Effects of ageing on pro-arrhythmic ventricular phenotypes in incrementally paced murine Pgc1β-/- hearts

A range of chronic clinical conditions accompany cardiomyocyte energetic dysfunction and constitute independent risk factors for cardiac arrhythmia. We investigated pro-arrhythmic and arrhythmic phenotypes in energetically deficient C57BL mice with genetic ablation of the mitochondrial promoter peroxisome proliferator activated receptor-γ coactivator-1β (Pgc-1β), a known model of ventricular arrhythmia. Pro-arrhythmic and cellular action potential (AP) characteristics were compared in intact Langendorff-perfused hearts from young (12-16 week) and aged (>52 week), WT and Pgc-1β-/- mice. Simultaneous electrocardiographic and intracellular microelectrode recordings were made through successive trains of 100 regular stimuli at progressively incremented heart rates. Aged Pgc-1β-/- hearts displayed an increased incidence of arrhythmia compared to other groups. Young and aged Pgc-1β-/- hearts showed higher incidences of alternans in both AP activation (maximum AP upshoot velocity (dV/dt)max and latency), recovery (action potential duration (APD90) and resting membrane potential (RMP)) characteristics compared to WT hearts. This was particularly apparent at lower pacing frequencies. These findings accompanied reduced (dV/dt)max and increased AP latency values in the Pgc-1β-/- hearts. APs observed prior to termination of the protocol showed lower (dV/dt)max and longer AP latencies, but indistinguishable APD90 and RMPs in arrhythmic compared to non-arrhythmic hearts. APD restitution analysis showed that Pgc-1β-/- and WT hearts showed similar limiting gradients. However, Pgc-1β-/- hearts had shortened plateau AP wavelengths, particularly in aged Pgc-1β-/- hearts. Pgc-1β-/- hearts therefore show pro-arrhythmic instabilities attributable to altered AP conduction and activation rather than recovery characteristics.We acknowledge the financial support from the Medical Research Council (MR/M001288/1); the Wellcome Trust (105727/Z/14/Z); the British Heart Foundation (PG/14/79/31102 and PG/15/12/31280), Sudden arrhythmic death syndrome (SADS) UK; The McVeigh Benefaction and by the Fundamental Research Grant Scheme (FRGS/2/2014/SKK01/PERDANA/02/1), Ministry of Education, Malaysia

A triangle model of criminality

This paper is concerned with a quantitative model describing the interaction of three sociological species, termed as owners, criminals and security guards, and denoted by X, Y and Z respectively. In our model, Y is a predator of the species X, and so is Z with respect to Y . Moreover, Z can also be thought of as a predator of X, since this last population is required to bear the costs of maintaining Z. We propose a system of three ordinary differential equations to account for the time evolution of X(t), Y (t) and Z(t) according to our previous assumptions. Out of the various parameters that appear in that system, we select two of them, denoted by H, and h, which are related with the efficiency of the security forces as a control parameter in our discussion. To begin with, we consider the case of large and constant owners population, which allows us to reduce (3)–(5) to a bidimensional system for Y (t) and Z(t). As a preliminary step, this situation is first discussed under the additional assumption that Y (t) + Z(t) is constant. A bifurcation study is then performed in terms of H and h, which shows the key role played by the rate of casualties in Y and Z, that results particularly in a possible onset of bistability. When the previous restriction is dropped, we observe the appearance of oscillatory behaviours in the full two-dimensional system. We finally provide a exploratory study of the complete model (3)–(5), where a number of bifurcations appear as parameter H changes, and the corresponding solutions behaviours are described

Transcriptional profiles of genes related to electrophysiological function in Scn5a+/− murine hearts

The Scn5a gene encodes the major pore-forming Nav1.5 (α) subunit, of the voltage-gated Na+ channel in cardiomyocytes. The key role of Nav1.5 in action potential initiation and propagation in both atria and ventricles predisposes organisms lacking Scn5a or carrying Scn5a mutations to cardiac arrhythmogenesis. Loss-of-function Nav1.5 genetic abnormalities account for many cases of the human arrhythmic disorder Brugada syndrome (BrS) and related conduction disorders. A murine model with a heterozygous Scn5a deletion recapitulates many electrophysiological phenotypes of BrS. This study examines the relationships between its Scn5a+/− genotype, resulting transcriptional changes, and the consequent phenotypic presentations of BrS. Of 62 selected protein-coding genes related to cardiomyocyte electrophysiological or homeostatic function, concentrations of mRNA transcribed from 15 differed significantly from wild type (WT). Despite halving apparent ventricular Scn5a transcription heterozygous deletion did not significantly downregulate its atrial expression, raising possibilities of atria-specific feedback mechanisms. Most of the remaining 14 genes whose expression differed significantly between WT and Scn5a+/− animals involved Ca2+ homeostasis specifically in atrial tissue, with no overlap with any ventricular changes. All statistically significant changes in expression were upregulations in the atria and downregulations in the ventricles. This investigation demonstrates the value of future experiments exploring for and clarifying links between transcriptional control of Scn5a and of genes whose protein products coordinate Ca2+ regulation and examining their possible roles in BrS

Transcriptional profiles of genes related to electrophysiological function in Scn5a+/- murine hearts.

The Scn5a gene encodes the major pore-forming Nav 1.5 (α) subunit, of the voltage-gated Na+ channel in cardiomyocytes. The key role of Nav 1.5 in action potential initiation and propagation in both atria and ventricles predisposes organisms lacking Scn5a or carrying Scn5a mutations to cardiac arrhythmogenesis. Loss-of-function Nav 1.5 genetic abnormalities account for many cases of the human arrhythmic disorder Brugada syndrome (BrS) and related conduction disorders. A murine model with a heterozygous Scn5a deletion recapitulates many electrophysiological phenotypes of BrS. This study examines the relationships between its Scn5a+/- genotype, resulting transcriptional changes, and the consequent phenotypic presentations of BrS. Of 62 selected protein-coding genes related to cardiomyocyte electrophysiological or homeostatic function, concentrations of mRNA transcribed from 15 differed significantly from wild type (WT). Despite halving apparent ventricular Scn5a transcription heterozygous deletion did not significantly downregulate its atrial expression, raising possibilities of atria-specific feedback mechanisms. Most of the remaining 14 genes whose expression differed significantly between WT and Scn5a+/- animals involved Ca2+ homeostasis specifically in atrial tissue, with no overlap with any ventricular changes. All statistically significant changes in expression were upregulations in the atria and downregulations in the ventricles. This investigation demonstrates the value of future experiments exploring for and clarifying links between transcriptional control of Scn5a and of genes whose protein products coordinate Ca2+ regulation and examining their possible roles in BrS

(3S)-3-(2,3-difluorophenyl)-3-methoxypyrrolidine (IRL752) - a novel cortical-preferring catecholamine transmission- and cognition-promoting agent

YesHere we describe for the first time the distinctive pharmacological profile for IRL752, a new phenyl-pyrrolidine derivative with regio-selective CNS transmission-enhancing properties. IRL752 (3.7-150 μmol/kg, s.c.) was characterised through extensive in vivo studies, using behavioural, tissue neurochemical and gene expression, as well as microdialysis methods. Behaviourally, the compound normalised tetrabenazine-induced hypoactivity, while unable to stimulate basal locomotion in normal animals or to either accentuate or reverse hyperactivity induced by amphetamine or MK-801. IRL752 induced but minor changes in monoaminergic tissue neurochemistry across NA- and DA-dominated brain regions. The expression of neuronal activity-, plasticity-, and cognition-related IEGs (immediate early genes) however increased by 1.5- to 2-fold. Furthermore, IRL752 dose-dependently enhanced cortical catecholamine dialysate output to 600-750% above baseline, while striatal DA remained unaltered and NA rose to ~250%; cortical and hippocampal dialysate ACh increased to ~250% and 190% above corresponding baseline, respectively. In line with this cortically preferential transmission-promoting action, the drug was also pro-cognitive in the novel object recognition and reversal learning tests. In vitro neurotarget affinity and functional data, coupled to drug exposure support the hypothesis that 5‑HT7 receptor and α2(C)-adrenoceptor antagonism are key contributors to the in vivo efficacy and original profile of IRL752. The cortical-preferring facilitatory impact on catecholamine (and ACh) neurotransmission, along with effects on IEG expression and cognition-enhancing features, are in line with the potential clinical usefulness of IRL752 in conditions where these aspects may be dysregulated, such as in axial motor and cognitive deficits in Parkinson's Disease

Association between 24-Hour Urinary Cadmium and Pulmonary Function among Community-Exposed Men: The VA Normative Aging Study

Background: High levels of cadmium exposure are known to cause emphysema in occupationally exposed workers, but little has been reported to date on the association between chronic environmental cadmium exposure and pulmonary function. Objective: In this study we examined the association between pulmonary function and cadmium body burden in a subcohort of the Normative Aging Study, a community-based study of aging. Methods: We examined 96 men who had cadmium measured in single 24-hr urinary specimens collected in 1994–1995 and who had one to three tests of pulmonary function between 1994 and 2002 (a total of 222 observations). We used mixed-effect models to predict pulmonary function based on individual 24-hr urinary cadmium output, adjusted for age, height, time elapsed from the baseline, and smoking status. We assessed effect modification by smoking status. Results: Among all subjects, a single log-unit increase in baseline urinary cadmium was inversely associated with forced expiratory volume in 1 sec (FEV1) percent predicted [β = −7.56%; 95% confidence interval (CI) −13.59% to −1.53%]; forced vital capacity (FVC) percent predicted (β = −2.70%; 95% CI −7.39% to 1.99%), and FEV1/FVC ratio (β = −4.13%; 95% CI −7.61% to −0.66%). In models including an interaction between urinary cadmium and smoking status, there was a graded, statistically significant reduction in FEV1/FVC ratio across smoking status in association with urinary cadmium. Conclusions: This study suggests that chronic cadmium exposure is associated with reduced pulmonary function, and cigarette smoking modifies this association. These results should be interpreted with caution because the sample size is small, and further studies are needed to confirm our findings

Acute health effects after accidental exposure to styrene from drinking water in Spain

OBJECTIVES: We studied subjective health symptoms in a population accidentally exposed to high styrene concentrations in drinking tap water. The contamination occurred during the reparation of a water tank. METHODS: Residents of 27 apartments in two buildings using the contaminated water were contacted. A questionnaire on subjective symptoms was administered to 84 out of 93 persons living in the apartments at the time of the accident. Styrene concentration was measured in samples of water collected two days after the accident. The means of exposure associated with appearance of symptoms were examined through case-control analyses. RESULTS: Styrene in water reached concentrations up to 900 μg/L. Symptoms were reported by 46 persons (attack rate 55 %). The most frequent symptoms were irritation of the throat (26%), nose (19%), eyes (18%) and the skin (14%). General gastrointestinal symptoms were observed with 11% reporting abdominal pain and 7% diarrhea. The factors most strongly associated with symptoms were drinking tap water (OR = 7.8, 95% CI 1.3–48), exposure to vapors from the basement (OR = 10.4, 2.3–47) and eating foods prepared with tap water (OR = 8.6, 1.9–40). All residents in the ground floor reported symptoms. CONCLUSIONS: This accidental contamination led to very high styrene concentrations in water and was related to a high prevalence of subjective symptoms of the eyes, respiratory tract and skin. Similar exposures have been described in workers but not in subjects exposed at their residence. Various gastrointestinal symptoms were also observed in this population probably due to a local irritative effect

A systematic review of musculoskeletal disorders among school teachers

<p>Abstract</p> <p>Background</p> <p>Musculoskeletal disorders (MSD) represent one of the most common and most expensive occupational health problems in both developed and developing countries. School teachers represent an occupational group among which there appears to be a high prevalence of MSD. Given that causes of MSD have been described as multi-factorial and prevalence rates vary between body sites and location of study, the objective of this systematic review was to investigate the prevalence and risk factors for MSD among teaching staff.</p> <p>Methods</p> <p>The study involved an extensive search of MEDLINE and EMBASE databases in 2011. All studies which reported on the prevalence and/or risk factors for MSD in the teaching profession were initially selected for inclusion. Reference lists of articles identified in the original search were then examined for additional publications. Of the 80 articles initially located, a final group of 33 met the inclusion criteria and were examined in detail.</p> <p>Results</p> <p>This review suggests that the prevalence of self-reported MSD among school teachers ranges between 39% and 95%. The most prevalent body sites appear to be the back, neck and upper limbs. Nursery school teachers appear to be more likely to report suffering from low back pain. Factors such as gender, age, length of employment and awkward posture have been associated with higher MSD prevalence rates.</p> <p>Conclusion</p> <p>Overall, this study suggests that school teachers are at a high risk of MSD. Further research, preferably longitudinal, is required to more thoroughly investigate the issue of MSD among teachers, with a greater emphasis on the possible wider use of ergonomic principles. This would represent a major step forward in the prevention of MSD among teachers, especially if easy to implement control measures could be recommended.</p

Understanding the effects of a decentralized budget on physicians' compliance with guidelines for statin prescription – a multilevel methodological approach

<p>Abstract</p> <p>Background</p> <p>Official guidelines that promote evidence-based and cost-effective prescribing are of main relevance for obvious reasons. However, to what extent these guidelines are followed and their conditioning factors at different levels of the health care system are still insufficiently known.</p> <p>In January 2004, a decentralized drug budget was implemented in the county of Scania, Sweden. Focusing on lipid-lowering drugs (i.e., statins), we evaluated the effect of this intervention across a 25-month period. We expected that increased local economic responsibility would promote prescribing of recommended statins.</p> <p>Methods</p> <p>We performed two separate multilevel regression analyses; on 110 827 individual prescriptions issued at 136 <it>publicly</it>-administered health care centres (HCCs) nested within 14 administrative areas (HCAs), and on 72 012 individual prescriptions issued by 115 <it>privately</it>-administered HCCs. Temporal trends in the prevalence of prescription of recommended statins were investigated by random slope analysis. Differences (i.e., variance) between HCCs and between HCAs were expressed by median odds ratio (MOR).</p> <p>Results</p> <p>After the implementation of the decentralized drug budget, adherence to guidelines increased continuously. At the end of the observation period, however, practice variation remained high. Prescription of recommended statins presented a high degree of clustering within both publicly (i.e., MOR_HCC= 2.18 and MOR_HCA= 1.31 respectively) and privately administered facilities (MOR_HCC= 3.47).</p> <p>Conclusion</p> <p>A decentralized drug budget seems to promote adherence to guidelines for statin prescription. However, the high practice differences at the end of the observation period may reflect inefficient therapeutic traditions, and indicates that rational statin prescription could be further improved.</p