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Latest Findings (latest + finding)
Selected AbstractsProgress in understanding the biology of the human mutagen LINE-1,,HUMAN MUTATION, Issue 6 2007Daria V. Babushok Abstract Long interspersed nucleotide element (LINE)-1 retrotransposon (L1) has emerged as the largest contributor to mammalian genome mass, responsible for over 35% of the human genome. Differences in the number and activity levels of L1s contribute to interindividual variation in humans, both by affecting an individual's likelihood of acquiring new L1-mediated mutations, as well as by differentially modifying gene expression. Here, we report on recent progress in understanding L1 biology, with a focus on mechanisms of L1-mediated disease. We discuss known details of L1 lifecycle, including L1 structure, transcriptional regulation, and the mechanisms of translation and retrotransposition. Current views on cell type specificity, timing, and control of retrotransposition are put forth. Finally, we discuss the role of L1 as a mutagen, using the latest findings in L1 biology to illuminate molecular mechanisms of L1-mediated gene disruption. Hum Mutat 28(6), 527,539, 2007. Published 2007 Wiley-Liss, Inc. [source] Latest news and product developmentsPRESCRIBER, Issue 12 2007Article first published online: 4 OCT 200 NAO: GPs still not prescribing efficiently The National Audit Office (NAO) says NHS funds are being wasted through inefficient GP prescribing and patients not taking their medicines. The NAO's long-awaited report, Prescribing Costs in Primary Care (www.nao.org.uk), found large variations between PCTs in generic prescribing of statins, ACE inhibitors and angiotensin-II antagonists, and protonpump inhibitors; PCTs were also paying widely differing prices for these products. There was a five-fold variation in prescribing volume for clopidogrel between PCTs. These four drugs accounted for only 19 per cent of total spending but, if all practices matched the performance of the best 25 per cent, the NHS would save £200 million annually. PCTs should do more to rationalise prescribing and support their GPs, the NAO concludes. The NAO says that the cost of medicines dispensed for but not taken by patients lies somewhere in the range £100-£800 million annually. Strategies to reduce waste include public awareness campaigns and restricting supplies to four weeks (or two weeks for new medicines). Rosiglitazone may increase CV death risk A meta-analysis of 42 clinical trials has suggested that rosiglitazone is associated with increased risks of myocardial infarction (MI) and cardiovascular death (N Engl J Med 2007; published online 21 May: doi 10.1056/ NEJMoa072761). Like the COX-2 inhibitors, rosiglitazone was licensed without determining its possible effects on long-term cardiovascular outcomes, and interpretation of the latest findings is complicated by the multiple comparisons involved. For risk of MI, there was no significant difference between rosiglitazone and placebo (though this was of borderline statistical signifi-cance , p=0.07), metformin, sulphonylureas or insulin. Rosiglitazone was associated with a statistically significant 43 per cent increased risk compared with all comparators combined but the absolute increase in risk was very small (0.02 per cent). The trends were similar for risk of cardiovascular death, though rosiglitazone was associated with a 64 per cent increased risk compared with all comparators combined that was of borderline statistical significance (p=0.06). The authors acknowledge that their analysis pooled short-term studies that excluded patients at risk of heart disease and was not designed to determine cardiovascular outcomes, and they had no access to patientlevel data; as a result, there is uncertainty about their findings. Nevertheless, they say there is now an urgent need to clarify the risk associated with rosiglitazone. GlaxoSmithKline has rebutted the findings, stating that the cardiovascular risk profile of rosiglitazone is comparable with that of other oral antidiabetic drugs. The MHRA says warnings in the current SPCs for Avandia and Avandamet already reflect most of the data in the latest US review. The possible effects of rosiglitazone on cardiovascular events is currently being evaluated in the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes (RECORD) study. Good management tool The Department of Health has published a disease management tool to enable PCTs to model local interventions that could reduce emergency admissions. The web-based ,voluntary good practice tool' will demonstrate how interventions in primary care and social care settings can improve the management of long-term conditions including cardiovascular disease, asthma and COPD, and dementia and depression. Counterfeit medicines The MHRA has issued an unprecedented three alerts about fake medicines in the legitimate supply chain, recalling all affected lot numbers. Three batches of Zyprexa 10mg tablets (olanzapine) were withdrawn after a company printing labels became suspicious and alerted Eli Lilly. Two of the batches, which contained 60 per cent of the stated active ingredient, had reached patients but no adverse events were reported. Two lots of parallel-imported Plavix 75mg tablets (clopidogrel) have been withdrawn after counterfeit packs were identified. The lots were in French original packaging but will have been overlabelled for the UK market. The counterfeits were mixed with genuine packs from Sanofi-Aventis. Fake Casodex 50mg tablets (bicalutamide) have been identified in a parallel import from France. The Royal Pharmaceutical Society reports that the fake contains 75 per cent of the stated dose of bicalutamide. Alcohol-free mometasone Schering-plough has introduced an alcohol-free formulation of mometasone furoate nasal spray (Nasonex) for hay fever. The company says that an alcohol vehicle causes nasal irritation and leaves an unpleasant aftertaste, adding that over 40 per cent of patients cite this as the main reason for stopping treatment, and over 50 per cent state a preference for an alcohol-free product. Aid to improve statin adherence Adherence to statin therapy can be improved if patients use a decision aid when they are offered treatment,US investigators say (Arch Intern Med 2007;167:1076-82). The decision aid estimated the individual's 10-year cardiovascular risk and the risk reduction from treatment, and summarised the disadvantages of statins.Patients with diabetes who used the aid knew more about their risk and were less indecisive about treatment than those who did not. The odds of having missed a dose over three months were three times higher for patients who had not used the aid. Online tool calculates switch savings A new online tool can help GPs estimate the savings achievable from switching patients to cheaper medicines. The Switch Saving Calculator, developed by the Prescribing Analysis & Support Team at the NHS Regional Drug and Therapeutics Centre in Newcastle, calculates potential savings based on past, current or projected use of the target drug. It can be applied to individual prescribers or scaled up to practice, commissioning group, PCT, health authority or even national level. Separate calculators are available for primary and secondary care. The current version calculates potential savings by switching from atorvastatin to simvastatin. The Newcastle team says other drugs will be added and they will update prices regularly. The calculator is at www.nyrdtc.nhs.uk:80/Services/presc_supp/ switch_saving_calculator/switch_saving_calculator.html. No improvement in drug information for patients leaving hospital The information given to patients discharged from hospital is not improving, according to the Healthcare Commission's annual patient survey (www.healthcare commission.org.uk). The 2006 survey found that the commonest reason patients were kept waiting for at least four hours to leave hospital was the delay in providing discharge medicines. Provision of written information increased from 62 per cent of patients in 2005 to 65 per cent in 2006. However, only 76 per cent said they had been told about their medicines in a way they could ,completely' understand (79 per cent in 2002). The proportion of patients reporting complete information about sideeffects also fell (from 40 per cent in 2005 to 37 per cent). Aspirin in preeclampsia A new meta-analysis has found that primary prevention with low-dose aspirin modestly but consistently reduces the risk of preeclampsia (Lancet 2007; published online 18 May). The study of 31 trials involving 32 217 women at low to moderate risk found that antiplatelet agents (mostly aspirin) reduced the risk of pre-eclampsia and preterm birth by 10 per cent without an increased risk of bleeding. The benefit was similar across subgroups. There were also nonsignificant reductions in the risk of small for age, stillborn and death before discharge. New from NICE NICE approves varenicline for NHS NICE has endorsed the use of varenicline (Champix) as an aid to smoking cessation within the NHS for England and Wales; it has already been approved for use in Scotland by the Scottish Medicines Consortium. Varenicline is a partial agonist at the ,4,2 nicotinic receptor. It alleviates craving and withdrawal symptoms, and reduces the rewarding and reinforcing effects of smoking. The commonest adverse effect is mild to moderate nausea, which improves with time.1 Varenicline is licensed for smoking cessation in adults; NICE says it should be offered as an option for smokers who say they want to quit as part of a programme of behavioural support. However, treatment should not be withheld if counselling and support are not available. NICE was critical of manufacturer Pfizer's economic arguments in favour of varenicline, which inappropriately included US data, assumed a single quit attempt and may have overestimated its efficacy. It nonetheless concluded that varenicline is more effective than nicotine replacement therapy (NRT) or bupropion (Zyban) in achieving continuous abstinence. NICE estimated that, compared with NRT, the odds of abstinence at one year with varenicline were 54 per cent greater. A Cochrane review1 concluded that abstinence was 66 per cent more likely with varenicline than with bupropion, and three times more likely than with placebo. There was also a benefit from offering smokers a wider choice of treatments. A 12-week course of varenicline costs £163.80; it is also licensed for an additional 12-week course and dose tapering may be considered for those at high risk of relapse. The final appraisal determination does not state which is the treatment of first choice for smoking cessation. NICE is currently preparing guidance on smoking cessation in pri-mary care, pharmacies and workplaces. Copyright © 2007 Wiley Interface Ltd [source] Smoking-Related Morbidity and Mortality in the Cardiovascular SettingPREVENTIVE CARDIOLOGY, Issue 2007William B. White MD It is estimated that during the 20th century, 100 million people died of tobacco-related illnesses worldwide. The outlook for the future is grim as this number is expected to increase 10-fold during the 21st century. Many of these deaths will occur in middle-aged adults and, while most tobacco-related deaths currently occur in men, female mortality is expected to increase markedly due to increased rates of smoking in women, especially in developing countries. The risk of coronary heart disease is strongly associated with smoking in both developed and undeveloped countries. In addition, other forms of tobacco exposure (chewing, inhalation through water, and secondhand smoke) have also been documented to be important causes of coronary disease worldwide. Fortunately, the news is not all bad. Recent large-scale studies show that much of the excess risk associated with smoking is attenuated 1 to 2 years after quitting, depending on the level of smoking during an individual's lifetime. These latest findings should stimulate efforts of health care workers to become more aggressive toward cessation of smoking in our practices. [source] Comparative genomics of the poultry major histocompatibility complexANIMAL SCIENCE JOURNAL, Issue 2 2006Takashi SHIINA ABSTRACT This review summarizes the latest findings regarding the avian major histocompatibility complex (MHC), focusing particularly on the genomics of MHC in the Japanese quail (Cotrnix japonica) and other birds, as well as haplotype, genomics, function and disease resistance in the chicken (Gallus gallus). This information provides important insight into the breeding of disease resistance in poultry, natural selection of disease resistance in wild birds, and the effects of recombination and hitchhiking on the evolution of multiple MHC gene families. [source] Elicitation and suppression of microbe-associated molecular pattern-triggered immunity in plant,microbe interactionsCELLULAR MICROBIOLOGY, Issue 6 2007Ping He Summary Recent studies have uncovered fascinating molecular mechanisms underlying plant,microbe interactions that coevolved dynamically. As in animals, the primary plant innate immunity is immediately triggered by the detection of common pathogen- or microbe-associated molecular patterns (PAMPs/MAMPs). Different MAMPs are often perceived by distinct cell-surface pattern-recognition receptors (PRRs) and activate convergent intracellular signalling pathways in plant cells for broad-spectrum immunity. Successful pathogens, however, have evolved multiple virulence factors to suppress MAMP-triggered immunity. Specifically, diverse pathogenic bacteria have employed the type III secretion system to deliver a repertoire of virulence effector proteins to interfere with host immunity and promote pathogenesis. Plants challenged by pathogens have evolved the secondary plant innate immunity. In particular, some plants possess the specific intracellular disease resistance (R) proteins to effectively counteract virulence effectors of pathogens for effector-triggered immunity. This potent but cultivar-specific effector-triggered immunity occurs rapidly with localized programmed cell death/hypersensitive response to limit pathogen proliferation and disease development. Remarkably, bacteria have further acquired virulence effectors to block effector-triggered immunity. This review covers the latest findings in the dynamics of MAMP-triggered immunity and its interception by virulence factors of pathogenic bacteria. [source] | |||||||||||||