We asked whether 35 genetic polymorphisms, previously found to be associated with cardiovascular disease, were associated with myocardial infarction (MI) in the CARE (Cholesterol and Recurrent ...Events) trial and with coronary heart disease (CHD) in the WOSCOPS (West of Scotland Coronary Prevention Study) trial and whether the risk associated with these polymorphisms could be reduced by pravastatin treatment.
Identification of genetic polymorphisms associated with CHD may improve assessment of CHD risk and understanding of disease pathophysiology.
We tested the association between genotype and recurrent MI in the CARE study and between genotype and primary CHD in the WOSCOPS trial using regression models that adjusted for conventional risk factors: Cox proportional hazards models for the CARE study and conditional logistic regression models for a nested case-control study of the WOSCOPS trial.
We found that Trp719Arg (rs20455) in KIF6 was associated with coronary events. KIF6 encodes kinesin-like protein 6, a member of the molecular motor superfamily. In placebo-treated patients, carriers of the KIF6 719Arg allele (59.4% of the CARE trial cohort) had a hazard ratio of 1.50 (95% confidence interval CI 1.05 to 2.15) in the CARE trial and an odds ratio of 1.55 (95% CI 1.14 to 2.09) in the WOSCOPS trial. Among carriers, the absolute risk reduction by pravastatin was 4.89% (95% CI 1.81% to 7.97%) in the CARE trial and 5.49% (95% CI 3.52% to 7.46%) in the WOSCOPS trial.
In both the CARE and the WOSCOPS trials, carriers of the KIF6 719Arg allele had an increased risk of coronary events, and pravastatin treatment substantially reduced that risk.
An incomplete understanding of the immunological mechanisms underlying protection against tuberculosis (TB) hampers the development of new vaccines against TB. We aimed to define host correlates of ...prospective risk of TB disease following bacille Calmette-Guérin (BCG) vaccination.
In this study, 5,726 infants vaccinated with BCG at birth were enrolled. Host responses in blood collected at 10 weeks of age were compared between infants who developed pulmonary TB disease during 2 years of follow-up (cases) and those who remained healthy (controls).
Comprehensive gene expression and cellular and soluble marker analysis failed to identify a correlate of risk. We showed that distinct host responses after BCG vaccination may be the reason: two major clusters of gene expression, with different myeloid and lymphoid activation and inflammatory patterns, were evident when all infants were examined together. Cases from each cluster demonstrated distinct patterns of gene expression, which were confirmed by cellular assays.
Distinct patterns of host responses to Mycobacterium bovis BCG suggest that novel TB vaccines may also elicit distinct patterns of host responses. This diversity should be considered in future TB vaccine development.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Administration of tuberculosis (TB) vaccines in participants with previous or current pulmonary TB may have the potential for causing harmful postvaccination immunologic (Koch-type) reactions.
To ...assess the safety and immunogenicity of three dose levels of the AERAS-402 live, replication-deficient adenovirus 35-vectored TB candidate vaccine, containing three mycobacterial antigens, in individuals with current or previous pulmonary TB.
We performed a phase II randomized, placebo-controlled, double-blinded dose-escalation study in an HIV-negative adult South African cohort (n = 72) with active pulmonary TB (on treatment for 1-4 mo) or pulmonary TB treated at least 12 months before study entry and considered cured. Safety endpoints included clinical assessment, flow volume curves, diffusing capacity of the lung for carbon monoxide, pulse oximetry, chest radiograph, and high-resolution thoracic computerized tomography scans. Cytokine expression by CD4 and CD8 T cells, after stimulation with Ag85A, Ag85B, and TB10.4 peptide pools, was examined by intracellular cytokine staining.
No apparent temporal or dose-related changes in clinical status (specifically acute, Koch phenomenon-like reactions), lung function, or radiology attributable to vaccine were observed. Injection site reactions were mild or moderate. Hematuria (by dipstick only) occurred in 25 (41%) of 61 AERAS-402 recipients and 3 (27%) of 11 placebo recipients, although no gross hematuria was reported. AERAS-402 induced robust CD8
and moderate CD4
T-cell responses, mainly to Ag85B in both vaccine groups.
Administration of the AERAS-402 candidate TB vaccine to participants with current or previous pulmonary TB induced a robust immune response and is not associated with clinically significant pulmonary complications. Clinical trial registered with www.clinicaltrials.gov (NCT 02414828) and in the South African National Clinical Trials Register ( www.sanctr.gov.za DOH 27-0808-2060).
Association of the Trp719Arg Polymorphism in Kinesin-Like Protein 6 With Myocardial Infarction and Coronary Heart Disease in 2 Prospective Trials: The CARE and WOSCOPS Trials Olga A. Iakoubova, ...Carmen H. Tong, Charles M. Rowland, Todd G. Kirchgessner, Bradford A. Young, Andre R. Arellano, Dov Shiffman, Marc S. Sabatine, Hannia Campos, Christopher J. Packard, Marc A. Pfeffer, Thomas J. White, Eugene Braunwald, James Shepherd, James J. Devlin, Frank M. Sacks The Trp719Arg polymorphism in KIF6 was associated with recurrent myocardial infarction in the CARE (Cholesterol And Recurrent Events) trial and with primary CHD in the WOSCOPS (West of Scotland Coronary Prevention Study) trial. In placebo-treated patients, carriers of the KIF6 719Arg allele (59.4% of the CARE trial cohort) had an adjusted hazard ratio of 1.50 (95% confidence interval CI 1.05 to 2.15) in the CARE trial and an adjusted odds ratio of 1.55 (95% CI 1.14 to 2.09) in the WOSCOPS trial. Among carriers of the KIF6 719Arg risk allele, the absolute risk reduction by pravastatin was 4.89% (95% CI 1.81% to 7.97%) in the CARE trial and 5.49% (95% CI 3.52% to 7.46%) in the WOSCOPS trial
Summary
The curative potential of allogeneic haematopoietic stem cell transplant (allo HSCT) in chronic lymphocytic leukaemia CLL is established, with a demonstrated role for graft‐versus‐leukaemia ...and less certainty for other factors in determining outcome. The first two decades of CLL patients proceeding to allo HSCT at the Leukaemia/Bone Marrow Transplant Program of British Columbia (n = 49 consecutive, 1991–2009) were studied to clarify factors predicting outcome. The donor was related in 29 (59%) and unrelated in 20 (41%). Conditioning was reduced‐intensity in 27 (55%) and myeloablative in 22 (45%). Thirty‐one of 49 patients survive with median follow‐up of 5 years (0·2–15). Cumulative incidence of non‐relapse mortality; complete remission (CR); clearance of fluorescence in situ hybridization (FISH) abnormality and progression at 10 years was 36%; 69%; 55% and 22%. Overall survival (OS) was 63% at 2 years; 55% at 5 years and beyond. Factors predicting OS (P value by log rank <0·05) were: comorbidity index <3, FISH rank (Dohner) and 17p deletion, alemtuzumab pre‐HSCT, achievement of CR post‐HSCT, donor chimerism >90%, clearance of FISH abnormality post‐HSCT and absence of high‐grade (3–4) graft‐versus‐host disease. Results from this province‐wide, two‐decade cohort demonstrated that a substantial proportion of patients with high‐risk CLL become long term disease‐free survivors.
We report progress in using the isotopic composition and concentration of Pb in the dentine and enamel of deciduous teeth to provide a high resolution time frame of exposure to Pb during fetal ...development and early childhood. Isotope measurements (total Pb and 208Pb/206Pb, 207Pb/206Pb ratios) were acquired by laser ablation inductively coupled mass spectrometry at contiguous 100 micron intervals across thin sections of the teeth; from the outer enamel surface to the pulp cavity. Teeth samples (n=10) were selected from two cohorts of children, aged 5–8 years, living in NE England. By integrating the isotope data with histological analysis of the teeth, using the daily incremental lines in dentine, we were able to assign true estimated ages to each ablation point (first 2–3 years for molars, first 1–2 years for incisors+pre-natal growth). Significant differences were observed in the isotope composition and concentration of Pb between children, reflecting differences in the timing and sources of exposure during early childhood. Those born in 2000, after the withdrawal of leaded petrol in 1999, have the lowest dentine Pb levels (<0.2µgPb/g) with 208Pb/206Pb (mean ±2σ: 2.126–2.079) 208Pb/206Pb (mean ±2σ: 0.879–0.856) ratios that correlate very closely with modern day Western European industrial aerosols (PM10, PM2.5) suggesting that diffuse airborne pollution was probably the primary source and exposure pathway. Legacy lead, if present, is insignificant. For those born in 1997, dentine lead levels are typically higher (>0.4µgPb/g) with 208Pb/206Pb (mean ±2σ: 2.145–2.117) 208Pb/206Pb (mean ±2σ: 0.898–0.882) ratios that can be modelled as a binary mix between industrial aerosols and leaded petrol emissions. Short duration, high intensity exposure events (1–2 months) were readily identified, together with evidence that dentine provides a good proxy for childhood changes in the isotope composition of blood Pb. Our pilot study confirms that laser ablation Pb isotope analysis of deciduous teeth, when carried out in conjunction with histological analysis, permits a reconstruction of the timing, duration and source of exposure to Pb during early childhood. With further development, this approach has the potential to study larger cohorts and appraise environments where the levels of exposure to Pb are much higher.
•Reconstructing a high resolution chronology of early childhood exposure to lead.•Combined laser ablation lead isotope – histological analysis of children's teeth.•Using dentine to recover information on the intensity, duration and source of lead.•Importance of industrial airborne lead pollution in a post-leaded petrol era.
Framework for well co-ordinated service provision - evaluation of two inter-agency supported housing programs for people with mental illness - importance of "integration coordinator" - collaborative ...mechanisms.
Laser ablation--inductively coupled plasma--mass spectrometry (LA-ICP-MS) has become recognized as a sensitive, efficient, and cost-effective approach to measuring the major-, minor-, and ...trace-solute compositions of individual fluid inclusions in minerals. As a prerequisite for the routine analysis of natural inclusions in our laboratory, the precision and accuracy of the technique was assessed using sets of multi-element synthetic fluid inclusions. Five multi-element standard solutions were prepared, and incorporated as fluid inclusions in quartz crystals at 750°C and 7 kbar. Fluid inclusions were ablated with a 193 nm ArF excimer laser and analyzed with a quadrupole ICP-MS, equipped with an octopole reaction cell for the removal of Ar-based interferences. The internal standard used in all cases was Na. Analytical precision for K, Rb, and Cs is typically better than 15% RSD, whereas Li, Mg, Ca, Sr, Ba, Mn, Fe, Cu, Zn, and Cl analyses are typically reproducible within 30% RSD. Measured concentrations approximate a Gaussian distribution, suggesting that analytical errors are random. Analyses for most elements are accurate within 15%. Limits of detection vary widely according to inclusion volume, but are 1 to 100 µg/g for most elements. These figures of merit are in excellent agreement with previous studies. We also demonstrate that, over the range investigated, precision and accuracy are insensitive to inclusion size and depth. Finally, the combination of our LA-ICP-MS analyses with microthermometric data shows that charge-balancing to NaCl-H2O equivalent chloride molality is the most valid approach to LA-ICP-MS data reduction, where chloride-dominated fluid inclusions are concerned.
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