Hormonal replacement therapy, prothrombotic mutations and the risk of venous thrombosis

Hormone replacement therapy (HRT) increases the risk of venous thrombosis. We investigated whether this risk is affected by carriership of hereditary prothrombotic abnormalities. Therefore, we determined the two most common prothrombotic mutations, factor V Leiden and prothrombin 20210A in women who participated in a case-control study on venous thrombosis. Relative risks were expressed as odds ratios (OR) with 95% confidence intervals (CI95). Among 7 7 women aged 45-64 years with a first venous thrombosis, 51% were receiving HRT at the time of thrombosis, compared with 24% of control women (OR = 3.3, CI95 1.8-5.8). Among the patients, 23% had a prothrombotic defect, versus 7% among the control women (OR = 3.8, CI95 1.7- 8.5). Women who had factor V Leiden and used HRT had a 15-fold increased risk (OR = 15.5, CI95 3.1-77), which exceeded the expected joint odds ratio of 6.1 (under an additive model). We conclude that the thrombotic risk of HRT may particularly affect women with prothrombotic mutations. Efforts to avoid HRT in women with increased risk of thrombosis are advisable

Socioeconomic inequalities in coronary heart disease risk in older age: contribution of established and novel coronary risk factors

Background:Evidence on socioeconomic inequalities in coronary heart disease (CHD) and their pathways in the elderly is limited. Little is also known about the contributions that novel coronary risk factors (particularly inflammatory/hemostatic markers) make to socioeconomic inequalities in CHD. Objectives:To examine the extent of socioeconomic inequalities in CHD in older age, and the contributions (relative and absolute) of established and novel coronary risk factors. Methods:A population-based cohort of 3761 British men aged 60–79 years was followed up for 6.5 years for CHD mortality and incidence (fatal and non-fatal). Social class was based on longest-held occupation recorded at 40–59 years. Results:There was a graded relationship between social class and CHD incidence. The hazard ratio for CHD incidence comparing social class V (unskilled workers) with social class I (professionals) was 2.70 [95% confidence interval (CI) 1.37–5.35; P-value for trend = 0.008]. This was reduced to 2.14 (95% CI 1.06–4.33; P-value for trend = 0.11) after adjustment for behavioral factors (cigarette smoking, physical activity, body mass index, and alcohol consumption), which explained 38% of the relative risk gradient (41% of absolute risk). Additional adjustment for inflammatory markers (C-reactive protein, interleukin-6, and von Willebrand factor) explained 55% of the relative risk gradient (59% of absolute risk). Blood pressure and lipids made little difference to these estimates; results were similar for CHD mortality. Conclusions:Socioeconomic inequalities in CHD persist in the elderly and are at least partly explained by behavioral risk factors; novel (inflammatory) coronary risk markers made some further contribution. Reducing inequalities in behavioral factors (especially cigarette smoking) could reduce these social inequalities by at least one-third

Metabolic, inflammatory and haemostatic effects of a low-dose continuous combined HRT in women with type 2 diabetes: potentially safer with respect to vascular risk?

BACKGROUND Conventional hormone replacement therapy (HRT) containing conjugated equine oestrogen (CEE) and medroxyprogesterone acetate (MPA) increases triglyceride, C- reactive protein (CRP) and coagulation Factor VII concentrations, potentially explaining their increased coronary heart disease (CHD) and stroke risk. OBJECTIVE To assess the metabolic effects of a continuous combined HRT containing 1 mg oestradiol and 0.5 mg norethisterone or matching placebo. DESIGN Double-blind, randomized placebo-controlled trial. PATIENTS Fifty women with type 2 diabetes. MEASUREMENTS Classical and novel risk factors for vascular disease. RESULTS Triglyceride concentration was not altered (P = 0.31, change in active arm relative to placebo) and low-density lipoprotein (LDL) cholesterol concentration declined 13% (P = 0.018). IL-6 concentration (mean difference -1.42 pg/ml, 95% CI: -2.55 to - 0.29 IU/dl, P = 0.015), Factor VII (-32 IU/dl, -43 to -21 IU/l, P lt 0.001) and tissue plasminogen activator antigen (by 13%, P = 0.005) concentrations fell, but CRP was not significantly altered (P = 0.62). Fasting glucose (P = 0.026) also declined significantly, but there are no significant effects on HBA1c, Factor IX or APC resistance. CONCLUSIONS HRT containing 1 mg oestradiol and 0.5 mg norethisterone may avoid the adverse metabolic effects potentially implicated in the elevated CHD and stroke risk induced by conventional higher dose HRT. This type of preparation may therefore be more suitable than conventional HRT for women at elevated CHD risk such as those with type 2 diabetes. Large randomized controlled trials of such low dose preparations, powered for cardiovascular end points, are now needed

Adrenocortical, autonomic, and inflammatory causes of the metabolic syndrome: nested case-control study.

BACKGROUND: The causes of metabolic syndrome (MS), which may be a precursor of coronary disease, are uncertain. We hypothesize that disturbances in neuroendocrine and cardiac autonomic activity (CAA) contribute to development of MS. We examine reversibility and the power of psychosocial and behavioral factors to explain the neuroendocrine adaptations that accompany MS. METHODS AND RESULTS: This was a double-blind case-control study of working men aged 45 to 63 years drawn from the Whitehall II cohort. MS cases (n=30) were compared with healthy controls (n=153). Cortisol secretion, sensitivity, and 24-hour cortisol metabolite and catecholamine output were measured over 2 days. CAA was obtained from power spectral analysis of heart rate variability (HRV) recordings. Twenty-four-hour cortisol metabolite and normetanephrine (3-methoxynorepinephrine) outputs were higher among cases than controls (+ 0.49, +0.45 SD, respectively). HRV and total power were lower among cases (both -0.72 SD). Serum interleukin-6, plasma C-reactive protein, and viscosity were higher among cases (+0.89, +0.51, and +0.72 SD). Lower HRV was associated with higher normetanephrine output (r=-0.19; P=0.03). Among former cases (MS 5 years previously, n=23), cortisol output, heart rate, and interleukin-6 were at the level of controls. Psychosocial factors accounted for 37% of the link between MS and normetanephrine output, and 7% to 19% for CAA. Health-related behaviors accounted for 5% to 18% of neuroendocrine differences. CONCLUSIONS: Neuroendocrine stress axes are activated in MS. There is relative cardiac sympathetic predominance. The neuroendocrine changes may be reversible. This case-control study provides the first evidence that chronic stress may be a cause of MS. Confirmatory prospective studies are required

Association Between Raised Inflammatory Markers and Cognitive Decline in Elderly People With Type 2 Diabetes: The Edinburgh Type 2 Diabetes Study

OBJECTIVE-To determine whether circulating levels of the inflammatory markers C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor (TNF)-alpha are associated with cognitive ability and estimated lifetime cognitive decline in an elderly population with type 2 diabetes. RESEARCH DESIGN AND METHODS-A cross-sectional study of 1,066 men and women aged 60-75 years with type 2 diabetes and living in Lothian, Scotland (the Edinburgh Type 2 Diabetes Study), was performed. Seven cognitive tests were used to measure abilities in memory, nonverbal reasoning, information processing speed, executive function, and mental flexibility. The results were used to derive a general intelligence factor (g). A vocabulary-based test was administered as an estimate of peak prior cognitive ability. Results on the cognitive tests were assessed for statistical association with inflammatory markers measured in a venous blood sample at the time of cognitive testing. RESULTS-Higher IL-6 and TNF-alpha levels were associated with poorer age- and sex-adjusted scores on the majority of the individual cognitive tests. They were also associated with g using standardized regression coefficients -0.074 to -0.173 (P < 0.05). After adjusting for vocabulary, education level, cardiovascular dysfunction, duration of diabetes, and glycemic control, R,6 remained associated with three of the cognitive tests and with g. CONCLUSIONS-In this representative population of people with type 2 diabetes, elevated circulating levels of inflammatory markers were associated with poorer cognitive ability. IL-6 levels were also associated with estimated lifetime cognitive decline. Diabetes 59:710-713, 201

Endotoxin, cytokines and lipid peroxides in children with intussusception

Background: Intussusception is a relatively common paediatric surgical emergency. The aim of this study was to investigate selected in¯ammatory mediators in children with acute intussusception and to identify potentially useful plasma markers of clinical outcome. Methods: Clinical, radiographic, operative and pathological details were recorded prospectively of all children presenting to a single institution with a con®rmed diagnosis of acute intussusception during 1 year. Paired acute and convalescent venous blood samples were collected in a standard manner for blinded analysis of the following: malondialdehyde, C-reactive protein (CRP), interleukin (IL) 6, neopterin, tumour necrosis factor a, endotoxin, and immunoglobulin (Ig) G and IgM antiendotoxin core antibody (EndoCAb). Results: Thirty-two consecutive children (23 boys, nine girls) with a median age of 4 months were studied. Acute ileocolic intussusception was managed by air enema reduction (n = 19), operative reduction (n = 8) or surgical resection (n = 5). Peripheral blood cultures were sterile. Acute levels of plasma IL-6, neopterin and CRP were signi®cantly raised in comparison to both normal laboratory ranges and convalescent samples (P < 0´001). Using stepwise discriminant analysis, CRP was identi®ed as the best variable at distinguishing between the three treatment groups (P < 0´001). IgM EndoCAb concentrations were signi®cantly greater in the convalescent sera of all the patients (P < 0´001). Conclusion: Acute ileocolic intussusception in childhood is associated with endotoxinaemia and signi®cantly raised levels of circulating in¯ammatory cytokines. Plasma CRP at diagnosis showed a statistically signi®cant positive correlation with disease severity

Inflammation, insulin resistance, and diabetes-mendelian randomization using CRP haplotypes points upstream

Background Raised C-reactive protein (CRP) is a risk factor for type 2 diabetes. According to the Mendelian randomization method, the association is likely to be causal if genetic variants that affect CRP level are associated with markers of diabetes development and diabetes. Our objective was to examine the nature of the association between CRP phenotype and diabetes development using CRP haplotypes as instrumental variables. Methods and Findings We genotyped three tagging SNPs (CRP + 2302G > A; CRP + 1444T > C; CRP + 4899T > G) in the CRP gene and measured serum CRP in 5,274 men and women at mean ages 49 and 61 y (Whitehall II Study). Homeostasis model assessment-insulin resistance (HOMA-IR) and hemoglobin A1c (HbA1c) were measured at age 61 y. Diabetes was ascertained by glucose tolerance test and self-report. Common major haplotypes were strongly associated with serum CRP levels, but unrelated to obesity, blood pressure, and socioeconomic position, which may confound the association between CRP and diabetes risk. Serum CRP was associated with these potential confounding factors. After adjustment for age and sex, baseline serum CRP was associated with incident diabetes (hazard ratio = 1.39 [95% confidence interval 1.29-1.51], HOMA-IR, and HbA1c, but the associations were considerably attenuated on adjustment for potential confounding factors. In contrast, CRP haplotypes were not associated with HOMA-IR or HbA1c (p=0.52-0.92). The associations of CRP with HOMA-IR and HbA1c were all null when examined using instrumental variables analysis, with genetic variants as the instrument for serum CRP. Instrumental variables estimates differed from the directly observed associations (p=0.007-0.11). Pooled analysis of CRP haplotypes and diabetes in Whitehall II and Northwick Park Heart Study II produced null findings (p=0.25-0.88). Analyses based on the Wellcome Trust Case Control Consortium (1,923 diabetes cases, 2,932 controls) using three SNPs in tight linkage disequilibrium with our tagging SNPs also demonstrated null associations. Conclusions Observed associations between serum CRP and insulin resistance, glycemia, and diabetes are likely to be noncausal. Inflammation may play a causal role via upstream effectors rather than the downstream marker CRP

An Integrated-Photonics Optical-Frequency Synthesizer

Integrated-photonics microchips now enable a range of advanced functionalities for high-coherence applications such as data transmission, highly optimized physical sensors, and harnessing quantum states, but with cost, efficiency, and portability much beyond tabletop experiments. Through high-volume semiconductor processing built around advanced materials there exists an opportunity for integrated devices to impact applications cutting across disciplines of basic science and technology. Here we show how to synthesize the absolute frequency of a lightwave signal, using integrated photonics to implement lasers, system interconnects, and nonlinear frequency comb generation. The laser frequency output of our synthesizer is programmed by a microwave clock across 4 THz near 1550 nm with 1 Hz resolution and traceability to the SI second. This is accomplished with a heterogeneously integrated III/V-Si tunable laser, which is guided by dual dissipative-Kerr-soliton frequency combs fabricated on silicon chips. Through out-of-loop measurements of the phase-coherent, microwave-to-optical link, we verify that the fractional-frequency instability of the integrated photonics synthesizer matches the $7.0*10^{-13}$ reference-clock instability for a 1 second acquisition, and constrain any synthesis error to $7.7*10^{-15}$ while stepping the synthesizer across the telecommunication C band. Any application of an optical frequency source would be enabled by the precision optical synthesis presented here. Building on the ubiquitous capability in the microwave domain, our results demonstrate a first path to synthesis with integrated photonics, leveraging low-cost, low-power, and compact features that will be critical for its widespread use.Comment: 10 pages, 6 figure