Ischaemic heart disease(IHD)is a major cause of morbidity and mortality worldwide.While there have been major advances in this field,these patients are still a higher risk subgroup.As such,strategies to mitigate risk ...Ischaemic heart disease(IHD)is a major cause of morbidity and mortality worldwide.While there have been major advances in this field,these patients are still a higher risk subgroup.As such,strategies to mitigate risk and tailor secondary prevention measures are of the utmost relevance.Cardiac rehabilitation(CR),encompassing several domains including exercise training,cardiovascular risk factor optimization,nutritional and psychological assessments,as well as other ancillary interventions has shown to be one of the pillars in the contemporary management of patients with IHD.Indeed,CR is associated with several benefits in this population,ranging from functional capacity to improvements in outcomes.Whilst this,there are still several issues concerning the optimal application of CR which are still not fully ascertained,such as lack of referral and completion,as well as questions related to programme design(particularly among patients with multiple comorbidities).In this review,we aim at presenting a pragmatic overview on the current role of CR in the management of individuals with IHD,while also discussing some of the caveats in the current data,as well as future concepts which could help improve the uptake and personalization of this pivotal time-tested intervention.展开更多
During the last years increasing evidence implies that human cytomegalovirus(CMV) can be attributed to human malignancies arising from numerous tissues. In this perspective, we will review and discuss the potential me...During the last years increasing evidence implies that human cytomegalovirus(CMV) can be attributed to human malignancies arising from numerous tissues. In this perspective, we will review and discuss the potential mechanisms through which CMV infection may contribute to brain tumors by affecting tumor cell initiation, progression and metastasis formation. Recent evidence also suggests that anti-CMV treatment results in impaired tumor growth of CMV positive xenografts in animal models and potentially increased survival in CMV positive glioblastoma patients. Based on these observations and the high tumor promoting capacity of this virus, the classical and novel antiviral therapies against CMV should be revisited as they may represent a great promise for halting tumor progression and lower cancer deaths.展开更多
AIM To investigate a comprehensive range of factors that contribute to long-term patient satisfaction post-total joint replacement(TJR) in people who had undergone knee or hip replacement for osteoarthritis.METHODS Pa...AIM To investigate a comprehensive range of factors that contribute to long-term patient satisfaction post-total joint replacement(TJR) in people who had undergone knee or hip replacement for osteoarthritis.METHODS Participants(n = 1151) were recruited from Nottinghamshire post-total hip or knee replacement. Questionnaire assessment included medication use, the pain-DETECT questionnaire(PDQ) to assess neuropathic pain-like symptoms(NP) and TJR satisfaction measured on average 4.8 years post-TJR. Individual factors were tested for an association with post-TJR satisfaction, before incorporating all factors into a full model. Data reduction was carried out using LASSO and receiveroperator characteristic(ROC) curve analysis was used to quantify the contribution of variables to post-TJR satisfaction.RESULTS After data reduction, the best fitting model for post-TJR satisfaction included various measures of pain, history of revision surgery, smoking, pre-surgical X-ray severity, WOMAC function scores and various comorbidities. ROC analysis of this model gave AUC = 0.83(95%CI: 0.80-0.85). PDQ scores were found to capture much of the variation in post-TJR satisfaction outcomes: AUC = 0.79(0.75-0.82). Pre-surgical radiographic severity was associated with higher post-TJR satisfaction: OR_(satisfied) = 2.06(95%CI: 1.15-3.69), P = 0.015.CONCLUSION These results highlight the importance of pre-surgical radiographic severity, post-TJR function, analgesic medication use and NP in terms of post-TJR satisfaction. The PDQ appears to be a useful tool in capturing factors that contribute to post-TJR satisfaction.展开更多
Parkinson’s disease(PD)is a widely spread neurodegenerative movement disorder,affecting approximately 10 million people worldwide.It is primarily caused by the loss of dopaminergic neurons in the substantia nigra,whi...Parkinson’s disease(PD)is a widely spread neurodegenerative movement disorder,affecting approximately 10 million people worldwide.It is primarily caused by the loss of dopaminergic neurons in the substantia nigra,which causes decreased secretion of dopamine leading to tremors,bradykinesia and rigid muscle movement.The development of PD is complex and needs to be better understood.Current treatment strategies primarily involve targeting disease symptoms,however,since there is a continuous loss of dopaminergic neurons in the brain,PD appears to be incurable.Moreover,treatment strategies often carry severe side effects related to dopamine production,where too little or too much can cause debilitating issues such as dyskinesia.The pool of neural stem/progenitor cells(NSCs)located in sub-ventricular zone and hippocampal dentate gyrus,proliferate and are responsible to give rise to neurons and glia in response to any cellular damage.Though this activation of NSCs is highly regulated,it is insufficient to overcome the loss of dopaminergic neurons in PD.In this line,non-coding RNAs(ncRNAs)are involved in the underlying mechanisms of PD and are known to have important functional roles in neural regeneration(Acharya et al.,2020).Thus,the study of ncRNAs in NSC activation and adult neurogenesis post PD development is an extremely attractive area of research with significant clinical application potential.展开更多
In human patients,drugs that block tumor vessel growth are widely used to treat a variety of cancer types.Many rigorous phase 3 clinical trials have demonstrated significant survival benefits;however,the addition of a...In human patients,drugs that block tumor vessel growth are widely used to treat a variety of cancer types.Many rigorous phase 3 clinical trials have demonstrated significant survival benefits;however,the addition of an anti-angiogenic component to conventional therapeutic modalities has generally produced modest survival benefits for cancer patients.Currently,it is unclear why these clinically available drugs targeting the same angiogenic pathways produce dissimilar effects in preclinical models and human patients.In this article,we discuss possible mechanisms of various anti-angiogenic drugs and the future development of optimized treatment regimens.展开更多
Background: The presence of pathological Q waves in the infarct leads on the surface electrocardiogram in an ST-elevation acute myocardial infarction indicates myocardial necrosis. Clinically it might be difficult to ...Background: The presence of pathological Q waves in the infarct leads on the surface electrocardiogram in an ST-elevation acute myocardial infarction indicates myocardial necrosis. Clinically it might be difficult to ascertain the onset of acute myocardial infarction. Our aim was to assess whether the presence or absence of Q waves at presentation could be used as an indicator of the duration of acute myocardial infarction and predict mortality. Methods: 15 222 patients with ST-elevation acute myocardial infarction and normal intraventricular conduction were randomly assigned streptokinase and aspirin plus bivalirudin or unfractionated heparin in the HERO-2 trial; randomisation did not alter 30-day mortality. 10 244 patients(67%) had Q waves in the infarct territory at the time of randomisation, and 4978(33%) did not. The primary endpoint was 30-day mortality. Findings: There were more deaths at 30 days in patients with initial Q waves than in those without(1044[10%] vs 344[7%], p< 0.0001). These findings were similar in patients with a first acute myocardial infarction and when stratified by time to randomisation(0-2, >2-4, >4 h) and by acute myocardial infarction location(anterior or inferior). Both the presence of initial Q waves and time to randomisation were positive univariate predictors, but only the presence of initial Q waves independently predicted 30-day mortality on multivariate analysis(adjusted OR 1.44, 95%CI 1.25-1.65 with clinical indices, and 1.31, 1.12-1.54 with clinical plus ST indices included as predictors). Interpretation: The presence of Q waves in the infarct leads at presentation of ST-elevation acute myocardial infarction independently predicts higher 30-day mortality in patients treated with fibrinolytic therapy. Therefore, a more aggressive approach to reperfusion might be warranted in these patients.展开更多
A large proportion of patients who have erectile dysfunction also have coronary artery disease(CAD). In these patients, nitrate therapy is a contraindication to the use of sildenafil. To assess whether the metabolic a...A large proportion of patients who have erectile dysfunction also have coronary artery disease(CAD). In these patients, nitrate therapy is a contraindication to the use of sildenafil. To assess whether the metabolic anti-ischemic agent, trimetazidine, is effective in controlling episodes ofmyocardial ischemia during sexual activity in patients who have CAD and use longterm nitrate therapy, we studied 38 men(57±6 years of age) who had proved CAD. Patients underwent 24-hour ambulatory electrocardiographic monitoring at baseline, after 1 week of oral nitrate therapy(20 mg 3 times a day), and after 1 week of trimetazidine(20 mg 3 times a day). Patients were asked to engage in< 1 session of sexual intercourse during each session of ambulatory electrocardiographic monitoring. They were instructed to take sildenafil(100 mg) 1 hour before sexual intercourse performed at baseline and during therapy with trimetazidine and sildenafil or placebo(blinded) during therapy with nitrates. A decrease in total ischemic burden was observed with nitrates and trimetazidine compared with baseline(-3±1.2 episodes/patient/24 hours vs-5±1.3 episodes/patient/24 hours and-6±5 min/patient/24 hours vs-8±3 min/patient/ 24 hours, p< 0.01 for nitrates and trimetazidine vs baseline). Trimetazidine plus sildenafil was more effective in controlling episodes of myocardial ischemia during sexual activity than nitrates alone(-45±11%vs-18±7%, p< 0.04). In conclusion, in patients who have CAD, combination therapy with sildenafil and trimetazidine is more effective than nitrate therapy in the control of ischemic episodes during sexual activity, suggesting that long-term nitrate therapy may be safely switched to trimetazidine therapy when therapy for erectile dysfunction is required.展开更多
Context: Clinical trial evidence indicates that estrogen therapy with or without progestins increases venous thrombotic risk. The findings from these trials, which used oral conjugated equine estrogens, may not be gen...Context: Clinical trial evidence indicates that estrogen therapy with or without progestins increases venous thrombotic risk. The findings from these trials, which used oral conjugated equine estrogens, may not be generalizable to other estrogen compounds. Objective: To compare risk of venous thrombosis among esterified estrogen users, conjugated equine estrogen users, and nonusers. Design, Setting, and Participants: This population based, case control study was conducted at a large health maintenance organization in Washington State. Cases were perimenopausal and postmenopausal women aged 30 to 89 years who sustained a first venous thrombosis between January 1995 and December 2001 and controls were matched on age, hypertension status, and calendar year. Main Outcome Measure: Risk of first venous thrombosis in relation to current use of esterified or conjugated equine estrogens, with or without concomitant progestin. Current use was defined as use at thrombotic event for cases and a comparable reference date for controls. Results: Five hundred eighty six incident venous thrombosis cases and 2268 controls were identified. Compared with women not currently using hormones, current users of esterified estrogen had no increase in venous thrombotic risk (odds ratio , 0.92; 95% confidence interval , 0.69- 1.22). In contrast, women currently taking conjugated equine estrogen had an elevated risk (OR, 1.65; 95% CI, 1.24- 2.19). When analyses were restricted to estrogen users, current users of conjugated equine estrogen had a higher risk than current users of esterified estrogen (OR, 1.78; 95% CI, 1.11- 2.84). Among conjugated equine estrogen users, increasing daily dose was associated with increased risk (trend P value = .02). Among all estrogen users, concomitant progestin use was associated with increased risk compared with use of estrogen alone (OR, 1.60; 95% CI, 1.13- 2.26). Conclusion: Our finding that conjugated equine estrogen but not esterified estrogen was associated with venous thrombotic risk needs to be replicated and may have implications for the choice of hormones in perimenopausal and postmenopausal women.展开更多
Background -Sympathetic activation influences the risk of ventricular arrhythmias and sudden cardiac death(SCD), mediated in part by the β2-adrenergic receptor(B2AR). We investigated whether variation in the B2AR gen...Background -Sympathetic activation influences the risk of ventricular arrhythmias and sudden cardiac death(SCD), mediated in part by the β2-adrenergic receptor(B2AR). We investigated whether variation in the B2AR gene is associated with SCD risk. Methods and Results -In this study, 4441 white and 808 black Cardiovascular Health Study(CHS) participants were followed up prospectively for SCD and genotyped for B2AR Gly16Arg and Gln27Glu polymorphisms. The study was replicated in 155 case and 144 control white subjects in a population-based case-control study of SCD, the Cardiac Arrest Blood Study(CABS). In CHS, Gly 16 and Gln27 allele frequencies were 62.4%and 57.1%among white and 50.1%and 81.4%among black participants. Over a median follow-up of 11.1 years, 156 and 39 SCD events occurred in white and black participants, respectively. The Gln27Glu variant was associated with SCD risk(P=0.008 for general model). SCD risk was higher in Gln27 homozygous participants than in Glu27 carriers(ethnicity-adjusted hazard ratio[HR], 1.56; 95%confidence interval[CI], 1.17 to 2.09; P=0.003). The increased risk did not differ significantly between white(HR, 1.62; 95%CI, 1.18 to 2.23) and black(HR, 1.23; 95%CI, 0.61 to 2.48) participants, although the confidence interval was wide in blacks. In the CABS replication study, Gln27 homozygous participants similarly had higher SCD risk than Glu27 carriers(odds ratio, 1.64; 95%CI, 1.02 to 2.63; P=0.040). Gly16Arg was not associated with SCD risk in either study. Conclusions -Gln27 homozygous individuals have an increased risk of SCD in 2 study populations. Our findings suggest that B2AR plays a role in SCD in humans. Study of genetic variation within the B2AR gene may help identify those at increased SCD risk.展开更多
RNA interference is a promising therapeutical approach presently hindered by delivery concerns such as rapid RNA degradation and targeting of individual tissues.Injectable hydrogels are one potentially simple and dire...RNA interference is a promising therapeutical approach presently hindered by delivery concerns such as rapid RNA degradation and targeting of individual tissues.Injectable hydrogels are one potentially simple and direct route towards overcoming these barriers.Here we report on the utility of a combination of a mildly modified form of the clinically utilised fibrin hydrogel with Invivofectamine^(■)3.0,a lipid nonviral transfection vector,for local and sustained release.PEGylation of fibrin allowed for controlled release of small interfering RNA(siRNA)-lipopolyplexes for at least 10 days and greatly increased the stability of fibrin in vitro and in vivo.A 3D cell culture model and a release study showed transfection efficacy of siRNA-lipopolyplexes was retained for a minimum of 7 days.Injection in conjunction with PEGylated-fibrinogen significantly increased retention of siRNA-lipopolyplexes in mouse skeletal muscle and enhanced knockdown of myostatin mRNA that correlated with muscle growth.Thus,the increased efficacy observed here for the combination of a lipid nanoparticle,the only type of nonviral vector approved for the clinic,with fibrin,might allow for more rapid translation of injectable hydrogel-based RNA interference.展开更多
文摘Ischaemic heart disease(IHD)is a major cause of morbidity and mortality worldwide.While there have been major advances in this field,these patients are still a higher risk subgroup.As such,strategies to mitigate risk and tailor secondary prevention measures are of the utmost relevance.Cardiac rehabilitation(CR),encompassing several domains including exercise training,cardiovascular risk factor optimization,nutritional and psychological assessments,as well as other ancillary interventions has shown to be one of the pillars in the contemporary management of patients with IHD.Indeed,CR is associated with several benefits in this population,ranging from functional capacity to improvements in outcomes.Whilst this,there are still several issues concerning the optimal application of CR which are still not fully ascertained,such as lack of referral and completion,as well as questions related to programme design(particularly among patients with multiple comorbidities).In this review,we aim at presenting a pragmatic overview on the current role of CR in the management of individuals with IHD,while also discussing some of the caveats in the current data,as well as future concepts which could help improve the uptake and personalization of this pivotal time-tested intervention.
基金Supported by Grants from Ragnar Soderbergs FoundationThe Swedish Children’s Cancer Foundation+9 种基金BILTEMA FoundationFamily Ehring Perssons FoundationSten A Olssons FoundationStichting af Jochnicks FoundationThe Swedish Cancer Society,The Swedish Research Council,the Marta and Gunnar V Philipson FoundationThe Hans and Marit Rausing Charitable FundThe Damman FoundationSwedish Society for Medical Research(SLS),Goljes Memory FoundationMagnus Bergvalls FoundationSwedish Society for Medical Research(SSMF)and Tore Nilsons Foundation
文摘During the last years increasing evidence implies that human cytomegalovirus(CMV) can be attributed to human malignancies arising from numerous tissues. In this perspective, we will review and discuss the potential mechanisms through which CMV infection may contribute to brain tumors by affecting tumor cell initiation, progression and metastasis formation. Recent evidence also suggests that anti-CMV treatment results in impaired tumor growth of CMV positive xenografts in animal models and potentially increased survival in CMV positive glioblastoma patients. Based on these observations and the high tumor promoting capacity of this virus, the classical and novel antiviral therapies against CMV should be revisited as they may represent a great promise for halting tumor progression and lower cancer deaths.
基金Supported by PhD studentship awarded by the University of Nottingham(to Warner SC)EULAR project grant to AMV,No.108239ARUK Pain Centre,No.18769
文摘AIM To investigate a comprehensive range of factors that contribute to long-term patient satisfaction post-total joint replacement(TJR) in people who had undergone knee or hip replacement for osteoarthritis.METHODS Participants(n = 1151) were recruited from Nottinghamshire post-total hip or knee replacement. Questionnaire assessment included medication use, the pain-DETECT questionnaire(PDQ) to assess neuropathic pain-like symptoms(NP) and TJR satisfaction measured on average 4.8 years post-TJR. Individual factors were tested for an association with post-TJR satisfaction, before incorporating all factors into a full model. Data reduction was carried out using LASSO and receiveroperator characteristic(ROC) curve analysis was used to quantify the contribution of variables to post-TJR satisfaction.RESULTS After data reduction, the best fitting model for post-TJR satisfaction included various measures of pain, history of revision surgery, smoking, pre-surgical X-ray severity, WOMAC function scores and various comorbidities. ROC analysis of this model gave AUC = 0.83(95%CI: 0.80-0.85). PDQ scores were found to capture much of the variation in post-TJR satisfaction outcomes: AUC = 0.79(0.75-0.82). Pre-surgical radiographic severity was associated with higher post-TJR satisfaction: OR_(satisfied) = 2.06(95%CI: 1.15-3.69), P = 0.015.CONCLUSION These results highlight the importance of pre-surgical radiographic severity, post-TJR function, analgesic medication use and NP in terms of post-TJR satisfaction. The PDQ appears to be a useful tool in capturing factors that contribute to post-TJR satisfaction.
基金This work is supported by COST(European Cooperation in Science and Technology)Action EU-CardioRNA CA17129the National Research Fund of Luxembourg(grants#C14/BM/8225223,C17/BM/11613033 and AFR 14566210)+1 种基金the Ministry of Higher Education and Research of Luxembourgthe Heart Foundation—Daniel Wagner.
文摘Parkinson’s disease(PD)is a widely spread neurodegenerative movement disorder,affecting approximately 10 million people worldwide.It is primarily caused by the loss of dopaminergic neurons in the substantia nigra,which causes decreased secretion of dopamine leading to tremors,bradykinesia and rigid muscle movement.The development of PD is complex and needs to be better understood.Current treatment strategies primarily involve targeting disease symptoms,however,since there is a continuous loss of dopaminergic neurons in the brain,PD appears to be incurable.Moreover,treatment strategies often carry severe side effects related to dopamine production,where too little or too much can cause debilitating issues such as dyskinesia.The pool of neural stem/progenitor cells(NSCs)located in sub-ventricular zone and hippocampal dentate gyrus,proliferate and are responsible to give rise to neurons and glia in response to any cellular damage.Though this activation of NSCs is highly regulated,it is insufficient to overcome the loss of dopaminergic neurons in PD.In this line,non-coding RNAs(ncRNAs)are involved in the underlying mechanisms of PD and are known to have important functional roles in neural regeneration(Acharya et al.,2020).Thus,the study of ncRNAs in NSC activation and adult neurogenesis post PD development is an extremely attractive area of research with significant clinical application potential.
基金supported by European Research Council advanced grant ANGIOFAT(Project No.250021)the Swedish Research Council+5 种基金the Swedish Cancer Foundationthe Karolinska Institute Foundationthe Karolinska Institute Distinguished Professor Awardthe Torsten Soderberg Foundationthe Novo Nordisk Foundationthe Knut and Alice Wallenberg Foundation
文摘In human patients,drugs that block tumor vessel growth are widely used to treat a variety of cancer types.Many rigorous phase 3 clinical trials have demonstrated significant survival benefits;however,the addition of an anti-angiogenic component to conventional therapeutic modalities has generally produced modest survival benefits for cancer patients.Currently,it is unclear why these clinically available drugs targeting the same angiogenic pathways produce dissimilar effects in preclinical models and human patients.In this article,we discuss possible mechanisms of various anti-angiogenic drugs and the future development of optimized treatment regimens.
文摘Background: The presence of pathological Q waves in the infarct leads on the surface electrocardiogram in an ST-elevation acute myocardial infarction indicates myocardial necrosis. Clinically it might be difficult to ascertain the onset of acute myocardial infarction. Our aim was to assess whether the presence or absence of Q waves at presentation could be used as an indicator of the duration of acute myocardial infarction and predict mortality. Methods: 15 222 patients with ST-elevation acute myocardial infarction and normal intraventricular conduction were randomly assigned streptokinase and aspirin plus bivalirudin or unfractionated heparin in the HERO-2 trial; randomisation did not alter 30-day mortality. 10 244 patients(67%) had Q waves in the infarct territory at the time of randomisation, and 4978(33%) did not. The primary endpoint was 30-day mortality. Findings: There were more deaths at 30 days in patients with initial Q waves than in those without(1044[10%] vs 344[7%], p< 0.0001). These findings were similar in patients with a first acute myocardial infarction and when stratified by time to randomisation(0-2, >2-4, >4 h) and by acute myocardial infarction location(anterior or inferior). Both the presence of initial Q waves and time to randomisation were positive univariate predictors, but only the presence of initial Q waves independently predicted 30-day mortality on multivariate analysis(adjusted OR 1.44, 95%CI 1.25-1.65 with clinical indices, and 1.31, 1.12-1.54 with clinical plus ST indices included as predictors). Interpretation: The presence of Q waves in the infarct leads at presentation of ST-elevation acute myocardial infarction independently predicts higher 30-day mortality in patients treated with fibrinolytic therapy. Therefore, a more aggressive approach to reperfusion might be warranted in these patients.
文摘A large proportion of patients who have erectile dysfunction also have coronary artery disease(CAD). In these patients, nitrate therapy is a contraindication to the use of sildenafil. To assess whether the metabolic anti-ischemic agent, trimetazidine, is effective in controlling episodes ofmyocardial ischemia during sexual activity in patients who have CAD and use longterm nitrate therapy, we studied 38 men(57±6 years of age) who had proved CAD. Patients underwent 24-hour ambulatory electrocardiographic monitoring at baseline, after 1 week of oral nitrate therapy(20 mg 3 times a day), and after 1 week of trimetazidine(20 mg 3 times a day). Patients were asked to engage in< 1 session of sexual intercourse during each session of ambulatory electrocardiographic monitoring. They were instructed to take sildenafil(100 mg) 1 hour before sexual intercourse performed at baseline and during therapy with trimetazidine and sildenafil or placebo(blinded) during therapy with nitrates. A decrease in total ischemic burden was observed with nitrates and trimetazidine compared with baseline(-3±1.2 episodes/patient/24 hours vs-5±1.3 episodes/patient/24 hours and-6±5 min/patient/24 hours vs-8±3 min/patient/ 24 hours, p< 0.01 for nitrates and trimetazidine vs baseline). Trimetazidine plus sildenafil was more effective in controlling episodes of myocardial ischemia during sexual activity than nitrates alone(-45±11%vs-18±7%, p< 0.04). In conclusion, in patients who have CAD, combination therapy with sildenafil and trimetazidine is more effective than nitrate therapy in the control of ischemic episodes during sexual activity, suggesting that long-term nitrate therapy may be safely switched to trimetazidine therapy when therapy for erectile dysfunction is required.
文摘Context: Clinical trial evidence indicates that estrogen therapy with or without progestins increases venous thrombotic risk. The findings from these trials, which used oral conjugated equine estrogens, may not be generalizable to other estrogen compounds. Objective: To compare risk of venous thrombosis among esterified estrogen users, conjugated equine estrogen users, and nonusers. Design, Setting, and Participants: This population based, case control study was conducted at a large health maintenance organization in Washington State. Cases were perimenopausal and postmenopausal women aged 30 to 89 years who sustained a first venous thrombosis between January 1995 and December 2001 and controls were matched on age, hypertension status, and calendar year. Main Outcome Measure: Risk of first venous thrombosis in relation to current use of esterified or conjugated equine estrogens, with or without concomitant progestin. Current use was defined as use at thrombotic event for cases and a comparable reference date for controls. Results: Five hundred eighty six incident venous thrombosis cases and 2268 controls were identified. Compared with women not currently using hormones, current users of esterified estrogen had no increase in venous thrombotic risk (odds ratio , 0.92; 95% confidence interval , 0.69- 1.22). In contrast, women currently taking conjugated equine estrogen had an elevated risk (OR, 1.65; 95% CI, 1.24- 2.19). When analyses were restricted to estrogen users, current users of conjugated equine estrogen had a higher risk than current users of esterified estrogen (OR, 1.78; 95% CI, 1.11- 2.84). Among conjugated equine estrogen users, increasing daily dose was associated with increased risk (trend P value = .02). Among all estrogen users, concomitant progestin use was associated with increased risk compared with use of estrogen alone (OR, 1.60; 95% CI, 1.13- 2.26). Conclusion: Our finding that conjugated equine estrogen but not esterified estrogen was associated with venous thrombotic risk needs to be replicated and may have implications for the choice of hormones in perimenopausal and postmenopausal women.
文摘Background -Sympathetic activation influences the risk of ventricular arrhythmias and sudden cardiac death(SCD), mediated in part by the β2-adrenergic receptor(B2AR). We investigated whether variation in the B2AR gene is associated with SCD risk. Methods and Results -In this study, 4441 white and 808 black Cardiovascular Health Study(CHS) participants were followed up prospectively for SCD and genotyped for B2AR Gly16Arg and Gln27Glu polymorphisms. The study was replicated in 155 case and 144 control white subjects in a population-based case-control study of SCD, the Cardiac Arrest Blood Study(CABS). In CHS, Gly 16 and Gln27 allele frequencies were 62.4%and 57.1%among white and 50.1%and 81.4%among black participants. Over a median follow-up of 11.1 years, 156 and 39 SCD events occurred in white and black participants, respectively. The Gln27Glu variant was associated with SCD risk(P=0.008 for general model). SCD risk was higher in Gln27 homozygous participants than in Glu27 carriers(ethnicity-adjusted hazard ratio[HR], 1.56; 95%confidence interval[CI], 1.17 to 2.09; P=0.003). The increased risk did not differ significantly between white(HR, 1.62; 95%CI, 1.18 to 2.23) and black(HR, 1.23; 95%CI, 0.61 to 2.48) participants, although the confidence interval was wide in blacks. In the CABS replication study, Gln27 homozygous participants similarly had higher SCD risk than Glu27 carriers(odds ratio, 1.64; 95%CI, 1.02 to 2.63; P=0.040). Gly16Arg was not associated with SCD risk in either study. Conclusions -Gln27 homozygous individuals have an increased risk of SCD in 2 study populations. Our findings suggest that B2AR plays a role in SCD in humans. Study of genetic variation within the B2AR gene may help identify those at increased SCD risk.
基金Project Vivafunded by the U.S. Environmental Protection Agency(RD83479801)the National Institutes of Health(K24 HD069408,R37 HD 034568, P01 ES009825)
文摘[背景]对成人的研究已表明,空气污染暴露与血压升高有关。[目的]研究产前暴露于空气污染物与新生儿收缩压(SBP)之间的关联。[方法]研究马萨诸塞州波士顿市地区出生前队列中的1 131对母婴,计算各妊娠期以及产前2~90 d在固定监测点测量的时间分辨的细颗粒物(≤2.5μm;PM2.5)、炭黑(BC)、一氧化氮(氮氧化合物)、二氧化氮(NO2)、臭氧(O3)和一氧化碳(CO)的平均暴露水平,并估计居住点水平上时空分辨的PM2.5和BC暴露。用自动仪器测量平均年龄为(30±18)h新生儿的收缩压,并使用混合效应模型检验空气污染物暴露与SBP之间的关联,分析中考虑了测量环境、孩子的出生体重、母亲的年龄、种族/族裔、社会经济地位、妊娠后期BP以及时间趋势。估计值表示为每一种污染物每增加一个四分位数间距(IQR)所致的SBP差异。[结果]在妊娠后期,较高的平均PM2.5和BC暴露与较高的SBP有关联[例如,居住地90 d BC平均值增加0.32μg/m3与SBP升高1.0(95%CI:0.1~1.8)mm Hg有关联]。相比之下,O3与SBP呈负相关[例如,产前90 d O3升高13.5×10-9与SBP降低2.3(95%CI:-4.4^-0.2)mm Hg有关联]。[结论]妊娠后期暴露于PM2.5和BC与新生儿SBP呈正相关,而O3与SBP呈负相关。纵向随访能够评估这些研究结果对这些新生儿随之的童年期和成年期的健康影响。
基金supported by the National Research Foundation of South Africa(93550)International Centre for Genetic Engineering and Biotechnology(CRP/ZAF14-01)the South African Medical Research Council(416007).
文摘RNA interference is a promising therapeutical approach presently hindered by delivery concerns such as rapid RNA degradation and targeting of individual tissues.Injectable hydrogels are one potentially simple and direct route towards overcoming these barriers.Here we report on the utility of a combination of a mildly modified form of the clinically utilised fibrin hydrogel with Invivofectamine^(■)3.0,a lipid nonviral transfection vector,for local and sustained release.PEGylation of fibrin allowed for controlled release of small interfering RNA(siRNA)-lipopolyplexes for at least 10 days and greatly increased the stability of fibrin in vitro and in vivo.A 3D cell culture model and a release study showed transfection efficacy of siRNA-lipopolyplexes was retained for a minimum of 7 days.Injection in conjunction with PEGylated-fibrinogen significantly increased retention of siRNA-lipopolyplexes in mouse skeletal muscle and enhanced knockdown of myostatin mRNA that correlated with muscle growth.Thus,the increased efficacy observed here for the combination of a lipid nanoparticle,the only type of nonviral vector approved for the clinic,with fibrin,might allow for more rapid translation of injectable hydrogel-based RNA interference.
