Smoking and stroke: A mendelian randomization study

Whether smoking is causally associated with risk of ischemic stroke and intracerebral hemorrhage is unknown. We used the Mendelian randomization design to explore the associations of genetic predisposition to smoking with ischemic stroke and its subtypes as well as intracerebral hemorrhage. Up to 372 single-nucleotide polymorphisms were used as instrumental variables for smoking initiation. We used summary statistics data for 438 847 individuals in the analyses of ischemic stroke (34 217 cases and 404 630 non-cases) and 3026 individuals in analyses of intracerebral hemorrhage (1545 cases and 1481 non-cases). Genetic predisposition to smoking initiation was statistically significantly positively associated with any ischemic stroke, large artery stroke, and small vessel stroke but not cardioembolic stroke or intracerebral hemorrhage. The odds ratios per one standard deviation higher log-odds of ever smoking regularly (smoking initiation) were 1.24 (95% CI 1.16-1.32; p = 1.310-10) for any ischemic stroke, 1.64 (95% CI 1.40-1.91; p = 2.810-10) for large artery stroke, 1.47 (95% CI 1.26-1.71; p = 1.110-6) for small vessel stroke, 1.12 (95% CI 0.99-1.27; p = 0.08) for cardioembolic stroke, and 1.13 (95% CI 0.81-1.58; p = 0.47) for intracerebral hemorrhage. This study provides genetic support for a causal association of smoking with ischemic stroke, particularly large artery and small vessel stroke.his work was supported by the Swedish Research Council for Health, Working Life and Welfare (Forskningsrådet för hälsa, arbetsliv och välfärd) and the Swedish Research Council. S.B. is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant number 204623/Z/16/Z)

Urinary phosphate is associated with cardiovascular disease incidence

Elevated phosphate (P) in urine may reflect a high intake of inorganic P salts from food additives. Elevated P in plasma is linked to vascular dysfunction and calcification. Objective, To explore associations between P in urine as well as in plasma and questionnaire-estimated P intake, and incidence of cardiovascular disease (CVD). Methods, We used the Swedish Mammography Cohort-Clinical, a population-based cohort study. At baseline (2004–2009), P was measured in urine and plasma in 1625 women. Dietary P was estimated via a food-frequency questionnaire. Incident CVD was ascertained via register-linkage. Associations were assessed using Cox proportional hazards regression. Results, After a median follow-up of 9.4 years, 164 composite CVD cases occurred (63 myocardial infarctions [MIs] and 101 strokes). Median P (percentiles 5–95) in urine and plasma were 2.4 (1.40–3.79) mmol/mmol creatinine and 1.13 (0.92–1.36) mmol/L, respectively, whereas dietary P intake was 1510 (1148–1918) mg/day. No correlations were observed between urinary and plasma P (r = −0.07) or dietary P (r = 0.10). Urinary P was associated with composite CVD and MI. The hazard ratio of CVD comparing extreme tertiles was 1.57 (95% confidence interval 1.05, 2.35; P trend 0.037)—independently of sodium excretion, the estimated glomerular filtration rate, both P and calcium in plasma, and diuretic use. Association with CVD for plasma P was 1.41 (0.96, 2.07; P trend 0.077). Conclusion, Higher level of urinary P, likely reflecting a high consumption of highly processed foods, was linked to CVD. Further investigation is needed to evaluate the potential cardiovascular toxicity associated with excessive intake of P beyond nutritional requirement

T-bet and Eomes Are Differentially Linked to the Exhausted Phenotype of CD8+T Cells in HIV Infection

CD8+ T cell exhaustion represents a major hallmark of chronic HIV infection. Two key transcription factors governing CD8+ T cell differentiation, T-bet and Eomesodermin (Eomes), have previously been shown in mice to differentially regulate T cell exhaustion in part through direct modulation of PD-1. Here, we examined the relationship between these transcription factors and the expression of several inhibitory receptors (PD-1, CD160, and 2B4), functional characteristics and memory differentiation of CD8+ T cells in chronic and treated HIV infection. The expression of PD-1, CD160, and 2B4 on total CD8+ T cells was elevated in chronically infected individuals and highly associated with a T-betdimEomeshi expressional profile. Interestingly, both resting and activated HIV-specific CD8+ T cells in chronic infection were almost exclusively T-betdimEomeshi cells, while CMV-specific CD8+ T cells displayed a balanced expression pattern of T-bet and Eomes. The T-betdimEomeshi virus-specific CD8+ T cells did not show features of terminal differentiation, but rather a transitional memory phenotype with poor polyfunctional (effector) characteristics. The transitional and exhausted phenotype of HIV-specific CD8+ T cells was longitudinally related to persistent Eomes expression after antiretroviral therapy (ART) initiation. Strikingly, these characteristics remained stable up to 10 years after ART initiation. This study supports the concept that poor human viral-specific CD8+ T cell functionality is due to an inverse expression balance between T-bet and Eomes, which is not reversed despite long-term viral control through ART. These results aid to explain the inability of HIV-specific CD8+ T cells to control the viral replication post-ART cessation

P and R Wave Detection in Complete Congenital Atrioventricular Block

Complete atrioventricular block (type III AVB) is characterized by an absence of P wave transmission to ventricles. This implies that QRS complexes are generated in an autonomous way and are not coordinated with P waves. This work introduces a new algorithm for the detection of P waves for this type of pathology using non-invasive electrocardiographic surface leads. The proposed algorithm is divided into three stages. In the first stage, the R waves located by a QRS detector are used to generate the RR series and time references for the other stages of the algorithm. In the second stage, the ventricular activity (QT segment) is removed by using an adaptive filter that obtains an averaged pattern of the QT segment. In the third stage, a new P wave detector is applied to the residual signal obtained after QT cancellation in order to detect P wave locations and get the PP time series. Eight Holter records from patients with congenital type III AVB were used to verify the proposed algorithm. Although further improvements should be made to improve the algorithm¿s performance, the results obtained show high average values of sensitivity (90.52 %) and positive prediction (90.98%)

Vitamin D and subsequent all-age and premature mortality: a systematic review

<br>Background: All-cause mortality in the population < 65 years is 30% higher in Glasgow than in equally deprived Liverpool and Manchester. We investigated a hypothesis that low vitamin D in this population may be associated with premature mortality via a systematic review and meta-analysis.</br> <br>Methods: Medline, EMBASE, Web of Science, the Cochrane Library and grey literature sources were searched until February 2012 for relevant studies. Summary statistics were combined in an age-stratified meta-analysis.</br> <br>Results: Nine studies were included in the meta-analysis, representing 24,297 participants, 5,324 of whom died during follow-up. The pooled hazard ratio for low compared to high vitamin D demonstrated a significant inverse association (HR 1.19, 95% CI 1.12-1.27) between vitamin D levels and all-cause mortality after adjustment for available confounders. In an age-stratified meta-analysis, the hazard ratio for older participants was 1.25 (95% CI 1.14-1.36) and for younger participants 1.12 (95% CI 1.01-1.24).</br> <br>Conclusions: Low vitamin D status is inversely associated with all-cause mortality but the risk is higher amongst older individuals and the relationship is prone to residual confounding. Further studies investigating the association between vitamin D deficiency and all-cause mortality in younger adults with adjustment for all important confounders (or using randomised trials of supplementation) are required to clarify this relationship.</br&gt

CD49a Expression Defines Tissue-Resident CD8+ T Cells Poised for Cytotoxic Function in Human Skin

Tissue-resident memory T (Trm) cells form a heterogeneous population that provides localized protection against pathogens. Here, we identify CD49a as a marker that differentiates CD8(+) Trm cells on a compartmental and functional basis. In human skin epithelia, CD8(+)CD49a(+) Trm cells produced interferon-γ, whereas CD8(+)CD49a(−) Trm cells produced interleukin-17 (IL-17). In addition, CD8(+)CD49a(+) Trm cells from healthy skin rapidly induced the expression of the effector molecules perforin and granzyme B when stimulated with IL-15, thereby promoting a strong cytotoxic response. In skin from patients with vitiligo, where melanocytes are eradicated locally, CD8(+)CD49a(+) Trm cells that constitutively expressed perforin and granzyme B accumulated both in the epidermis and dermis. Conversely, CD8(+)CD49a(–) Trm cells from psoriasis lesions predominantly generated IL-17 responses that promote local inflammation in this skin disease. Overall, CD49a expression delineates CD8(+) Trm cell specialization in human epithelial barriers and correlates with the effector cell balance found in distinct inflammatory skin diseases

Mid-term echocardiographic follow up of left ventricular function with permanent right ventricular pacing in pediatric patients with and without structural heart disease

BACKGROUND: Chronic right ventricular apical pacing may have detrimental effect on left ventricular function and may promote to heart failure in adult patients with left ventricular dysfunction. METHODS: A group of 99 pediatric patients with previously implanted pacemaker was studied retrospectively. Forty-three patients (21 males) had isolated congenital complete or advanced atrioventricular block. The remaining 56 patients (34 males) had pacing indication in the presence of structural heart disease. Thirty-two of them (21 males) had isolated structural heart disease and the remaining 24 (13 males) had complex congenital heart disease. Patients were followed up for an average of 53 ± 41.4 months with 12-lead electrocardiogram and transthoracic echocardiography. Left ventricular shortening fraction was used as a marker of ventricular function. QRS duration was assessed using leads V(5 )or II on standard 12-lead electrocardiogram. RESULTS: Left ventricular shortening fraction did not change significantly after pacemaker implantation compared to preimplant values overall and in subgroups. In patients with complex congenital heart malformations shortening fraction decreased significantly during the follow up period. (0.45 ± 0.07 vs 0.35 ± 0.06, p = 0.015). The correlation between the change in left ventricular shortening fraction and the mean increase of paced QRS duration was not significant. Six patients developed dilated cardiomyopathy, which was diagnosed 2 months to 9 years after pacemaker implantation. CONCLUSION: Chronic right ventricular pacing in pediatric patients with or without structural heart disease does not necessarily result in decline of left ventricular function. In patients with complex congenital heart malformations left ventricular shortening fraction shows significant decrease

Association of epicardial adipose tissue with proteomics, coronary flow reserve, cardiac structure and function, and quality of life in heart failure with preserved ejection fraction: insights from the PROMIS-HFpEF study

Aim: Epicardial adipose tissue (EAT) may play a role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). We investigated associations of EAT with proteomics, coronary flow reserve (CFR), cardiac structure and function, and quality of life (QoL) in the prospective multinational PROMIS-HFpEF cohort.Methods and results: Epicardial adipose tissue was measured by echocardiography in 182 patients and defined as increased if ≥9 mm. Proteins were measured using high-throughput proximity extension assays. Microvascular dysfunction was evaluated with Doppler-based CFR, cardiac structural and functional indices with echocardiography and QoL by Kansas City Cardiomyopathy Questionnaire (KCCQ). Patients with increased EAT (n = 54; 30%) had higher body mass index (32 [28-40] vs. 27 [23-30] kg/m2 ; p Conclusion: Increased EAT was associated with cardiac structural alterations and proteins expressing adiposity, inflammation, lower insulin sensitivity and endothelial dysfunction related to HFpEF pathology, probably driven by general obesity. Potential local mechanical or paracrine effects mediated by EAT remain to be elucidated.</p

Haplotypes of intron 4 of the estrogen receptor alpha gene and hip fractures: a replication study in Caucasians

<p>Abstract</p> <p>Background</p> <p>Despite their great impact, few genetic association studies have used hip fractures as an endpoint. However, the association of two polymorphisms on intron 4 of estrogen receptor alpha (<it>ESR1</it>) with hip fractures was recently reported in a Chinese population. The aim of this study was to investigate whether such association is also present in Caucasians.</p> <p>Methods</p> <p>We analyzed those two SNPs and another neighbour SNP located on the exon 4 of <it>ESR1 </it>in 787 patients with hip fractures and 953 controls from Spain.</p> <p>Results</p> <p>The allelic frequencies differed markedly from those reported in Asian populations. Nevertheless, haplotypes including the rs3020314 and rs1884051 loci in intron 4 showed a significant association with hip fractures (omnibus test p = 0.006 in the whole group and 0.00005 in women). In the sex-stratified analysis, the association was significant in females, but not in males. In women, the CA haplotype appeared to have a protective influence, being present in 6.5% of the controls, but only in 3% of patients with fractures (odds ratio 0.39; 95% confidence interval 0.26-0.59; estimated population preventive fraction 3.5%). The inclusion of the rs1801132 SNP of exon 4 further increased the statistical significance of the association (odds ratio 0.17; 95% CI 0.08-0.37; p = 0.00001). Each SNP appeared to contribute independently to the association. No genotype-related differences in gene expression were found in 42 femoral bone samples.</p> <p>Conclusions</p> <p>This study confirms the association of some polymorphisms in the region of exon 4/intron 4 of <it>ESR1 </it>and hip fractures in women. However, there are marked differences in allele frequencies between Asian and Caucasian populations.</p

Hip Fracture Incidence in Relation to Age, Menopausal Status, and Age at Menopause: Prospective Analysis

Using data from the UK Million Women Study, Emily Banks and colleagues investigate the relationships between the incidence of hip fracture and a woman's age, menopausal status, and age at menopause