Central arterial stiffness and diastolic dysfunction are associated with insulin resistance and abdominal obesity in young women but polycystic ovary syndrome does not confer additional risk.

STUDY QUESTION: Are arterial stiffness, carotid intima-media thickness and diastolic dysfunction increased in young women with polycystic ovary syndrome (PCOS) independently of the effects of obesity? SUMMARY ANSWER: Insulin resistance and central obesity are associated with subclinical cardiovascular dysfunction in young women, but a diagnosis of PCOS does not appear to confer additional risk at this age. WHAT IS KNOWN ALREADY: Some studies have shown that young women with PCOS may have increased measures of cardiovascular risk, including arterial stiffness, carotid intima-media thickness and myocardial dysfunction. However, it is difficult to establish how much of this risk is due to PCOS per se and how much is due to obesity and insulin resistance, which are common in PCOS and themselves associated with greater vascular risk. STUDY DESIGN, SIZE, DURATION: This cross-sectional study comprised 84 women with PCOS and 95 healthy volunteers, aged 16-45 years. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study was conducted in a university hospital. Subjects underwent a comprehensive assessment of body composition (including computed tomography (CT) assessment of visceral fat; VF), measurements of arterial stiffness (aortic pulse wave velocity; aPWV), common carotid intima-media thickness (ccIMT), diastolic function (longitudinal tissue velocity; e':a') and endocrinological measures. A sample size of 80 in each group gave 80% power for detecting a difference of 0.45 m/s in aPWV or a difference of 0.25 in e':a'. MAIN RESULTS AND THE ROLE OF CHANCE: After adjustment for age and body mass index (BMI), PCOS subjects had a greater insulin response (insulin area under the curve-IAUC) following glucose challenge (adjusted difference [AD] 35 900 pmol min/l, P < 0.001) and higher testosterone (AD 0.57 nmol/l, P < 0.001) and high molecular weight adiponectin than controls (AD 3.01 µg/ml, P = 0.02), but no significant differences in aPWV (AD -0.13 m/s, P = 0.33), ccIMT (AD -0.01 mm, P = 0.13), or e':a' (AD -0.01, P = 0.86) were observed. After adjustment for age, height and central pulse pressure, e':a' and aPWV were associated with logVF and IAUC. ccIMT was not related to logVF. The relationships between e':a' or aPWV and insulin resistance were only partly attenuated by adjusting for logVF. There was no significant relationship between aPWV or e':a' and either testosterone or adiponectin. LIMITATIONS, REASONS FOR CAUTION: The study recruited young women meeting the Rotterdam criteria for PCOS diagnosis; hence our findings may not be generalizable to older patients or those meeting other definitions of the syndrome. Biochemical hyperandrogenism was based solely on measurement of total testosterone. Cases and controls were not matched in advance for age and BMI, although the influence of these variables on the cardiovascular outcome measures was adjusted for. WIDER IMPLICATIONS OF THE FINDINGS: This study shows that central arterial stiffness and diastolic dysfunction are not increased in young women with PCOS, whereas they are associated with both insulin resistance and central obesity. Obesity thus represents the greatest modifiable risk factor for cardiovascular disease in young women with PCOS and lifestyle measures which target weight reduction are critical. STUDY FUNDING/COMPETING INTERESTS: This study received no specific grant support from any funding body. The authors have no conflicts of interest to declare.

Improved clinical investigation and evaluation of high-risk medical devices: the rationale and objectives of CORE-MD (Coordinating Research and Evidence for Medical Devices).

In the European Union (EU) the delivery of health services is a national responsibility but there are concerted actions between member states to protect public health. Approval of pharmaceutical products is the responsibility of the European Medicines Agency, whereas authorizing the placing on the market of medical devices is decentralized to independent 'conformity assessment' organizations called notified bodies. The first legal basis for an EU system of evaluating medical devices and approving their market access was the medical device directives, from the 1990s. Uncertainties about clinical evidence requirements, among other reasons, led to the EU Medical Device Regulation (2017/745) that has applied since May 2021. It provides general principles for clinical investigations but few methodological details-which challenges responsible authorities to set appropriate balances between regulation and innovation, pre- and post-market studies, and clinical trials and real-world evidence. Scientific experts should advise on methods and standards for assessing and approving new high-risk devices, and safety, efficacy, and transparency of evidence should be paramount. The European Commission recently awarded a Horizon 2020 grant to a consortium led by the European Society of Cardiology and the European Federation of National Associations of Orthopaedics and Traumatology, that will review methodologies of clinical investigations, advise on study designs, and develop recommendations for aggregating clinical data from registries and other real-world sources. The CORE-MD project (Coordinating Research and Evidence for Medical Devices) will run until March 2024; here we describe how it may contribute to the development of regulatory science in Europe.

PTPN2 but not PTPN22 is associated with Crohn's disease in a New Zealand population.

Recent genome-wide association studies have provided evidence for the involvement of the genes PTPN2 and PTPN22 in the pathogenesis of Crohn's disease (CD). We investigated whether genetic variants in these genes were associated with CD in a New Zealand population. Single-nucleotide polymorphisms (SNPs) rs2542151 (PTPN2) and rs2476601 (PTPN22) were genotyped in 315 CD cases and 481 controls. In this sample, we were able to confirm an association between CD and PTPN2 (genotypic P = 0.019 and allelic P = 0.011), and phenotypic analysis showed an association of this SNP with late age at first diagnosis, inflammatory and penetrating CD behaviour, requirement of bowel resection and being a smoker at diagnosis. There was no evidence for an association with PTPN22.

Prevalence of subclinical cardiac abnormalities in patients with metal-on-metal hip replacements.

BACKGROUND: Metal-on-metal (MOM) hip prostheses have a higher failure rate than conventional prostheses and leaching of cobalt and chromium has been linked to cardiomyopathy. We screened MOM subjects to evaluate if cobalt and chromium are related to subclinical cardiac dysfunction. METHODS: A single centre, non-randomised, observational study using echocardiography in 95 patients who had undergone MOM hip prostheses, and 15 age matched controls with non-MOM hip replacement. Serial plasma cobalt and chromium levels were recorded, and data compared by tertiles of cobalt exposure. RESULTS: Indexed left ventricular (LV) end-diastolic and end-systolic volumes (EDVi and ESVi) increased with tertile of cobalt (omnibus p = 0.003 for EDVi and ESVi), as did indexed left atrial (LA) volumes (p = 0.003). MOM subjects had 25% larger EDVi than controls, 32% larger ESVi (40 ml vs. 32 ml, and 15 ml vs. 11 ml, p = 0.003 for both) and 28% larger indexed LA (23 ml vs. 18 ml, p = 0.002). There were no differences in LV systolic or diastolic function, including ejection fraction, tissue velocity and mitral E/e'. Estimated glomerular filtration rate was 18% lower in the highest tertile compared with the lowest (p = 0.01) and correlated inversely with LA volume (r = -0.36, p < 0.001) and LV EDV (r = -0.24, p = 0.02). CONCLUSIONS: No correlations between sensitive measures of systolic or diastolic cardiac function or serum cobalt/chromium levels were observed in this study. However, there was a relationship between increasing left ventricular and left atrial volumes and declining renal function with high cobalt levels which requires further evaluation in MOM patients.

Caenorhabditis elegans inhibitor of apoptosis protein (IAP) homologue BIR-1 plays a conserved role in cytokinesis.

BACKGROUND: Inhibitor of apoptosis proteins (IAPs) suppress apoptotic cell death in several model systems and are highly conserved between insects and mammals. All IAPs contain at least one copy of the approximately 70 amino-acid baculovirus IAP repeat (BIR), and this domain is essential for the anti-apoptotic activity of the IAPs. Both the marked structural diversity of IAPs and the identification of BIR-containing proteins (BIRPs) in yeast, however, have led to the suggestion that BIRPs might play roles in other, as yet unidentified, cellular processes besides apoptosis. Survivin, a human BIRP, is upregulated 40-fold at G2-M phase and binds to mitotic spindles, although its role at the spindle is still unclear. RESULTS: We have identified and characterised two Caenorhabditis elegans BIRPs,BIR-1 and BIR-2; these proteins are the only BIRPs in C. elegans. The bir-1 gene is highly expressed during embryogenesis with detectable expression throughout other stages of development; bir-2 expression is detectable only in adults and embryos. Overexpression of bir-1 was unable to inhibit developmentally occurring cell death in C. elegans and inhibition of bir-1 expression did not increase cell death. Instead, embryos lacking bir-1 were unable to complete cytokinesis and they became multinucleate. This cytokinesis defect could be partially suppressed by transgenic expression of survivin, the mammalian BIRP most structurally related to BIR-1, suggesting a conserved role for BIRPs in the regulation of cytokinesis. CONCLUSIONS: BIR-1, a C. elegans BIRP, is probably not involved in the general regulation of apoptosis but is required for embryonic cytokinesis. We suggest that BIRPs may regulate cytoskeletal changes in diverse biological processes including cytokinesis and apoptosis.

Subclinical hypothyroidism, arterial stiffness, and myocardial reserve.

CONTEXT: Subclinical hypothyroidism (SCH) is associated with increased risk of cardiac disease; its impact on arterial function is less clear. OBJECTIVE: The objective of the study was the assessment of arterial and cardiac function. DESIGN: The study was a 6-month controlled observational study using pulse wave analysis and tissue Doppler dobutamine stress echocardiography. SETTING: The study was conducted at a thyroid clinic. PATIENTS: Nineteen female SCH patients with raised TSH, normal free T(4), and no cardiovascular disease [aged 49.2 +/- 3.8 yr; body mass index (BMI) 29.9 +/- 6.7 kg/m(2)] were recruited from the thyroid clinic, and 10 female controls (aged 50.2 +/- 3.4 yr; BMI 29.7 +/- 7.2 kg/m(2)) also participated in the study. INTERVENTIONS: Incremental doses of l-thyroxine were used. MAIN OUTCOME MEASURES: Indices of vascular stiffness and left ventricular echocardiographic function were measured. RESULTS: Baseline augmentation gradient was elevated in SCH, compared with controls [10.3 +/- 5.1 (sd) mm Hg vs. 8.0 +/- 4.2, P < 0.05]; when euthyroid (mean T(4) dose 114 mug/d), it fell to 8.8 +/- 5.3 mm Hg (P < 0.05). Heart rate-corrected augmentation index was 26.7 +/- 9.9 vs. 18.8 +/- 9.9% (P < 0.02), falling to 19.7 +/- 9.6% (P < 0.001) after treatment. Time of travel of the reflected wave was 139.3 +/- 11.7 msec, compared with 141.5 +/- 8.8 msec in controls (P < 0.05), increasing to 144.9 +/- 11.9 msec (P < 0.05). There were no differences in resting global, regional left ventricular function, or regional myocardial velocities during maximal dobutamine stress between SCH patients and controls, or in treated patients, compared with baseline. CONCLUSIONS: Arterial stiffness was increased in SCH and improved with l-thyroxine, which may be beneficial, whereas myocardial functional reserve was similar to controls and remained unaltered after treatment.

Genome-wide RNAi identifies p53-dependent and -independent regulators of germ cell apoptosis in C. elegans.

We used genome-wide RNA interference (RNAi) to identify genes that affect apoptosis in the C. elegans germ line. RNAi-mediated knockdown of 21 genes caused a moderate to strong increase in germ cell death. Genetic epistasis studies with these RNAi candidates showed that a large subset (16/21) requires p53 to activate germ cell apoptosis. Apoptosis following knockdown of the genes in the p53-dependent class also depended on a functional DNA damage response pathway, suggesting that these genes might function in DNA repair or to maintain genome integrity. As apoptotic pathways are conserved, orthologues of the worm germline apoptosis genes presented here could be involved in the maintenance of genomic stability, p53 activation, and fertility in mammals.

Assessment of ventricular septal defect closure by intraoperative epicardial ultrasound.

Intraoperative epicardial two-dimensional echocardiographic imaging, color flow mapping and contrast echocardiography were used in 31 patients after patch closure of a ventricular septal defect to determine their respective values in the assessment of residual shunting after cardiopulmonary bypass and for the prediction of long-term results. Epicardial imaging showed no incidence of patch dehiscence. Residual shunting detected by color flow mapping or contrast echocardiography was graded into one of four categories (0 to III). Real time analysis of color flow mapping studies suggested no shunting (grade 0) in 2 patients, grade I shunting in 20, grade II in 8 and grade III in 1; contrast studies suggested grade 0 in 15, grade I in 6, grade II in 8 and grade III in 2. Interobserver variation in real time encoding of grade I or II shunting was 25% by color flow mapping and 6% by contrast echocardiography. Subsequent frame by frame analysis revealed that both diastolic and early systolic right ventricular turbulence gave rise to false positive results during real time analysis of color flow mapping studies. Color flow mapping allowed exact localization of residual shunting, whereas contrast echocardiography allowed better semiquantification. Postbypass results were correlated in 30 patients with late postoperative precordial studies (mean interval 7.5 months). Persistent shunts were found in 6 (20%) of 30 patients. No patient required reoperation for residual shunting. The predictive value of immediate grade I or II shunting as a marker for persistent long-term shunting was poor, whereas both patients with immediate grade III shunting had shunt persistence, indicating that immediate revision should be considered in such patients. Intraoperative epicardial ultrasound is valuable for the immediate exclusion of important residual shunting after ventricular septal defect closure. Maximal information is obtained when color flow mapping and contrast echocardiography are used in combination.

Surgery for Ebstein's anomaly: the clinical and echocardiographic evaluation of a new technique.

Ten consecutive patients (age range 4 to 44 years, mean 22) underwent surgical repair of Ebstein's anomaly by vertical plication of the right ventricle and reimplantation of the tricuspid valve leaflets. No patient died during or after operation. Intraoperative postbypass echocardiography documented a good result in nine patients but severe tricuspid regurgitation in one patient, who then underwent prosthetic valve replacement during a second period of cardiopulmonary bypass. Two of four patients who had had right ventricular papillary muscle dysfunction in the early postoperative period showed improved papillary muscle function with concomitant reduction of tricuspid regurgitation 6 months later. All patients were evaluated clinically and by echocardiography 2 to 23 months later. All patients showed clinical improvement, seven by one functional class and three by two classes. All were in sinus rhythm. The mean cardiothoracic ratio decreased by 6% (p less than 0.05). On bicycle ergometry performed in six patients, peak oxygen consumption exceeded 20 ml/kg per min in five. Tricuspid regurgitation diminished in eight patients (by three grades in two patients, by two grades in five and by one grade in one patient); it remained unchanged in two. Comparison of preoperative and postoperative pulsed Doppler flow velocities across the pulmonary valve showed an increase in the peak velocity of flow across the valve (mean 83 +/- 14 versus 97 +/- 11 cm/s, p less than 0.005) and a decrease in the time to peak velocity (mean 130 +/- 16 versus 91 +/- 23 ms, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic interactions between alcohol and other drugs.

The frequent use of alcohol (ethanol) together with prescription drugs gives any described pharmacokinetic interaction significant clinical implications. The issue is both the effect of alcohol on the pharmacokinetics of various drugs and also the effect of those drugs on the pharmacokinetics of alcohol. This review discusses these pharmacokinetic interactions but also briefly describes some other effects of alcohol that are clinically relevant to drug prescribing. The use of several different study designs may be required before we can confidently state the presence or absence of any alcohol-drug interaction. Short term administration of alcohol in volunteers is the most common study design but studies of social drinking and prolonged moderate alcohol intake can be important in some situations. Community-based studies may illustrate the clinical relevance of any interaction. Alcohol can affect the pharmacokinetics of drugs by altering gastric emptying or liver metabolism (by inducing cytochrome P450 2E1). Drugs may affect the pharmacokinetics of alcohol by altering gastric emptying and inhibiting gastric alcohol dehydrogenase. The role of gastric alcohol dehydrogenase in the first-pass metabolism of alcohol is reviewed in this article and the arguments for and against any potential interaction between alcohol and H2 receptor antagonists are also discussed. The inhibition of the metabolism of acetaldehyde may cause disulfiram-like reactions. Pharmacodynamic interactions between alcohol and prescription drugs are common, particularly the additive sedative effects with benzodiazepines and also with some of the antihistamine drugs; other interactions may occur with tricyclic antidepressants. Alcohol intake may be a contributing factor to the disease state which is being treated and may complicate treatment because of various pathophysiological effects (e.g. impairment of gluconeogenesis and the risk of hypoglycaemia with oral hypoglycaemic agents). The combination of nonsteroidal anti-inflammatory drugs and alcohol intake increases the risk of gastrointestinal haemorrhage.

Differentiation between pathologic and physiologic left ventricular hypertrophy by tissue Doppler assessment of long-axis function in patients with hypertrophic cardiomyopathy or systemic hypertension and in athletes.

To identify new echocardiographic indexes of long-axis function that might differentiate between pathologic and physiologic left ventricular (LV) hypertrophy, we compared 60 subjects with different types of LV hypertrophy (group I: 15 patients with hypertrophic cardiomyopathy, group II: 15 patients with systemic hypertension, and group III: 30 athletes) with 20 normal subjects (group IV). The peak velocities of mitral annular motion at 4 sites were measured from the apex by tissue Doppler echocardiography. There were no differences in mean age and global ejection fraction between groups. Groups I and II had lower long-axis systolic and early diastolic velocities than the athletes (p <0.01) for all 4 sites. The best differentiation of pathologic from physiologic hypertrophy was provided by a mean systolic annular velocity <9 cm/s (sensitivity 87%, specificity 97%). Heterogeneity of annular velocities discriminated between group I and group II. Thus, long-axis systolic and early diastolic velocities are decreased in patients with pathologic hypertrophy, but preserved in athletes. These simple new echocardiographic parameters can differentiate between pathologic and physiologic hypertrophy.

Review article: gastro-oesophageal reflux and laryngeal symptoms.

There is some evidence from clinical, experimental and multiprobe ambulatory pH studies that gastro-oesophageal reflux is more common in patients with laryngeal symptoms and could potentially play a role in the causation of these symptoms. The proportion of unselected patients with laryngeal symptoms who have gastro-oesophageal reflux as the primary aetiology may be overestimated in some series. The symptom that has been most evaluated is hoarseness, but even for this symptom the proportion of patients who have significant reflux varies widely. There is even less agreement for other symptoms, and the data on globus sensation remains confused. It is likely that these patients present to ear, nose and throat (ENT) clinics because of the relative insensitivity of the oesophageal mucosa to acid exposure. Given the lack of specificity for routine diagnostic tests for gastro-oesophageal reflux, it is necessary to perform ambulatory pH monitoring for a secure diagnosis in these patients. Treatment studies have been surprisingly few and inadequate in design. It is suspected that there is a strong placebo response for these symptoms. No clear information on efficacy can be provided until placebo-controlled randomised studies are available.

Gastric persorption of bismuth from ranitidine bismuth citrate.

AIM: To determine whether bismuth penetrates the gastric mucosa after dosing with ranitidine bismuth citrate. METHODS: Twelve patients presenting with dyspepsia were randomized to receive either ranitidine bismuth citrate or placebo, 20-40 min prior to endoscopy. Biopsies were taken from four sites during endoscopy: the first and second parts of the duodenum, the antrum, and the body of the stomach. Biopsies were analysed by electron microscopy and X-ray microanalysis. RESULTS: Bismuth particles were found to be interposed between epithelial cells in the antral mucosa of three of eight patients who were dosed with ranitidine bismuth citrate. Columns of bismuth particles could be tracked down the lamina propria and were seen to be surrounding blood vessels. Bismuth particles were observed in the inter- and intra-cellular channels of the endothelial cells of the blood vessels in the lamina propria and also close to the luminal surface of the endothelial cell. This process of persorption was similar to that described in a previous report of electron microscopy appearances of the gastric antrum after dosing with tripotassium dicitrato bismuthate, but was quantifiably smaller and not observed in all the patients dosed with ranitidine bismuth citrate. No penetration of the mucosa by bismuth particles was seen in the body of the stomach or the duodenum. CONCLUSION: Penetration of bismuth particles into the gastric mucosa may occur after oral dosing with ranitidine bismuth citrate.

Short report: the effect of ranitidine on the post-prandial absorption of a low dose of alcohol.

Twenty healthy male subjects were studied twice using a double-blind, randomized placebo controlled, cross-over study design. Alcohol absorption (integrated 2-h plasma alcohol concentration, peak plasma alcohol concentration, and time to reach peak concentration) was measured after 8 daily doses of either placebo or 300 mg ranitidine. They were given alcohol, 0.15 g/kg of body weight by month after an evening meal. Compared with placebo, there was a trend towards higher integrated 2-h plasma alcohol concentrations (3.17 and 3.89 mg. h/dL, respectively, P = 0.07), and a statistically significant increase in mean peak plasma alcohol concentration after dosing with ranitidine (4.92 and 6.47 mg/dL, respectively, P = 0.05).

Short report: twenty-four-hour hyperpepsinogenaemia in Helicobacter pylori-positive subjects is abolished by eradication of the infection.

Twenty-four-hour plasma pepsinogen I and II concentrations were determined in 8 healthy subjects with antibody to Helicobacter pylori, before and after treatment with tripotassium dicitrato bismuthate, amoxycillin and metronidazole, Therapy was successful in the 5 subjects with active H. pylori infection. In these subjects, median integrated 24-h plasma pepsinogen I and II concentrations significantly decreased from 2288 and 357 micrograms.h/L before treatment, respectively, to 1811 and 171 micrograms.h/L at 4-6 weeks after treatment, and 1643 and 150 micrograms.h/L at 20-24 weeks. By contrast, in the 3 subjects without evidence of active H. pylori infection, pre-treatment plasma pepsinogen I and II concentrations were similar to values found in the H. pylori-infected subjects after successful therapy, and they did not change significantly in response to therapy. H. pylori infection is associated with reversible hyperpepsinogenaemia.

Comparison of one-day oral dosing with three bismuth compounds for the suppression of Helicobacter pylori assessed by the 13C-urea breath test.

Assessment of intragastric urease activity by the 13C-urea breath test was performed before and after one day of dosing with either De-Noltabs (tripotassium dicitrato bismuthate, one tablet 1 q.d.s.), Pepto-Bismol liquid (bismuth salicylate 30 ml q.d.s.), or Roter tablets (bismuth subnitrate, one tablet q.d.s.) in twelve Helicobacter pylori-positive patient volunteers. There was a significant decrease in the excess of 13CO2 after one day of dosing with each of the three bismuth compounds, but analysis of variance could detect no difference between the effects of the three compounds. Systemic absorption of bismuth following oral dosing with either Pepto-Bismol or Roter is minimal, yet both compounds have a suppressive effect on H. pylori similar to that of De-Noltab. This study suggests that the action of all three bismuth compounds is within the gastric lumen, and that systemic absorption of bismuth is not necessary for activity against H. pylori.

Ranitidine, cimetidine, famotidine have no effect on post-prandial absorption of ethanol 0.8 g/kg taken after an evening meal.

Forty-seven healthy male subjects were studied twice using a randomized, placebo-controlled design. Each subject took an 8-day course of two of the following four regimens; 300 mg ranitidine, 800 mg cimetidine, 40 mg famotidine or placebo (identical either to 300 mg ranitidine or 800 mg cimetidine). The systemic bioavailability of ethanol (integrated 6-h plasma ethanol concentration, peak plasma ethanol concentration, and the time to peak plasma ethanol concentration) was measured after the oral ingestion of 0.8 g of ethanol per kg body weight, given one hour after an evening meal on Day 8 of each regimen. There was no significant difference of integrated 6-h plasma ethanol concentration, peak ethanol concentration, or time to reach peak ethanol concentration after dosing with either ranitidine, cimetidine or famotidine or placebo.

The efficacy of methotrexate for maintaining remission in inflammatory bowel disease.

BACKGROUND: The management of patients with inflammatory bowel disease who are resistant to or intolerant of azathioprine remains a challenge. Low-dose methotrexate has been shown to be effective in inducing remission in Crohn's disease. AIM: This review was conducted because there are limited long-term follow-up data during and after stopping treatment. There are also limited data on the use of methotrexate in ulcerative colitis. METHODS: The study was a retrospective review of clinical notes. Remission was defined as minimal bowel symptoms without the need for oral steroids for 3 months. Relapse was defined as bowel symptoms that required steroid treatment or surgery. RESULTS: Seventy patients were reviewed; 48 had Crohn's disease and 22 had ulcerative colitis. The mean duration of treatment was 17.1 months; the mean maintenance dose was 20 mg weekly. Remission was achieved in 34 of 55 patients who completed more than 3 months of treatment (62%). Life-table analysis showed that the chances of remaining in remission at 12, 24 and 36 months (if treatment was continued) were 90%, 73% and 51%, respectively. The chances of remaining in remission after stopping treatment at 6, 12 and 18 months were 42%, 21% and 16%, respectively. The dose of methotrexate (mg/kg) was associated with the induction of remission (P=0.02). Treatment was equally effective for Crohn's disease and ulcerative colitis. CONCLUSIONS: Maintenance methotrexate treatment gives acceptable remission rates for treatment periods up to 3 years. After stopping treatment, relapse is frequent and occurs early (usually within 1 year).

Effect of eradication of Helicobacter pylori on gastric epithelial cell proliferation.

BACKGROUND: Helicobacter pylori is associated with B-type gastritis, duodenal ulcer disease, and possibly gastric carcinoma. The object of this study was to assess the effect of eradication of H. pylori infection on gastric epithelial cell proliferation. METHODS: Gastric epithelial cell proliferation was assessed in 22 H. pylori-positive duodenal ulcer patients before and 6 weeks after 'triple therapy' with bismuth, tetracycline and metronidazole. Cell proliferation was studied either by immunostaining for the proliferating cell nuclear antigen (PCNA) or by a microdissection technique. RESULTS: Eradication was successful in 10 of the 22 H. pylori-positive patients. Treatment with 'triple therapy' resulted in a significant fall in the rate of gastric epithelial cell proliferation; this effect was seen in both the gastric body and antrum. There was a significant correlation between the number of PCNA-labelled cells and the histological grade of activity (neutrophil inflammation) (r = 0.49, P = 0.02); the same correlation was found for the number of mitoses per gland (r = 0.5, P = 0.02). There was no significant difference in the treatment effect for eradicated or non-eradicated patients or either the body or antrum. Six patients, who had at least one antral biopsy that showed evidence of focal intestinal metaplasia, had a higher rate of cell proliferation. CONCLUSIONS: The reduction in epithelial cell proliferation in the body and antrum after triple therapy is independent of successful eradication of H. pylori, and it may be due to an anti-inflammatory effect of triple therapy.

Morning versus evening dosing of lansoprazole 30 mg daily on twenty-four-hour intragastric acidity in healthy subjects.

BACKGROUND: Morning dosing is usually recommended with proton pump inhibitors, but there are few data from 24-h intragastric acidity studies comparing times of dosing. METHODS: A double-blind, placebo-controlled study was performed on the seventh day of dosing to compare the effects of lansoprazole 30 mg given either in the morning or evening on 24-h intragastric acidity in 32 healthy volunteers. RESULTS: The median integrated 24-h intragastric acidity on the seventh day of morning dosing with lansoprazole 30 mg was decreased to 36% of the placebo value, compared with 42% for evening dosing. For each daytime meal-related interval, morning dosing was significantly more effective for controlling acidity, but there was no significant difference between the regimens during the night interval (23.00-08.00 h). CONCLUSIONS: These data favour morning dosing of lansoprazole 30 mg for routine use, but patients with mainly nocturnal symptoms may be best treated by evening dosing.