Worldwide F_ST Estimates Relative to Five Continental-Scale Populations

We estimate the population genetics parameter inline image (also referred to as the fixation index) from short tandem repeat (STR) allele frequencies, comparing many worldwide human subpopulations at approximately the national level with continental-scale populations. inline image is commonly used to measure population differentiation, and is important in forensic DNA analysis to account for remote shared ancestry between a suspect and an alternative source of the DNA. We estimate inline image comparing subpopulations with a hypothetical ancestral population, which is the approach most widely used in population genetics, and also compare a subpopulation with a sampled reference population, which is more appropriate for forensic applications. Both estimation methods are likelihood-based, in which inline image is related to the variance of the multinomial-Dirichlet distribution for allele counts. Overall, we find low inline image values, with posterior 97.5 percentiles inline image when comparing a subpopulation with the most appropriate population, and even for inter-population comparisons we find inline image inline image. These are much smaller than single nucleotide polymorphism-based inter-continental inline image estimates, and are also about half the magnitude of STR-based estimates from population genetics surveys that focus on distinct ethnic groups rather than a general population. Our findings support the use of inline image up to 3% in forensic calculations, which corresponds to some current practice

Circadian activity of the endogenous fibrinolytic system in stable coronary artery disease:effects of beta-adrenoreceptor blockers and angiotensin-converting enzyme inhibitors

AbstractObjectives. To examine circadian changes in the sympathovagal balance, the activity of the renin-angiotensin system and hemostatic variables in patients with stable coronary artery disease, and the effects of beta-adrenoceptor blockade and angiotensin-converting enzyme inhibition.Background. Sympathovagal balance and key components of the fibrinolytic system show circadian variability. The effects of beta-adrenergic blocking agents and angiotensin-converting enzyme inhibitors on these autonomic and hemostatic rhythms are not well defined.Methods. Twenty patients with coronary artery disease underwent 24-h Holter monitoring for heart rate variability and blood sampling (6 hourly for 24 hours) after three consecutive treatment phases, (firstly with placebo, then bisoprolol, and finally quinapril). The effects on sympathovagal balance, hemostatic variables and the renin-angiotensin system activity were measured.Results. The fibrinolytic capacity showed marked circadian variation at the end of the placebo phase (p = 0.002), plasminogen activator inhibitor-1 (PAI-1) activity peaking at 06.00 amwhen tissue plasminogen activator (tPA) activity was at its nadir. Sympathovagal balance showed a sharp increase at approximately the same time but plasma renin activity did not rise until later in the day. Inspection of the 24-h profiles suggested that bisoprolol reduced sympathovagal balance and the morning peak of PAI-1 activity and antigen, with a small increase in tPA activity, although these changes were not significant. Quinapril produced a substantial rise in renin (p = 0.01) but did not significantly affect either PAI-1 or tPA. Sympathovagal balance was unaffected by quinapril.Conclusions. In patients with stable coronary artery disease, angiotensin-converting enzyme inhibition with quinapril does not affect either sympathovagal balance or the endogenous fibrinolytic system. Our data suggest that the sympathoadrenal system may modify fibrinolytic activity, judged by the response to beta-adrenoreceptor blockade with bisoprolol

Role for CCG-trinucleotide repeats in the pathogenesis of chronic lymphocytic leukemia

Abstract Chromosome 11q deletions are frequently observed in chronic lymphocytic leukemia (CLL) in association with progressive disease and a poor prognosis. A minimal region of deletion has been assigned to 11q22-q23. Trinucleotide repeats have been associated with anticipation in disease, and evidence of anticipation has been observed in various malignancies including CLL. Loss of heterozygosity at 11q22-23 is common in a wide range of cancers, suggesting this is an unstable area prone to chromosome breakage. The location of 8 CCG-trinucleotide repeats on 11q was determined by Southern blot analysis of a 40-Mb YAC and PAC contig spanning 11q22-qter. Deletion breakpoints in CLL are found to co-localize at specific sites on 11q where CCG repeats are located. In addition, a CCG repeat has been identified within the minimal region of deletion. Specific alleles of this repeat are associated with worse prognosis. Folate-sensitive fragile sites are regions of late replication and are characterized by CCG repeats. The mechanism for chromosome deletion at 11q could be explained by a delay in replication. Described here is an association between CCG repeats and chromosome loss suggesting that in vivo “fragile sites” exist on 11q and that the instability of CCG repeats may play an important role in the pathogenesis of CLL.</jats:p

Streptokinase induced defibrination assessed by thrombin time: effects on residual coronary stenosis and left ventricular ejection fraction

Objective—To evaluate laboratory markers of defibrination early after thrombolytic therapy and to determine their relation to residual stenosis and left ventricular ejection fraction measured angiographically before discharge from hospital. Design—Prospective analysis of defibrination after streptokinase measured by fibrinogen assay and thrombin time to provide a comparison of these coagulation variables for predicting angiographic responses to treatment in patients with acute myocardial infarction. Setting—The coronary care unit of a district general hospital. Patients—44 patients with acute myocardial infarction treated by streptokinase infusion, all of whom underwent paired blood sampling before and one hour after streptokinase and cardiac catheterisation at a median of six (interquartile range 3–9) days later. Main outcome measures—Assay of thrombin time and plasma fibrinogen concentrations one hour after streptokinase infusion. Relations between these coagulation variables and residual stenosis in the infarct related coronary artery and left ventricular ejection fraction. Separate analyses are presented for all patients (n = 44) and those with patency of the infarct related artery (n = 35). Results—Streptokinase infusion produced profound defibrination in every patient as shown by changes in thrombin time and circulating fibrinogen. Thrombin time after streptokinase infusion correlated significantly with both residual stenosis (r = −0·43, p < 0·005) and left ventricular ejection fraction (r = 0·38, p < 0·02). The importance of these correlations was emphasised by the interquartile group comparison which showed that a thrombin time ≥49 seconds predicted a residual stenosis of 74% and an ejection fraction of 65%, compared with 90% and 49% for a thrombin time ≤31 seconds (p < 0·01). When the analysis was restricted to patients with patency of the infarct related artery, the correlation between thrombin time and residual stenosis remained significant and group comparisons continued to show that patients in the highest quartile range had more widely patent arteries and better preservation of ejection fraction. Analysis of the fibrinogen data, on the other hand, showed insignificant or only marginally significant correlations with these angiographic variables. Conclusions—Early after streptokinase infusion for acute myocardial infarction, the level of defibrination measured by thrombin time has an important influence on residual coronary stenosis and left ventricular ejection fraction at discharge from hospital, values above 49 seconds being associated with the best angiographic result