Cardiac Angiogenic Imbalance Leads to Peripartum Cardiomyopathy

Peripartum cardiomyopathy (PPCM) is an often fatal disease that affects pregnant women who are near delivery, and it occurs more frequently in women with pre-eclampsia and/or multiple gestation. The aetiology of PPCM, and why it is associated with pre-eclampsia, remain unknown. Here we show that PPCM is associated with a systemic angiogenic imbalance, accentuated by pre-eclampsia. Mice that lack cardiac PGC-$1\alpha$, a powerful regulator of angiogenesis, develop profound PPCM. Importantly, the PPCM is entirely rescued by pro-angiogenic therapies. In humans, the placenta in late gestation secretes VEGF inhibitors like soluble FLT1 (sFLT1), and this is accentuated by multiple gestation and pre-eclampsia. This anti-angiogenic environment is accompanied by subclinical cardiac dysfunction, the extent of which correlates with circulating levels of sFLT1. Exogenous sFLT1 alone caused diastolic dysfunction in wild-type mice, and profound systolic dysfunction in mice lacking cardiac PGC-$1\alpha$. Finally, plasma samples from women with PPCM contained abnormally high levels of sFLT1. These data indicate that PPCM is mainly a vascular disease, caused by excess anti-angiogenic signalling in the peripartum period. The data also explain how late pregnancy poses a threat to cardiac homeostasis, and why pre-eclampsia and multiple gestation are important risk factors for the development of PPCM

Method for Quantitative Study of Airway Functional Microanatomy Using Micro-Optical Coherence Tomography

We demonstrate the use of a high resolution form of optical coherence tomography, termed micro-OCT (μOCT), for investigating the functional microanatomy of airway epithelia. μOCT captures several key parameters governing the function of the airway surface (airway surface liquid depth, periciliary liquid depth, ciliary function including beat frequency, and mucociliary transport rate) from the same series of images and without exogenous particles or labels, enabling non-invasive study of dynamic phenomena. Additionally, the high resolution of μOCT reveals distinguishable phases of the ciliary stroke pattern and glandular extrusion. Images and functional measurements from primary human bronchial epithelial cell cultures and excised tissue are presented and compared with measurements using existing gold standard methods. Active secretion from mucus glands in tissue, a key parameter of epithelial function, was also observed and quantified

Across-Experiment Transcriptomics of Sheep Rumen Identifies Expression of Lipid/Oxo-Acid Metabolism and Muscle Cell Junction Genes Associated With Variation in Methane-Related Phenotypes

Ruminants are significant contributors to the livestock generated component of the greenhouse gas, methane (CH4). The CH4 is primarily produced by the rumen microbes. Although the composition of the diet and animal intake amount have the largest effect on CH4 production and yield (CH4 production/dry matter intake, DMI), the host also influences CH4 yield. Shorter rumen feed mean retention time (MRT) is associated with higher dry matter intake and lower CH4 yield, but the molecular mechanism(s) by which the host affects CH4 production remain unclear. We integrated rumen wall transcriptome data and CH4 phenotypes from two independent experiments conducted with sheep in Australia (AUS, n = 62) and New Zealand (NZ, n = 24). The inclusion of the AUS data validated the previously identified clusters and gene sets representing rumen epithelial, metabolic and muscular functions. In addition, the expression of the cell cycle genes as a group was consistently positively correlated with acetate and butyrate concentrations (p 4 production (p p AKR1C ) family. Several AKR1C family genes appear to have ruminant specific evolution patterns, supporting their specialized roles in the ruminants. Combining differential gene expression in the rumen wall muscle of the shortest and longest MRT AUS animals (no data available for the NZ animals) with correlation and network analysis, we identified a set of rumen muscle genes involved in cell junctions as potential regulators of MRT, presumably by influencing contraction rates of the smooth muscle component of the rumen wall. Higher rumen expression of these genes, including SYNPO (synaptopodin, p NEXN (nexilin, p 4 yield in both AUS and NZ datasets. Unlike the metabolic genes, the variations in the expression of which may reflect the availability of rumen metabolites, the muscle genes are currently our best candidates for causal genes that influence CH4 yield

Genetic contributions to stability and change in intelligence from childhood to old age

Understanding the determinants of healthy mental ageing is a priority for society today1,2. So far, we know that intelligence differences show high stability from childhood to old age3,4 and there are estimates of the genetic contribution to intelligence at different ages5,6. However, attempts to discover whether genetic causes contribute to differences in cognitive ageing have been relatively uninformative7–10. Here we provide an estimate of the genetic and environmental contributions to stability and change in intelligence across most of the human lifetime. We used genome-wide single nucleotide polymorphism (SNP) data from 1,940 unrelated individuals whose intelligence was measured in childhood (age 11 years) and again in old age (age 65, 70 or 79 years)11,12. We use a statistical method that allows genetic (co)variance to be estimated from SNP data on unrelated individuals13–17. We estimate that causal genetic variants in linkage disequilibrium with common SNPs account for 0.24 of the variation in cognitive ability change from childhood to old age. Using bivariate analysis, we estimate a genetic correlation between intelligence at age 11 years and in old age of 0.62. These estimates, derived from rarely available data on lifetime cognitive measures, warrant the search for genetic causes of cognitive stability and change

A participatory action research approach to strengthening health managers’ capacity at district level in Eastern Uganda

BACKGROUND: Many approaches to improving health managers’ capacity in poor countries, particularly those pursued by external agencies, employ non-participatory approaches and often seek to circumvent (rather than strengthen) weak public management structures. This limits opportunities for strengthening local health managers’ capacity, improving resource utilisation and enhancing service delivery. This study explored the contribution of a participatory action research approach to strengthening health managers’ capacity in Eastern Uganda. METHODS: This was a qualitative study that used open-ended key informant interviews, combined with review of meeting minutes and observations to collect data. Both inductive and deductive thematic analysis was undertaken. The Competing Values Framework of organisational management functions guided the deductive process of analysis and the interpretation of the findings. The framework builds on four earlier models of management and regards them as complementary rather than conflicting, and identifies four managers’ capacities (collaborate, create, compete and control) by categorising them along two axes, one contrasting flexibility versus control and the other internal versus external organisational focus. RESULTS: The findings indicate that the participatory action research approach enhanced health managers’ capacity to collaborate with others, be creative, attain goals and review progress. The enablers included expanded interaction spaces, encouragement of flexibility, empowerment of local managers, and the promotion of reflection and accountability. Tension and conflict across different management functions was apparent; for example, while there was a need to collaborate, maintaining control over processes was also needed. These tensions meant that managers needed to learn to simultaneously draw upon and use different capacities as reflected by the Competing Values Framework in order to maximise their effectiveness. CONCLUSIONS: Improved health manager capacity is essential if sustained improvements in health outcomes in lowincome countries are to be attained. The expansion of interaction spaces, encouragement of flexibility, empowerment of local managers, and the promotion of reflection and accountability were the key means by which participatory action research strengthened health managers’ capacity. The participatory approach to implementation therefore created opportunities to strengthen health managers’ capacity

A prospective cohort study of long-term cognitive changes in older Medicare beneficiaries

<p>Abstract</p> <p>Background</p> <p>Promoting cognitive health and preventing its decline are longstanding public health goals, but long-term changes in cognitive function are not well-documented. Therefore, we first examined long-term changes in cognitive function among older Medicare beneficiaries in the Survey on Assets and Health Dynamics among the Oldest Old (AHEAD), and then we identified the risk factors associated with those changes in cognitive function.</p> <p>Methods</p> <p>We conducted a secondary analysis of a prospective, population-based cohort using baseline (1993-1994) interview data linked to 1993-2007 Medicare claims to examine cognitive function at the final follow-up interview which occurred between 1995-1996 and 2006-2007. Besides traditional risk factors (i.e., aging, age, race, and education) and adjustment for baseline cognitive function, we considered the reason for censoring (entrance into managed care or death), and post-baseline continuity of care and major health shocks (hospital episodes). Residual change score multiple linear regression analysis was used to predict cognitive function at the final follow-up using data from telephone interviews among 3,021 to 4,251 (sample size varied by cognitive outcome) baseline community-dwelling self-respondents that were ≥ 70 years old, not in managed Medicare, and had at least one follow-up interview as self-respondents. Cognitive function was assessed using the 7-item Telephone Interview for Cognitive Status (TICS-7; general mental status), and the 10-item immediate and delayed (episodic memory) word recall tests.</p> <p>Results</p> <p>Mean changes in the number of correct responses on the TICS-7, and 10-item immediate and delayed word recall tests were -0.33, -0.75, and -0.78, with 43.6%, 54.9%, and 52.3% declining and 25.4%, 20.8%, and 22.9% unchanged. The main and most consistent risks for declining cognitive function were the baseline values of cognitive function (reflecting substantial regression to the mean), aging (a strong linear pattern of increased decline associated with greater aging, but with diminishing marginal returns), older age at baseline, dying before the end of the study period, lower education, and minority status.</p> <p>Conclusions</p> <p>In addition to aging, age, minority status, and low education, substantial and differential risks for cognitive change were associated with sooner vs. later subsequent death that help to clarify the terminal drop hypothesis. No readily modifiable protective factors were identified.</p

Rheumatoid arthritis - clinical aspects: 134. Predictors of Joint Damage in South Africans with Rheumatoid Arthritis

Background: Rheumatoid arthritis (RA) causes progressive joint damage and functional disability. Studies on factors affecting joint damage as clinical outcome are lacking in Africa. The aim of the present study was to identify predictors of joint damage in adult South Africans with established RA. Methods: A cross-sectional study of 100 black patients with RA of >5 years were assessed for joint damage using a validated clinical method, the RA articular damage (RAAD) score. Potential predictors of joint damage that were documented included socio-demographics, smoking, body mass index (BMI), disease duration, delay in disease modifying antirheumatic drug (DMARD) initiation, global disease activity as measured by the disease activity score (DAS28), erythrocyte sedimentation rate (ESR), C reactive protein (CRP), and autoantibody status. The predictive value of variables was assessed by univariate and stepwise multivariate regression analyses. A p value <0.05 was considered significant. Results: The mean (SD) age was 56 (9.8) years, disease duration 17.5 (8.5) years, educational level 7.5 (3.5) years and DMARD lag was 9 (8.8) years. Female to male ratio was 10:1. The mean (SD) DAS28 was 4.9 (1.5) and total RAAD score was 28.3 (12.8). The mean (SD) BMI was 27.2 kg/m2 (6.2) and 93% of patients were rheumatoid factor (RF) positive. More than 90% of patients received between 2 to 3 DMARDs. Significant univariate predictors of a poor RAAD score were increasing age (p = 0.001), lower education level (p = 0.019), longer disease duration (p < 0.001), longer DMARD lag (p = 0.014), lower BMI (p = 0.025), high RF titre (p < 0.001) and high ESR (p = 0.008). The multivariate regression analysis showed that the only independent significant predictors of a higher mean RAAD score were older age at disease onset (p = 0.04), disease duration (p < 0.001) and RF titre (p < 0.001). There was also a negative association between BMI and the mean total RAAD score (p = 0.049). Conclusions: Patients with longstanding established RA have more severe irreversible joint damage as measured by the clinical RAAD score, contrary to other studies in Africa. This is largely reflected by a delay in the initiation of early effective treatment. Independent of disease duration, older age at disease onset and a higher RF titre are strongly associated with more joint damage. The inverse association between BMI and articular damage in RA has been observed in several studies using radiographic damage scores. The mechanisms underlying this paradoxical association are still widely unknown but adipokines have recently been suggested to play a role. Disclosure statement: C.I. has received a research grant from the Connective Tissue Diseases Research Fund, University of the Witwatersrand. All other authors have declared no conflicts of interes

Inheritance of DNA methylation level in healthy human tissues

DNA methylation (DNAm) is the covalent modification of DNA by addition of a methyl group primarily at the cytosine directly upstream of a guanine. DNAm level plays a central role in transcriptional regulation and is linked to disease. Therefore, understanding genetic and environmental influences on DNAm level in healthy tissue is an important step in the elucidation of trait and disease etiology. However, at present only a minority of easy to access human tissues and ethnicities have been investigated. Therefore, we studied DNAm level measured in five human tissues: cerebellum, frontal cortex, pons, temporal cortex and colon in either North American or South American samples. We applied a novel statistical approach to estimate the heritability attributable to genomic regions (regional heritability, ĥ²/r,g ) for DNAm level at thousands of individual DNAm sites genome-wide. In all five tissues, DNAm level was significantly associated with the local genomic region for more DNAm sites than expected by chance. Moreover, DNAm level could be predicted from the local sequence variants with an accuracy that scaled with the estimated ĥ²/r,g . Our results inform on molecular mechanisms regulating DNAm level and trait etiology in several ways. Firstly, DNAm level at DNAm sites located in genomic risk regions and measured in a tissue relevant to the disease can be influenced by the local genetic variants. Specifically, we found that genetic variation within a region associated with Fluid Intelligence was also associated with local DNAm level at the proline-rich coiled-coil 1 (PRRC1) gene in healthy temporal cortex tissue. Additionally, we replicated the finding of a Colorectal Cancer risk variant (rs4925386) associated with two DNAm sites in healthy colon tissue. More generally, we showed that DNAm sites located within a susceptibility region and measured in a relevant tissue exhibit a similar overall pattern of estimated ĥ²/r,g to DNAm sites outwith a susceptibility region. Secondly, the propensity for DNAm level to be associated with the local sequence variation differs with respect to CpG dinucleotide density and genic location. Most notably, DNAm sites located in CpG dense regions of the genome are less likely to be heritable than DNAm sites located in CpG sparse regions of the genome. Additionally, within both CpG dense and CpG sparse regions of the genome intergenic DNAm sites are more likely to be heritable than intragenic DNAm sites. Overall, our study suggests that variation in DNAm level at some DNAm sites is at least partially controlled by nuclear genetic variation. Moreover, DNAm level in healthy tissue has the potential to act as an intermediary in trait variation and etiology