The factor VII activating protease G511E (Marburg) variant and cardiovascular risk

A previous study had shown a strong relationship between a variant in factor VII activating protease (FSAP G511E) and advanced carotid atheroma. In-vitro, the variant has reduced fibrinolytic but normal pro-coagulant activity, which may constitute a prothrombotic state. The current study has addressed risk for coronary heart disease in a prospective study of cardio vascular disorders (Northwick Park Heart Study II). An interactive effect upon risk was found between the 511E allele and elevated levels of cholesterol and triglyceride. Fibrinogen could substitute for triglyceride levels in this risk-interaction analysis. The findings support the proposal that the FSAP 511E allele exacerbates atherosclerosis or its clinical sequelae

Increased plasma markers of oxidative stress are associated with coronary heart disease in males with diabetes mellitus and with 10-year risk in a prospective sample of males

Background: Increased oxidative stress is associated with coronary heart disease (CHD). We examined the association between plasma markers of oxidative stress and CHD in a cross-sectional sample of patients with diabetes and prospective CHD risk in a sample of men predominantly without diabetes. Methods: Plasma total antioxidant status (TAOS) and the ratio of oxidized LDL (Ox-LDL) to LDL-cholesterol (LDL-C) were determined in a cross-section of 761 Caucasian individuals with diabetes (UDACS study). Plasma TAOS was also determined in 310 baseline samples from a 10-year prospective cohort of 3012 healthy males (NPHSII). Results: Within UDACS, males with CHD had lower mean (SD) plasma TAOS [no CHD, 43.4 (13.2)%; CHD, 40.3 (13.8)%; P = 0.04]. The prevalence of CHD was higher in the lowest compared with the upper quartiles (32.7% vs 19.7%; P = 0.004). We observed a significant association between plasma Ox-LDL:LDL-C and CHD status [no CHD vs CHD, 16.9 (3.1) vs 19.3 (5.0) units/mmol; P = 0.04], with the prevalence of CHD being higher among men in the upper compared with lower quartiles (18.4% vs 35.1%; P = 0.003). No association was observed in females. In NPHSII, TAOS was lower in those who developed CHD [35.1 (8.0)% vs 37.1 (7.9)%; P = 0.04]. The odds ratio for CHD in the lowest compared with the upper quartile was 1.91 (95% confidence interval, 0.99–3.70; P = 0.04). This remained unchanged after adjustment for classic risk factors. Conclusions: A cross-sectional and prospective association exists between baseline plasma measures of oxidative stress and CHD risk. The association with prospective CHD risk remained after adjustment for "traditional" risk factors, implying an independent role for oxidative stress in CHD risk

Apolipoprotein AIV gene variant S347 is associated with increased risk of coronary heart disease and lower plasma apolipoprotein AIV levels

The impact of common variants in the apolipoprotein gene cluster (APOC3-A4-A5) on prospective coronary heart disease (CHD) risk was examined in healthy UK men. Of the 2808 men followed over 9 years, 187 had a clinically defined CHD event. Examination of 9 single nucleotide polymorphisms (SNPs) in this group revealed that homozygotes for APOA4 S347 had significantly increased risk of CHD [hazard ratio (HR) of 2.07 (95%CI 1.04 to 4.12)], whereas men homozygous for APOC3 1100T were protected [HR 0.28 (95%CI 0.09 to 0.87)]. In stepwise multiple regression analysis, after entering all the variants and adjusting for established risk factors APOA4 T347S alone remained in the model. Using all nine SNPs, the highest risk-estimate haplotypes carried APOA4 S347 and rare alleles of the two flanking intergenic markers. The protective effect of APOC3 1100T could be explained by negative linkage disequilibrium with these alleles. To determine the association of APOA4 T347S with apoAIV levels, the relationship was examined in 1600 healthy young European men and women. S347 homozygotes had significantly lower apoAIV plasma levels (13.64±0.59 mg/dL) compared with carriers of the T347 allele (14.90±0.12 mg/dL) (P=0.035). These results demonstrate that genetic variation in and around APOA4, independent of the effects of triglyceride, is associated with risk of CHD and apoAIV levels, supporting an antiatherogenic role for apoAIV

Updated recommendations for HER2 testing in the UK

This paper serves to update previously published guidance on rationale and methodology for HER2 laboratory testing following the recommendation for the use of HER2 targeted treatment in the management of advanced breast cancer in the UK. Emphasis is placed on the standardisation of methodology and assessment and strategies to achieve high quality performance. A two phase testing algorithm based on first line immunocytochemistry evaluation and second line fluorescence in situ hybridisation assessment of borderline cases is recommended. To ensure maintenance of expertise, an annual caseload volume of at least 250 cases is recommended for laboratories providing a testing service

Deep Hole States in the Mirror Nuclei 23-Mg and 23-Na

This work was supported by National Science Foundation Grant PHY 76-84033 and Indiana Universit

Conformationally restricted calpain inhibitors

The cysteine protease calpain-I is linked to several diseases and is therefore a valuable target for inhibition. Selective inhibition of calpain-I has proved difficult as most compounds target the active site and inhibit a broad spectrum of cysteine proteases as well as other calpain isoforms. Selective inhibitors might not only be potential drugs but should act as tools to explore the physiological and pathophysiological roles of calpain-I. α-Mercaptoacrylic acid based calpain inhibitors are potent, cell permeable and selective inhibitors of calpain-I and calpain-II. These inhibitors target the calcium binding domain PEF(S) of calpain-I and -II. Here X-ray diffraction analysis of co-crystals of PEF(S) revealed that the disulfide form of an α-mercaptoacrylic acid bound within a hydrophobic groove that is also targeted by a calpastatin inhibitory region and made a greater number of favourable interactions with the protein than the reduced sulfhydryl form. Measurement of the inhibitory potency of the α-mercaptoacrylic acids and X-ray crystallography revealed that the IC50 values decreased significantly on oxidation as a consequence of the stereo-electronic properties of disulfide bonds that restrict rotation around the S–S bond. Consequently, thioether analogues inhibited calpain-I with potencies similar to those of the free sulfhydryl forms of α-mercaptoacrylic acids

Off-shell Behavior of the π ⁣− ⁣η\pi\!-\!\eta Mixing Amplitude

We extend a recent calculation of the momentum dependence of the $\rho-\omega$ mixing amplitude to the pseudoscalar sector. The $\pi\!-\!\eta$ mixing amplitude is calculated in a hadronic model where the mixing is driven by the neutron-proton mass difference. Closed-form analytic expressions are presented in terms of a few nucleon-meson parameters. The observed momentum dependence of the mixing amplitude is strong enough as to question earlier calculations of charge-symmetry-breaking observables based on the on-shell assumption. The momentum dependence of the $\pi\!-\!\eta$ amplitude is, however, practically identical to the one recently predicted for $\rho-\omega$ mixing. Hence, in this model, the ratio of pseudoscalar to vector mixing amplitudes is, to a good approximation, a constant solely determined from nucleon-meson coupling constants. Furthermore, by selecting these parameters in accordance with charge-symmetry-conserving data and SU(3)-flavor symmetry, we reproduce the momentum dependence of the $\pi\!-\!\eta$ mixing amplitude predicted from chiral perturbation theory. Alternatively, one can use chiral-perturbation-theory results to set stringent limits on the value of the $NN\eta$ coupling constant.Comment: 13 pages, Latex with Revtex, 3 postscript figures (not included) available on request, SCRI-03089

Evidence for Adiabatic Magnetization of cold Dy_N Clusters

Magnetic properties of Dy_N clusters in a molecular beam generated with a liquid helium cooled nozzle are investigated by Stern-Gerlach experiments. The cluster magnetizations \mu_z are measured as a function of magnetic field (B = 0 - 1.6T) and cluster size (16 < N < 56). The most important observation is the saturation of the magnetization \mu_z(B) at large field strengths. The magnetization approaches saturation following the power law |\mu_z-\mu_0| proportional to 1/\sqrt{B}, where \mu_0 denotes the magnetic moment. This gives evidence for adiabatic magnetization.Comment: 4 pages, 3 figure

Simulations of preindustrial, present-day, and 2100 conditions in the NASA GISS composition and climate model G-PUCCINI

International audienceA model of atmospheric composition and climate has been developed at the NASA Goddard Institute for Space Studies (GISS) that includes composition seamlessly from the surface to the lower mesosphere. The model is able to capture many features of the observed magnitude, distribution, and seasonal cycle of trace species. The simulation is especially realistic in the troposphere. In the stratosphere, high latitude regions show substantial biases during period when transport governs the distribution as meridional mixing is too rapid in this model version. In other regions, including the extrapolar tropopause region that dominates radiative forcing (RF) by ozone, stratospheric gases are generally well-simulated. The model's stratosphere-troposphere exchange (STE) agrees well with values inferred from observations for both the global mean flux and the ratio of Northern (NH) to Southern Hemisphere (SH) downward fluxes. Simulations of preindustrial (PI) to present-day (PD) changes show tropospheric ozone burden increases of 11% while the stratospheric burden decreases by 18%. The resulting tropopause RF values are ?0.06 W/m2 from stratospheric ozone and 0.40 W/m2 from tropospheric ozone. Global mean mass-weighted OH decreases by 16% from the PI to the PD. STE of ozone also decreased substantially during this time, by 14%. Comparison of the PD with a simulation using 1979 pre-ozone hole conditions for the stratosphere shows a much larger downward flux of ozone into the troposphere in 1979, resulting in a substantially greater tropospheric ozone burden than that seen in the PD run. This implies that reduced STE due to stratospheric ozone depletion may have offset as much as 2/3 of the tropospheric ozone burden increase from PI to PD. However, the model overestimates the downward flux of ozone at high Southern latitudes, so this estimate is likely an upper limit. In the future, the tropospheric ozone burden increases by 101% in 2100 for the A2 scenario including both emissions and climate changes. The primary reason is enhanced STE, which increases by 124% (168% in the SH extratropics, and 114% in the NH extratropics). Climate plays a minimal role in the SH increases, but contributes 38% in the NH. Chemistry and dry deposition both change so as to reduce tropospheric ozone, partially in compensation for the enhanced STE, but the increased ozone influx dominates the burden changes. The net RF due to projected ozone changes is 0.8 W/m2 for A2. The influence of climate change alone is ?0.2 W/m2, making it a substantial contributor to the net RF. The tropospheric oxidation capacity increases seven percent in the full A2 simulation, and 36% due to A2 climate change alone

Exact Solutions for Matter-Enhanced Neutrino Oscillations

The analogy between supersymmetric quantum mechanics and matter-enhanced neutrino oscillations is exploited to obtain exact solutions for a class of electron density profiles. This integrability condition is analogous to the shape-invariance in supersymmetric quantum mechanics. This method seems to be the most direct way to obtain the exact survival probabilities for a number of density profiles of interest, such as linear and exponential density profiles. The resulting neutrino amplitudes can also be utilized as comparison amplitudes for the uniform semiclassical treatment of neutrino propagation in arbitrary electron density profiles.Comment: Submitted to Physical Review D. Latex file, 8 pages. This paper is also available at http://nucth.physics.wisc.edu/preprints