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The Laryngoscope Jul 2020P2RX2 encoding P2X purinoreceptor 2 has been identified as the gene responsible for autosomal dominant deafness-41 (DFNA41) as well as mediating vulnerability to...
OBJECTIVES/HYPOTHESIS
P2RX2 encoding P2X purinoreceptor 2 has been identified as the gene responsible for autosomal dominant deafness-41 (DFNA41) as well as mediating vulnerability to noise-induced hearing loss (NIHL). The objective of this study was to investigate the audiological and molecular characteristics of P2RX2-related deafness, with emphasis on its role in NIHL by determining the audiological characteristics of a previously reported six-generation DFNA41 family with a 10-year follow-up. We have also summarized phenotype-genotype correlations of P2RX2-related deafness in human and mouse models.
STUDY DESIGN
We describe clinical longitudinal follow-up in the DFNA41 family with P2RX2 (p.Val60Leu) mutation and perform a systematic literature search in PubMed and poster presentations on meeting/conference websites to identify current insights into P2RX2-mediated NIHL.
METHODS
Clinical and physical examinations of the family members were performed, and audiograms were obtained to assess the hearing thresholds. Clinical follow-up features in this DFNA41 family are presented along with correlation analyses of phenotype-genotype in all reported families with P2RX2-related deafness.
RESULTS
Progressive hearing impairment was confirmed by history and by audiological follow-up testing in all the patients. The onset of hearing loss was between age 25 and 35 years. All affected subjects had bilateral sensorineural hearing loss involving all frequencies with some significant gender differences.
CONCLUSIONS
Our study and the review of the literature suggest that P2RX2 plays a crucial role in predisposition to noise-induced and age-related hearing loss. A better knowledge about the P2RX2-associated genetic variants can help in developing novel therapeutic strategies.
LEVEL OF EVIDENCE
2b Laryngoscope, 130:1657-1663, 2020.
Topics: Adult; Disease Progression; Female; Follow-Up Studies; Genotype; Hearing Loss, Sensorineural; Humans; Longitudinal Studies; Male; Middle Aged; Mutation; Pedigree; Phenotype; Receptors, Purinergic P2X2; Sex Factors
PubMed: 31593348
DOI: 10.1002/lary.28318 -
Current Pharmaceutical Design 2019Adenosine receptors (ARs) are classified as A1, A2A, A2B, and A3 subtypes belong to the superfamily of G-protein coupled receptors (GPCRs). More than 40% of modern...
BACKGROUND
Adenosine receptors (ARs) are classified as A1, A2A, A2B, and A3 subtypes belong to the superfamily of G-protein coupled receptors (GPCRs). More than 40% of modern medicines act through either activation or inhibition of signaling processes associated with GPCRs. In particular, A2B AR signaling pathways are implicated in asthma, inflammation, cancer, ischemic hyperfusion, diabetes mellitus, cardiovascular diseases, gastrointestinal disorders, and kidney disease.
METHODS
This article reviews different disease segments wherein A2B AR is implicated and discusses the potential role of subtype-selective A2B AR ligands in the management of such diseases or disorders. All the relevant publications on this topic are reviewed and presented scientifically.
RESULTS
This review provides an up-to-date highlight of the recent advances in the development of novel and selective A2B AR ligands and their therapeutic role in treating various disease conditions. A special focus has been given to the therapeutic potentials of selective A2B AR ligands in the management of airway inflammatory conditions and cancer.
CONCLUSIONS
This systematic review demonstrates the current status and perspectives of A2B AR ligands as therapeutically useful agents that would assist medicinal chemists and pharmacologists in discovering novel and subtype-selective A2B AR ligands as potential drug candidates.
Topics: Adenosine A2 Receptor Agonists; Adenosine A2 Receptor Antagonists; Drug Discovery; Humans; Ligands; Receptor, Adenosine A2B; Signal Transduction
PubMed: 31333084
DOI: 10.2174/1381612825666190717105834 -
Medicina (Kaunas, Lithuania) Jun 2019Background and : Several studies inspected the impact of polymorphisms on individual susceptibility to tuberculosis (TB), but the findings are still controversial and... (Meta-Analysis)
Meta-Analysis
Background and : Several studies inspected the impact of polymorphisms on individual susceptibility to tuberculosis (TB), but the findings are still controversial and inconclusive. To achieve a more precise estimation, we conducted a meta-analysis of all eligible studies on the association between polymorphisms and TB risk. Relevant studies were identified by searching the PubMed, Web of Science, Scopus and Google scholar databases up to November 2018. Twenty-four full-text articles were included in our meta-analysis. The strength of association between polymorphisms and TB risk was evaluated by odds ratios (ORs) and 95% confidence intervals (95% CIs) under five genetic models. The findings of this meta-analysis revealed that the rs3751143 variant significantly increased the risk of TB in heterozygous codominant (OR = 1.44, 95%CI = 1.17-1.78, = 0.0006, AC vs. AA), homozygous codominant (OR = 1.87, 95% CI = 1.40-2.49, = 0.0004, CC vs. AA), dominant (OR = 1.50, 95% CI = 1.22-1.85, = 0.0002, AC + CC vs. AA), recessive (OR = 1.61, 95% CI = 1.25-2.07, = 0.001, CC vs. AC + AA), and allele (OR = 1.41, 95% CI = 1.19-1.67, < 0.0001, C vs. A) genetic models. Stratified analysis showed that rs3751143 increased the risk of pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) in all genetic models. Furthermore, the rs3751143 increased risk of TB in the Asian population. The findings did not support an association between the rs2393799, rs1718119, rs208294, rs7958311, and rs2230911 polymorphisms of and TB risk. The findings of this meta-analysis suggest that rs3751143 polymorphism may play a role in susceptibility to TB in the Asian population. More well-designed studies are required to elucidate the exact role of polymorphisms on TB development.
Topics: Case-Control Studies; Chi-Square Distribution; Genetic Predisposition to Disease; Humans; Odds Ratio; Polymorphism, Genetic; Receptors, Purinergic P2X7; Risk Adjustment; Risk Factors; Tuberculosis
PubMed: 31234470
DOI: 10.3390/medicina55060298 -
Lower Urinary Tract Symptoms May 2019Underactive bladder (UAB) is a multifactorial symptom complex often related to detrusor underactivity (DU). Although recognized as a common cause of lower urinary tract...
Underactive bladder (UAB) is a multifactorial symptom complex often related to detrusor underactivity (DU). Although recognized as a common cause of lower urinary tract symptoms and with significant effects on quality of life, UAB/DU is largely underresearched. Herein, we review up-to-date knowledge on the pathophysiological mechanisms of UAB/DU, with an emphasis on the relationship between UAB and bladder outlet obstruction (BOO). Original articles and reviews concerning UAB/DU were identified through a search of the PubMed/Medline and Scopus databases. DU can result from several pathological mechanisms, which can be categorized as idiopathic, neurogenic, myogenic, or functional. The main etiological factors of UAB/DU are aging, diabetes mellitus, neurogenic disorders, and BOO. Although conventional models focus primarily on efferent nerve and myogenic mechanisms, contemporary views highlight the importance of the afferent pathway. Specifically, recent findings in BOO showed that afferent dysfunction, such as altered expression of muscarinic and purinergic P2X receptors or diminished urothelial ATP may play a role in the initial and reversible stages of DU, with potential diagnostic and therapeutic implications.
Topics: Afferent Pathways; Age Factors; Animals; Diabetes Complications; Humans; Nervous System Diseases; Urinary Bladder; Urinary Bladder Neck Obstruction; Urinary Bladder, Underactive
PubMed: 30864243
DOI: 10.1111/luts.12257 -
Platelets 2020Cigarette smoking is an important cardiovascular risk factor, causing morbidity and mortality. There are many original studies on the impact of smoking, but its... (Meta-Analysis)
Meta-Analysis
Cigarette smoking is an important cardiovascular risk factor, causing morbidity and mortality. There are many original studies on the impact of smoking, but its influence on platelet ADP-P2Y12 receptor inhibitors lack consistency. Thus, we conducted a systematic review and meta-analysis of already existing data/studies to further explore this issue. PubMed, Web of science, EMBASE, Clinical Trials, and the Cochrane Library were searched from inception to March 2018. Studies investigating the residual platelet reactivity categorized by smoking status and patients treated with platelet ADP-P2Y12 receptor inhibitors qualified the inclusion criteria. The primary outcome was P2Y12 reaction unit (PRU) value measured by VerifyNow P2Y12 assay, compared with different smoking status in ADP-P2Y12 receptor inhibitors treatment groups. Secondary outcome was post-treatment with 5 μmol/L ADP-inhibition of platelet aggregation (ADP-IPA) measured by light transmittance aggregometry (LTA). Of the 4954 citations retrieved, 12 studies involving 16 296 patients with acute coronary syndrome and/or stent deployment using platelet ADP-P2Y12 receptor inhibitors were included for meta-analysis. Pooled analysis revealed that PRU values of current smokers were 25.70 lower than nonsmokers (95% CI -38.81 to -12.60, = 0.0001), getting better effects of antiplatelet treatment. In the smoking extent subgroup analysis, patients smoking >10 cigarettes/day shown about 46.49 lower of PRU values than patients smoking <10 cigarettes/day ( < 0.00001). Racial subgroup analyses found that smokers had increased platelet inhibition in the Caucasian population. Further, pooled analysis of ADP-IPA values for 1658 patients from five studies showed a significantly lower residual platelet reactivity in current smokers compared to that in nonsmokers (MD = -4.19; 95% CI -6.55 to -1.83; = 0.0005). This systematic review and meta-analysis suggested that smokers have increased platelet inhibition and lower aggregation in response to clopidogrel than nonsmokers. These residual platelet reactivity observations may help to explain differential clinical outcomes in smokers vs. nonsmokers in large scale clinical trials.
Topics: Adult; Aged; Biomarkers; Blood Platelets; Clopidogrel; Humans; Middle Aged; Platelet Activation; Platelet Aggregation Inhibitors; Platelet Function Tests; Publication Bias; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y12; Smoking
PubMed: 30744477
DOI: 10.1080/09537104.2019.1572878 -
Impact of Genetic Variability on Physiological Responses to Caffeine in Humans: A Systematic Review.Nutrients Sep 2018Emerging research has demonstrated that genetic variation may impact physiological responses to caffeine consumption. The purpose of the present review was to...
Emerging research has demonstrated that genetic variation may impact physiological responses to caffeine consumption. The purpose of the present review was to systematically recognize how select single nucleotide polymorphisms (SNPs) impact habitual use of caffeine as well as the ergogenic and anxiogenic consequences of caffeine. Two databases (PubMed and EBSCO) were independently searched using the same algorithm. Selected studies involved human participants and met at least one of the following inclusion criteria: (a) genetic analysis of individuals who habitually consume caffeine; (b) genetic analysis of individuals who underwent measurements of physical performance with the consumption of caffeine; (c) genetic analysis of individuals who underwent measurements of mood with the consumption of caffeine. We included 26 studies (10 randomized controlled trials, five controlled trials, seven cross-sectional studies, three single-group interventional studies and one case-control study). Single nucleotide polymorphisms in or near the cytochrome P450 () and aryl hydrocarbon receptor () genes were consistently associated with caffeine consumption. Several studies demonstrated that the anxiogenic consequences of caffeine differed across adenosine 2a receptor () genotypes, and the studies that investigated the effects of genetic variation on the ergogenic benefit of caffeine reported equivocal findings () or warrant replication ().
Topics: Adult; Anxiety; Basic Helix-Loop-Helix Transcription Factors; Caffeine; Cytochrome P-450 CYP1A2; Female; Genotype; Humans; Male; Middle Aged; Performance-Enhancing Substances; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Receptor, Adenosine A2A; Receptors, Aryl Hydrocarbon
PubMed: 30257492
DOI: 10.3390/nu10101373 -
Nutrition Reviews Jun 2018Type 2 diabetes (T2D) is a major health problem worldwide that is associated with increased morbidity and mortality. There is increased interest in the value of... (Meta-Analysis)
Meta-Analysis
CONTEXT
Type 2 diabetes (T2D) is a major health problem worldwide that is associated with increased morbidity and mortality. There is increased interest in the value of different nutrition-based strategies for preventing the development of T2D.
OBJECTIVE
This review aims to cover current knowledge regarding the effects of coffee consumption on development of T2D or modulation of adverse complications. A meta-analysis on coffee consumption and the risk of T2D was conducted. Moreover, bioactive components in coffee, polymorphisms, and potential underlying mechanism(s) in relation to T2D and adverse complications are discussed.
DATA SOURCES
PubMed was searched up to December 1, 2017, and prospective cohort and nested case-control studies of the association between coffee consumption and T2D risk were selected.
DATA EXTRACTION
Two investigators independently extracted data from included studies.
RESULTS
A total of 30 prospective studies with 1 185 210 participants and 53 018 incident T2D cases were included in the meta-analysis. The pooled relative risk (RR) was 0.71 (95% confidence interval [CI], 0.67-0.76) for the highest category of coffee consumption (median consumption, 5 cups/d) vs the lowest category (median consumption, 0 cups/d). The risk of T2D decreased by 6% (RR = 0.94; 95%CI, 0.93-0.95) for each cup-per-day increase in coffee consumption. Results were similar for caffeinated coffee consumption (per additional cup of coffee per day: RR = 0.93; 95%CI, 0.90-0.96) and decaffeinated coffee consumption (corresponding RR = 0.94; 95%CI, 0.90-0.98).
CONCLUSIONS
Available evidence indicates that coffee consumption is inversely associated with risk of T2D. Possible mechanisms behind this association include thermogenic, antioxidative, and anti-inflammatory effects; modulation of adenosine receptor signaling; and microbiome content and diversity.
Topics: Anti-Inflammatory Agents; Antioxidants; Beverages; Case-Control Studies; Coffee; Cohort Studies; Diabetes Mellitus, Type 2; Humans; Prospective Studies; Receptors, Purinergic P1; Risk; Risk Factors; Thermogenesis
PubMed: 29590460
DOI: 10.1093/nutrit/nuy014 -
Gene May 2018Investigate the association between P2Y12 Purinoceptor (P2RY12) polymorphisms and adverse clinical events in coronary artery disease (CAD) patients treated with... (Meta-Analysis)
Meta-Analysis Review
Association between P2RY12 gene polymorphisms and adverse clinical events in coronary artery disease patients treated with clopidogrel: A systematic review and meta-analysis.
OBJECTIVE
Investigate the association between P2Y12 Purinoceptor (P2RY12) polymorphisms and adverse clinical events in coronary artery disease (CAD) patients treated with clopidogrel.
METHODS
We performed a comprehensive database search, with a particular focus on P2RY12 polymorphisms and their effects on clopidogrel-treated CAD patients, in the PubMed, EMBASE, Cochrane Library, clinicaltrials.gov, Web of Science, and Chinese databases from their inceptions to April 8, 2017. The primary endpoints were composite ischemic events (including cardiovascular and cerebrovascular ischemic events), the secondary endpoints were independent cardiovascular events (mortality, non-fatal myocardial infarction, stent thrombosis, unstable angina, and target vessel revascularization) and the safety endpoints were bleeding events.
RESULTS
Overall 10 studies and 10,810 clopidogrel-treated CAD patients were studied in the present work. Subjects of the common alleles of P2RY12 polymorphisms showed higher risk for composite ischemic events compared to non-carriers (n = 434 of 3268[13.3%] vs. n = 646 of 6133[10.5%]; RR: 1.39, 95%CI: 1.14-1.69; p = 0.001). These allele carriers also showed increased risk for stent thrombosis (RR: 2.67, 95%CI: 1.03-6.91; p = 0.04), myocardial infarction (RR: 1.60, 95%CI: 1.06-2.42; p = 0.03), and unstable angina (RR: 1.72, 95%CI: 1.37-2.16; p < 0.00001) (vs. non-carriers). There was no significant difference between two groups in terms of mortality risk, target vessel revascularization or bleeding (p = 0.29; p = 0.48, respectively).
CONCLUSIONS
P2RY12 gene polymorphisms might associate with higher risk of composite ischemic events, stent thrombosis, non-fatal myocardial infarction, unstable angina. While we found no significant effect on mortality, target vessel revascularization or bleeding.
Topics: Clinical Trials as Topic; Clopidogrel; Coronary Artery Disease; Female; Humans; Male; Mutation; Platelet Aggregation Inhibitors; Polymorphism, Single Nucleotide; Receptors, Purinergic P2Y12; Research Design; Ticlopidine
PubMed: 29510176
DOI: 10.1016/j.gene.2018.03.007 -
Current Medical Research and Opinion Aug 2016Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndromes (ACS) and/or undergoing percutaneous coronary interventions.... (Review)
Review
Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndromes (ACS) and/or undergoing percutaneous coronary interventions. Non-adherence to medication after ACS may lead to increased morbidity, mortality, and costs to the healthcare system due to elevated risk of stent thrombosis, myocardial infarction or death. Medication adherence is an issue of growing concern regarding the improvement of health system performance. Promoting medication adherence offers a rare opportunity to simultaneously improve health outcomes while reducing costs of treatment in patients with coronary artery disease (CAD). The aim of this systematic review was to critically discuss adherence to antiplatelet treatment with P2Y12 receptor inhibitors in CAD patients. After a systematic investigation of the literature in databases including PubMed, CENTRAL and Google Scholar, using appropriate keywords, and considering clinical randomized, prospective observational and retrospective studies, reporting on adherence to treatment with inhibitors of P2Y12 platelet receptors or educational interventions aimed to improve medication adherence in patients with CAD, seven articles were considered eligible for inclusion in this systematic review. Reported adherence to clopidogrel, despite catastrophic consequences of its premature discontinuation, is low. We identified several determinants of low adherence and early discontinuation of clopidogrel. We also present data on the usefulness, utilization and credibility of different methods of medication adherence assessment, and suggest and critically discuss available interventions aimed at improvement of adherence to clopidogrel, still showing the need for innovative approaches to achieve enhanced medication adherence and improve health outcomes after acute myocardial infarction.
Topics: Clopidogrel; Coronary Artery Disease; Humans; Medication Adherence; Platelet Aggregation Inhibitors; Prospective Studies; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Retrospective Studies; Ticlopidine
PubMed: 27112628
DOI: 10.1080/03007995.2016.1182901 -
Atherosclerosis Jun 2015The efficacy of antiplatelet drugs may differ in specific patient subgroups. We aimed to assess the efficacy and safety of the P2Y12 inhibitors clopidogrel, ticlopidine,... (Meta-Analysis)
Meta-Analysis Review
Efficacy and safety of P2Y12 inhibitors according to diabetes, age, gender, body mass index and body weight: systematic review and meta-analyses of randomized clinical trials.
OBJECTIVE
The efficacy of antiplatelet drugs may differ in specific patient subgroups. We aimed to assess the efficacy and safety of the P2Y12 inhibitors clopidogrel, ticlopidine, prasugrel, ticagrelor, and cangrelor according to diabetes status, age, gender, body mass index, and body weight.
METHODS
Randomized clinical trials (RCTs) of P2Y12 inhibitors reporting information on cardiovascular disease (defined as myocardial infarction, stroke, or cardiovascular death) and bleeding (defined as any bleeding) events among the subgroups diabetes and non-diabetes, age ≥65 and <65 year-old, men and women, body mass index ≥30 and <30 kg/m(2), and body weight ≥60 and <60 kg, were identified in Medline, Embase, Web of Science, and Cochrane Library on August 31st, 2014. For each inhibitor, random-effects meta-analyses were used to estimate the ratio of relative risks (rRR) for cardiovascular and bleeding events among patient subgroups.
RESULTS
Twenty distinct RCTs (233 285 participants, 21 323 cardiovascular and 5183 bleeding events) were identified. Cardiovascular risk reduction with clopidogrel did not significantly differ according to diabetes (rRR: 1.04; 95% CI: 0.95 to 1.13; p = 0.395), age (0.98; 0.88 to 1.09; p = 0.347), gender (0.97; 0.90 to 1.04; p = 0.382), or body mass index (1.11, 0.95 to 1.31; p = 0.191). Results for other inhibitors were comparable, although available data were sparse. Limited data on bleeding events were available.
CONCLUSION
Data from RCTs did not show a different cardiovascular efficacy of clopidogrel in diabetes mellitus and other clinically relevant subgroups. Limited information was available on the efficacy and safety of other P2Y12 inhibitors in specific subgroups.
Topics: Age Factors; Aged; Blood Platelets; Body Mass Index; Body Weight; Cardiovascular Diseases; Comorbidity; Diabetes Mellitus; Drug Resistance; Female; Hemorrhage; Humans; Male; Middle Aged; Obesity; Odds Ratio; Platelet Aggregation; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Randomized Controlled Trials as Topic; Receptors, Purinergic P2Y12; Risk Assessment; Risk Factors; Sex Factors; Treatment Outcome
PubMed: 25897998
DOI: 10.1016/j.atherosclerosis.2015.04.015