Publications

Multidrug resistance protein 2 (MRP2, ABCC2) is an efflux membrane transporter highly expressed in liver, kidney and intestine with important physiological and pharmacological roles. The goal of this study was to investigate the functional significance of promoter region polymorphisms in ABCC2 and potential allele-specific expression. Twelve polymorphisms in the 1.6 kb region upstream of the translation start site were identified by resequencing 247 DNA samples from ethnically diverse individuals. Luciferase reporter gene assays showed that ABCC2 -24C>T both alone and as part of a common haplotype (-24C>T/-1019A>G/-1549G>A) increased promoter function 35% compared with the reference sequence (P<0.0001). No other common variants or haplotypes affected ABCC2 promoter activity. Allele-specific expression was also investigated as a mechanism to explain reported associations of the synonymous ABCC2 3972C>T variant with pharmacokinetic phenotypes. In Caucasian liver samples (n=41) heterozygous for the 3972C>T polymorphism, the 3972C allele was preferentially transcribed relative to the 3972T allele (P<0.0001). This allelic imbalance was particularly apparent in samples with haplotypes containing two or three promoter/untranslated region variants (-1549G>A, -1019A>G and -24C>T). The observed allelic imbalance was not associated with hepatic or renal ABCC2 mRNA expression. Additional mechanisms will need to be explored to account for the interindividual variation in ABCC2 expression and MRP2 function.

BACKGROUND

Since its emergence in 2000, epidemic spread of the methicillin-resistant Staphylococcus aureus (MRSA) clone USA300 has led to a high burden of skin and soft tissue infections (SSTIs) in the United States, yet its impact on MRSA bloodstream infections (BSIs) is poorly characterized.

METHODS

To assess clonality of the MRSA isolates causing SSTI and BSI during the epidemic period, a stratified, random sample of 1350 unique infection isolates (from a total of 7252) recovered at the Community Health Network of San Francisco from 2000 to 2008 were selected for genotyping. Risk factors and outcomes for 549 BSI cases caused by the USA300 epidemic clone and non-USA300 MRSA clones were assessed by retrospective review of patient medical records.

RESULTS

From 2000 to 2008, secular trends of USA300 SSTI and USA300 BSI were strongly correlated (Pearson r = 0.953). USA300 accounted for 55% (304/549) of BSIs as it was the predominant MRSA clone that caused community-associated (115/160), healthcare-associated community-onset (125/207), and hospital-onset (64/182) BSIs. Length of hospitalization after BSI diagnosis and mortality rates for USA300 and non-USA300 were similar. Two independent risk factors for USA300 BSI were identified: concurrent SSTI (adjusted relative risk, 1.4 [95% confidence interval {CI}, 1.2-1.6]) and anti-MRSA antimicrobial use in the preceding 30 days (0.7 [95% CI, .6-.8]). Isolates from concurrent SSTI were indistinguishable genotypically from the USA300 isolates that caused BSI.

CONCLUSIONS

USA300 SSTIs serve as a source for BSI. Strategies to control the USA300 SSTI epidemic may lessen the severity of the concurrent USA300 BSI epidemic.

Epigenetic mechanisms provide an adaptive layer of control in the regulation of gene expression that enables an organism to adjust to a changing environment. Epigenetic regulation increases the functional complexity of deoxyribonucleic acid (DNA) by altering chromatin structure, nuclear organization, and transcript stability. These changes may additively or synergistically influence gene expression and result in long-term molecular and functional consequences independent of the DNA sequence that may ultimately define an individual's phenotype. This article (1) describes histone modification, DNA methylation, and expression of small noncoding RNA species; (2) reviews the most common methods used to measure these epigenetic changes; and (3) presents factors that need to be considered when choosing a specific tissue to evaluate for epigenetic changes.

The International Conference on Human Immunity to Tuberculosis, held in April 2012 in Atlanta, Georgia, USA provided the opportunity to discuss the current state of knowledge, important knowledge gaps, and approaches to overcoming obstacles to better understand protective and pathological immunity.

Vitamin D deficiency is a common condition that has well-documented effects on musculoskeletal health. A growing body of literature has related vitamin D deficiency to other chronic disorders, including cardiovascular disease. Several plausible biological mechanisms have been postulated to explain this association, including the effect of poor vitamin D status on intermediate risk factors (eg, hypertension and diabetes), neurohormonal activation, inflammation, and cardiac remodeling. These mechanisms have been explored in experimental and animal studies, as well as several small interventional studies. The results of the controlled trials have not been conclusive to date. In this review, we summarize the existing studies investigating the effects of vitamin D on cardiovascular health, and propose that additional well-designed, prospective, randomized controlled trials are necessary to delineate the appropriate role of vitamin D supplementation in reducing the burden of cardiovascular disease.