The in vivo study of cardiac mechano-electric and mechano-mechanical coupling during heart development in zebrafish

In the adult heart, acute adaptation of electrical and mechanical activity to changes in mechanical load occur

Patterns of hospitalisation before and following initiation of haemodialysis: a 5 year single centre study

ABSTRACT Background The utilisation of healthcare resources by prevalent haemodialysis patients has been robustly evaluated with regard to the provision of outpatient haemodialysis; however, the impact of hospitalisation among such patients is poorly defined. Minimal information is available in the UK to estimate the health and economic burden associated with the inpatient management of prevalent haemodialysis patients. The aim of this study was to assess the pattern of hospitalisation among a cohort of haemodialysis patients, before and following their initiation of haemodialysis. In addition the study sought to assess the impact of their admissions on bed occupancy in a large tertiary referral hospital in a single region in the UK. Methods All admission episodes were reviewed and those receiving dialysis with the Belfast City Hospital Programme were identified over a 5 year period from January 2001 to December 2005. This tertiary referral centre provides dialysis services for a population of approximately 700 000 and additional specialist renal services for the remainder of Northern Ireland. The frequency and duration of hospitalisation, and contribution to bed day occupancy of haemodialysis patients, was determined and compared to other common conditions which are known to be associated with high bed occupancy. In addition, the pattern and timing of admissions in dialysis patients in relation to their dialysis initiation date was assessed. Results Over the 5 year study period, 798 haemodialysis patients were admitted a total of 2882 times. These accounted for 2.5% of all admissions episodes; the median number of admissions for these patients was 3 (2–5) which compared with 1 (1–2) for non-dialysis patients. The majority of first hospitalisations (54%) were within 100 days before or after commencement of maintenance dialysis therapy. In all clinical specialties the median length of stay for haemodialysis patients was significantly longer than for patients not on haemodialysis (p=0.004). In multivariate analysis with adjustment for age, gender, and other clinically relevant diagnostic codes, maintenance haemodialysis patients stayed on average 3.75 times longer than other patient groups (ratio of geometric means 3.75, IQR 3.46–4.06). Conclusions Maintenance haemodialysis therapy is an important risk factor for prolonged hospitalisation regardless of the primary reason for admission. Such patients require admission more frequently than the general hospital population, particularly within 100 days before and after initiation of their first dialysis treatment. </jats:sec

Neurohumoral control of sinoatrial node activity and heart rate: insight from experimental models and findings from humans

The sinoatrial node is perhaps one of the most important tissues in the entire body: it is the natural pacemaker of the heart, making it responsible for initiating each-and-every normal heartbeat. As such, its activity is heavily controlled, allowing heart rate to rapidly adapt to changes in physiological demand. Control of sinoatrial node activity, however, is complex, occurring through the autonomic nervous system and various circulating and locally released factors. In this review we discuss the coupled-clock pacemaker system and how its manipulation by neurohumoral signaling alters heart rate, considering the multitude of canonical and non-canonical agents that are known to modulate sinoatrial node activity. For each, we discuss the principal receptors involved and known intracellular signaling and protein targets, highlighting gaps in our knowledge and understanding from experimental models and human studies that represent areas for future research

An In-Silico Study on Integrated Mechanisms of Mechano-Electric Coupling in Ischaemic Arrhythmogenesis

Heterogeneous mechanical dyskinesis during acute myocardial ischaemia is thought to contribute to arrhythmogenic alterations to cardiac electrophysiology. Various forms of mechano-electric coupling (MEC) mechanisms have been suggested to contribute to these changes, with two primary mechanisms being: (1) myofilament-dependent calcium release events, and (2) the activation of stretch-activated currents (SACs). In this computational investigation, we assessed the collective impact of these processes on mechanically-induced alternans that create an arrhythmogenic substrate during acute ischaemia. To appraise the potential involvement of MEC in ischaemia-induced arrhythmias, we developed a coupled model of ventricular myocyte electrophysiology and contraction including SACs and stretch-dependent calcium buffering and release. The model, reflecting observed electrophysiological changes during ischaemia, was exposed to a series of stretch protocols that replicated both physiological and pathological mechanical conditions. Pathologically realistic myofiber stretch variations revealed calcium sensitivity changes dependent on myofilament, leading to alterations in cytosolic calcium concentrations. Under calcium overload conditions, these changes resulted in electrical alternans. The study implies that strain impacts cellular electrophysiology through myofilament calcium release and SAC opening in ventricular mechano-electrical models, parameterised to available data. This supports experimental evidence suggesting that both calcium-driven instability via MEC and SAC-induced effects contribute to electrical alternans in acute ischaemia.Comment: 20 pages; 8 figures; original pape

Evolutionary life history theory as an organising framework for cohort studies : insights from the Cebu Longitudinal Health and Nutrition Survey

By tracking a group of individuals through time, cohort studies provide fundamental insights into the developmental time course and causes of health and disease. Evolutionary life history theory seeks to explain patterns of growth, development, reproduction and senescence, and inspires a range of hypotheses that are testable using the longitudinal data from cohort studies. Here we review two decades of life history theory-motivated work conducted in collaboration with the Cebu Longitudinal Health and Nutrition Survey (CLHNS), a birth cohort study that enrolled more than 3000 pregnant women in the Philippines in 1983 and has since followed these women, their offspring and grandoffspring. This work has provided evidence that reproduction carries “costs” to cellular maintenance functions, potentially speeding senescence, and revealed an unusual form of genetic plasticity in which the length of telomeres inherited across generations is influenced by reproductive timing in paternal ancestors. Men in Cebu experience hormonal and behavioural changes in conjunction with changes in relationship and fatherhood status that are consistent with predictions based upon other species that practice bi-parental care. The theoretical expectation that early life cues of mortality or environmental unpredictability will motivate a “fast” life history strategy are confirmed for behavioural components of reproductive decision making, but not for maturational tempo, while our work points to a broader capacity for early life developmental calibration of systems like immunity, reproductive biology and metabolism. Our CLHNS findings illustrate the power of life history theory as an integrative, lifecourse framework to guide longitudinal studies of human populations

Genome-wide DNA methylation analysis for diabetic nephropathy in type 1 diabetes mellitus

BACKGROUND: Diabetic nephropathy is a serious complication of diabetes mellitus and is associated with considerable morbidity and high mortality. There is increasing evidence to suggest that dysregulation of the epigenome is involved in diabetic nephropathy. We assessed whether epigenetic modification of DNA methylation is associated with diabetic nephropathy in a case-control study of 192 Irish patients with type 1 diabetes mellitus (T1D). Cases had T1D and nephropathy whereas controls had T1D but no evidence of renal disease. METHODS: We performed DNA methylation profiling in bisulphite converted DNA from cases and controls using the recently developed Illumina Infinium(R) HumanMethylation27 BeadChip, that enables the direct investigation of 27,578 individual cytosines at CpG loci throughout the genome, which are focused on the promoter regions of 14,495 genes. RESULTS: Singular Value Decomposition (SVD) analysis indicated that significant components of DNA methylation variation correlated with patient age, time to onset of diabetic nephropathy, and sex. Adjusting for confounding factors using multivariate Cox-regression analyses, and with a false discovery rate (FDR) of 0.05, we observed 19 CpG sites that demonstrated correlations with time to development of diabetic nephropathy. Of note, this included one CpG site located 18 bp upstream of the transcription start site of UNC13B, a gene in which the first intronic SNP rs13293564 has recently been reported to be associated with diabetic nephropathy. CONCLUSION: This high throughput platform was able to successfully interrogate the methylation state of individual cytosines and identified 19 prospective CpG sites associated with risk of diabetic nephropathy. These differences in DNA methylation are worthy of further follow-up in replication studies using larger cohorts of diabetic patients with and without nephropathy

Charmless Hadronic Two-Body B Meson Decays

We report the results of a study of two-body B meson decays to the complete set of K pi, pi pi, and K K final states. The study is performed on a data sample of 31.7 +/- 0.3 million B B-bar events recorded on the Upsilon(4S) resonance by the Belle experiment at KEKB. We observe significant signals in all K pi final states and in the pi+ pi- and pi+ pi0 final states. We set limits on the pi0 pi0 and K K final states. A search is performed for partial-rate asymmetries between conjugate states for flavor-specific final states.Comment: Submitted to PR

Multiwavelength Observations of LS I +61 303 with VERITAS, Swift and RXTE

We present results from a long-term monitoring campaign on the TeV binary LSI +61 303 with VERITAS at energies above 500 GeV, and in the 2-10 keV hard X-ray bands with RXTE and Swift, sampling nine 26.5 day orbital cycles between September 2006 and February 2008. The binary was observed by VERITAS to be variable, with all integrated observations resulting in a detection at the 8.8 sigma (2006/2007) and 7.3 sigma (2007/2008) significance level for emission above 500 GeV. The source was detected during active periods with flux values ranging from 5 to 20% of the Crab Nebula, varying over the course of a single orbital cycle. Additionally, the observations conducted in the 2007-2008 observing season show marginal evidence (at the 3.6 sigma significance level) for TeV emission outside of the apastron passage of the compact object around the Be star. Contemporaneous hard X-ray observations with RXTE and Swift show large variability with flux values typically varying between 0.5 and 3.0*10^-11 ergs cm^-2 s^-1 over a single orbital cycle. The contemporaneous X-ray and TeV data are examined and it is shown that the TeV sampling is not dense enough to detect a correlation between the two bands.Comment: 30 pages, 5 figures, 2 table, Accepted for publication in The Astrophysical Journa