Approach to Dyslipidemia, Lipodystrophy, and Cardiovascular Risk in Patients with HIV Infection

There is a significant prevalence (20%–80% depending on the population and the study) of lipid disorders and other cardiovascular risk factors in people living with HIV infection. This review focuses on HIV and HIV treatment–associated metabolic and cardiovascular concerns, including dyslipidemias, lipodystrophy syndromes, endothelial dysfunctions, and associated metabolic events such as insulin resistance. Emerging hypotheses of the underlying pathophysiology of these issues, with impact on selection of specific antiretroviral treatment (ART) strategies, therapy, and preventive approaches to decreasing cardiovascular risk and other problems associated with these syndromes are discussed. Screening for cardiovascular risk as part of the decision of starting antiretroviral therapy, and during care of patients with HIV regardless of ART therapy status, is suggested with particular areas of focus. Statins, other hyperlipidemic therapies, treatment for specific problems arising due to lipodystrophy, and implications on ART selection to avoid drug interactions and adverse effects are also discussed

Molecular Poltergeists: Mitochondrial DNA Copies (numts) in Sequenced Nuclear Genomes

The natural transfer of DNA from mitochondria to the nucleus generates nuclear copies of mitochondrial DNA (numts) and is an ongoing evolutionary process, as genome sequences attest. In humans, five different numts cause genetic disease and a dozen human loci are polymorphic for the presence of numts, underscoring the rapid rate at which mitochondrial sequences reach the nucleus over evolutionary time. In the laboratory and in nature, numts enter the nuclear DNA via non-homolgous end joining (NHEJ) at double-strand breaks (DSBs). The frequency of numt insertions among 85 sequenced eukaryotic genomes reveal that numt content is strongly correlated with genome size, suggesting that the numt insertion rate might be limited by DSB frequency. Polymorphic numts in humans link maternally inherited mitochondrial genotypes to nuclear DNA haplotypes during the past, offering new opportunities to associate nuclear markers with mitochondrial markers back in time

Effective DNA/RNA Co-Extraction for Analysis of MicroRNAs, mRNAs, and Genomic DNA from Formalin-Fixed Paraffin-Embedded Specimens

Background: Retrospective studies of archived human specimens, with known clinical follow-up, are used to identify predictive and prognostic molecular markers of disease. Due to biochemical differences, however, formalin-fixed paraffinembedded (FFPE) DNA and RNA have generally been extracted separately from either different tissue sections or from the same section by dividing the digested tissue. The former limits accurate correlation whilst the latter is impractical when utilizing rare or limited archived specimens. Principal Findings: For effective recovery of genomic DNA and total RNA from a single FFPE specimen, without splitting the proteinase-K digested tissue solution, we optimized a co-extraction method by using TRIzol and purifying DNA from the lower aqueous and RNA from the upper organic phases. Using a series of seven different archived specimens, we evaluated the total amounts of genomic DNA and total RNA recovered by our TRIzol-based co-extraction method and compared our results with those from two commercial kits, the Qiagen AllPrep DNA/RNA FFPE kit, for co-extraction, and the Ambion RecoverAll TM Total Nucleic Acid Isolation kit, for separate extraction of FFPE-DNA and-RNA. Then, to accurately assess the quality of DNA and RNA co-extracted from a single FFPE specimen, we used qRT-PCR, gene expression profiling and methylation assays to analyze microRNAs, mRNAs, and genomic DNA recovered from matched fresh and FFPE MCF10A cells. These experiments show that the TRIzol-based co-extraction method provides larger amounts of FFPE-DNA and –RNA tha

Primula vulgaris (primrose) genome assembly, annotation and gene expression, with comparative genomics on the heterostyly supergene

Primula vulgaris (primrose) exhibits heterostyly: plants produce self-incompatible pin- or thrum-form flowers, with anthers and stigma at reciprocal heights. Darwin concluded that this arrangement promotes insect-mediated cross-pollination; later studies revealed control by a cluster of genes, or supergene, known as the S (Style length) locus. The P. vulgaris S locus is absent from pin plants and hemizygous in thrum plants (thrum-specific); mutation of S locus genes produces self-fertile homostyle flowers with anthers and stigma at equal heights. Here, we present a 411 Mb P. vulgaris genome assembly of a homozygous inbred long homostyle, representing ~87% of the genome. We annotate over 24,000 P. vulgaris genes, and reveal more genes up-regulated in thrum than pin flowers. We show reduced genomic read coverage across the S locus in other Primula species, including P. veris, where we define the conserved structure and expression of the S locus genes in thrum. Further analysis reveals the S locus has elevated repeat content (64%) compared to the wider genome (37%). Our studies suggest conservation of S locus genetic architecture in Primula, and provide a platform for identification and evolutionary analysis of the S locus and downstream targets that regulate heterostyly in diverse heterostylous species

Collaborative care for the detection and management of depression among adults with hypertension in South Africa: study protocol for the PRIME-SA randomised controlled trial

Background: The high co-morbidity of mental disorders, particularly depression, with non-communicable diseases (NCDs) such as cardiovascular disease (CVD), is concerning given the rising burden of NCDs globally, and the role depression plays in confounding prevention and treatment of NCDs. The objective of this randomised control trial (RCT) is to determine the real-world effectiveness of strengthened depression identification and management on depression outcomes in hypertensive patients attending primary health care (PHC) facilities in South Africa (SA). Methods/design: The study design is a pragmatic, two-arm, parallel-cluster RCT, the unit of randomisation being the clinics, with outcomes being measured for individual participants. The 20 largest eligible clinics from one district in the North West Province are enrolled in the trial. Equal numbers of hypertensive patients (n = 50) identified as having depression using the Patient Health Questionnaire (PHQ-9) are enrolled from each clinic, making up a total of 1000 participants with 500 in each arm. The nurse clinicians in the control facilities receive the standard training in Primary Care 101 (PC101), a clinical decision support tool for integrated chronic care that includes guidelines for hypertension and depression care. Referral pathways available include referrals to PHC physicians, clinical or counselling psychologists and outpatient psychiatric and psychological services. In the intervention clinics, this training is supplemented with strengthened training in the depression components of PC101 as well as training in clinical communication skills for nurse-led chronic care. Referral pathways are strengthened through the introduction of a facility-based behavioural health counsellor, trained to provide structured manualised counselling for depression and adherence counselling for all chronic conditions. The primary outcome is defined as at least 50% reduction in PHQ-9 score measured at 6 months. Discussion: This trial should provide evidence of the real world effectiveness of strengtheneddepression identification and collaborative management on health outcomes of hypertensive patients withcomorbid depression attending PHC facilities in South Africa

New Insight into the Colonization Processes of Common Voles: Inferences from Molecular and Fossil Evidence

Elucidating the colonization processes associated with Quaternary climatic cycles is important in order to understand the distribution of biodiversity and the evolutionary potential of temperate plant and animal species. In Europe, general evolutionary scenarios have been defined from genetic evidence. Recently, these scenarios have been challenged with genetic as well as fossil data. The origins of the modern distributions of most temperate plant and animal species could predate the Last Glacial Maximum. The glacial survival of such populations may have occurred in either southern (Mediterranean regions) and/or northern (Carpathians) refugia. Here, a phylogeographic analysis of a widespread European small mammal (Microtus arvalis) is conducted with a multidisciplinary approach. Genetic, fossil and ecological traits are used to assess the evolutionary history of this vole. Regardless of whether the European distribution of the five previously identified evolutionary lineages is corroborated, this combined analysis brings to light several colonization processes of M. arvalis. The species' dispersal was relatively gradual with glacial survival in small favourable habitats in Western Europe (from Germany to Spain) while in the rest of Europe, because of periglacial conditions, dispersal was less regular with bottleneck events followed by postglacial expansions. Our study demonstrates that the evolutionary history of European temperate small mammals is indeed much more complex than previously suggested. Species can experience heterogeneous evolutionary histories over their geographic range. Multidisciplinary approaches should therefore be preferentially chosen in prospective studies, the better to understand the impact of climatic change on past and present biodiversity

Risk of cardiovascular events from current, recent, and cumulative exposure to abacavir among persons living with HIV who were receiving antiretroviral therapy in the United States: a cohort study

Abstract Background There is ongoing controversy regarding abacavir use in the treatment of HIV infection and the risk of subsequent development of cardiovascular disease. It is unclear how the risk varies as exposure accumulates. Methods Using an administrative health-plan dataset, risk of cardiovascular disease events (CVDe), defined as the first episode of an acute myocardial infarction or a coronary intervention procedure, associated with abacavir exposure was assessed among HIV-infected individuals receiving antiretroviral therapy across the U.S. from October 2009 through December 2014. The data were longitudinal, and analyzed using marginal structural models. Results Over 114,470 person-years (n = 72,733) of ART exposure, 714 CVDe occurred at an incidence rate (IR) (95% CI) of 6·23 (5·80, 6·71)/1000 person-years. Individuals exposed to abacavir had a higher IR of CVDe of 9·74 (8·24, 11·52)/1000 person-years as compared to 5·75 (5·30, 6·24)/1000 person-years for those exposed to other antiretroviral agents. The hazard (HR; 95% CI) of CVDe was increased for current (1·43; 1·18, 1·73), recent (1·41; 1·16, 1·70), and cumulative [(1·18; 1·06, 1·31) per year] exposure to abacavir. The risk for cumulative exposure followed a bell-shaped dose-response curve peaking at 24-months of exposure. Risk was similarly elevated among participants free of pre-existing heart disease or history of illicit substance use at baseline. Conclusion Current, recent, and cumulative use of abacavir was associated with an increased risk of CVDe. The findings were consistent irrespective of underlying cardiovascular risk factors