Vacuolating cytotoxin (vacA) alleles of Helicobacter pylori comprise two geographically widespread types, m1 and m2, and have evolved through limited recombination

Vacuolating cytotoxin (vacA) alleles of Helicobacter pylori vary, particularly in their mid region (which may be type m1 or m2) and their signal peptide coding region (type s1 or s2). We investigated nucleotide diversity among vacA alleles in strains from several locales in Asia, South America, and the USA. Phylogenetic analysis of vacA mid region sequences from 18 strains validated the division into two main groups (m1 and m2) and showed further significant divisions within these groups. Informative site analysis demonstrated one example of recombination between m1 and m2 alleles, and several examples of recombination among alleles within these groups. Recombination was not sufficiently extensive to destroy phylogenetic structure entirely. Synonymous nucleotide substitution rates were markedly different between regions of vacA, suggesting different evolutionary divergence times and implying horizontal transfer of genetic elements within vacA. Non-synonymous/synonymous rate ratios were greater between m1 and m2 sequences than among m1 sequences, consistent with m1 and m2 alleles encoding functions fitting strains for slightly different ecological niches

A 6-week, multicentre, randomised, double-blind, double-dummy, active-controlled, clinical safety study of lumiracoxib and rofecoxib in osteoarthritis patients

<p>Abstract</p> <p>Background</p> <p>Lumiracoxib is a selective cyclooxygenase-2 inhibitor effective in the treatment of osteoarthritis (OA) with a superior gastrointestinal (GI) safety profile as compared to traditional non-steroidal anti-inflammatory drugs (NSAIDs, ibuprofen and naproxen). This safety study compared the GI tolerability, the blood pressure (BP) profile and the incidence of oedema with lumiracoxib and rofecoxib in the treatment of OA. Rofecoxib was withdrawn worldwide due to an associated increased risk of CV events and lumiracoxib has been withdrawn from Australia, Canada, Europe and a few other countries following reports of suspected adverse liver reactions.</p> <p>Methods</p> <p>This randomised, double-blind study enrolled 309 patients (aged greater than or equal to 50 years) with primary OA across 51 centres in Europe. Patients were randomly allocated to receive either lumiracoxib 400 mg od (four times the recommended dose in OA) (<it>n </it>= 154) or rofecoxib 25 mg od (<it>n </it>= 155). The study was conducted for 6 weeks and assessments were performed at Weeks 3 and 6. The primary safety measures were the incidence of predefined GI adverse events (AEs) and peripheral oedema. The secondary safety measures included effect of treatment on the mean sitting systolic and diastolic blood pressure (msSBP and msDBP). Tolerability of lumiracoxib 400 mg was assessed by the incidence of AEs.</p> <p>Results</p> <p>Lumiracoxib and rofecoxib displayed similar GI safety profiles with no statistically significant difference in predefined GI AEs between the two groups (43.5% <it>vs</it>. 37.4%, respectively). The incidence and severity of individual predefined GI AEs was comparable between the two groups. The incidence of peripheral oedema was low and identical in both the groups (<it>n </it>= 9, 5.8%). Only one patient in the lumiracoxib group and three patients in the rofecoxib group had a moderate or severe event. At Week 6 there was a significantly lower msSBP and msDBP in the lumiracoxib group compared to the rofecoxib group (<it>p </it>< 0.05). A similar percentage of patients in both groups showed an improvement in target joint pain and disease activity. The tolerability profile was similar in both the treatment groups.</p> <p>Conclusion</p> <p>Lumiracoxib 400 mg od (four times the recommended dose in OA) provided a comparable GI safety profile to rofecoxib 25 mg od (therapeutic dose). However, lumiracoxib was associated with a significantly better BP profile as compared to rofecoxib.</p> <p>Trial registration number -</p> <p>NCT00637949</p

The helicobacter eradication aspirin trial (HEAT): demographic data for randomised (H.pylori positive) patients

Introduction The Helicobacter Eradication Aspirin Trial (HEAT) is a multicentre, double blind, randomised controlled trial investigating whether Helicobacter pylori eradication reduces the incidence of hospitalisation for peptic ulcer bleeding [1]. Participants are subjects aged over 60, taking low dose aspirin for at least four months at the time of recruitment; all participants were recruited from primary care. H. pylori positive participants were randomised to receive one week active trial treatment (lansoprazole 30mg, clarithromycin 500mg and metronidazole 400mg twice daily) or placebo. Recruitment to the trial started in 2012 and completed in 2017; follow-up is endpoint driven and is ongoing. Methods Participants are followed up using a bespoke web-based trial management system that communicates directly with HEAT Toolkit software downloaded at participating GP practices, which issues MIQUEST [2] queries searching follow-up criteria. The primary endpoint of the study is the rate of hospitalisation due to definite or probable peptic ulcer bleeding. The study will end when 87 adjudicated events have occurred. Events are tracked by accumulating information from MIQUEST searches of GP databases via the HEAT toolkit, patient contact, review of national secondary care admission and mortality data. Results HEAT is being conducted in practices across the whole of the UK with 188,428 invitation letters sent from 1,208 GP practices. A total of 37,247 positive responses were received, representing a 20% response rate. Of those, 30,025 patients were consented to the study of whom 5,356 H. pylori positive patients were randomised. The percent of H. pylori positive patients varied from 13% to 39% throughout the country. Multiple deprivation scores applied to the data indicated an increase in response with less deprivation, but a decrease in the number of randomised patients. The mean age at randomisation for all participants was 73.6 ± 7.0 (SD) years, and 73.8% of participants are male. Only 7.2% of participants are smokers although 52.9% are ex-smokers. A total of 15% of the randomised patients have withdrawn from the trial, and 100 patients have died so far. Discussion The trial methodology has shown that recruitment of large numbers of patients from primary care is attainable, with the assistance of the NIHR Clinical Research Network, and could be applied to other outcomes studies at relatively low cost. Last year, there were almost 17,000 hospital admissions for gastric ulcers [3] and more than 1,850 recorded deaths [4] for gastric and duodenal ulcers. If successful, the study will help to reduce NHS costs and improve health outcomes by reducing hospital admissions, increasing patient safety and preventing premature deaths

Decreasing incidence of peptic ulcer complications after the introduction of the proton pump inhibitors, a study of the Swedish population from 1974–2002

<p>Abstract</p> <p>Background</p> <p>Despite a decreasing incidence of peptic ulcer disease, most previous studies report a stabile incidence of ulcer complications. We wanted to investigate the incidence of peptic ulcer complications in Sweden before and after the introduction of the proton pump inhibitors (PPI) in 1988 and compare these data to the sales of non-steroid anti-inflammatory drugs (NSAID) and acetylsalicylic acid (ASA).</p> <p>Methods</p> <p>All cases of gastric and duodenal ulcer complications diagnosed in Sweden from 1974 to 2002 were identified using the National hospital discharge register. Information on sales of ASA/NSAID was obtained from the National prescription survey.</p> <p>Results</p> <p>When comparing the time-periods before and after 1988 we found a significantly lower incidence of peptic ulcer complications during the later period for both sexes (p < 0.001). Incidence rates varied from 1.5 to 7.8/100000 inhabitants/year regarding perforated peptic ulcers and from 5.2 to 40.2 regarding peptic ulcer bleeding. The number of sold daily dosages of prescribed NSAID/ASA tripled from 1975 to 2002. The number of prescribed sales to women was higher than to males. Sales of low-dose ASA also increased. The total volume of NSAID and ASA, i.e. over the counter sale and sold on prescription, increased by 28% during the same period.</p> <p>Conclusion</p> <p>When comparing the periods before and after the introduction of the proton pump inhibitors we found a significant decrease in the incidence of peptic ulcer complications in the Swedish population after 1988 when PPI were introduced on the market. The cause of this decrease is most likely multifactorial, including smoking habits, NSAID consumption, prevalence of Helicobacter pylori and the introduction of PPI. Sales of prescribed NSAID/ASA increased, especially in middle-aged and elderly women. This fact seems to have had little effect on the incidence of peptic ulcer complications.</p

Long-term retention on treatment with lumiracoxib 100 mg once or twice daily compared with celecoxib 200 mg once daily: A randomised controlled trial in patients with osteoarthritis

BACKGROUND: The efficacy, safety and tolerability of lumiracoxib, a novel selective cyclooxygenase-2 (COX-2) inhibitor, has been demonstrated in previous studies of patients with osteoarthritis (OA). As it is important to establish the long-term safety and efficacy of treatments for a chronic disease such as OA, the present study compared the effects of lumiracoxib at doses of 100 mg once daily (o.d.) and 100 mg twice daily (b.i.d.) with those of celecoxib 200 mg o.d. on retention on treatment over 1 year. METHODS: In this 52-week, multicentre, randomised, double-blind, parallel-group study, male and female patients (aged at least 40 years) with symptomatic primary OA of the hip, knee, hand or spine were randomised (1:2:1) to lumiracoxib 100 mg o.d. (n = 755), lumiracoxib 100 mg b.i.d. (n = 1,519) or celecoxib 200 mg o.d. (n = 758). The primary objective of the study was to demonstrate non-inferiority of lumiracoxib at either dose compared with celecoxib 200 mg o.d. with respect to the 1-year retention on treatment rate. Secondary outcome variables included OA pain in the target joint, patient's and physician's global assessments of disease activity, Short Arthritis assessment Scale (SAS) total score, rescue medication use, and safety and tolerability. RESULTS: Retention rates at 1 year were similar for the lumiracoxib 100 mg o.d., lumiracoxib 100 mg b.i.d. and celecoxib 200 mg o.d. groups (46.9% vs 47.5% vs 45.3%, respectively). It was demonstrated that retention on treatment with lumiracoxib at either dose was non-inferior to celecoxib 200 mg o.d. Similarly, Kaplan-Meier curves for the probability of premature discontinuation from the study for any reason were similar across the treatment groups. All three treatments generally yielded comparable results for the secondary efficacy variables and all treatments were well tolerated. CONCLUSION: Long-term treatment with lumiracoxib 100 mg o.d., the recommended dose for OA, was as effective and well tolerated as celecoxib 200 mg o.d. in patients with OA. TRIAL REGISTRATION: clinicaltrials.gov NCT00145301

A comprehensive study on the role of the Yersinia pestis virulence markers in an animal model of pneumonic plague

We determined the role of Yersinia pestis virulence markers in an animal model of pneumonic plague. Eleven strains of Y. pestis were characterized using PCR assays to detect the presence of known virulence genes both encoded by the three plasmids as well as chromosomal markers. The virulence of all Y. pestis strains was compared in a mouse model for pneumonic plague. The presence of all known virulence genes correlated completely with virulence in the Balb/c mouse model. Strains which lacked HmsF initially exhibited visible signs of disease whereas all other strains (except wild-type strains) did not exhibit any disease signs. Forty-eight hours post-infection, mice which had received HmsF– strains regained body mass and were able to control infection; those infected with strains possessing a full complement of virulence genes suffered from fatal disease. The bacterial loads observed in the lung and other tissues reflected the observed clinical signs as did the cytokine changes measured in these animals. We can conclude that all known virulence genes are required for the establishment of pneumonic plague in mammalian animal models, the role of HmsF being of particular importance in disease progression

Cyclo-oxygenase inhibition reduces tumour growth and metastasis in an orthotopic model of breast cancer

The effect of selective and non-selective cyclo-oxygenase inhibition on tumour growth and metastasis in an orthotopic model of breast cancer was investigated. 4T1 mammary adenocarcinoma cells were injected into the mammary fat pad of female BALB/c mice. When tumours reached a mean tumour diameter of 8.4±0.4 mm, mice were randomised into three groups (n=6 per group) and received daily intraperitoneal injections of the selective cyclo-oxygenase-2 inhibitor, SC-236, the non selective cyclo-oxygenase inhibitor, Indomethacin, or drug vehicle. Tumour diameter was recorded on alternate days. From 8 days after initiation of treatment, tumour diameter in animals treated with either SC-236 or indomethacin was significantly reduced relative to controls. Both primary tumour weight and the number of lung metastases were significantly reduced in the SC-236 and indomethacin treated mice. Microvessel density was reduced and tumor cell apoptosis increased in the primary tumour of mice treated with either the selective or non-selective cyclo-oxygenase inhibitor. In vitro, cyclo-oxygenase inhibition decreased vascular endothelial growth factor production and increased apoptosis of tumour cells. Our results suggest that cyclo-oxygenase inhibitors will be of value in the treatment of both primary and metastatic breast cancer

Strategies to reduce medication errors with reference to older adults

Background  In Australia, around 59% of the general population uses prescription medication with this number increasing to about 86% in those aged 65 and over and 83% of the population over 85 using two or more medications simultaneously. A recent report suggests that between 2% and 3% of all hospital admissions in Australia may be medication related with older Australians at higher risk because of higher levels of medicine intake and increased likelihood of being admitted to hospital. The most common medication errors encountered in hospitals in Australia are prescription/medication ordering errors, dispensing, administration and medication recording errors. Contributing factors to these errors have largely not been reported in the hospital environment. In the community, inappropriate drugs, prescribing errors, administration errors, and inappropriate dose errors are most common. Objectives  To present the best available evidence for strategies to prevent or reduce the incidence of medication errors associated with the prescribing, dispensing and administration of medicines in the older persons in the acute, subacute and residential care settings, with specific attention to persons aged 65 years and over. Search strategy  Bibliographic databases PubMed, Embase, Current contents, The Cochrane Library and others were searched from 1986 to present along with existing health technology websites. The reference lists of included studies and reviews were searched for any additional literature. Selection criteria  Systematic reviews, randomised controlled trials and other research methods such as non-randomised controlled trials, longitudinal studies, cohort or case-control studies, or descriptive studies that evaluate strategies to identify and manage medication incidents. Those people who are involved in the prescribing, dispensing or administering of medication to the older persons (aged 65 years and older) in the acute, subacute or residential care settings were included. Where these studies were limited, evidence available on the general patient population was used. Data collection and analysis  Study design and quality were tabulated and relative risks, odds ratios, mean differences and associated 95% confidence intervals were calculated from individual comparative studies containing count data where possible. All other data were presented in a narrative summary. Results  Strategies that have some evidence for reducing medication incidents are: •  computerised physician ordering entry systems combined with clinical decision support systems; •  individual medication supply systems when compared with other dispensing systems such as ward stock approaches; •  use of clinical pharmacists in the inpatient setting; •  checking of medication orders by two nurses before dispensing medication; •  a Medication Administration Review and Safety committee; and •  providing bedside glucose monitors and educating nurses on importance of timely insulin administration. In general, the evidence for the effectiveness of intervention strategies to reduce the incidence of medication errors is weak and high-quality controlled trials are needed in all areas of medication prescription and delivery

The genetic basis and evolution of red blood cell sickling in deer

Crescent-shaped red blood cells, the hallmark of sickle-cell disease, present a striking departure from the biconcave disc shape normally found in mammals. Characterized by increased mechanical fragility, sickled cells promote haemolytic anaemia and vaso-occlusions and contribute directly to disease in humans. Remarkably, a similar sickle-shaped morphology has been observed in erythrocytes from several deer species, without obvious pathological consequences. The genetic basis of erythrocyte sickling in deer, however, remains unknown. Here, we determine the sequences of human β-globin orthologues in 15 deer species and use protein structural modelling to identify a sickling mechanism distinct from the human disease, coordinated by a derived valine (E22V) that is unique to sickling deer. Evidence for long-term maintenance of a trans-species sickling/non-sickling polymorphism suggests that sickling in deer is adaptive. Our results have implications for understanding the ecological regimes and molecular architectures that have promoted convergent evolution of sickling erythrocytes across vertebrates

A Prospective Study of Aspirin Use and the Risk of Gastrointestinal Bleeding in Men

Data regarding the influence of dose and duration of aspirin use on risk of gastrointestinal bleeding are conflicting.We conducted a prospective cohort study of 32,989 men enrolled in the Health Professionals Follow-up Study (HPFS) in 1994 who provided biennial aspirin data. We estimated relative risk of major gastrointestinal bleeding requiring hospitalization or a blood transfusion.During 14 years of follow-up, 707 men reported an episode of major gastrointestinal bleeding over 377,231 person-years. After adjusting for risk factors, regular aspirin use (≥2 times/week) had a multivariate relative risk (RR) of gastrointestinal bleeding of 1.32 (95% confidence interval [CI], 1.12-1.55) compared to non-regular use. The association was particularly evident for upper gastrointestinal bleeding (multivariate RR, 1.49; 95% CI, 1.16-1.92). Compared to men who denied any aspirin use, multivariate RRs of upper gastrointestinal bleeding were 1.05 (95% CI 0.71-1.52) for men who used 0.5-1.5 standard tablets/week, 1.31 (95% CI 0.88-1.95) for 2-5 aspirin/week, 1.63 (95% CI, 1.15-2.32) for 6-14 aspirin/week and 2.40 (95% CI, 1.10-5.22) for >14 aspirin/week (P(trend)<0.001). The relative risk also appeared to be dose-dependent among short-term users <5 years; P(trend)<.001) and long-term users (≥5 years; P(trend) = 0.015). In contrast, after controlling for dose, increasing duration of use did not appear to be associated with risk (P(trend) = 0.749).Regular aspirin use increases the risk of gastrointestinal bleeding, especially from the upper tract. However, risk of bleeding appears to be more strongly related to dose than to duration of use. Risk of bleeding should be minimized by using the lowest effective dose among short-term and long-term aspirin users