Electrophysiological Mechanisms of Brugada Syndrome: Insights from Pre-clinical and Clinical Studies.

This is the final version of the article. It first appeared from Frontiers via https://doi.org/10.3389/fphys.2016.00467Brugada syndrome (BrS), is a primary electrical disorder predisposing affected individuals to sudden cardiac death via the development of ventricular tachycardia and fibrillation (VT/VF). Originally, BrS was linked to mutations in the SCN5A, which encodes for the cardiac Na+ channel. To date, variants in 19 genes have been implicated in this condition, with 11, 5, 3, and 1 genes affecting the Na+, K+, Ca2+, and funny currents, respectively. Diagnosis of BrS is based on ECG criteria of coved- or saddle-shaped ST segment elevation and/or T-wave inversion with or without drug challenge. Three hypotheses based on abnormal depolarization, abnormal repolarization, and current-load-mismatch have been put forward to explain the electrophysiological mechanisms responsible for BrS. Evidence from computational modeling, pre-clinical, and clinical studies illustrates that molecular abnormalities found in BrS lead to alterations in excitation wavelength (λ), which ultimately elevates arrhythmic risk. A major challenge for clinicians in managing this condition is the difficulty in predicting the subset of patients who will suffer from life-threatening VT/VF. Several repolarization risk markers have been used thus far, but these neglect the contributions of conduction abnormalities in the form of slowing and dispersion. Indices incorporating both repolarization and conduction and based on the concept of λ have recently been proposed. These may have better predictive values than the existing markers.GT received a BBSRC Doctoral CASE Studentship at the University of Cambridge and thanks the Croucher Foundation of Hong Kong for the support of his Clinical Assistant Professorship. YC is supported by the ESRC for her Ph.D. studies at the University of Cambridge. BY received funding from the Research Grant Council of Hong Kong for his research

Evidence for a non-supersymmetric 5d CFT from deformations of 5d SU(2) SYM

We study supersymmetry breaking deformations of the $\mathcal{N}=1$ 5d fixed point known as $E_1$, the UV completion of $SU(2)$ super-Yang-Mills. The phases of the non-supersymmetric theory can be characterized by Chern-Simons terms involving background $U(1)$ gauge fields, allowing us to identify a phase transition at strong coupling. We propose that this may signify the emergence of a non-trivial, non-supersymmetric CFT in $d=4+1$ dimensions

The performance and exhaust emissions of a diesel engine fuelled with Calophyllum inophyllum- palm biodiesel

© 2019 by the authors. Nowadays, increased interest among the scientific community to explore the Calophyllum inophyllum as alternative fuels for diesel engines is observed. This research is about using mixed Calophyllum inophyllum-palm oil biodiesel production and evaluation that biodiesel in a diesel engine. The Calophyllum inophyllum-palm oil methyl ester (CPME) is processed using the following procedure: (1) the crude Calophyllum inophyllum and palm oils are mixed at the same ratio of 50:50 volume %, (2) degumming, (3) acid-catalysed esterification, (4) purification, and (5) alkalinecatalysed transesterification. The results are indeed encouraging which satisfy the international standards, CPME shows the high heating value (37.9 MJ/kg) but lower kinematic viscosity (4.50 mm2/s) due to change the fatty acid methyl ester (FAME) composition compared to Calophyllum inophyllum methyl ester (CIME). The average results show that the blended fuels have higher Brake Specific Fuel Consumption (BSFC) and NOx emissions, lower Brake Thermal Efficiency (BTE), along with CO and HC emissions than diesel fuel over the entire range of speeds. Among the blends, CPME5 offered better performance compared to other fuels. It can be recommended that the CPME blend has great potential as an alternative fuel because of its excellent characteristics, better performance, and less harmful emission than CIME blends

Shoulder pain due to cervical radiculopathy: an underestimated long-term complication of herpes zoster virus reactivation?

Purpose To evaluate if herpes zoster virus (HZV) reactivation may be considered in the aetiology of cervical radiculopathy. Methods The study group was composed of 110 patients (52 M-58F;mean age ± SD:46.5 ± 6.12; range:40-73) with a clinical diagnosis of cervical radiculopathy. Patients with signs of chronic damage on neurophysiological studies were submitted to an X-ray and to an MRI of the cervical spine in order to clarify the cause of the cervical radiculopathy and were investigated for a possible reactivation of HZV; HZV reactivation was considered as “recent” or “antique” if it occurs within or after 24 months from the onset of symptoms, respectively. Data were submitted to statistics. Results Thirty-eight patients (34,5%,16 M-22F) had a history of HZV reactivation: four (2 M-2F) were “recent” and 34 (14 M-20F) were “antique”. In 68 of 110 participants (61,8%,30 M-38F), pathological signs on X-ray and/or MRI of the cervical spine appeared; in the remaining 42 (38,2%,22 M-20F) X-ray and MRI resulted as negative. Among patients with HZV reactivation, seven (18,4%) had a “positive” X-ray-MRI while in 31 (81,6%) the instrumental exams were considered as negative. The prevalence of “antique” HZV reactivations was statistically greater in the group of patients with no pathological signs on X-ray/MRI of the cervical spine with respect to the group with a pathological instrumental exam (p < 0.01). Conclusions It may be useful to investigate the presence of a positive history of HZV reactivation and to consider it as a long-term complication of a cervical root inflammation especially in patients in which X-ray and MRI of the cervical spine did not show pathological findings

Bioinformatics approaches for cross-species liver cancer analysis based on microarray gene expression profiling

BACKGROUND: The completion of the sequencing of human, mouse and rat genomes and knowledge of cross-species gene homologies enables studies of differential gene expression in animal models. These types of studies have the potential to greatly enhance our understanding of diseases such as liver cancer in humans. Genes co-expressed across multiple species are most likely to have conserved functions. We have used various bioinformatics approaches to examine microarray expression profiles from liver neoplasms that arise in albumin-SV40 transgenic rats to elucidate genes, chromosome aberrations and pathways that might be associated with human liver cancer. RESULTS: In this study, we first identified 2223 differentially expressed genes by comparing gene expression profiles for two control, two adenoma and two carcinoma samples using an F-test. These genes were subsequently mapped to the rat chromosomes using a novel visualization tool, the Chromosome Plot. Using the same plot, we further mapped the significant genes to orthologous chromosomal locations in human and mouse. Many genes expressed in rat 1q that are amplified in rat liver cancer map to the human chromosomes 10, 11 and 19 and to the mouse chromosomes 7, 17 and 19, which have been implicated in studies of human and mouse liver cancer. Using Comparative Genomics Microarray Analysis (CGMA), we identified regions of potential aberrations in human. Lastly, a pathway analysis was conducted to predict altered human pathways based on statistical analysis and extrapolation from the rat data. All of the identified pathways have been known to be important in the etiology of human liver cancer, including cell cycle control, cell growth and differentiation, apoptosis, transcriptional regulation, and protein metabolism. CONCLUSION: The study demonstrates that the hepatic gene expression profiles from the albumin-SV40 transgenic rat model revealed genes, pathways and chromosome alterations consistent with experimental and clinical research in human liver cancer. The bioinformatics tools presented in this paper are essential for cross species extrapolation and mapping of microarray data, its analysis and interpretation

Sequential activation of different pathway networks in ischemia-affected and non-affected myocardium, inducing intrinsic remote conditioning to prevent left ventricular remodeling

We have analyzed the pathway networks of ischemia-affected and remote myocardial areas after repetitive ischemia/reperfusion (r-I/R) injury without ensuing myocardial infarction (MI) to elaborate a spatial- and chronologic model of cardioprotective gene networks to prevent left ventricular (LV) adverse remodeling. Domestic pigs underwent three cycles of 10/10 min r-I/R by percutaneous intracoronary balloon inflation/deflation in the mid left anterior descending artery, without consecutive MI. Sham interventions (n = 8) served as controls. Hearts were explanted at 5 h (n = 6) and 24 h (n = 6), and transcriptomic profiling of the distal (ischemia-affected) and proximal (non-affected) anterior myocardial regions were analyzed by next generation sequencing (NGS) and post-processing with signaling pathway impact and pathway network analyses. In ischemic region, r-I/R induced early activation of Ca-, adipocytokine and insulin signaling pathways with key regulator STAT3, which was also upregulated in the remote areas together with clusterin (CLU) and TNF-alpha. During the late phase of cardioprotection, antigen immunomodulatory pathways were activated with upregulation of STAT1 and CASP3 and downregulation of neprilysin in both zones, suggesting r-I/R induced intrinsic remote conditioning. The temporo-spatially differently activated pathways revealed a global myocardial response, and neprilysin and the STAT family as key regulators of intrinsic remote conditioning for prevention of adverse remodeling

Neurobehavioral consequences of chronic intrauterine opioid exposure in infants and preschool children: a systematic review and meta-analysis

&lt;b&gt;Background&lt;/b&gt;&lt;p&gt;&lt;/p&gt; It is assumed within the accumulated literature that children born of pregnant opioid dependent mothers have impaired neurobehavioral function as a consequence of chronic intrauterine opioid use.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Quantitative and systematic review of the literature on the consequences of chronic maternal opioid use during pregnancy on neurobehavioral function of children was conducted using the Meta-analysis of Observational Studies in Epidemiology (MOOSE) and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. We searched Cinahl, EMBASE, PsychINFO and MEDLINE between the periods of January 1995 to January 2012.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Results&lt;/b&gt;&lt;p&gt;&lt;/p&gt; There were only 5 studies out of the 200 identified that quantitatively reported on neurobehavioral function of children after maternal opioid use during pregnancy. All 5 were case control studies with the number of exposed subjects within the studies ranging from 33–143 and 45–85 for the controls. This meta-analysis showed no significant impairments, at a non-conservative significance level of p &#60; 0.05, for cognitive, psychomotor or observed behavioural outcomes for chronic intra-uterine exposed infants and pre-school children compared to non-exposed infants and children. However, all domains suggested a trend to poor outcomes in infants/children of opioid using mothers. The magnitude of all possible effects was small according to Cohen’s benchmark criteria.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions&lt;/b&gt;&lt;p&gt;&lt;/p&gt; Chronic intra-uterine opioid exposed infants and pre-school children experienced no significant impairment in neurobehavioral outcomes when compared to non-exposed peers, although in all domains there was a trend to poorer outcomes. The findings of this review are limited by the small number of studies analysed, the heterogenous populations and small numbers within the individual studies. Longitudinal studies are needed to determine if any neuropsychological impairments appear after the age of 5 years and to help investigate further the role of environmental risk factors on the effect of ‘core’ phenotypes

A computational model of excitation and contraction in uterine myocytes from the pregnant rat

Aberrant uterine myometrial activities in humans are major health issues. However, the cellular and tissue mechanism(s) that maintain the uterine myometrium at rest during gestation, and that initiate and maintain long-lasting uterine contractions during delivery are incompletely understood. In this study we construct a computational model for describing the electrical activity (simple and complex action potentials), intracellular calcium dynamics and mechanical contractions of isolated uterine myocytes from the pregnant rat. The model reproduces variant types of action potentials – from spikes with a smooth plateau, to spikes with an oscillatory plateau, to bursts of spikes – that are seen during late gestation under different physiological conditions. The effects of the hormones oestradiol (via reductions in calcium and potassium selective channel conductance), oxytocin (via an increase in intracellular calcium release) and the tocolytic nifedipine (via a block of L-type calcium channels currents) on action potentials and contractions are also reproduced, which quantitatively match to experimental data. All of these results validated the cell model development. In conclusion, the developed model provides a computational platform for further investigations of the ionic mechanism underlying the genesis and control of electrical and mechanical activities in the rat uterine myocytes

The Complexity of Vascular and Non-Vascular Complications of Diabetes: The Hong Kong Diabetes Registry

Diabetes is a complex disease characterized by chronic hyperglycemia and multiple phenotypes. In 1995, we used a doctor-nurse-clerk team and structured protocol to establish the Hong Kong Diabetes Registry in a quality improvement program. By 2009, we had accrued 2616 clinical events in 9588 Chinese type 2 diabetic patients with a follow-up duration of 6 years. The detailed phenotypes at enrollment and follow-up medications have allowed us to develop a series of risk equations to predict multiple endpoints with high sensitivity and specificity. In this prospective database, we were able to validate findings from clinical trials in real practice, confirm close links between cardiovascular and renal disease, and demonstrate the emerging importance of cancer as a leading cause of death. In addition to serving as a tool for risk stratification and quality assurance, ongoing data analysis of the registry also reveals secular changes in disease patterns and identifies unmet needs