Is PPARγ a Prospective Player in HIV-1-Associated Bone Disease?

Currently infection with the human immunodeficiency virus-1 (HIV-1) is in most instances a chronic disease that can be controlled by effective antiretroviral therapy (ART). However, chronic use of ART has been associated with a number of toxicities; including significant reductions in bone mineral density (BMD) and disorders of the fat metabolism. The peroxisome proliferator-activated receptor gamma (PPARγ) transcription factor is vital for the development and maintenance of mature and developing adipocytes. Alterations in PPARγ expression have been implicated as a factor in the mechanism of HIV-1-associated lipodystrophy. Both reduced BMD and lipodystrophy have been well described as complications of HIV-1 infection and treatment, and a question remains as to their interdependence. Interestingly, both adipocytes and osteoblasts are derived from a common precursor cell type; the mesenchymal stem cell. The possibility that dysregulation of PPARγ (and the subsequent effect on both osteoblastogenesis and adipogenesis) is a contributory factor in the lipid- and bone-abnormalities observed in HIV-1 infection and treatment has also been investigated. This review deals with the hypothesis that dysregulation of PPARγ may underpin the bone abnormalities associated with HIV-1 infection, and treats the current knowledge and prospective developments, in our understanding of PPARγ involvement in HIV-1-associated bone disease

Recommendations for HER2 testing in the UK

Determining the HER2 status of breast carcinomas is a prerequisite for the use of the monoclonal antibody trastuzumab (Herceptin(R)), which has recently been licensed for the treatment of metastatic disease. This necessitates a test based on archival material. The preferred analyses are immunohistochemistry with fluorescent in situ hybridisation (FISH) as a follow up test for ambiguous results. Guidelines have been developed for standardised, well controlled procedures for the provision of reliable results. A group of three reference laboratories has been established to provide advice, quality assurance, and materials, where needed

The Explication Defence of Arguments from Reference

In a number of influential papers, Machery, Mallon, Nichols and Stich have presented a powerful critique of so-called arguments from reference, arguments that assume that a particular theory of reference is correct in order to establish a substantive conclusion. The critique is that, due to cross-cultural variation in semantic intuitions supposedly undermining the standard methodology for theorising about reference, the assumption that a theory of reference is correct is unjustified. I argue that the many extant responses to Machery et al.’s critique do little for the proponent of an argument from reference, as they do not show how to justify the problematic assumption. I then argue that it can in principle be justified by an appeal to Carnapian explication. I show how to apply the explication defence to arguments from reference given by Andreasen (for the biological reality of race) and by Churchland (against the existence of beliefs and desires)

Drivers of Holocene peatland carbon accumulation across a climate gradient in northeastern North America

Peatlands are an important component of the Holocene global carbon (C) cycle and the rate of C sequestration and storage is driven by the balance between net primary productivity and decay. A number of studies now suggest that climate is a key driver of peatland C accumulation at large spatial scales and over long timescales, with warmer conditions associated with higher rates of C accumulation. However, other factors are also likely to play a significant role in determining local carbon accumulation rates and these may modify past, present and future peatland carbon sequestration. Here, we test the importance of climate as a driver of C accumulation, compared with hydrological change, fire, nitrogen content and vegetation type, from records of C accumulation at three sites in northeastern North America, across the N-S climate gradient of raised bog distribution. Radiocarbon age models, bulk density values and %C measurements from each site are used to construct C accumulation histories commencing between 11,200 and 8000cal. years BP. The relationship between C accumulation and environmental variables (past water table depth, fire, peat forming vegetation and nitrogen content) is assessed with linear and multivariate regression analyses. Differences in long-term rates of carbon accumulation between sites support the contention that a warmer climate with longer growing seasons results in faster rates of long-term carbon accumulation. However, mid-late Holocene accumulation rates show divergent trends, decreasing in the north but rising in the south. We hypothesise that sites close to the moisture threshold for raised bog distribution increased their growth rate in response to a cooler climate with lower evapotranspiration in the late Holocene, but net primary productivity declined over the same period in northern areas causing a decrease in C accumulation. There was no clear relationship between C accumulation and hydrological change, vegetation, nitrogen content or fire, but early successional stages of peatland growth had faster rates of C accumulation even though temperatures were probably lower at the time. We conclude that climate is the most important driver of peatland accumulation rates over millennial timescales, but that successional vegetation change is a significant additional influence. Whilst the majority of northern peatlands are likely to increase C accumulation rates under future warmer climates, those at the southern limit of distribution may show reduced rates. However, early succession peatlands that develop under future warming at the northern limits of peatland distribution are likely to have high rates of C accumulation and will compensate for some of the losses elsewhere

Respiratory symptoms and chronic bronchitis in people with and without HIV infection

Objectives High rates of respiratory symptoms and chronic bronchitis (CB) are reported in people with HIV infection (PWH). We investigated the prevalence of respiratory symptoms and CB in PWH and HIV‐negative people in the Pharmacokinetic and clinical Observations in PeoPle over fiftY (POPPY) study. Methods Assessment of respiratory symptoms and CB was undertaken using the modified form of the St. George’s Respiratory Questionnaire for chronic obstructive pulmonary disease (COPD). Univariate (χ2 tests, Mann–Whitney U tests and Spearman’s rank correlation) and multivariable (linear and logistic regression) analyses were performed to consider associations of respiratory symptoms with demographic, lifestyle and HIV‐related parameters, and with depressive symptoms and quality of life. Results Among the 619 participants, respiratory Symptom scores were higher in older and younger PWH compared to older HIV‐negative people, with median (interquartile range) scores of 17.7 (6.2, 39.5), 17.5 (0.9, 30.0) and 9.0 (0.9, 17.5), respectively (P = 0.0001); these differences remained significant after confounder adjustment. Sixty‐three participants (10.2%) met the criteria for CB [44 (14.0%) older PWH, 14 (9.2%) younger PWH, and five (3.3%) older HIV‐negative people; P = 0.002], with these differences also remaining after adjustment for confounding variables, particularly smoking status [older vs. younger PWH: odds ratio (OR) 4.48 (95% confidence interval (CI) 1.64, 12.30); P = 0.004; older PWH vs. HIV‐negative people: OR 4.53 (95% CI 1.12, 18.28); P = 0.03]. Respiratory symptoms and CB were both associated with greater depressive symptom scores and poorer quality of life. No strong associations were reported between CB and immune function, HIV RNA or previous diagnosis of any AIDS event. Conclusions Respiratory symptoms and CB are more common in PWH than in demographically and lifestyle‐similar HIV‐negative people and are associated with poorer mental health and quality of life

Single event and TREE latchup mitigation for a star tracker sensor: An innovative approach to system level latchup mitigation

Electronic packages designed for spacecraft should be fault-tolerant and operate without ground control intervention through extremes in the space radiation environment. If designed for military use, the electronics must survive and function in a nuclear radiation environment. This paper presents an innovative ``blink`` approach rather than the typical ``operate through`` approach to achieve system level latchup mitigation on a prototype star tracker camera. Included are circuit designs, flash x-ray test data, and heavy ion data demonstrating latchup mitigation protecting micro-electronics from current latchup and burnout due to Single Event Latchup (SEL) and Transient Radiation Effects on Electronics (TREE)

Development of a framework for genotyping bovine-derived Cryptosporidium parvum, using a multilocus fragment typing tool

Background: There is a need for an integrated genotyping approach for C. parvum; no sufficiently discriminatory scheme to date has been fully validated or widely adopted by veterinary or public health researchers. Multilocus fragment typing (MLFT) can provide good differentiation and is relatively quick and cheap to perform. A MLFT tool was assessed in terms of its typeability, specificity, precision (repeatability and reproducibility), accuracy and ability to genotypically discriminate bovine-derived Cryptosporidium parvum. Methods: With the aim of working towards a consensus, six markers were selected for inclusion based on their successful application in previous studies: MM5, MM18, MM19, TP14, MS1 and MS9. Alleles were assigned according to the fragment sizes of repeat regions amplified, as determined by capillary electrophoresis. In addition, a region of the GP60 gene was amplified and sequenced to determine gp60 subtype and this was added to the allelic profiles of the 6 markers to determine the multilocus genotype (MLG). The MLFT tool was applied to 140 C. parvum samples collected in two cross-sectional studies of UK calves, conducted in Cheshire in 2004 (principally dairy animals) and Aberdeenshire/Caithness in 2011 (beef animals). Results: Typeability was 84 %. The primers did not amplify tested non-parvum species frequently detected in cattle. In terms of repeatability, within- and between-run fragment sizes showed little variability. Between laboratories, fragment sizes differed but allele calling was reproducible. The MLFT had good discriminatory ability (Simpson’s Index of Diversity, SID, was 0.92), compared to gp60 sequencing alone (SID 0.44). Some markers were more informative than others, with MS1 and MS9 proving monoallelic in tested samples. Conclusions: Further inter-laboratory trials are now warranted with the inclusion of human-derived C. parvum samples, allowing progress towards an integrated, standardised typing scheme to enable source attribution and to determine the role of livestock in future outbreaks of human C. parvum

Distinct Inflammatory Phenotypes are associated with subclinical and clinical Cardiovascular disease in People living with HIV

Despite inflammation being implicated in cardiovascular disease (CVD) in people with HIV (PWH), considerable heterogeneity within populations of PWH exists. Stratifying CVD risk based on inflammatory phenotype could play an important role. Using principal component analyses and unsupervised hierarchical clustering, we examined 38 biomarkers to identify inflammatory phenotypes in two independent cohorts of PWH. We identified three distinct inflammatory clusters present in both cohorts that associated with altered risk of both subclinical CVD (cohort 1) and prevalent clinical CVD (cohort 2) after adjusting for CVD risk factors. These data support precision medicine approaches to enhance CVD risk assessment in PWH

Community-based distributive medical education: Advantaging society

This paper presents a narrative summary of an increasingly important trend in medical education by addressing the merits of community-based distributive medical education (CBDME). This is a relatively new and compelling model for teaching and training physicians in a manner that may better meet societal needs and expectations. Issues and trends regarding the growing shortage and imbalanced distribution of physicians in the USA are addressed, including the role of international medical graduates. A historical overview of costs and funding sources for medical education is presented, as well as initiatives to increase the training and placement of physicians cost-effectively through new and expanded medical schools, two- and four-year regional or branch campuses and CBDME. Our research confirms that although medical schools have responded to Association of American Medical Colleges calls for higher student enrollment and societal concerns about the distribution and placement of physicians, significant opportunities for improvement remain. Finally, the authors recommend further research be conducted to guide policy on incentives for physicians to locate in underserved communities, and determine the cost-effectiveness of the CBDME model in both the near and long terms

High‐risk behaviours, and their associations with mental health, adherence to antiretroviral therapy and HIV parameters, in HIV ‐positive men who have sex with men

Objectives To investigate the patterns and frequency of multiple risk behaviours (alcohol, drugs, smoking, higher risk sexual activity) among men who have sex with men (MSM) living with HIV. Methods Cross sectional study. Results 819 HIV-positive MSM exhibited a high-risk phenotype (defined as >3 of smoking, excess alcohol, sexually transmitted infection and recent recreational drug use). This phenotype was associated with younger age, depressive symptoms and <90% adherence in multivariable logistic regression. Conclusion In a cohort of MSM, a small, but significant proportion exhibited multiple concurrent risk behaviours