Alcohol use, particularly alcohol abuse and dependence, are associated with increased risk of depression. Current diagnostic criteria suggest that the relationship is causal, but the evidence has ...only been derived from observational studies that are subject to confounding and bias. Given the logistic and ethical constraints that would be associated with a trial of alcohol use to prevent depression, we aimed to complete a Mendelian randomization study to determine if a genetic polymorphism associated with alcohol abuse and dependence (ADH1B rs1229984 G-->A) contributed to modulate the risk of depression in a community-derived cohort of older men. This retrospective analysis of a cohort of 3873 community-dwelling men aged 65-83 years living in the metropolitan region of Perth, Western Australia, investigated the triangular association between the rs1229984 G-->A polymorphism and alcohol use and, after 3.2-8.2 years, the presence of current depression or history of depression. The mean number of standard drinks consumed per week (n; standard deviation; range) according to genotype was AA 1.8 (17; 2.7; 0-7), GA 5.9 (262; 7.5; 0-35), GG 8.5 (3594; 10.9; 0-140) (GG>AA, GG>GA; P<0.001). Consumption of 1 or 2 drinks per day decreased the odds of depression (n=610) by 30 and 40%, whereas consumption of more than six drinks daily more than doubled the odds of depression (odds ratio: 2.12, 95% confidence interval: 1.02, 4.40). The ADH1B rs1229984 G-->A polymorphism was not associated with current or past depression (P=0.857). In addition, the presence of the A allele did not interact with the alcohol use to modulate the risk of depression (P=0.725). These results suggest that alcohol consumption does not cause or prevent depression in older men.
Stroke is a major cause of death and disability in the world. The main causes of stroke are atherothromboembolism and cardiogenic embolism. The main causal and treatable risk factors for ...atherothromboembolic ischemic stroke are increasing blood pressure (BP), increasing cholesterol, cigarette smoking and diabetes; and the main risk factors for cardiogenic ischemic stroke are atrial fibrillation (AF) and ischemic heart disease. Strategies to reduce the incidence of stroke include prevention of first‐ever and recurrent stroke, and treatment of patients with acute stroke to reduce death and disability. The two main strategies of stroke prevention are the ‘population’ (or ‘mass’) approach and the ‘high risk’ approach. The ‘population’ approach aims to reduce stroke by lowering the prevalence and mean level of causal risk factors in the community, by means of public education and government legislation. The ‘high risk’ approach aims to reduce stroke by identifying individuals at high risk of stroke, and lowering their risk by means of optimal medical therapies. Level 1 evidence from randomized controlled trials indicates that effective treatments for high risk patients include control of causal risk factors (lowering BP, lowering blood cholesterol), antithrombotic therapy (antiplatelet therapy with aspirin, clopidogrel, or the combination of aspirin and dipyridamole for patients in sinus rhythm, and anticoagulation with warfarin or ximelagatran for patients in AF) and, where appropriate, carotid revascularization for patients with severe carotid stenosis.
Summary
In older men, both lower and higher total osteocalcin levels predict increased all-cause mortality, with comparable associations for cardiovascular and non-cardiovascular deaths. Differences ...in osteocalcin levels might influence glucose metabolism and thereby cardiovascular risk, or reflect changes in bone turnover thus representing a marker for poorer health outcomes.
Introduction
Reduced levels of total osteocalcin (TOC) are associated with adiposity, insulin resistance and type 2 diabetes, implying this bone-derived peptide might modulate cardiovascular risk. However, there are few longitudinal data relating TOC levels to survival. We examined associations of TOC level with all-cause and cardiovascular mortality in older men.
Methods
We conducted a prospective cohort study of community-dwelling men aged 70–89 years. Aliquots of plasma collected at baseline (2001–2004) were assayed for TOC. Incidence and causes of death to 31 December 2008 were ascertained using data linkage. Cox regression analyses were performed with adjustment for conventional cardiovascular risk factors.
Results
From 3,542 men followed for median 5.2 years there were 572 deaths (16.1%). Mortality was lowest in men with TOC levels in the second quintile (12.6%). In multivariate analyses, men with TOC in the lowest and highest quintiles of values had increased all-cause mortality (Q1 vs Q2: hazard ratio HR, 1.36; 95% confidence interval 1.02–1.80 and Q5 vs Q2: HR, 1.53, 95% CI 1.18–1.98). Men with low TOC levels had similar HR for cardiovascular and non-cardiovascular deaths (Q1 vs Q2: HR, 1.35 and 1.30 respectively). Higher TOC levels predicted cardiovascular disease (CVD)-related mortality (Q5 vs Q2, HR, 1.69, 95% CI 1.09–2.64).
Conclusions
TOC predicts all-cause and CVD-related mortality in community-dwelling older men. However, the relationship is U shaped with men at both ends of the distribution at increased risk. Further investigation is required to clarify whether the underlying mechanisms involve altered bone turnover or relate specifically to the biological activity of osteocalcin.
Pravastatin Therapy and the Risk of Stroke White, Harvey D; Simes, R. John; Anderson, Neil E ...
The New England journal of medicine,
08/2000, Letnik:
343, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Cerebrovascular disease is the second leading cause of death worldwide
1
,
2
and the leading cause of long-term disability in developed countries.
3
,
4
There has been controversy about whether there ...is an association between cholesterol levels and the risk of stroke; a meta-analysis found no clear evidence of such an association.
5
Most of the studies made no distinction between ischemic and hemorrhagic strokes, which have different pathophysiologic mechanisms. A positive association between increasing cholesterol levels and ischemic stroke due to atherothrombosis in a large artery may be offset by a possible association between low cholesterol levels and hemorrhagic stroke.
Studies of . . .
Summary
Background
Idrabiotaparinux, a long‐acting inhibitor of factor Xa, was shown to be effective in the treatment of patients with venous thromboembolism.
Objective
To assess non‐inferiority for ...the efficacy of idrabiotaparinux versus warfarin in patients with atrial fibrillation (AF) at risk of stroke and systemic embolism. Bleeding was also assessed.
Methods
This randomized, double‐blind trial enrolled patients with electrocardiogram‐documented AF. Idrabiotaparinux was administered weekly via subcutaneous injection, and warfarin was administered daily with dose adjustment to maintain the international normalized ratio between 2.0 and 3.0. Each idrabiotaparinux injection was 3 mg for the first 7 weeks, followed by 2 mg thereafter, except in patients with a creatinine clearance of 30–50 mL min−1 or aged ≥ 75 years. The patients received 1.5 mg after the first 7 weeks. The efficacy outcome was the composite of all fatal or non‐fatal strokes and systemic embolism. The safety outcome was clinically relevant bleeding (major and clinically relevant non‐major bleeding).
Results
The study was terminated prematurely by the sponsor for strategic/commercial, not scientific, reasons, with 39% of the planned number of patients included and an average duration of treatment of 240 days. Of the 1886 idrabiotaparinux recipients, 20 developed stroke or systemic embolism (1.5% per year), whereas this occurred in 22 of the 1887 warfarin patients (1.6% per year, hazard ratio 0.98, 95% confidence interval 0.49–1.66). The annual incidence of bleeding was 6.1% in the idrabiotaparinux and 10.0% in the warfarin group (hazard ratio 0.61, 95% confidence interval 0.46–0.81).
Conclusion
If anything, despite its early termination, the idrabiotaparinux regimen studied suggested a comparable efficacy to dose‐adjusted warfarin, with a lower bleeding risk.
Elevated plasma homocyst(e)ine may be a causal and modifiable risk factor for ischemic stroke, but the results of previous studies have been conflicting. One possible explanation is that ...homocyst(e)ine may only be associated with certain pathophysiological subtypes of ischemic stroke.
We conducted a case-control study of 219 hospital cases with a first-ever ischemic stroke and 205 randomly selected community control subjects stratified by age, sex, and postal code. With the use of established criteria, cases of stroke were classified by etiologic subtype in a blinded fashion. The prevalence of conventional vascular risk factors, fasting plasma homocyst(e)ine levels, vitamin levels, and nucleotide 677 methylene tetrahydrofolate reductase (MTHFR) genotypes were determined in cases and controls.
Increasing homocyst(e)ine was a strong and independent risk factor for ischemic stroke (adjusted OR 2.7, 95% CI 1.4 to 5.1 for a 5-micromol/L increase in fasting plasma homocyst(e)ine from 10 to 15 micromol/L). Compared with the lowest quartile, the highest quartile of homocyst(e)ine was associated with an adjusted OR of ischemic stroke of 2.2 (95% CI 1.1 to 4.2). Mean plasma homocyst(e)ine was significantly higher in cases of ischemic stroke due to large-artery disease (14.1 micromol/L, 95% CI 12.5 to 15.9, P<0.001) and small-artery disease (12.7 micromol/L, 95% CI 11. 4 to 14.1, P=0.004) compared with control subjects (10.5 micromol/L; 95% CI 10.0 to 11.0) but not in cardioembolic or other etiologic subtypes of ischemic stroke. Compared with the lowest quartile of homocyst(e)ine, the upper 3 quartiles were associated with an adjusted OR of ischemic stroke due to large-artery disease of 3.0 (95% CI 0.8 to 10.8) for the second quartile, 5.6 (95% CI 1.6 to 20) for the third quartile, and 8.7 (95% CI 2.4 to 32) for the fourth quartile (P for trend=0.0005). However, despite a clear association between the TT MTHFR genotype and elevated fasting plasma homocyst(e)ine, there was no association between MTHFR genotype and ischemic stroke or subtype of ischemic stroke.
There is a strong, graded association between increasing plasma homocyst(e)ine and ischemic stroke caused by large-artery atherosclerosis and, to a much lesser extent, small-artery disease, but not cardioembolic or other etiologic subtypes of ischemic stroke. Our results are consistent with the hypothesis that the deleterious effect of high homocyst(e)ine is mediated primarily via a proatherogenic effect.
We aimed to determine whether A-13G or G79A polymorphisms of the protein Z gene that have been reported to be an important determinant of blood concentrations of protein Z are associated with risk of ...ischemic stroke in a broad range of stroke patients and controls.
We conducted a case control study of 151 hospital cases of first-ever ischemic stroke and 164 randomly selected community controls. Protein Z genotype was determined for the A-13G promoter polymorphism and the G79A intron F polymorphism, and plasma protein Z concentrations were measured during the first 7 days and at 3 to 6 months after the acute stroke event.
Geometric mean concentrations of protein Z measured within 7 days of acute stroke were significantly higher in cases compared with controls (1.51 microg/mL versus 1.13 microg/mL; P<0.0001). Protein Z concentrations were highest among subjects with the A-13G AA genotype, intermediate among those with the AG genotype, and lowest among those with the GG genotype (1.39 microg/mL versus 1.05 microg/mL versus 0.76 microg/mL; P<0.0001); and highest among those with the G79A GG genotype, intermediate among those with the GA genotype, and lowest among those with the AA genotype (1.47 microg/mL versus 1.13 microg/mL versus 0.66 microg/mL; P<0.0001). The prevalence of A-13G and G79A genotypes was not significantly different between cases of ischemic stroke and controls. However, compared with the G79A GG genotype (reference), the odds of ischemic stroke was progressively lower for the heterozygote GA (odds ratio OR, 0.83; 95% CI, 0.52 to 1.33) and the homozygote AA genotype (OR, 0.63; 95% CI, 0.20 to 1.98). A pooled analysis showed that compared with the G79A GG genotype (reference), the odds of ischemic stroke was progressively lower for the heterozygote GA (OR, 0.78; 95% CI, 0.57 to 1.07) and the homozygote AA genotype (OR, 0.31; 95% CI, 0.14 to 0.69).
The consistency of the association between protein Z genotypes, blood concentrations of protein Z, and ischemic stroke, determined using 2 different methods that have different sources of bias strengthens the evidence that increased blood concentrations of protein Z concentrations are associated causally with an increased risk of ischemic stroke.
Few community-based studies have examined the long-term risk of recurrent stroke after an acute first-ever stroke. This study aimed to determine the absolute and relative risks of a first recurrent ...stroke over the first 5 years after a first-ever stroke and the predictors of such recurrence in a population-based series of people with first-ever stroke in Perth, Western Australia.
Between February 1989 and August 1990, all people with a suspected acute stroke or transient ischemic attack of the brain who were resident in a geographically defined region of Perth, Western Australia, with a population of 138 708 people, were registered prospectively and assessed according to standardized diagnostic criteria. Patients were followed up prospectively at 4 months, 12 months, and 5 years after the index event.
Three hundred seventy patients with a first-ever stroke were registered, of whom 351 survived >2 days. Data were available for 98% of the cohort at 5 years, by which time 199 patients (58%) had died and 52 (15%) had experienced a recurrent stroke, 12 (23%) of which were fatal within 28 days. The 5-year cumulative risk of first recurrent stroke was 22.5% (95% confidence limits CL, 16.8%, 28.1%). The risk of recurrent stroke was greatest in the first 6 months after stroke, at 8.8% (95% CL, 5.4%, 12.1%). After adjustment for age and sex, the prognostic factors for recurrent stroke were advanced, but not extreme, age (75 to 84 years) (hazard ratio HR, 2.6; 95% CL, 1.1, 6.2), hemorrhagic index stroke (HR, 2.1; 95% CL, 0.98, 4.4), and diabetes mellitus (HR, 2.1; 95% CL, 0.95, 4.4).
Approximately 1 in 6 survivors (15%) of a first-ever stroke experience a recurrent stroke over the next 5 years, of which 25% are fatal within 28 days. The pathological subtype of the recurrent stroke is the same as that of the index stroke in 88% of cases. The predictors of first recurrent stroke in this study were advanced age, hemorrhagic index stroke, and diabetes mellitus, but numbers of recurrent events were modest. Because the risk of recurrent stroke is highest (8.8%) in the first 6 months after stroke, strategies for secondary prevention should be initiated as soon as possible after the index event.
To assess the rate, degree, and predictors of recovery from a disabled to nondisabled state in patients disabled after recurrent ischemic stroke.
Patients with ischemic stroke enrolled in the ...Management of Atherothrombosis with Clopidogrel in High Risk Patients (MATCH) Study underwent prospective assessment of their modified Rankin score (mRS) at 1, 3, 6, 12, and 18 months after enrollment and after recurrent stroke. Patients disabled (defined as mRS > or = 3) after recurrence were analyzed for recovery (defined as mRS < 3) during the 18 months, and predictors of recovery were sought using a Cox proportional-hazard multiple regression analysis.
Three hundred forty-five (54%) of 637 patients were disabled after recurrent ischemic stroke; 115 (33%) patients had been disabled and 230 (66%) nondisabled before stroke recurrence. At recurrence, the degree of disability was moderate (mRS 3) in 135 (39%) patients, severe (mRS 4) in 139 (40%), and very severe (mRS 5) in 71 (21%). After 12 months' median follow-up, 117 (34%, 95% CI: 29 to 39%) had recovered: 68 (50%, 42 to 59%) of 135 moderately disabled, 45 (32%, 25 to 41%) of 139 severely disabled, and 4 (6%, 2 to 14%) of 71 very severely disabled; 70 (20.3%) patients died. From recurrence, median time to recovery was 6 months (mRS 3) and 18 months (mRS 4); 94% with very severe disability had not recovered at 18 months. Independent predictors of recovery were moderate disability at recurrence (mRS 3) compared with severe (mRS 4: hazard ratio HR 1.5; 95% CI 1.04 to 2.3) or very severe disability (mRS 5: HR 7.6; 2.7 to 20) and a nondisabled vs disabled state before recurrence (HR 4.0; 2.3 to 6.8).
The rate of recovery from recurrent ischemic stroke was greatest in the first 6 months; one-third of patients recovered within 12 months. The significant predictors of recovery were a nondisabled state before recurrence and increasing severity of the recurrent stroke.
In light of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants potentially undermining humoral immunity, it is important to understand the fine specificity of the antiviral ...antibodies. We screened 20 COVID-19 patients for antibodies against 9 different SARS-CoV-2 proteins observing responses against the spike (S) proteins, the receptor-binding domain (RBD), and the nucleocapsid (N) protein which were of the IgG1 and IgG3 subtypes. Importantly, mutations which typically occur in the B.1.351 "South African" variant, significantly reduced the binding of anti-RBD antibodies. Nine of 20 patients were critically ill and were considered high-risk (HR). These patients showed significantly higher levels of transforming growth factor beta (TGF-β) and myeloid-derived suppressor cells (MDSC), and lower levels of CD4
T cells expressing LAG-3 compared to standard-risk (SR) patients. HR patients evidenced significantly higher anti-S1/RBD IgG antibody levels and an increased neutralizing activity. Importantly, a large proportion of S protein-specific antibodies were glycosylation-dependent and we identified a number of immunodominant linear epitopes within the S1 and N proteins. Findings derived from this study will not only help us to identify the most relevant component of the anti-SARS-CoV-2 humoral immune response but will also enable us to design more meaningful immunomonitoring methods for anti-COVID-19 vaccines.
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