Androgen deprivation decreases prostate specific antigen in the absence of tumor: implications for interpretation of PSA results

Background: Prostate-specific antigen (PSA) is used as an outcome measure for relapsed disease in prostate cancer. Nonetheless, there are considerable concerns about its indiscriminate use as a surrogate endpoint for cell growth or survival. We hypothesized that treatment with a luteinizing hormone releasing hormone (LHRH) analog would decrease PSA levels even in the absence of malignant disease. Methods: We determined testosterone and PSA levels in 30 healthy volunteers after a single intramuscular injection of a LHRH depot formulation. Testosterone and PSA levels were quantified by radioimmunoassay and electrochemi-luminescence immunoassay, respectively. Results: After an initial flare-up during the first 3 days testosterone decreased reaching castration levels in 18 of the 30 young men (60%). After the nadir on day 28, testosterone levels increased to normal again. Changes in PSA paralleled those of testosterone. Castration reduced PSA levels by 29% (95% CI 19%-39%) compared to baseline (p<0.0001). Conclusions: LHRH superagonists decrease PSA levels by testosterone deprivation. Conferring these findings to tumor patients, decreases in PSA after treatment with LHRH analogs might not only reflect disease regression but also a direct testosterone mediated effect on PSA. Thus, PSA levels should be cautiously interpreted when patients receive hormonal therap

Phenotyping vs. genotyping for prediction of clopidogrel efficacy and safety: the PEGASUS-PCI study

Background: Prognostic values of genotyping and phenotyping for assessment of clopidogrel responsiveness have been shown in independent studies. Objectives: To compare different assays for prediction of events during long-term follow-up. Methods: In this prospective cohort study polymorphisms of CYP2C19*2 and CYP2C19*17 alleles, vasodilator- stimulated phosphoprotein phosphorylation (VASP) assay, multiple electrode aggregometry (MEA), cone and platelet analyser (CPA) and platelet function analyser (PFA- 100) were performed in 416 patients undergoing percutaneous coronary intervention. The rates of events were recorded during a 12-month follow-up. Results: Platelet aggregation by MEA predicted stent thrombosis (2.4%) better (c-index = 0.90; P < 0.001; sensitivity = 90%; specificity = 83%) than the VASP assay, CPA or PFA-100 (c-index 0.05; sensitivity < 70%; specificity < 70% for all) or even the CYP2C19*2 polymorphism (c-index 0.05; sensitivity = 30%; specificity = 71%). Survival analysis indicated that patients classified as poor responders by MEA had a substantially higher risk of developing stent thrombosis or MACE than clopidogrel responders (12.5% vs. 0.3%, P < 0.001, and 18.5% vs. 11.3%, P = 0.022, respectively), whereas poor metabolizers (CYP2C19*1/*2 or *2/*2 carriers) were not at increased risks (stent thrombosis, 2.7% vs. 2.5%, P > 0.05; MACE, 13.5% vs. 12.1%, P = 0.556). The incidence of major bleedings (2.6%) was numerically higher in patients with an enhanced vs. poor response to clopidogrel assessed by MEA (4% vs. 0%) or in ultra-metabolizers vs. regular metabolizers (CYP2C19*17/*17 vs. CYP2C19*1/*1; 9.5% vs. 2%). The classification tree analysis demonstrated that acute coronary syndrome at hospitalization and diabetes mellitus were the best discriminators for clopidogrel responder status. Conclusions: Phenotyping of platelet response to clopidogrel was a better predictor of stent thrombosis than genotyping

Efficacy and Safety of Ticagrelor Monotherapy in Patients Undergoing Percutaneous Coronary Intervention: A Meta-Analysis

Dual antiplatelet therapy (DAPT) and subsequent P2Y12 inhibitor monotherapy, particularly ticagrelor, is an emerging treatment strategy in patients undergoing percutaneous coronary intervention (PCI). This meta-analysis was designed to investigate whether short-term DAPT followed by ticagrelor monotherapy is associated with a favorable outcome as compared with standard DAPT (1–3 months of DAPT was termed “short-term” DAPT, 6–12 months DAPT was termed “standard” DAPT). The primary outcome was the composite of major adverse cardiovascular events (MACE) comprising myocardial infarction, stroke, and cardiovascular death. Secondary outcomes included all-cause mortality and net adverse clinical events (NACE; myocardial infarction, stroke, all-cause death, stent thrombosis, and major bleeding). The primary safety outcome was major bleeding. Three studies comprising 26,143 patients were included. The risk of MACE was similar between the two treatment groups (risk ratio (RR) 0.86, 95% confidence interval (CI), 0.72–1.02, P = 0.08, I2 = 22%). Short-term DAPT followed by ticagrelor monotherapy resulted in a 20% relative risk reduction of all-cause mortality (RR 0.80, 95% CI, 0.65–0.98, P = 0.03, I2 = 0%) and an 18% relative risk reduction of NACE (RR 0.82, 95% CI, 0.71–0.94, P = 0.005, I2 = 33%) as compared with standard DAPT. Short-term DAPT followed by ticagrelor monotherapy significantly decreased the risk of major bleeding (RR 0.67, 95% CI, 0.49–0.92, P = 0.01, I2 = 65%). In patients with acute coronary syndrome, short-term DAPT followed by ticagrelor monotherapy resulted in an unchanged ischemic risk but a significantly lower bleeding risk compared with standard DAPT. Short-term DAPT followed by ticagrelor monotherapy compared with standard DAPT resulted in a favorable safety and efficacy profile. Direct comparisons of aspirin vs. ticagrelor monotherapy following PCI are needed

Switched Spatial Impulse Response Convolution as an Ambisonic Distance-Panning Function

Ambisonics offers a robust and effective approach to the recording, processing and delivery of Spatial Audio. The Ambisonic system is often considered to provide a perceptually and computationally advantageous Spatial Audio experience in comparison to typical Binaural systems. This is true even when an end-step Binaural render is required, as is typical in Virtual or Augmented Reality systems which naturally imply audio delivery via headphones. Standard Ambisonic processing allows for the rotation of a sound field around an origin position. There is not, however, a strongly established means of modulating the radial distance of a virtual sound source from the origin. This paper presents a potential solution to an Ambisonic distance-panning function for both static and dynamic virtual sources in the form of a FOA (First Order Ambisonics) Switched-SIR (Spatial Impulse Response) Convolution Reverberator. This includes a presentation of the framework for such a function, and an analysis of audio rendered using prototype scripts

The interactive role of type 2 diabetes mellitus and E-selectin S128R mutation on susceptibility to coronary heart disease

<p>Abstract</p> <p>Background</p> <p>The role of gene-environment interactions as risk factors for coronary heart disease (CAD) remains largely undefined. Such interactions may involve gene mutations and disease conditions such as type 2 diabetes mellitus (DM2) predisposing individuals to acquiring the disease.</p> <p>Methods</p> <p>In the present study, we assessed the possible interactive effect of DM2 and E-selectin S128R polymorphism with respect to its predisposing individuals to CAD, using as a study model a population of 1,112 patients and 427 angiographed controls of Saudi origin. E-selectin genotyping was accomplished by polymerase chain reaction (PCR) amplification followed by <it>Pst</it>I restriction enzyme digestion.</p> <p>Results</p> <p>The results show that DM2 is an independent risk factor for CAD. In the absence of DM2, the presence of the R mutant allele alone is not significantly associated with CAD (p = 0.431, OR 1.28). In contrast, in the presence of DM2 and the S allele, the likelihood of an individual acquiring CAD is significant (odds ratio = 5.44; p = < 0.001). This effect of DM2 becomes remarkably greater in the presence of the mutant 128R allele, as can be observed from the odds ratio of their interaction term (odds ratio = 6.11; p = < 0.001).</p> <p>Conclusion</p> <p>Our findings indicate therefore that the risk of acquiring CAD in patients with DM2 increases significantly in the presence of the 128R mutant allele of the E-selectin gene.</p

Reference values for exhaled nitric oxide (reveno) study

BACKGROUND: Despite the widespread use of fractional exhaled nitric oxide (FE(NO)) as a biomarker of airways inflammation, there are no published papers describing normal FE(NO )values in a large group of healthy adults. OBJECTIVE: The aim of this study was to establish adult FE(NO )reference values according to the international guidelines. METHODS: FE(NO )was measured in 204 healthy, non-smoking adults with normal spirometry values using the on-line single-breath technique, and the results were analysed chemiluminescently. RESULTS: The main result of the study was the significant difference in FE(NO )values between men and women, thus indicating that gender-based reference FE(NO )values are necessary. The FE(NO )levels obtained at expiratory flows of 50 ml/s ranged from 2.6 to 28.8 ppb in men, and from 1.6 to 21.5 ppb in women. CONCLUSION: We propose reference FE(NO )values for healthy adult men and women that could be used for clinical and research purposes

Targeted temperature management after cardiac arrest is associated with reduced metabolism of pantoprazole - a probe drug of CYP2C19 metabolism

OBJECTIVE\nMETHODS\nRESULTS\nCONCLUSION\nTargeted temperature management (TTM) is part of standard post-resuscitation care. TTM may downregulate cytochrome enzyme activity and thus impact drug metabolism. This study compared the pharmacokinetics (PK) of pantoprazole, a probe drug of CYP2C19-dependent metabolism, at different stages of TTM following cardiac arrest.\nThis prospective controlled study was performed at the Medical University of Vienna and enrolled 16 patients following cardiac arrest. The patients completed up to three study periods (each lasting 24 h) in which plasma concentrations of pantoprazole were quantified: (P1) hypothermia (33 °C) after admission, (P2) normothermia after rewarming (36 °C, intensive care), and (P3) normothermia during recovery (normal ward, control group). PK was analysed using non-compartmental analysis and nonlinear mixed-effects modelling.\n16 patients completed periods P1 and P2; ten completed P3. The median half-life of pantoprazole was 2.4 h (quartiles: 1.8-4.8 h) in P1, 2.8 h (2.1-6.8 h, p = 0.046 vs. P1, p = 0.005 vs. P3) in P2 and 1.2 h (0.9 - 2.3 h, p = 0.007 vs. P1) in P3. A two-compartment model described the PK data best. Typical values for clearance were estimated separately for each study period, indicating 40% and 29% reductions during P1 and P2, respectively, compared to P3. The central volume of distribution was estimated separately for P2, indicating a 64% increase compared to P1 and P3.\nCYP2C19-dependent drug metabolism is downregulated during TTM following cardiac arrest. These results may influence drug choice and dosing of similarly metabolized drugs and may be helpful for designing studies in similar clinical situations.Pharmacolog

A MicroRNA Next-Generation-Sequencing Discovery Assay (miND) for Genome-Scale Analysis and Absolute Quantitation of Circulating MicroRNA Biomarkers

The plasma levels of tissue-specific microRNAs can be used as diagnostic, disease severity and prognostic biomarkers for chronic and acute diseases and drug-induced injury. Thereby, the combination of diverse microRNAs into biomarker signatures using multivariate statistics seems especially powerful from the perspective of tissue and condition specific microRNA shedding into the plasma. Although next-generation sequencing (NGS) technology enables one to analyse circulating microRNAs on a genome-scale level, it suffers from potential biases (e.g., adapter ligation bias) and lacks absolute transcript quantitation as well as tailor-made quality controls. In order to develop a robust NGS discovery assay for genome-scale quantitation of circulating microRNAs, we first evaluated the sensitivity, repeatability and ligation bias of four commercially available small RNA library preparation protocols. The protocol from RealSeq Biosciences was selected based on its performance and usability and coupled with a novel panel of exogenous small RNA spike-in controls to enable quality control and absolute quantitation, thus ensuring comparability of data across independent NGS experiments. The established microRNA Next-Generation-Sequencing Discovery Assay (miND) was validated for its relative accuracy, precision, analytical measurement range and sequencing bias and was considered fit-for-purpose for microRNA biomarker discovery. Summarized, all these criteria were met, and thus, our analytical platform is considered fit-for-purpose for microRNA biomarker discovery from biofluids in the setting of any diagnostic, prognostic or patient stratification need. The established miND assay was tested on serum, cerebrospinal fluid (CSF), synovial fluid (SF) and extracellular vesicles (EV) extracted from cell culture medium of primary cells and proved its potential to be used across different sample types