Effect of Statins on Functional Expression of Membrane Transporters in L6 Rat Skeletal Muscle Cells

Statins reduce LDL-cholesterol and the risk of atherosclerosis. They are generally safe, although statin-induced myopathy is relatively common. Membrane transporters play a crucial role in determining statin side effects. Little is known regarding the interaction of drug transporters in muscle cells with statins. Study aims: The present study aimed to determine the effect of statins on functional expression of monocarboxylate transporters (MCTs) and multidrug resistance-associated proteins (MRPs) in L6 rat skeletal myotube cells. Methods: Relative gene expression at mRNA level was confirmed by RT2 ProfilerTM Rat Drug Transporter PCR array. The uptake of 3H-labelled DL-lactate (1 μCi/ml) was measured to functionally expressed MCT function. The inhibition of [3H]-DL-lactate uptake was assessed in the presence or absence of statins and compared to that of the MCT inhibitors, phloretin and CHC. Transporter-mediated dye efflux was used as functional assay for the MRP efflux transporters. Results: In L6 rat skeletal myotubes, relatively high mRNA expression level was observed for Mct1and Mrp1for uptake and efflux transporters, respectively. The [3H]-DL-lactate uptake was shown to be a concentration-, pH-dependent and Na+-independent manner with Michaelis-Menten constant (Km) value of 16.17 ± 2.4 mM vs 15.63 ± 3.0 mM in the presence and absence of Na+, respectively. The maximum velocity of substrate binding (Vmax) of the DL-lactate uptake inhibition by lipophilic statins; simvastatin and atorvastatin, were in the same order as phloretin and CHC, while no significant inhibitory magnitude with hydrophilic statins; pravastatin and rosuvastatin. However, the L6 rat skeletal myotubes did not exhibit lactate efflux function. Among four of statins used, only simvastatin showed an affinity inhibition of MRP function in L6 cells. Conclusions: This study has shown that lipophilic statins significantly inhibit functional expression of MCTs, even though they have not shown relatively high inhibition impact on MRPs

Anticoagulation control and cost of monitoring of older patients on chronic warfarin therapy in three settings in North East England

Abstract Background: novel oral anticoagulants may be particularly cost-effective when INR control (TTR) with warfarin is poor or monitoring difficult. Setting: the Newcastle upon Tyne monitoring service, set in hospital or general practice and a domiciliary-based service for housebound patients. Objectives: to examine anticoagulation stability and costs of monitoring. Subjects: three hundred and twenty-six atrial fibrillation patients, 75 years and over, with target INR of two to three, accessing hospital (n = 100), general practice (n = 122) and domiciliary (n = 104) service. Methods: age, co-morbidities, length of warfarin treatment, medications, INR values and dose changes from January to December 2011 were recorded, and costs analysed. Results: home-monitored patients had taken warfarin for longer, mean 5.2 years, than hospital (3.7) or general practice (3.1) patients. Age and total number of drugs prescribed chronically were negatively related to TTR. INR measurements and dose changes were negatively associated with the duration of treatment, positively correlated with co-morbidities. The mean TTR was 78% in hospital, 71% in general practice and 68% in domiciliary monitored patients. INR was monitored more often in hospital and domiciliary groups than in general practice and more dose changes occurred in the domiciliary group than in others. Costs of warfarin and monitoring were £128 per patient per year for hospital, £126 for general practice and £222 for domiciliary patients. Conclusions: further exploration of the clinical effectiveness of novel anticoagulants in dependent patients is warranted to determine to what extent trial outcomes so far achieved in a fitter elderly population are influenced by the chronic co-morbidities of old age

A multi-factorial analysis of response to warfarin in a UK prospective cohort

Background Warfarin is the most widely used oral anticoagulant worldwide, but it has a narrow therapeutic index which necessitates constant monitoring of anticoagulation response. Previous genome-wide studies have focused on identifying factors explaining variance in stable dose, but have not explored the initial patient response to warfarin, and a wider range of clinical and biochemical factors affecting both initial and stable dosing with warfarin. Methods A prospective cohort of 711 patients starting warfarin was followed up for 6 months with analyses focusing on both non-genetic and genetic factors. The outcome measures used were mean weekly warfarin dose (MWD), stable mean weekly dose (SMWD) and international normalised ratio (INR) > 4 during the first week. Samples were genotyped on the Illumina Human610-Quad chip. Statistical analyses were performed using Plink and R. Results VKORC1 and CYP2C9 were the major genetic determinants of warfarin MWD and SMWD, with CYP4F2 having a smaller effect. Age, height, weight, cigarette smoking and interacting medications accounted for less than 20 % of the variance. Our multifactorial analysis explained 57.89 % and 56.97 % of the variation for MWD and SMWD, respectively. Genotypes for VKORC1 and CYP2C9*3, age, height and weight, as well as other clinical factors such as alcohol consumption, loading dose and concomitant drugs were important for the initial INR response to warfarin. In a small subset of patients for whom data were available, levels of the coagulation factors VII and IX (highly correlated) also played a role. Conclusion Our multifactorial analysis in a prospectively recruited cohort has shown that multiple factors, genetic and clinical, are important in determining the response to warfarin. VKORC1 and CYP2C9 genetic polymorphisms are the most important determinants of warfarin dosing, and it is highly unlikely that other common variants of clinical importance influencing warfarin dosage will be found. Both VKORC1 and CYP2C9*3 are important determinants of the initial INR response to warfarin. Other novel variants, which did not reach genome-wide significance, were identified for the different outcome measures, but need replication

Verbal Autopsy: Reliability and Validity Estimates for Causes of Death in the Golestan Cohort Study in Iran

BACKGROUND: Verbal autopsy (VA) is one method to obtain valid estimates of causes of death in the absence of valid medical records. We tested the reliability and validity of a VA questionnaire developed for a cohort study in Golestan Province in northeastern Iran. METHOD: A modified version of the WHO adult verbal autopsy was used to assess the cause of death in the first 219 Golestan Cohort Study (GCS) subjects who died. The GCS cause of death was determined by two internists who independently reviewed all available medical records. Two other internists ("reviewers") independently reviewed only the VA answers and classified the cause of death into one of nine general categories; they repeated this evaluation one month later. The reliability of the VA was measured by calculating intra-reviewer and inter-reviewer kappa statistics. The validity of the VA was measured using the GCS cause of death as the gold standard. RESULTS: VA showed both good validity (sensitivity, specificity, PPV, and NPV all above 0.81) and reliability (kappa>0.75) in determining the general cause of death independent of sex and place of residence. The overall multi-rater agreement across four reviews was 0.84 (95%CI: 0.78-0.89). The results for identifying specific cancer deaths were also promising, especially for upper GI cancers (kappa = 0.95). The multi-rater agreement in cancer subgroup was 0.93 (95%CI: 0.85-0.99). CONCLUSIONS: VA seems to have good reliability and validity for determining the cause of death in a large-scale adult follow up study in a predominantly rural area of a middle-income country

درک تجربه عدم اشتغال در افراد مبتلا به ضایعات نخاعی در روند برگشت به کار

مقدمه: از دست دادن کار و موانع موجود در راه بازگشت به کار از پیامدهای ابتلا به ضایعات نخاعی است. این مقاله شامل بخشی از نتایج پژوهش کیفی تحت عنوان "درک تجربه زیسته افراد مبتلا به ضایعات نخاعی در روند برگشت به کار در شهر قم" بود که با هدف شناخت عوامل زمینه‌ساز عدم موفقیت در برگشت به کار پس از ابتلا به ضایعه نخاعی تنظیم شد. مواد و روش‌ها: پژوهش فوق به روش کیفی و شیوه پدیده‌ شناسی انجام شد. شرکت کنندگان، مردان مبتلا به ضایعه نخاعی پاراپلژی دارای پرونده در اداره بهزیستی استان قم بودند. نمونه‌گیری به روش هدفمند بود و تا اشباع کامل اطلاعات ادامه یافت. تعداد شرکت کنندگان به 20 نفر رسید که در دو گروه 10 نفری شاغل و غیر شاغل قرار داشتند. جمع‌آوری داده‌ها با استفاده از مصاحبه نیمه ساختار یافته باز عمیق فردی و تفسیر داده‌ها به روش Van Mannen انجام شد. یافته‌ها: در مجموع 6 مضمون محوری در این پژوهش ظهور یافت که بیانگر تجارب شرکت کنندگان از مشکلات و موانع موجود در راه بازگشت به کار بود. نتیجه گیری: بررسی‌ها نشان داد که در برخی زیرمضمون‌ها تفاوت‌هایی در گفته‌های افراد غیر شاغل با شاغلین وجود دارد که بیانگر عوامل تعیین کننده موفقیت یا عدم موفقیت در برگشت به کار بود. در واقع می‌توان گفت درک نادرست افراد از مشکلات جسمی، نوع شخصیت وابسته و غیرفعال، نگرش منفی نسبت به مسایل و فقدان حمایت‌های روحی- روانی خانواده از موانع برگشت به کار اختصاصی افراد غیر شاغل در این مطالعه بود. کلید واژه‌ها: ضایعه نخاعی، اشتغال، بازگشت به کا

Factors influencing alcohol and illicit drug use amongst medical students. Drug and alcohol dependence

Abstract Alcohol, illicit drug use, and other lifestyle variables, as well as stress, anxiety and personality were evaluated in 194 first year medical students. 45% of the students reported drinking above the recommended UK limits for alcohol consumption. The age at which the first full drink of alcohol was taken was predictive of the current level of alcohol use. Cannabis was the most frequently used illicit drug (45%). There were significant positive associations between alcohol consumption and experiences such as missing study, becoming more sexually involved and getting into a physical fight or argument. There were also significant positive associations between the personality characteristic of psychoticism and alcohol and illicit drug consumption. The effectiveness of current health education on alcohol and illicit drugs is questioned

Exploring Techniques of Addressing Grammar in CLT Classes: A Qualitative Study

Learners who have learned English through the audio-lingual method have a profound knowledge of grammar, but they cannot use it to communicate their knowledge and experience fluently. To solve this problem, there was a shift towards communicative language teaching (CLT). This shift towards CLT solved the fluency problem but created another unwanted effect since learners were communicatively competent but linguistically incompetent. While many teachers weed out form as irrelevant, some CLT teachers try to respond to this problem by addressing from in CLT classes. This study aims at conceptualizing these teachers’ perspectives and uncover the strategies they use in addressing grammar in communicative instruction. Following the constructivist grounded theory procedures, participants’ perspectives were theoretically sampled through in-depth, open-ended interviews. Abstraction and thematic analysis of participants’ experiences clearly revealed that the participants helped learners not only discover the target form but also connect it to their experience. It was also found that they used contrastive analysis, contextualization of input flood, and the integrated skill approach to address form in predominantly communicative classes. These findings have clear implications for teachers, teacher trainers and school policy makers