Increased platelet expression of FcGammaRIIa and its potential impact on platelet reactivity in patients with end stage renal disease

<p>Abstract</p> <p>Background</p> <p>Increased platelet reactivity has been implicated in cardiovascular disease – the major cause of death in patients with end stage renal disease (ESRD). FcGammaRIIA is a component of glycoprotein VI and Ib-IX-V that mediate activation of platelets by collagen and von Willebrand factor. To determine whether expression of FcGammaRIIA impacts platelet reactivity we quantified its expression and platelet reactivity in 33 patients with ESRD who were undergoing hemodialysis.</p> <p>Methods</p> <p>Blood samples were obtained from patients immediately before hemodialysis and before administration of heparin. Platelet expression of FcGammaRIIA and the activation of platelets in response to low concentrations of convulxin (1 ng/ml, selected to mimic effects of collagen), thrombin (1 nM), adenosine diphosphate (ADP, 0.2 uM), or platelet activating factor (PAF, 1 nM) were determined with the use of flow cytometry in samples of whole blood anticoagulated with corn trypsin inhibitor (a specific inhibitor of Factor XIIa).</p> <p>Results</p> <p>Patients were stratified with respect to the median expression of FcGammaRIIA. Patients with high platelet expression of FcGammaRIIA exhibited 3-fold greater platelet reactivity compared with that in those with low expression in response to convulxin (p < 0.01) and 2-fold greater activation in response to thrombin, ADP, and PAF (p < 0.05 for each). For each agonist, expression of FcGammaRIIA correlated modestly but positively with platelet reactivity. The strongest correlation was with thrombin-induced activation (r = 0.6, p < 0.001).</p> <p>Conclusion</p> <p>Increased platelet reactivity in response to low concentrations of diverse agonists is associated with high expression of FcGammaRIIA and may contribute to an increased risk of thrombosis in patients with ESRD.</p

Importance of continued activation of thrombin reflected by fibrinopeptide A to the efficacy of thrombolysis

Factors responsible for initial success or failure of coronary thrombolysis and persistent recanalization or early reocclusion have not been thoroughly elucidated. Both adequate initial clot lysis and preclusion of rethrombosis are required. Failure may reflect clot lysis followed immediately or somewhat later by rethrombosis. To determine whether differences in the intensity and persistence of the activation of thrombin are determinants of success or failure of recanalization, plasma fibrinopeptide A, a fibrinogen product liberated by thrombin, was serially assayed in 19 patients treated with intravenous streptokinase. In patients exhibiting recanalization (n = 9), plasma fibrinopeptide A decreased after administration of streptokinase but before administration of heparin. In patients without initially apparent recanalization, fibrinopeptide A increased, suggesting ongoing thrombosis, and subsequently decreased promptly after heparin. In patients with initial recanalization followed by overt reocclusion the pattern was different. Despite recanalization, fibrinopeptide A continued to rise markedly. Elevations persisted despite administration of heparin. Thus, inhibition of activation of thrombin is associated with successful recanalization. Conversely, persistent activation of thrombin may be a predisposing factor to both apparent initial failure of recanalization and nvprt early reocclusion

Oral Ibrexafungerp for Vulvovaginal Candidiasis Treatment: An Analysis of VANISH 303 and VANISH 306

Background: Ibrexafungerp is a novel antifungal treatment for acute vulvovaginal candidiasis (VVC). Using pooled data from two phase three studies (VANISH 303 and 306) in the treatment of acute VVC, this analysis sought to determine the effectiveness of ibrexafungerp in various patient subgroups that may impact outcomes. Materials and Methods: Data from VANISH 303 (NCT03734991) and VANISH 306 (NCT03987620) evaluating ibrexafungerp 300 mg twice daily (BID) for 1 day versus placebo, were pooled and analyzed to determine clinical cure rate, clinical improvement, and mycological cure at the test-of-cure visit (day 11 ± 3) and symptom resolution at the follow-up visit (day 25 ± 4) in the overall population. Patient subgroups analyzed included race, body mass index (BMI), baseline vulvovaginal signs and symptoms (VSS) score, and Candida species. Results: At the test-of-cure visit, patients receiving ibrexafungerp, compared with those who received placebo, had significantly higher rates of clinical cure (56.9% [214/376 patients] vs. 35.7% [65/182 patients]), clinical improvement (68.4% [257/376 patients] vs. 45.1% [82/182 patients]), and mycological cure (54.0% [203/376 patients] vs. 24.2% [44/182 patients]; all p \u3c 0.0001). At the follow-up visit, patients receiving ibrexafungerp had sustained responses with higher symptom resolution rates (66.8% [251/376 patients]) versus placebo (48.4% [88/182 patients]; p \u3c 0.0001). Race, BMI, baseline VSS score (including VSS severity score 13-18), and Candida species infection did not adversely affect clinical cure rates. Safety analysis results were consistent with the individual studies. Conclusions: Ibrexafungerp provides a safe and well-tolerated first-in-class fungicidal, 1-day oral treatment for patients with acute VVC, the first new therapy in \u3e20 years. Clinical Trial Registration Number: NCT03734991

Inference with interference between units in an fMRI experiment of motor inhibition

An experimental unit is an opportunity to randomly apply or withhold a treatment. There is interference between units if the application of the treatment to one unit may also affect other units. In cognitive neuroscience, a common form of experiment presents a sequence of stimuli or requests for cognitive activity at random to each experimental subject and measures biological aspects of brain activity that follow these requests. Each subject is then many experimental units, and interference between units within an experimental subject is likely, in part because the stimuli follow one another quickly and in part because human subjects learn or become experienced or primed or bored as the experiment proceeds. We use a recent fMRI experiment concerned with the inhibition of motor activity to illustrate and further develop recently proposed methodology for inference in the presence of interference. A simulation evaluates the power of competing procedures.Comment: Published by Journal of the American Statistical Association at http://www.tandfonline.com/doi/full/10.1080/01621459.2012.655954 . R package cin (Causal Inference for Neuroscience) implementing the proposed method is freely available on CRAN at https://CRAN.R-project.org/package=ci

Mapping Urban Performance Culture: A Common Ground for Architecture and Theater

Our co-taught course focuses on theater history, with an emphasis on performance architecture. Assignments are designed to illuminate the ways in which architectural design and technology inform performance practices and audience reception. The pivotal assignment for exploring interdisciplinarity is a three-week module on mapping historical theaters in New York City. Open-source Global Information Systems (GIS) software serves as a common mechanism for students to situate theatrical productions in the context of the built urban environment, deepening their understanding of the social, economic, and artistic forces that contributed to performance culture. Mapping is a shared pedagogy for analyzing and presenting research findings from different fields. Learning how to collect, analyze, and map data is also a general education skill that can be applied to disciplines across undergraduate curricula

Effect of combination glipizide GITS/metformin on fibrinolytic and metabolic parameters in poorly controlled type 2 diabetic subjects

WSTĘP. Wyniki badań epidemiologicznych wskazują, że podwyższone stężenie inhibitora aktywatora plazminogenu 1 (PAI-1) w surowicy krwi może być wskaźnikiem lub predyktorem przyspieszonego rozwoju choroby wieńcowej u chorych na cukrzycę typu 2. Celem pracy było określenie, czy poprawa wyrównania metabolicznego, niezależnie od rodzaju stosowanych leków doustnych, wpływa na stężenie PAI-1 u chorych ze znaczną hiperglikemią. MATERIAŁ I METODY. Do badania zakwalifikowano 91 chorych. Po okresie 4 tygodni, w którym pacjenci nie przyjmowali żadnych leków, chorych losowo przydzielono do grupy leczonej glipizydem GITS (w dawce maksymalnej 20 mg, n = 46) lub grupy otrzymującej metforminę (maksymalnie 2550 mg, n = 45) w monoterapii. Po okresie monoterapii wprowadzono leczenie skojarzone, dodając drugi lek do preparatu już stosowanego. U wszystkich pacjentów przed i po randomizacji oraz podczas badania oznaczono glikemię (na czczo i po posiłku), stężenie HbA1c, fruktozaminy oraz PAI-1. U części chorych zmierzono również wątrobową produkcję glukozy (HGO, hepatic glucose output) oraz oznaczono rozkład brzusznej tkanki tłuszczowej. WYNIKI. Wyrównanie glikemii na początku badania było niezadowalające (średnie stężenie HbA1c 10,4 &plusmn; 0,2% w grupie glipizydu GITS; 10,0 &plusmn; 0,2% w grupie metforminy), ale poprawiło się istotnie w obu grupach, stosujących monoterapię oraz w wyniku leczenia skojarzonego (p < 0,0001 vs. wyniki wyjściowe), co oceniono na podstawie badania tolerancji posiłku, stężenia fruktozaminy oraz HGO. Masa ciała oraz rozkład brzusznej tkanki tłuszczowej nie zmieniły się istotnie w żadnej z grup. Stężenie PAI-1 było wyjątkowo wysokie (5-10-krotnie wyższe od wartości prawidłowych) na początku badania (202 &plusmn; 12 ng/ml w grupie glipizydu GITS; 201 &plusmn; 13 ng/ml w grupie metforminy), ale istotnie obniżyło się podczas badania, w sposób porównywalny w monoterapii w obu grupach. Podczas leczenia skojarzonego stężenie to uległo dalszemu obniżeniu. WNIOSKI. W przypadkach nasilonej hiperglikemii stężenie PAI-1 jest również znacznie podwyższone. Obniżenie hiperglikemii za pomocą leku nasilającego wydzielanie insuliny, glipizydu GITS lub metforminy, stosowanych w monoterapii, w porównywalny sposób powoduje obniżenie stężenia PAI-1.INTRODUCTION. Epidemiological studies have implicated increased plasminogen-activated inhibitor 1 (PAI-1) as a marker or predictor of accelerated coronary atherosclerotic disease in type 2 diabetes. We sought to determine whether metabolic control, independent of its oral mode of implementation, affects PAI-1 in patients with marked hyperglycemia. MATERIAL AND METHODS. A total of 91 subjects were screened, subjected to a 4-week drug washout, and randomized to daily treatment with glipizide GITS (maximum 20 mg, n = 46) or metformin (maximum 2,550 mg, n = 45) as monotherapy. After monotherapy, combination therapy was initiated by adding the second agent to the regimen. Plasma glucose (fasting and postprandial), HbA1c, fructosamine, and PAI-1 were assayed before and after randomization and sequentially thereafter in all subjects; hepatic glucose output (HGO) and abdominal fat distribution were each measured in a subset of subjects. RESULTS. Glycemic control was markedly impaired at baseline (mean HbA1c 10.4 &#177; 0.2% glipizide GITS; 10.0 &#177; 0.2% metformin) but improved comparably with each agent as monotherapy and in combination (P < 0.0001 vs. baseline), as assessed with meal tolerance studies, fructosamine values, and HGO. Body weight and abdominal fat distribution did not change significantly in either group. PAI-1 concentrations were extraordinarily high (5- to 10-fold more than normal) at baseline (202 &#177; 12 ng/ml glipizide GITS; 201 &#177; 13 ng/ml metformin) but declined comparably, and significantly, after treatment with either agent as monotherapy and decreased further with combination therapy. CONCLUSIONS. When hyperglycemia is profound, increases in PAI-1 are also profound. Control of hyperglycemia with either glipizide GITS, an insulin secretagogue, or metformin as monotherapy comparably ameliorates elevated PAI-1