. 4.8 +/- 1.2 mm2 (mean +/- SEM)] and smaller ulcer depth (383 +/- 31 vs. 488 +/- 41 microns) after 10 days of treatment. Prostaglandins did not affect ulcer healing despite thickening of gastric corpus mucosa. Indomethacin delayed ulcer healing and reduced the labeling index. Omeprazole induced a marked hypergastrinemia (208 +/- 12 vs. 66 +/- 12 pmol/L on day 5, and 469 +/- 23 vs. 58 +/- 16 pmol/L on day 10). The results indicate that abolishment of acid secretion by omeprazole accelerates healing. Trophic actions and "cytoprotective" effects by prostaglandins are not relevant for ulcer healing in this model.