INR variability in atrial fibrillation: A risk model for cerebrovascular events

BackgroundUse of vitamin K antagonists (VKAs) for stroke prophylaxis in patients with non-valvular atrial fibrillation (NVAF) necessitates frequent monitoring of the international normalized ratio (INR) to avoid the increased risk of hemorrhage associated with excess anticoagulation, or ischemic stroke due to insufficient anticoagulation. We therefore developed a model to estimate the excess morbidity attributable to inadequate INR control in NVAF populations.MethodsEquations expressing the risk of cerebrovascular events as a function of INR were generated using published data. Additional functions were developed to estimate the excess risk attributable to inferior INR control, using the clinical trial setting as the reference.ResultsThe derived risk functions were applied to French NVAF patients receiving anticoagulation in routine medical practice. This population achieved a time in therapeutic range (INR 2.0–3.0) of 59%, compared with 68% time in therapeutic range (TTR) in the SPORTIF III and V clinical trials. However, there was considerable variation in the TTR among patients in routine care, of whom 36% were in range for less than 50% of the time. Among this latter group, the relative risk, compared with the clinical trial setting, was 1.47 for ischemic stroke and 2.68 for intracranial hemorrhage. Conversely, for patients achieving a TTR greater than 50%, the relative risks for ischemic stroke and intracranial hemorrhage were 0.99 and 1.16, respectively.ConclusionsThis model permits estimation of the excess risk attributable to inferior INR control in NVAF populations receiving VKA anticoagulation, and has implications for public health planning and management.     

Evaluating the association of common APOA2 variants with type 2 diabetes

Background  

APOA2 is a positional and biological candidate gene for type 2 diabetes at the chromosome 1q21-q24 susceptibility locus. The aim of this study was to examine if HapMap phase II tag SNPs in APOA2 are associated with type 2 diabetes and quantitative traits in French Caucasian subjects.     

A rapid flow cytometry assay for the assessment of calcium mobilization in human neutrophils in a small volume of lysed whole-blood

Flow cytometry-based methods have been developed to measure most neutrophil responses. The assessment of the mobilization of calcium, however, is routinely performed on neutrophils isolated from whole blood. This report describes a flow cytometry-based assay to measure the mobilization of calcium in neutrophils directly in whole blood. This method requires minimal sample manipulation, small volumes of blood and is performed in a short period of time. Both clinical and research laboratories will be able to assess neutrophil function and the quality of granulocyte preparations using a more time and cost effective calcium mobilization test.     

Influence of cholesteryl ester transfer protein, peroxisome proliferator-activated receptor α, apolipoprotein E, and apolipoprotein A-I polymorphisms on high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein A-I, and lipoprotein A-I:A-II concentrations: the Prospective Epidemiological Study of Myocardial Infarction study

The plasma level of high-density lipoprotein cholesterol (HDL-C) is known to be inversely associated with cardiovascular risk. However, besides lifestyle, gene polymorphism may influence the HDL-C concentration. The aim of this study was to investigate the possibility of interactions between CETP, PPARA, APOE, and APOAI polymorphisms and HDL-C, apolipoprotein (apo) A-I, lipoprotein (Lp) A-I, and Lp A-I:A-II in a sample selected from the Prospective Epidemiological Study of Myocardial Infarction (PRIME) study population who remained free of cardiovascular events over 5 years of follow-up. Healthy individuals (857) were randomly selected for genotyping the PRIME study subjects. The population was selected so as to provide 25% of subjects in the lowest tertile of HDL-C (≤28 mg/dL) in the whole PRIME study sample, 25% of subjects in the highest tertile of HDL-C (≥73 mg/dL), and 50% of subjects in the medium tertile of HDL-C (28-73 mg/dL). Genotyping was performed by using a polymerase chain reaction system with predeveloped TaqMan allelic discrimination assay. The CETP A373P rare allele c was less frequent in the group of subjects with high HDL-C, apo A-I, Lp A-I, and Lp A-I:A-II concentrations. Apolipoprotein A-I and Lp A-I were also found to be higher in the presence of the ?2 allele coding for APOE. The effect of the CETP A373P rare allele c on HDL-C was independent of all tested parameters except triglycerides. The respective effect of these polymorphisms and triglycerides on cardiovascular risk should be evaluated prospectively.     

Transmission of Facial Expressions of Emotion Co-Evolved with Their Efficient Decoding in the Brain: Behavioral and Brain Evidence

Competent social organisms will read the social signals of their peers. In primates, the face has evolved to transmit the organism's internal emotional state. Adaptive action suggests that the brain of the receiver has co-evolved to efficiently decode expression signals. Here, we review and integrate the evidence for this hypothesis. With a computational approach, we co-examined facial expressions as signals for data transmission and the brain as receiver and decoder of these signals. First, we show in a model observer that facial expressions form a lowly correlated signal set. Second, using time-resolved EEG data, we show how the brain uses spatial frequency information impinging on the retina to decorrelate expression categories. Between 140 to 200 ms following stimulus onset, independently in the left and right hemispheres, an information processing mechanism starts locally with encoding the eye, irrespective of expression, followed by a zooming out to processing the entire face, followed by a zooming back in to diagnostic features (e.g. the opened eyes in “fear”, the mouth in “happy”). A model categorizer demonstrates that at 200 ms, the left and right brain have represented enough information to predict behavioral categorization performance.     

Extended efficacy and safety of denosumab in breast cancer patients with bone metastases not receiving prior bisphosphonate therapy

PURPOSE: Denosumab, a fully human monoclonal antibody to RANKL, suppresses bone resorption. This study evaluated the effects of denosumab in i.v. bisphosphonate (IV BP)-na?ve patients with breast cancer-related bone metastases. EXPERIMENTAL DESIGN: Eligible women (n = 255), stratified by type of antineoplastic therapy, were randomized to 1 of 5 blinded denosumab cohorts or an open-label IV BP cohort. Denosumab was administered s.c. every 4 weeks (30, 120, or 180 mg) or every 12 weeks (60 or 180 mg) through 21 weeks. Final efficacy results for up to 25 weeks are reported, including percentage change from baseline in urine N-telopeptide corrected for creatinine (uNTx/Cr) and incidence of skeletal-related events (SRE). Safety results are reported through the end of follow-up (up to 57 weeks). RESULTS: At week 13 and 25, the median percent changes in uNTx/creatinine (Cr) among patients with measurable uNTx were -73% and -75% for the pooled denosumab groups and -79% and -71% for the IV BP group. Among patients with > or =1 postbaseline measurement of uNTx at week 25, 52% (109 of 208) of denosumab-treated patients and 46% (19 of 41) of IV BP-treated patients achieved >65% uNTx/Cr reduction. On-study SREs occurred in 12% (26 of 211) of denosumab-treated patients and 16% (7 of 43) of IV BP-treated patients. Overall rates of adverse events were 95% in denosumab and IV BP groups. No denosumab-related serious or fatal adverse events occurred. CONCLUSIONS: In IV BP-na?ve breast cancer patients with bone metastases, denosumab suppresses bone turnover and seems to reduce SRE risk similarly to IV BPs, with a safety profile consistent with an advanced cancer population receiving systemic therapy.