The novel genetic variant predisposing to coronary artery disease in the region of the PSRC1 and CELSR2 genes on chromosome 1 associates with serum cholesterol

Through genome-wide association studies, we have recently identified seven novel loci that confer a substantial increase in risk for coronary artery disease (CAD). Elucidating the mechanisms by which these loci affect CAD risk could have important clinical utility. Here, we investigated whether these loci act through mechanisms involving traditional cardiovascular risk factors. We genotyped 2,037 adult individuals from 520 nuclear families characterised for body mass index, waist-hip ratio, 24-h ambulatory blood pressure, total cholesterol, high-density lipoprotein cholesterol and glucose for the lead single nucleotide polymorphisms (SNPs) in the seven CAD-associated loci. SNP rs599839, representing the locus in the vicinity of the PSRC1 and CELSR2 genes on chromosome 1p13.3, showed a strong association with total cholesterol. The CAD-associated risk allele A of rs599839 (allele frequency 0.78) was associated with a 0.17-mmol/l (95% CI 0.10 to 0.24 mmol/l) higher serum cholesterol level per allele copy (P = 3.84 × 10⁻⁶). The association of the A allele with higher total cholesterol was confirmed in an independent cohort (n = 847) of healthy adults (P = 1.0 × 10⁻⁴) and related to an effect on low-density lipoprotein (LDL) cholesterol (P = 8.56 × 10⁻⁵). An association of rs599839 with LDL cholesterol was also shown in 1,090 cases with myocardial infarction (P = 0.0026). None of the other variants showed a strong association with the measured cardiovascular risk factors, suggesting that these loci act through other mechanisms. However, the novel CAD-associated locus in the vicinity of the PSRC1 and CELSR2 genes on chromosome 1 probably enhances CAD risk through an effect on plasma LDL cholesterol. The findings support further investigation of the role of these genes in cholesterol metabolism and coronary risk. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. Nilesh J. Samani, Peter S. Braund and Jeanette Erdmann contributed equally to this work.     

Economic incentives and nutritional behavior of children in the school setting: a systematic review

The aim of the present review was to examine the existing literature on the effectiveness of economic incentives for producing sound nutritional behavior in schools. Studies published in the English-language literature that included baseline and/or outcome data regarding food and beverage intake of schoolchildren were eligible for inclusion. A systematic search of the literature was conducted to identify relevant primary studies and relevant systematic reviews of primary studies. Altogether, 3,472 research publications were identified in the systematic search, of which 50 papers were retrieved. Of these, 30 publications representing 28 studies fulfilled the criteria for inclusion. The studies addressing price incentives suggest that such incentives are effective for altering consumption in the school setting. Other types of economic incentives have been included in combined intervention schemes, but the inclusion of other intervention elements makes it difficult to draw conclusions about the effectiveness of the economic incentive instruments per se in these studies.     

Factors associated with severe illness in pandemic 2009 influenza a (H1N1) infection: implications for triage in primary and secondary care

Pandemic (H1N1) 2009 influenza virus (pH1N1/09) infection spread rapidly around the globe, leading to a phase 6 pandemic level of alert declared in June 2009. The WHO declared the end of the pandemic in August 2010. Although for the majority of infected patients, it manifest as a mild, self-limiting illness, a proportion appeared to follow an adverse clinical course, requiring higher level care and aggressive management strategies. Experience with previous pandemics suggests that H1N1 will continue to circulate for many years. The aim of this review is to evaluate data from published case series reporting patients with pH1N1/09 influenza to identify clinical markers of severe disease. Comorbid illnesses including chronic lung disease, obesity and pregnancy have been shown to confer increased risk of severe infection. Admission vital signs, laboratory investigations and chest radiographic features can guide admitting clinicians to stratify patients’ risk of severe disease, however, the currently available severity scoring tools have only a limited role in risk assessment. Knowledge of high risk parameters remains important for clinicians triaging patients with suspected pH1N1/09 influenza and to inform strategies for future pandemics.     

Development and implementation of an alcohol withdrawal protocol using a 5-item scale,the Brief Alcohol Withdrawal Scale (BAWS)

Background: The standard of care for management of alcohol withdrawal is symptom-triggered treatment using the Clinical Institute Withdrawal Assessment for Alcohol (CIWA-Ar). Many items of this 10-question scale rely on subjective assessments of withdrawal symptoms, making it time-consuming and cumbersome to use. Therefore, there is interest in shorter and more objective methods to assess alcohol withdrawal symptoms. Methods: A 6-item withdrawal scale developed at another institution was piloted. Based on comparison with the CIWA-Ar, this was adapted into a 5-item scale named the Brief Alcohol Withdrawal Scale (BAWS). The BAWS was compared with the CIWA-Ar and a withdrawal protocol utilizing the BAWS was developed. The new protocol was implemented on an inpatient unit dedicated to treating substance withdrawal. Data was collected on the first 3 months of implementation and compared with the 3 months prior to that. Results: A BAWS score of 3 or more predicted CIWA-Ar score ≥8 with a sensitivity of 85.3% and specificity of 65.8%. The demographics of the patients in the 2 time periods were similar: the mean age was 45.9; 70.6% were male; 30.9% received concurrent treatment for opioid withdrawal; and 14.2% were receiving methadone maintenance. During the BAWS phase, patients received significantly less diazepam (mean dose 81.4 vs. 60.3 mg, P < .001). There was no significant difference in length of stay. No patients experienced a seizure, delirium, or required transfer to a higher level of care during any of the 664 admissions in either phase. Conclusions: This simple protocol utilizing a 5-item withdrawal scale performed well in this setting. Its use in other settings, particularly with patients with concurrent medical illnesses or more severe withdrawal, needs to be explored further.     

History of physical abuse and periconceptional drinking in pregnant women

This study examines the relationship between physical abuse and periconceptional drinking in women presenting to a mid-Atlantic, urban hospital-based OB/GYN clinic serving a largely indigent population between April 2003 and May 2004. During their first prenatal visit, 308 women completed a screening battery that included the Abuse Assessment Screen (AAS) and measures of alcohol use, including the CAGE, T-ACE, TWEAK, and the PRIME-MD Patient Health Questionnaire (PHQ). Bivariate analyses, including odds ratios (ORs) and 95% confidence intervals (CIs), revealed that women with a history of physical abuse were more likely to report drinking alcohol within the 3 months prior to their prenatal care visit and were significantly more likely to meet criteria for risk drinking on multiple measures. A history of physical abuse appears to be associated with higher self-reported rates of periconceptional drinking in pregnant women. Study findings support the need for assessment of abuse history as a potential risk factor for alcohol use in pregnant women.     

Synthesis and characterization of a BODIPY conjugate of the BCR-ABL kinase inhibitor Tasigna (nilotinib): evidence for transport of Tasigna and its fluorescent derivative by ABC drug transporters

Tasigna (Nilotinib) is a BCR-ABL kinase inhibitor recently approved by the Food and Drug Administration, which is indicated for the treatment of drug-resistant chronic myelogenous leukemia (CML). The efflux of tyrosine kinase inhibitors by ATP-binding cassette (ABC) drug transporters, which actively pump these drugs out of cells utilizing ATP as an energy source, has been linked to the development of drug resistance in CML patients. We report here the synthesis and characterization of a fluorescent derivative of Tasigna to study its interaction with two major ABC transporters, P-glycoprotein (Pgp) and ABCG2, in in vitro and ex vivo assays. A fluorescent derivative of Tasigna, BODIPY FL Tasigna, inhibited the BCR-ABL kinase activity in K562 cells and was also effluxed by Pgp- and ABCG2-expressing cells in both cultured cells and rat brain capillaries expressing Pgp and ABCG2. In addition, [(3)H]-Tasigna was found to be transported by Pgp-expressing polarized LLC-PK1 cells in a transepithelial transport assay. Consistent with these results, both Tasigna and BODIPY FL Tasigna were less effective at inhibiting the phosphorylation of Crkl (a substrate of BCR-ABL kinase) in Pgp- and ABCG2-expressing K562 cells due to their reduced intracellular concentration. Taken together, these data provide evidence that BODIPY FL Tasigna is transported by Pgp and ABCG2, and Tasigna is transported by Pgp. Further, we propose that BODIPY FL Tasigna can potentially be used as a probe for functional analysis of Pgp and ABCG2 in cancer cells and in other preclinical studies.