Proton endor study of the photoexcited triplet state PT in Rps. sphaeroides R-26 photosynthetic reaction centres

The photoexcited triplet state PT of Rhodopseudomonas sphaeroides R-26 has been investigated by ENDOR measurements performed on frozen photosynthetic reaction centre solutions. For the first time hyperfine data could be obtained for PT. These data indicate a delocalisation of the triplet state over two bacteriochlorophyll a molecules

Stimulation of Adenosine A 3 Receptors in Cerebral Ischemia: Neuronal Death, Recovery, or Both?

The role of the adenosine A 3 receptor continues to baffle, and, despite an increasing number of studies, the currently available data add to, rather than alleviate, the existing confusion. The reported effects of adenosine A 3 receptor stimulation appear to depend on the pattern of drug administration (acute vs. chronic), dose, and type of the target tissue. Thus, while acute exposure to A 3 receptor agonists protects against myocardial ischemia, it is severely damaging when these agents are given shortly prior to cerebral ischemia. Mast cells degranulate when their A 3 receptors are stimulated. Degranulation of neutrophils is, on the other hand, impaired. While reduced production of reactive nitrogen species has been reported following activation of A 3 receptors in collagen-induced arthritis, the process appears to be enhanced in cerebral ischemia. Indeed, immunocytochemical studies indicate that both pre- and postischemic treatment with A 3 receptor antagonist dramatically reduces nitric oxide synthase in the affected hippocampus. Even more surprisingly, low doses of A 3 receptor agonists seem to enhance astrocyte proliferation, while high doses induce their apoptosis. This review concentrates on the studies of cerebral A 3 receptors and, based on the available evidence, discusses the possibility of adenosine A 3 receptor serving as an integral element of the endogenous cerebral neuroprotective complex consisting of adenosine and its receptors.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75391/1/j.1749-6632.1999.tb07984.x.pd

Oral Anticoagulant Therapy Prescription in Patients With Atrial Fibrillation Across the Spectrum of Stroke Risk: Insights From the NCDR PINNACLE Registry

IMPORTANCE: Patients with atrial fibrillation (AF) are at a proportionally higher risk of stroke based on accumulation of well-defined risk factors. OBJECTIVE: To examine the extent to which prescription of an oral anticoagulant (OAC) in US cardiology practices increases as the number of stroke risk factors increases. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional registry study of outpatients with AF enrolled in the American College of Cardiology National Cardiovascular Data Registry's PINNACLE (Practice Innovation and Clinical Excellence) Registry between January 1, 2008, and December 30, 2012. As a measure of stroke risk, we calculated the CHADS2 score and the CHA2DS2-VASc score for all patients. Using multinomial logistic regression models adjusted for patient, physician, and practice characteristics, we examined the association between increased stroke risk score and prescription of an OAC. MAIN OUTCOMES AND MEASURES: The primary outcome was prescription of an OAC with warfarin sodium or a non-vitamin K antagonist OAC. RESULTS: The study cohort comprised 429 417 outpatients with AF. Their mean (SD) age was 71.3 (12.9) years, and 55.8% were male. Prescribed treatment consisted of an OAC (192 600 [44.9%]), aspirin only (111 134 [25.9%]), aspirin plus a thienopyridine (23 454 [5.5%]), or no antithrombotic therapy (102 229 [23.8%]). Each 1-point increase in risk score was associated with increased odds of OAC prescription compared with aspirin-only prescription using the CHADS2 score (adjusted odds ratio, 1.158; 95% CI, 1.144-1.172; P < .001) and the CHA2DS2-VASc score (adjusted odds ratio, 1.163; 95% CI, 1.157-1.169; P < .001). Overall, OAC prescription prevalence did not exceed 50% even in higher-risk patients with a CHADS2 score exceeding 3 or a CHA2DS2-VASc score exceeding 4. CONCLUSIONS AND RELEVANCE: In a large quality improvement registry of outpatients with AF, prescription of OAC therapy increased with a higher CHADS2 score and CHA2DS2-VASc score. However, a plateau of OAC prescription was observed, with less than half of high-risk patients receiving an OAC prescription

Adenosine A2A receptor modulation of hippocampal CA3-CA1 synapse plasticity during associative learning in behaving mice

© 2009 Nature Publishing Group All rights reservedPrevious in vitro studies have characterized the electrophysiological and molecular signaling pathways of adenosine tonic modulation on long-lasting synaptic plasticity events, particularly for hippocampal long-term potentiation(LTP). However, it remains to be elucidated whether the long-term changes produced by endogenous adenosine in the efficiency of synapses are related to those required for learning and memory formation. Our goal was to understand how endogenous activation of adenosine excitatory A2A receptors modulates the associative learning evolution in conscious behaving mice. We have studied here the effects of the application of a highly selective A2A receptor antagonist, SCH58261, upon a well-known associative learning paradigm - classical eyeblink conditioning. We used a trace paradigm, with a tone as the conditioned stimulus (CS) and an electric shock presented to the supraorbital nerve as the unconditioned stimulus(US). A single electrical pulse was presented to the Schaffer collateral–commissural pathway to evoke field EPSPs (fEPSPs) in the pyramidal CA1 area during the CS–US interval. In vehicle-injected animals, there was a progressive increase in the percentage of conditioning responses (CRs) and in the slope of fEPSPs through conditioning sessions, an effect that was completely prevented (and lost) in SCH58261 (0.5 mg/kg, i.p.)-injected animals. Moreover, experimentally evoked LTP was impaired in SCH58261- injected mice. In conclusion, the endogenous activation of adenosine A2A receptors plays a pivotal effect on the associative learning process and its relevant hippocampal circuits, including activity-dependent changes at the CA3-CA1 synapse.This study was supported by grants from the Spanish Ministry of Education and Research (BFU2005-01024 and BFU2005-02512), Spanish Junta de Andalucía (BIO-122 and CVI-02487), and the Fundación Conocimiento y Cultura of the Pablo de Olavide University (Seville, Spain).B. Fontinha was in receipt of a studentship from a project grant (POCI/SAU-NEU/56332/2004) supported by Fundação para a Ciência e Tecnologia (FCT, Portugal), and of an STSM from Cost B30 concerted action of the EU

Risks of ozonated oil and ozonated water on human skin: A systematic review

Ozonated water and oil are emerging as potential dermatologic therapeutics, particularly for the treatment of various wounds. However, the safety of these liquids has not been extensively studied. The aim of this systematic review was to evaluate the risks of ozonated liquids to human skin tissue based on the available literature. We completed a structured search of five scientific databases and identified 378 articles for consideration. Based on pre-established inclusion/exclusion criteria, nine studies were included in this review. Two studies specifically evaluated the cytotoxicity of ozonated liquids on human cells, five studies evaluated ozonated liquids in randomised controlled trials(RCTs), one was a post-market surveillance study, and one was a cross over study in humans. None of the included studies found any significant human dermatologic risks associated with ozonated water or liquid. Because of the small sample size, however, additional short- and long-term RCTs specifically designed to evaluate the dermatological risks of ozonated liquids are recommended.This study was funded by an unrestricted grant from 3Oe Scientific, Inc., a technology company evaluating human applications for aqueous ozone

2020 APHRS/HRS Expert Consensus Statement on the Investigation of Decedents with Sudden Unexplained Death and Patients with Sudden Cardiac Arrest, and of Their Families.

This international multidisciplinary document intends to provide clinicians with evidence-based practical patient-centered recommendations for evaluating patients and decedents with (aborted) sudden cardiac arrest and their families. The document includes a framework for the investigation of the family allowing steps to be taken, should an inherited condition be found, to minimize further events in affected relatives. Integral to the process is counseling of the patients and families, not only because of the emotionally charged subject, but because finding (or not finding) the cause of the arrest may influence management of family members. The formation of multidisciplinary teams is essential to provide a complete service to the patients and their families, and the varied expertise of the writing committee was formulated to reflect this need. The document sections were divided up and drafted by the writing committee members according to their expertise. The recommendations represent the consensus opinion of the entire writing committee, graded by Class of Recommendation and Level of Evidence. The recommendations were opened for public comment and reviewed by the relevant scientific and clinical document committees of the Asia Pacific Heart Rhythm Society (APHRS) and the Heart Rhythm Society (HRS); the document underwent external review and endorsement by the partner and collaborating societies. While the recommendations are for optimal care, it is recognized that not all resources will be available to all clinicians. Nevertheless, this document articulates the evaluation that the clinician should aspire to provide for patients with sudden cardiac arrest, decedents with sudden unexplained death, and their families

Investigation of the Stationary and Transient A1·− Radical in Trp → Phe Mutants of Photosystem I

Photosystem I (PS I) contains two symmetric branches of electron transfer cofactors. In both the A- and B-branches, the phylloquinone in the A1 site is π-stacked with a tryptophan residue and is H-bonded to the backbone nitrogen of a leucine residue. In this work, we use optical and electron paramagnetic resonance (EPR) spectroscopies to investigate cyanobacterial PS I complexes, where these tryptophan residues are changed to phenylalanine. The time-resolved optical data show that backward electron transfer from the terminal electron acceptors to P700·+ is affected in the A- and B-branch mutants, both at ambient and cryogenic temperatures. These results suggest that the quinones in both branches take part in electron transport at all temperatures. The electron-nuclear double resonance (ENDOR) spectra of the spin-correlated radical pair P700·+A1·− and the photoaccumulated radical anion A1·−, recorded at cryogenic temperature, allowed the identification of characteristic resonances belonging to protons of the methyl group, some of the ring protons and the proton hydrogen-bonded to phylloquinone in the wild type and both mutants. Significant changes in PS I isolated from the A-branch mutant are detected, while PS I isolated from the B-branch mutant shows the spectral characteristics of wild-type PS I. A possible short-lived B-branch radical pair cannot be detected by EPR due to the available time resolution; therefore, only the A-branch quinone is observed under conditions typically employed for EPR and ENDOR spectroscopies

Genetic Risk Score to Identify Risk of Venous Thromboembolism in Patients With Cardiometabolic Disease

BACKGROUND –: Venous thromboembolism (VTE) is a major cause of cardiovascular morbidity and mortality with a known genetic contribution. We tested the performance of a genetic risk score (GRS) for its ability to predict VTE in three cohorts of patients with cardiometabolic disease. METHODS –: We included patients from the FOURIER, PEGASUS-TIMI 54, and SAVOR-TIMI 53 trials (history of atherosclerosis, myocardial infarction, and diabetes, respectively) who consented for genetic testing and were not on baseline anticoagulation. We calculated a VTE GRS based on 297 SNPs with established genome-wide significance. Patients were divided into tertiles of genetic risk. Cox proportional hazards models were used to calculate hazard ratios for VTE across genetic risk groups. The polygenic risk score was compared to available clinical risk factors (age, obesity, smoking, history of heart failure, diabetes) and common monogenic mutations. RESULTS –: A total of 29,663 patients were included in the analysis with a median follow-up of 2.4 years, of whom 174 had a VTE event. There was a significantly increased gradient of risk across VTE genetic risk tertiles (p-trend <0.0001). After adjustment for clinical risk factors, patients in the intermediate and high genetic risk groups had a 1.88-fold (95% CI 1.23–2.89, p=0.004) and 2.70-fold (95% CI 1.81–4.06, p<0.0001) higher risk of VTE compared to patients with low genetic risk. In a continuous model adjusted for clinical risk factors, each standard deviation increase in the GRS was associated with a 47% (95% CI 29–68) increased risk of VTE (p<0.0001). CONCLUSIONS –: In a broad spectrum of patients with cardiometabolic disease, a polygenic risk score is a strong, independent predictor of VTE after accounting for available clinical risk factors, identifying 1/3 of patients who have a risk of VTE comparable to that seen with established monogenic thrombophilia

Association between Variants on Chromosome 4q25, 16q22 and 1q21 and Atrial Fibrillation in the Polish Population

Genome-wide studies have shown that polymorphisms on chromosome 4q25, 16q22 and 1q21 correlate with atrial fibrillation (AF). However, the distribution of these polymorphisms differs significantly among populations.To test the polymorphisms on chromosome 4q25, 16q22 and 1q21 in a group of patients (pts) that underwent catheter ablation of AF.Four hundred and ten patients with AF that underwent pulmonary vein isolation were included in the study. Control group (n = 550) was taken from healthy population, matched for age, sex and presence of hypertension. All participants were genotyped for the presence of the rs2200733, rs10033464, rs17570669, rs3853445, rs6838973 (4q25), rs7193343 (16q22) and rs13376333 (1q21) polymorphisms.All the polymorphisms tested (except rs17570669) correlated significantly with AF in univariate analysis (p values between 0.039 for rs7193343 and 2.7e-27 for rs2200733), with the odds ratio (OR) 0.572 and 0.617 for rs3853445 and rs6838973, respectively (protective role) and OR 1.268 to 3.52 for the other polymorphisms. All 4q25 SNPs tested but rs3853445 were independently linked with AF in multivariate logistic regression analysis. In haplotype analysis six out of nine 4q25 haplotypes were significantly linked with AF. The T allele of rs2200733 favoured increased number of episodes of AF per month (p = 0.045) and larger pulmonary vein diameter (recessive model, p = 0.032).Patients qualified for catheter ablation of AF have a significantly higher frequency of 4q25, 16q22 and 1q21 variants than the control group. The T allele of rs2200733 favours larger pulmonary veins and increased number of episodes of AF

Identification of SERPINA1 as single marker for papillary thyroid carcinoma through microarray meta analysis and quantification of its discriminatory power in independent validation

<p>Abstract</p> <p>Background</p> <p>Several DNA microarray based expression signatures for the different clinically relevant thyroid tumor entities have been described over the past few years. However, reproducibility of these signatures is generally low, mainly due to study biases, small sample sizes and the highly multivariate nature of microarrays. While there are new technologies available for a more accurate high throughput expression analysis, we show that there is still a lot of information to be gained from data deposited in public microarray databases. In this study we were aiming (1) to identify potential markers for papillary thyroid carcinomas through meta analysis of public microarray data and (2) to confirm these markers in an independent dataset using an independent technology.</p> <p>Methods</p> <p>We adopted a meta analysis approach for four publicly available microarray datasets on papillary thyroid carcinoma (PTC) nodules versus nodular goitre (NG) from N2-frozen tissue. The methodology included merging of datasets, bias removal using distance weighted discrimination (DWD), feature selection/inference statistics, classification/crossvalidation and gene set enrichment analysis (GSEA). External Validation was performed on an independent dataset using an independent technology, quantitative RT-PCR (RT-qPCR) in our laboratory.</p> <p>Results</p> <p>From meta analysis we identified one gene (SERPINA1) which identifies papillary thyroid carcinoma against benign nodules with 99% accuracy (n = 99, sensitivity = 0.98, specificity = 1, PPV = 1, NPV = 0.98). In the independent validation data, which included not only PTC and NG, but all major histological thyroid entities plus a few variants, SERPINA1 was again markedly up regulated (36-fold, p = 1:3*10^-10) in PTC and identification of papillary carcinoma was possible with 93% accuracy (n = 82, sensitivity = 1, specificity = 0.90, PPV = 0.76, NPV = 1). We also show that the extracellular matrix pathway is strongly activated in the meta analysis data, suggesting an important role of tumor-stroma interaction in the carcinogenesis of papillary thyroid carcinoma.</p> <p>Conclusions</p> <p>We show that valuable new information can be gained from meta analysis of existing microarray data deposited in public repositories. While single microarray studies rarely exhibit a sample number which allows robust feature selection, this can be achieved by combining published data using DWD. This approach is not only efficient, but also very cost-effective. Independent validation shows the validity of the results from this meta analysis and confirms SERPINA1 as a potent mRNA marker for PTC in a total (meta analysis plus validation) of 181 samples.</p