Stochastic Feedback and the Regulation of Biological Rhythms

We propose a general approach to the question of how biological rhythms spontaneously self-regulate, based on the concept of ``stochastic feedback''. We illustrate this approach by considering the neuroautonomic regulation of the heart rate. The model generates complex dynamics and successfully accounts for key characteristics of cardiac variability, including the $1/f$ power spectrum, the functional form and scaling of the distribution of variations, and correlations in the Fourier phases. Our results suggest that in healthy systems the control mechanisms operate to drive the system away from extreme values while not allowing it to settle down to a constant output.Comment: 15 pages, latex2e using rotate and epsf, with 4 ps figures. Submitted to PR

Stability of Top-Points in Scale Space

Abstract. This paper presents an algorithm for computing stability of top-points in scale-space. The potential usefulness of top-points in scalespace has already been shown for a number of applications, such as image reconstruction and image retrieval. In order to improve results only reliable top-points should be used. The algorithm is based on perturbation theory and noise propagation

MicroRNAs in cardiac arrhythmia: DNA sequence variation of MiR-1 and MiR-133A in long QT syndrome.

Long QT syndrome (LQTS) is a genetic cardiac condition associated with prolonged ventricular repolarization, primarily a result of perturbations in cardiac ion channels, which predisposes individuals to life-threatening arrhythmias. Using DNA screening and sequencing methods, over 700 different LQTS-causing mutations have been identified in 13 genes worldwide. Despite this, the genetic cause of 30-50% of LQTS is presently unknown. MicroRNAs (miRNAs) are small (∼ 22 nucleotides) noncoding RNAs which post-transcriptionally regulate gene expression by binding complementary sequences within messenger RNAs (mRNAs). The human genome encodes over 1800 miRNAs, which target about 60% of human genes. Consequently, miRNAs are likely to regulate many complex processes in the body, indeed aberrant expression of various miRNA species has been implicated in numerous disease states, including cardiovascular diseases. MiR-1 and MiR-133A are the most abundant miRNAs in the heart and have both been reported to regulate cardiac ion channels. We hypothesized that, as a consequence of their role in regulating cardiac ion channels, genetic variation in the genes which encode MiR-1 and MiR-133A might explain some cases of LQTS. Four miRNA genes (miR-1-1, miR-1-2, miR-133a-1 and miR-133a-2), which encode MiR-1 and MiR-133A, were sequenced in 125 LQTS probands. No genetic variants were identified in miR-1-1 or miR-133a-1; but in miR-1-2 we identified a single substitution (n.100A> G) and in miR-133a-2 we identified two substitutions (n.-19G> A and n.98C> T). None of the variants affect the mature miRNA products. Our findings indicate that sequence variants of miR-1-1, miR-1-2, miR-133a-1 and miR-133a-2 are not a cause of LQTS in this cohort

Rupture of the atherosclerotic plaque: does a good animal model exist?

By its very nature, rupture of the atherosclerotic plaque is difficult to study directly in humans. A good animal model would help us not only to understand how rupture occurs but also to design and test treatments to prevent it from happening. However, several difficulties surround existing models of plaque rupture, including the need for radical interventions to produce the rupture, lack of direct evidence of rupture per se, and absence of convincing evidence of platelet- and fibrin-rich thrombus at the rupture site. At the present time, attention should therefore focus on the processes of plaque breakdown and thrombus formation in humans, whereas the use of animal models should probably be reserved for studying the function of particular genes and for investigating isolated features of plaques, such as the relationship between cap thickness and plaque stability

Quality of life in patients treated with first-line antiretroviral therapy containing nevirapine or efavirenz in Uganda: A prospective non-randomized study

© 2015 Mwesigire et al. Background: The goal of antiretroviral therapy (ART) is to suppress viral replication, reduce morbidity and mortality, and improve quality of life (QoL). For resource-limited settings, the World Health Organization recommends a first-line regimen of two-nucleoside reverse-transcriptase inhibitors and one non-nucleoside transcriptase inhibitor (nevirapine (NVP) or efavirenz (EFV)). There are few data comparing the QoL impact of NVP versus EFV. This study assessed the change in QoL and factors associated with QoL among HIV patients receiving ART regimens based on EFV or NVP. Methods: We enrolled 640 people with HIV eligible for ART who received regimens including either NVP or EFV. QoL was assessed at baseline, three months and six months using Physical Health Summary (PHS) and Mental Health Summary (MHS) scores and the Global Person Generated Index (GPGI). Data were analyzed using generalized estimating equations, with ART regimen as the primary exposure, to identify associations between patient and disease factors and QoL. Results: QoL increased on ART. The mean QoL scores did not differ significantly for regimens based on NVP versus EFV during follow-up for MHS and GPGI regardless of CD4 stratum and for PHS among patients with a CD4 count >250 cells/μL. The PHS-adjusted β coefficients for ART regimens based on EFV versus NVP by CD4 count strata were as follows: -1.61 (95 % CI -2.74, -0.49) for CD4 count 250 cells/μL. The corresponding MHS-adjusted β coefficients were as follows: -0.39 (-1.40, 0.62) for CD4∈250 cells/μL. The GPGI-adjusted odds ratios for EFV versus NVP were 0.51 (0.25, 1.04) for CD4 count ∈250 cells/μL. QoL improved among patients on EFV over the 6-month follow-up period (MHS p

Genetic architecture of spatial electrical biomarkers for cardiac arrhythmia and relationship with cardiovascular disease

The 3-dimensional spatial and 2-dimensional frontal QRS-T angles are measures derived from the vectorcardiogram. They are independent risk predictors for arrhythmia, but the underlying biology is unknown. Using multi-ancestry genome-wide association studies we identify 61 (58 previously unreported) loci for the spatial QRS-T angle (N = 118,780) and 11 for the frontal QRS-T angle (N = 159,715). Seven out of the 61 spatial QRS-T angle loci have not been reported for other electrocardiographic measures. Enrichments are observed in pathways related to cardiac and vascular development, muscle contraction, and hypertrophy. Pairwise genome-wide association studies with classical ECG traits identify shared genetic influences with PR interval and QRS duration. Phenome-wide scanning indicate associations with atrial fibrillation, atrioventricular block and arterial embolism and genetically determined QRS-T angle measures are associated with fascicular and bundle branch block (and also atrioventricular block for the frontal QRS-T angle). We identify potential biology involved in the QRS-T angle and their genetic relationships with cardiovascular traits and diseases, may inform future research and risk prediction

The regulation of IL-10 expression

Interleukin (IL)-10 is an important immunoregulatory cytokine and an understanding of how IL-10 expression is controlled is critical in the design of immune intervention strategies. IL-10 is produced by almost all cell types within the innate (including macrophages, monocytes, dendritic cells (DCs), mast cells, neutrophils, eosinophils and natural killer cells) and adaptive (including CD4(+) T cells, CD8(+) T cells and B cells) immune systems. The mechanisms of IL-10 regulation operate at several stages including chromatin remodelling at the Il10 locus, transcriptional regulation of Il10 expression and post-transcriptional regulation of Il10 mRNA. In addition, whereas some aspects of Il10 gene regulation are conserved between different immune cell types, several are cell type- or stimulus-specific. Here, we outline the complexity of IL-10 production by discussing what is known about its regulation in macrophages, monocytes, DCs and CD4(+) T helper cells

Common and Rare Coding Genetic Variation Underlying the Electrocardiographic PR Interval

Background: Electrical conduction from the cardiac sinoatrial node to the ventricles is critical for normal heart function. Genome-wide association studies have identified more than a dozen common genetic loci that are associated with PR interval. However, it is unclear whether rare and low-frequency variants also contribute to PR interval heritability. Methods: We performed large-scale meta-analyses of the PR interval that included 83 367 participants of European ancestry and 9436 of African ancestry. We examined both common and rare variants associated with the PR interval. Results: We identified 31 genetic loci that were significantly associated with PR interval after Bonferroni correction (P<1.2×10−6), including 11 novel loci that have not been reported previously. Many of these loci are involved in heart morphogenesis. In gene-based analysis, we found that multiple rare variants at MYH6 (P=5.9×10−11) and SCN5A (P=1.1×10−7) were associated with PR interval. SCN5A locus also was implicated in the common variant analysis, whereas MYH6 was a novel locus. Conclusions: We identified common variants at 11 novel loci and rare variants within 2 gene regions that were significantly associated with PR interval. Our findings provide novel insights to the current understanding of atrioventricular conduction, which is critical for cardiac activity and an important determinant of health