Deformation imaging of the atria using 2D strain: A noninvasive modality to characterize operating compliance?

This viewpoint with two illustrated case summaries of biventricular and biatrial mechanical function/dysfunction emphasizes the importance of continued research in deformation imaging beyond the left ventricle, as there are no Cinderellas in the heart and we just cannot afford to be nonchalant toward the atria, particularly the right atrium.     

Dual targeting is the rule for organellar aminoacyl-tRNA synthetases in Arabidopsis thaliana

In plants, protein synthesis occurs in the cytosol, mitochondria, and plastids. Each compartment requires a full set of tRNAs and aminoacyl-tRNA synthetases. We have undertaken a systematic analysis of the targeting of organellar aminoacyl-tRNA synthetases in the model plant Arabidopsis thaliana. Dual targeting appeared to be a general rule. Among the 24 identified organellar aminoacyl-tRNA synthetases (aaRSs), 15 (and probably 17) are shared between mitochondria and plastids, and 5 are shared between cytosol and mitochondria (one of these aaRSs being present also in chloroplasts). Only two were shown to be uniquely chloroplastic and none to be uniquely mitochondrial. Moreover, there are no examples where the three aaRS genes originating from the three ancestral genomes still coexist. These results indicate that extensive exchange of aaRSs has occurred during evolution and that many are now shared between two or even three compartments. The findings have important implications for studies of the translation machinery in plants and on protein targeting and gene transfer in general.     

An inverse association between self-reported arthritis and mortality in the elderly: findings from the national long-term care survey

Major musculoskeletal conditions including arthritis represent an increasing burden on individuals and societies. We analyzed the association between self-reported arthritis and mortality in the U.S. elderly disabled and non-disabled individuals using unique disability-focused data from the large-scale population-based National Long Term Care Survey. It was found that males and females who reported arthritis/rheumatism have, generally, smaller risks of death than those who did not report those conditions. This inverse relationship is more pronounced in disabled individuals. This finding holds for both short-term (relative risk [RR] = 0.81; 95% confidence interval [CI] = 0.75-0.88 for males and RR = 0.76; CI = 0.71-0.82 for females) and long-term follow-ups (RR = 0.82; CI = 0.78-0.87 for males and RR = 0.83; CI = 0.79-0.87 for females). For females, this effect is age insensitive, while for males it is limited to ages below 85. Demographic and 19 major self-reported geriatric conditions have trivial effect on these risks, supporting the view that a better survival of diseased individuals can be attributed to the effects of medical treatment. Given the widespread prevalence of arthritis/rheumatism and disability in elderly populations and the increasing population of the elderly, these findings call for comprehensive analyses of factors driving better survival and medical costs associated with extended lives.     

The last decade of microbicide clinical trials in Africa: from hypothesis to facts

Microbicide clinical trials have dominated biomedical HIV prevention research in the past decade. Two generations of microbicides have gone through large-scale human clinical trials. Candidate microbicides assessed in clinical trials in Africa have fallen into the categories of surfactants, polyanionic entry inhibitors, or vaginal milieu protectors. These include compounds such as nonoxynol-9, SAVVY, cellulose sulphate, Carraguard, PRO 2000, and BufferGel. Disappointingly, none of the products have shown efficacy against HIV. Each successive trial has benefited from the lessons learned in preceding trials. The trials have provided important lessons in basic, clinical, social, and behavioural science. More importantly, we have learned that the concept of a vaginally inserted product for HIV prevention is acceptable by women. We have now reached an end of an era of clinical testing with non-HIV-specific microbicides and move forward to testing novel strategies of antiretroviral therapeutic products such as preexposure prophylaxis (PrEP) for HIV prevention. PrEP for vaginal administration in various formulations is being tested to continue our commitment to providing more HIV prevention options to millions of women worldwide.     

Dose escalation and switching of biologics in ulcerative colitis: a systematic literature review in real-world evidence

Background: Biologics used to treat ulcerative colitis (UC) may lose their effect over time, requiring patients to undergo dose escalation or treatment switching, and systematic literature reviews of real-world evidence on these topics are lacking.

Aim: To summarize the occurrence and outcomes of dose escalation and treatment switching in UC patients in real-world evidence.

Methods: Studies were searched through MEDLINE, MEDLINE IN PROCESS, Embase and Cochrane (2006–2017) as well as proceedings from three major scientific meetings.

Results: In total, 41 studies were included in the review among which 35 covered dose escalation and 12 covered treatment switching of biologics. Tumor necrosis factor antagonist (anti-TNF) escalation for all patients included at induction ranged from 5% (6?months) to 50% (median 0.67?years) and 15.2% to 70.8% (8?weeks) for anti-TNF induction responders. Mean/median time to dose escalation on anti-TNF ranged from 1.84 to 11?months. The most common switching pattern, infliximab → adalimumab, occurred in 3.8% (median 5.6?years) to 25.5% (mean 3.3?years) of patients.

Conclusions: Dose escalation and treatment switching of biologics may be considered as indicators of suboptimal therapy suggesting a lack of long-term remission and response under current therapies.     

“Predicting” parental longevity from offspring endophenotypes: Data from the Long Life Family Study (LLFS)

While there is evidence that longevity runs in families, the study of long-lived families is complicated by the fact that longevity-related information is available only for the oldest old, many of whom may be deceased and unavailable for testing, and information on other living family members, primarily descendents, is censored. This situation requires a creative approach for analyzing determinants of longevity in families. There are likely biomarkers that predict an individual's longevity, suggesting the possibility that those biomarkers which are heritable may constitute valuable endophenotypes for exceptional survival. These endophenotypes could be studied in families to identify human longevity genes and elucidate possible mechanisms of their influence on longevity. In this paper, we analyze data collected in the Long Life Family Study (LLFS) investigating whether indicators of physiological state, cognitive functioning and health/well-being among offspring predict longevity in parents. Good predictors can be used as endophenotypes for exceptional survival. Our analyses revealed significant associations between cumulative indices describing physiological state, as well as a number of offspring phenotypes, and parental lifespan, supporting both their familial basis and relevance to longevity. We conclude that the study of endophenotypes within families is a valid approach to the genetics of human longevity.     

KInNeSS: A Modular Framework for Computational Neuroscience

Making use of very detailed neurophysiological, anatomical, and behavioral data to build biologically-realistic computational models of animal behavior is often a difficult task. Until recently, many software packages have tried to resolve this mismatched granularity with different approaches. This paper presents KInNeSS, the KDE Integrated NeuroSimulation Software environment, as an alternative solution to bridge the gap between data and model behavior. This open source neural simulation software package provides an expandable framework incorporating features such as ease of use, scalability, an XML based schema, and multiple levels of granularity within a modern object oriented programming design. KInNeSS is best suited to simulate networks of hundreds to thousands of branched multi-compartmental neurons with biophysical properties such as membrane potential, voltage-gated and ligand-gated channels, the presence of gap junctions or ionic diffusion, neuromodulation channel gating, the mechanism for habituative or depressive synapses, axonal delays, and synaptic plasticity. KInNeSS outputs include compartment membrane voltage, spikes, local-field potentials, and current source densities, as well as visualization of the behavior of a simulated agent. An explanation of the modeling philosophy and plug-in development is also presented. Further development of KInNeSS is ongoing with the ultimate goal of creating a modular framework that will help researchers across different disciplines to effectively collaborate using a modern neural simulation platform.

Accelerated accumulation of health deficits as a characteristic of aging

Cross-sectional analyses show that an index of aging-associated health/well-being deficits, called the "frailty index", can characterize the aging process in humans. This study provides support for such characterization from a longitudinal analysis of the frailty index properties. The data are from the National Long Term Care Survey assessed longitudinally health and functioning of the U.S. elderly in the period 1982-1999. In cross-sectional analysis, the frailty index exhibits accelerated increase with age till oldest-old ages (95+), with possible deceleration thereafter. Longitudinal analysis confirms the accelerated accumulation of deficits in aging individuals. The time-dynamics of the frailty index is affected by two sex-sensitive processes: (i) selection of robust individuals, resulting in a decline of the mean frailty index with age and (ii) accumulation of deficits associated with physiological aging and its interaction with environment, which results in an accelerated increase of individual frailty index prior to death irrespective of chronological age. Current frailty index levels in individuals are more predictive of death than the index past values. Longitudinal analysis provides strong evidence that the cumulative index of health/well-being deficits can characterize aging-associated processes in humans and predict death better than chronological age during short-term periods.     

Why is 11beta-hydroxysteroid dehydrogenase type 1 facing the endoplasmic reticulum lumen? Physiological relevance of the membrane topology of 11beta-HSD1

11Beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) is essential for the local activation of glucocorticoid receptors (GR). Unlike unliganded cytoplasmic GR, 11beta-HSD1 is an endoplasmic reticulum (ER)-membrane protein with lumenal orientation. Cortisone might gain direct access to 11beta-HSD1 by free diffusion across membranes, indirectly via intracellular binding proteins or, alternatively, by insertion into membranes. Membranous cortisol, formed by 11beta-HSD1 at the ER-lumenal side, might then activate cytoplasmic GR or bind to ER-lumenal secretory proteins. Compartmentalization of 11beta-HSD1 is important for its regulation by hexose-6-phosphate dehydrogenase (H6PDH), which regenerates cofactor NADPH in the ER lumen and stimulates oxoreductase activity. ER-lumenal orientation of 11beta-HSD1 is also essential for the metabolism of the alternative substrate 7-ketocholesterol (7KC), a major cholesterol oxidation product found in atherosclerotic plaques and taken up from processed cholesterol-rich food. An 11beta-HSD1 mutant adopting cytoplasmic orientation efficiently catalyzed the oxoreduction of cortisone but not 7KC, indicating access to cortisone from both sides of the ER-membrane but to 7KC only from the lumenal side. These aspects may be relevant for understanding the physiological role of 11beta-HSD1 and for developing therapeutic interventions to control glucocorticoid reactivation.