Heart Rate and Cardiovascular Disease: An Alternative to Beta Blockers

Ivabradine, an If inhibitor, acts primarily on the sinoatrial node and is used to reduce the heart rate with minimal effect on myocardial contractility, blood pressure, and intracardiac conduction. Heart rate reduction is an important aspect of care in patients with chronic stable angina and heart failure. Many patients with coronary artery disease have coexisting asthma or chronic obstructive airway disease, and most of them are unable to tolerate beta blockers. Ivabradine may thus be a useful medicine in therapeutic heart rate management especially in patients who are intolerant of beta-blockers

The Vulnerable Plaque: the Real Villain in Acute Coronary Syndromes

The term "vulnerable plaque" refers to a vascular lesion that is prone to rupture and may result in life-threatening events which include myocardial infarction. It consists of thin-cap fibroatheroma and a large lipid core which is highly thrombogenic. Acute coronary syndromes often result from rupture of vulnerable plaques which frequently are only moderately stenosed and not visible by conventional angiography. Several invasive and non-invasive strategies have been developed to assess the burden of vulnerable plaques. Intravascular ultrasound provides a two-dimensional cross-sectional image of the arterial wall and can help assess the plaque burden and composition. Optical coherent tomography offers superior resolution over intravascular ultrasound. High-resolution magnetic resonance imaging provides non-invasive imaging for visualizing fibrous cap thickness and rupture in plaques. In addition, it may be of value in assessing the effects of treatments, such as lipid-lowering therapy. Technical issues however limit its clinical applicability. The role of multi-slice computed tomography, a well established screening tool for coronary artery disease, remains to be determined. Fractional flow reserve (FFR) may provide physiological functional assessment of plaque vulnerability; however, its role in the management of vulnerable plaque requires further studies. Treatment of the vulnerable patient may involve systemic therapy which currently include statins, ACE inhibitors, beta-blockers, aspirin, and calcium-channel blockers and in the future local therapeutic options such as drug-eluting stents or photodynamic therapy

Analysis of Rare, Exonic Variation amongst Subjects with Autism Spectrum Disorders and Population Controls

We report on results from whole-exome sequencing (WES) of 1,039 subjects diagnosed with autism spectrum disorders (ASD) and 870 controls selected from the NIMH repository to be of similar ancestry to cases. The WES data came from two centers using different methods to produce sequence and to call variants from it. Therefore, an initial goal was to ensure the distribution of rare variation was similar for data from different centers. This proved straightforward by filtering called variants by fraction of missing data, read depth, and balance of alternative to reference reads. Results were evaluated using seven samples sequenced at both centers and by results from the association study. Next we addressed how the data and/or results from the centers should be combined. Gene-based analyses of association was an obvious choice, but should statistics for association be combined across centers (meta-analysis) or should data be combined and then analyzed (mega-analysis)? Because of the nature of many gene-based tests, we showed by theory and simulations that mega-analysis has better power than meta-analysis. Finally, before analyzing the data for association, we explored the impact of population structure on rare variant analysis in these data. Like other recent studies, we found evidence that population structure can confound case-control studies by the clustering of rare variants in ancestry space; yet, unlike some recent studies, for these data we found that principal component-based analyses were sufficient to control for ancestry and produce test statistics with appropriate distributions. After using a variety of gene-based tests and both meta- and mega-analysis, we found no new risk genes for ASD in this sample. Our results suggest that standard gene-based tests will require much larger samples of cases and controls before being effective for gene discovery, even for a disorder like ASD. © 2013 Liu et al

Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis

Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07

The impact of the metabotropic glutamate receptor and other gene family interaction networks on autism.

International audienceAlthough multiple reports show that defective genetic networks underlie the aetiology of autism, few have translated into pharmacotherapeutic opportunities. Since drugs compete with endogenous small molecules for protein binding, many successful drugs target large gene families with multiple drug binding sites. Here we search for defective gene family interaction networks (GFINs) in 6,742 patients with the ASDs relative to 12,544 neurologically normal controls, to find potentially druggable genetic targets. We find significant enrichment of structural defects (P≤2.40E-09, 1.8-fold enrichment) in the metabotropic glutamate receptor (GRM) GFIN, previously observed to impact attention deficit hyperactivity disorder (ADHD) and schizophrenia. Also, the MXD-MYC-MAX network of genes, previously implicated in cancer, is significantly enriched (P≤3.83E-23, 2.5-fold enrichment), as is the calmodulin 1 (CALM1) gene interaction network (P≤4.16E-04, 14.4-fold enrichment), which regulates voltage-independent calcium-activated action potentials at the neuronal synapse. We find that multiple defective gene family interactions underlie autism, presenting new translational opportunities to explore for therapeutic interventions

Health equity in the New Zealand health care system: a national survey

<p>Abstract</p> <p>Introduction</p> <p>In all countries people experience different social circumstances that result in avoidable differences in health. In New Zealand, Māori, Pacific peoples, and those with lower socioeconomic status experience higher levels of chronic illness, which is the leading cause of mortality, morbidity and inequitable health outcomes. Whilst the health system can enable a fairer distribution of good health, limited national data is available to measure health equity. Therefore, we sought to find out whether health services in New Zealand were equitable by measuring the level of development of components of chronic care management systems across district health boards. Variation in provision by geography, condition or ethnicity can be interpreted as inequitable.</p> <p>Methods</p> <p>A national survey of district health boards (DHBs) was undertaken on macro approaches to chronic condition management with detail on cardiovascular disease, chronic obstructive pulmonary disease, congestive heart failure, stroke and diabetes. Additional data from expert informant interviews on program reach and the cultural needs of Māori and Pacific peoples was sought. Survey data were analyzed on dimensions of health equity relevant to strategic planning and program delivery. Results are presented as descriptive statistics and free text. Interviews were transcribed and NVivo 8 software supported a general inductive approach to identify common themes.</p> <p>Results</p> <p>Survey responses were received from the majority of DHBs (15/21), some PHOs (21/84) and 31 expert informants. Measuring, monitoring and targeting equity is not systematically undertaken. The Health Equity Assessment Tool is used in strategic planning but not in decisions about implementing or monitoring disease programs. Variable implementation of evidence-based practices in disease management and multiple funding streams made program implementation difficult. Equity for Māori is embedded in policy, this is not so for other ethnic groups or by geography. Populations that conventional practitioners find hard to reach, despite recognized needs, are often underserved. Nurses and community health workers carried a disproportionate burden of care. Cultural and diversity training is not a condition of employment.</p> <p>Conclusions</p> <p>There is a struggle to put equity principles into practice, indicating will without enactment. Equity is not addressed systematically below strategic levels and equity does not shape funding decisions, program development, implementation and monitoring. Equity is not incentivized although examples of exceptional practice, driven by individuals, are evident across New Zealand.</p

An Early Cambrian Rift to Post-Rift Transition in the Cordillera of Western North America

The upper Proterozoic and lower Palaeozoic wedge of miogeoclinal strata in the North American Cordillera is widely regarded as evidence for a proto-Pacific passive margin. The rifting history of this margin appears to have been protracted, possibly spanning more than 200 Myr in a tectonic setting that is not well understood. Quantitative subsidence analyses of lower Palaeozoic strata between British Columbia and Utah, however, provide indirect evidence that the transition from rifting to post-rift cooling occurred within a relatively short interval of time, although probably not synchronously, between 600 and 555 Myr. This age is significantly younger than that implied in previous studies. We describe here new field data, which, together with published geological data, provide direct evidence of a latest Proterozoic or early Cambrian age for the rift to post-rift transition. The data support recent arguments for widespread initiation of passive margins around the edge of the North American craton close to the Cambrian-Precambrian boundary

Protocol for Improving Care by FAster risk-STratification through use of high sensitivity point-of-care troponin in patients presenting with possible acute coronary syndrome in the EmeRgency department (ICare-FASTER):a stepped-wedge cluster randomised quality improvement initiative

Introduction Clinical assessment in emergency departments (EDs) for possible acute myocardial infarction (AMI) requires at least one cardiac troponin (cTn) blood test. The turn-around time from blood draw to posting results in the clinical portal for central laboratory analysers is ~1–2 hours. New generation, high-sensitivity, point-of-care cardiac troponin I (POC-cTnI) assays use whole blood on a bedside (or near bedside) analyser that provides a rapid (8 min) result. This may expedite clinical decision-making and reduce length of stay. Our purpose is to determine if utilisation of a POC-cTnI testing reduces ED length of stay. We also aim to establish an optimised implementation process for the amended clinical pathway.Methods and analysis This quality improvement initiative has a pragmatic multihospital stepped-wedge cross-sectional cluster randomised design. Consecutive patients presenting to the ED with symptoms suggestive of possible AMI and having a cTn test will be included. Clusters (comprising one or two hospitals each) will change from their usual-care pathway to an amended pathway using POC-cTnI—the ‘intervention’. The dates of change will be randomised. Changes occur at 1 month intervals, with a minimum 2 month ‘run-in’ period. The intervention pathway will use a POC-cTnI measurement as an alternate to the laboratory-based cTn measurement. Clinical decision-making steps and logic will otherwise remain unchanged. The POC-cTnI is the Siemens (Erlangen Germany) Atellica VTLi high-sensitivity cTnI assay. The primary outcome is ED length of stay. The safety outcome is cardiac death or AMI within 30 days for patients discharged directly from the ED.Ethics and dissemination Ethics approval has been granted by the New Zealand Southern Health and Disability Ethics Committee, reference 21/STH/9. Results will be published in a peer-reviewed journal. Lay and academic presentations will be made. Māori-specific results will be disseminated to Māori stakeholders.Trial registration number ACTRN12619001189112

The unfolded protein response is activated in disease-affected brain regions in progressive supranuclear palsy and Alzheimer’s disease

Abstract Background Progressive supranuclear palsy (PSP) is a neurodegenerative disorder pathologically characterized by intracellular tangles of hyperphosphorylated tau protein distributed throughout the neocortex, basal ganglia, and brainstem. A genome-wide association study identified EIF2AK3 as a risk factor for PSP. EIF2AK3 encodes PERK, part of the endoplasmic reticulum’s (ER) unfolded protein response (UPR). PERK is an ER membrane protein that senses unfolded protein accumulation within the ER lumen. Recently, several groups noted UPR activation in Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis, multiple system atrophy, and in the hippocampus and substantia nigra of PSP subjects. Here, we evaluate UPR PERK activation in the pons, medulla, midbrain, hippocampus, frontal cortex and cerebellum in subjects with PSP, AD, and in normal controls. Results We found UPR activation primarily in disease-affected brain regions in both disorders. In PSP, the UPR was primarily activated in the pons and medulla and to a much lesser extent in the hippocampus. In AD, the UPR was extensively activated in the hippocampus. We also observed UPR activation in the hippocampus of some elderly normal controls, severity of which positively correlated with both age and tau pathology but not with Aβ plaque burden. Finally, we evaluated EIF2AK3 coding variants that influence PERK activation. We show that a haplotype associated with increased PERK activation is genetically associated with increased PSP risk. Conclusions The UPR is activated in disease affected regions in PSP and the genetic evidence shows that this activation increases risk for PSP and is not a protective response. </jats:sec