Melanoma cells break down LPA to establish local gradients that drive chemotactic dispersal.

The high mortality of melanoma is caused by rapid spread of cancer cells, which occurs unusually early in tumour evolution. Unlike most solid tumours, thickness rather than cytological markers or differentiation is the best guide to metastatic potential. Multiple stimuli that drive melanoma cell migration have been described, but it is not clear which are responsible for invasion, nor if chemotactic gradients exist in real tumours. In a chamber-based assay for melanoma dispersal, we find that cells migrate efficiently away from one another, even in initially homogeneous medium. This dispersal is driven by positive chemotaxis rather than chemorepulsion or contact inhibition. The principal chemoattractant, unexpectedly active across all tumour stages, is the lipid agonist lysophosphatidic acid (LPA) acting through the LPA receptor LPAR1. LPA induces chemotaxis of remarkable accuracy, and is both necessary and sufficient for chemotaxis and invasion in 2-D and 3-D assays. Growth factors, often described as tumour attractants, cause negligible chemotaxis themselves, but potentiate chemotaxis to LPA. Cells rapidly break down LPA present at substantial levels in culture medium and normal skin to generate outward-facing gradients. We measure LPA gradients across the margins of melanomas in vivo, confirming the physiological importance of our results. We conclude that LPA chemotaxis provides a strong drive for melanoma cells to invade outwards. Cells create their own gradients by acting as a sink, breaking down locally present LPA, and thus forming a gradient that is low in the tumour and high in the surrounding areas. The key step is not acquisition of sensitivity to the chemoattractant, but rather the tumour growing to break down enough LPA to form a gradient. Thus the stimulus that drives cell dispersal is not the presence of LPA itself, but the self-generated, outward-directed gradient

Baseline values from the electrocardiograms of children and adolescents with ADHD

<p>Abstract</p> <p>Background</p> <p>An important issue in pediatric pharmacology is the determination of whether medications affect cardiac rhythm parameters, in particular the QT interval, which is a surrogate marker for the risk of adverse cardiac events and sudden death. To evaluate changes while on medication, it is useful to have a comparison of age appropriate values while off medication. The present meta-analysis provides baseline ECG values (i.e., off medication) from approximately 6000 children and adolescents with attention-deficit/hyperactivity disorder (ADHD).</p> <p>Methods</p> <p>Subjects were aged 6–18 years and participated in global trials within the atomoxetine registration program. Patients were administered a 12-lead ECG at study screening and cardiac rhythm parameters were recorded. Baseline QT intervals were corrected for heart rate using 3 different methods: Bazett's, Fridericia's, and a population data-derived formula.</p> <p>Results</p> <p>ECG data were obtained from 5289 North American and 641 non-North American children and adolescents. Means and percentiles are presented for each ECG measure and QTc interval based on pubertal status as defined by age and sex. Prior treatment history with stimulants and racial origin (Caucasian) were each associated with significantly longer mean QTc values.</p> <p>Conclusion</p> <p>Baseline ECG and QTc data from almost 6000 children and adolescents presenting with ADHD are provided to contribute to the knowledge base regarding mean values for pediatric cardiac parameters. Consistent with other studies of QT interval in children and adolescents, Bazett correction formula appears to overestimate the prevalence of prolonged QTc in the pediatric population.</p

Trends in the mortality of non-traumatic subarachnoid hemorrhage in Colombia: a 10-year analysis of a nationwide registry

Objective To assess trends in mortality from 1999 to 2008 resulting from non-traumatic subarachnoid hemorrhage (SAH) in the Colombian population. Method This population-based study analyzed all deaths by assuming a Poisson model. Results Subarachnoid hemorrhage-related deaths showed a statistically significant increase of 1.6% per year (p<0.001). The age-standardized analysis demonstrated an increased mortality trend of 3.3% per year (p<0.001) in people older than 70 years, but a decreased mortality trend in people younger than 50. It remained stable in patients 50-69 years old. Conclusion The overall SAH-related mortality rate in Colombia has increased because increased mortality among the elderly has been counterbalanced by reduced mortality rates in younger age groups. These disparities may reflect epidemiologic transition, treatment inequities, or a less favorable comorbid profile

Heart Rate Variability Characteristics in Sedentary Postmenopausal Women Following Six Months of Exercise Training: The DREW Study

Article on heart rate variability characteristics in sedentary postmenopausal women following six months of exercise training

Coffee, Alcohol, Smoking, Physical Activity and QT Interval Duration: Results from the Third National Health and Nutrition Examination Survey

Abnormalities in the electrocardiographic QT interval duration have been associated with an increased risk of ventricular arrhythmias and sudden cardiac death. However, there is substantial uncertainty about the effect of modifiable factors such as coffee intake, cigarette smoking, alcohol consumption, and physical activity on QT interval duration.We studied 7795 men and women from the Third National Health and Nutrition Survey (NHANES III, 1988-1994). Baseline QT interval was measured from the standard 12-lead electrocardiogram. Coffee and tea intake, alcohol consumption, leisure-time physical activities over the past month, and lifetime smoking habits were determined using validated questionnaires during the home interview.In the fully adjusted model, the average differences in QT interval comparing participants drinking ≥6 cups/day to those who did not drink any were -1.2 ms (95% CI -4.4 to 2.0) for coffee, and -2.0 ms (-11.2 to 7.3) for tea, respectively. The average differences in QT interval duration comparing current to never smokers was 1.2 ms (-0.6 to 2.9) while the average difference in QT interval duration comparing participants drinking ≥7 drinks/week to non-drinkers was 1.8 ms (-0.5 to 4.0). The age, race/ethnicity, and RR-interval adjusted differences in average QT interval duration comparing men with binge drinking episodes to non-drinkers or drinkers without binge drinking were 2.8 ms (0.4 to 5.3) and 4.0 ms (1.6 to 6.4), respectively. The corresponding differences in women were 1.1 (-2.9 to 5.2) and 1.7 ms (-2.3 to 5.7). Finally, the average differences in QT interval comparing the highest vs. the lowest categories of total physical activity was -0.8 ms (-3.0 to 1.4).Binge drinking was associated with longer QT interval in men but not in women. QT interval duration was not associated with other modifiable factors including coffee and tea intake, smoking, and physical activity

Investigating the stratified efficacy and safety of pharmacological blood pressure-lowering: an overall protocol for individual patient-level data meta-analyses of over 300 000 randomised participants in the new phase of the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC)

Introduction Previous research from the Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC) and others has shown that pharmacological blood pressure (BP)- lowering substantially reduces the risk of major cardiovascular events, including ischaemic heart disease, heart failure and stroke. In this new phase, the aim is to conduct individual patient-level data (IPD) meta-analyses involving eligible BP-lowering randomised controlled trials (RCTs) to address uncertainties relating to efficacy and safety of BP-lowering treatment. Methods and analysis RCTs investigating the effect of pharmacological BP-lowering, with a minimum of 1000 patient-years of follow-up in each trial arm, are eligible. Our systematic review identified 100 potentially eligible trials. We requested their investigators/sponsors to contribute baseline, follow-up and outcomes data. As of June 2018, the collaboration has obtained data from 49 trials (n=315 046 participants), with additional data currently in the process of being transferred from four RCTs (n=34 642 participants). In addition, data harmonisation has commenced. Scientific activities of the collaboration are overseen by the Steering Committee with input from all collaborators. Detailed protocols for individual meta-analyses will be developed and registered on public platforms. Ethics and dissemination Ethics approval has been obtained for this new and extended phase of the BPLTTC, the largest collaboration of de-identified IPD from RCTs. It offers an efficient and ethical manner of re-purposing existing data to answer clinically important questions relating to BP treatment as well as methodological questions relating to IPD meta-analyses. Among the immediate impacts will include reliable quantification of effects of treatment modifiers, such as baseline BP, age and prior disease, on both vascular and non-vascular outcomes. Analyses will further assess the impact of BP-lowering on important, but less well understood, outcomes, such as new-onset diabetes and renal disease. Findings will be published in peer-reviewed medical journals on behalf of the collaboration