Multiple Independent Genetic Factors at NOS1AP Modulate the QT Interval in a Multi-Ethnic Population

Extremes of electrocardiographic QT interval are associated with increased risk for sudden cardiac death (SCD); thus, identification and characterization of genetic variants that modulate QT interval may elucidate the underlying etiology of SCD. Previous studies have revealed an association between a common genetic variant in NOS1AP and QT interval in populations of European ancestry, but this finding has not been extended to other ethnic populations. We sought to characterize the effects of NOS1AP genetic variants on QT interval in the multi-ethnic population-based Dallas Heart Study (DHS, n = 3,072). The SNP most strongly associated with QT interval in previous samples of European ancestry, rs16847548, was the most strongly associated in White (P = 0.005) and Black (P = 3.6×10−5) participants, with the same direction of effect in Hispanics (P = 0.17), and further showed a significant SNP × sex-interaction (P = 0.03). A second SNP, rs16856785, uncorrelated with rs16847548, was also associated with QT interval in Blacks (P = 0.01), with qualitatively similar results in Whites and Hispanics. In a previously genotyped cohort of 14,107 White individuals drawn from the combined Atherosclerotic Risk in Communities (ARIC) and Cardiovascular Health Study (CHS) cohorts, we validated both the second locus at rs16856785 (P = 7.63×10−8), as well as the sex-interaction with rs16847548 (P = 8.68×10−6). These data extend the association of genetic variants in NOS1AP with QT interval to a Black population, with similar trends, though not statistically significant at P<0.05, in Hispanics. In addition, we identify a strong sex-interaction and the presence of a second independent site within NOS1AP associated with the QT interval. These results highlight the consistent and complex role of NOS1AP genetic variants in modulating QT interval

The production and reproduction of inequality in the UK in times of austerity

Inequality appears to be back on the intellectual and political agenda. This paper provides a commentary on this renewed interest, drawing on an empirical discussion of inequality in the UK. The paper argues that inequality should be seen as produced in the inherently unequal social relations of production, drawing attention to the role of social struggle in shaping dynamics of inequality. However, inequality is not just produced in dynamic class struggle in the formal economy, but also through the social reproduction of labour power on a day-to-day and inter-generational basis. As such, inequalities of household resources at any point in time may be reproductive of greater future inequality. It is argued that inequality has risen in the UK over recent decades because of changes in the social relations of production in the formal economy and social reproduction in the domestic sector, both of which have witnessed significant state interventions that have increased structural inequalities. It is argued that, absent of significant change, the underpinning structural dynamics in the UK will lead to further increases in inequality over the short and longer-term. Given this, we might expect to see an already emergent ‘New Politics of Inequality’ intensifying in the coming decades.n/

Rifampicin reduces plasma concentration of linezolid in patients with infective endocarditis

BACKGROUND\nOBJECTIVES\nPATIENTS AND METHODS\nRESULTS\nCONCLUSIONS\nLinezolid in combination with rifampicin has been used in treatment of infective endocarditis especially for patients infected with staphylococci.\nBecause rifampicin has been reported to reduce the plasma concentration of linezolid, the present study aimed to characterize the population pharmacokinetics of linezolid for the purpose of quantifying an effect of rifampicin cotreatment. In addition, the possibility of compensation by dosage adjustments was evaluated.\nPharmacokinetic measurements were performed in 62 patients treated with linezolid for left-sided infective endocarditis in the Partial Oral Endocarditis Treatment (POET) trial. Fifteen patients were cotreated with rifampicin. A total of 437 linezolid plasma concentrations were obtained. The pharmacokinetic data were adequately described by a one-compartment model with first-order absorption and first-order elimination.\nWe demonstrated a substantial increase of linezolid clearance by 150% (95% CI: 78%-251%), when combined with rifampicin. The final model was evaluated by goodness-of-fit plots showing an acceptable fit, and a visual predictive check validated the model. Model-based dosing simulations showed that rifampicin cotreatment decreased the PTA of linezolid from 94.3% to 34.9% and from 52.7% to 3.5% for MICs of 2 mg/L and 4 mg/L, respectively.\nA substantial interaction between linezolid and rifampicin was detected in patients with infective endocarditis, and the interaction was stronger than previously reported. Model-based simulations showed that increasing the linezolid dose might compensate without increasing the risk of adverse effects to the same degree.Pharmacolog

Neoproterozoic to early Paleozoic extensional and compressional history of East Laurentian margin sequences: The Moine Supergroup, Scottish Caledonides

Neoproterozoic siliciclastic-dominated sequences are widespread along the eastern margin of Laurentia and are related to rifting associated with the breakout of Laurentia from the supercontinent Rodinia. Detrital zircons from the Moine Supergroup, NW Scotland, yield Archean to early Neoproterozoic U-Pb ages, consistent with derivation from the Grenville-Sveconorwegian orogen and environs and accumulation post–1000 Ma. U-Pb zircon ages for felsic and associated mafic intrusions confirm a widespread pulse of extension-related magmatism at around 870 Ma. Pegmatites yielding U-Pb zircon ages between 830 Ma and 745 Ma constrain a series of deformation and metamorphic pulses related to Knoydartian orogenesis of the host Moinerocks. Additional U-Pb zircon and monazite data, and 40Ar/39Ar ages for pegmatites and host gneisses indicate high-grade metamorphic events at ca. 458–446 Ma and ca. 426 Maduring the Caledonian orogenic cycle.The presence of early Neoproterozoic silici clastic sedimentation and deformation in the Moine and equivalent successions around the North Atlantic and their absence along strike in eastern North America reflect contrasting Laurentian paleogeography during the breakup of Rodinia. The North Atlantic realm occupied an external location on the margin of Laurentia, and this region acted as a locus for accumulation of detritus (Moine Supergroup and equivalents) derived from the Grenville-Sveconorwegian orogenic welt, which developed as a consequence of collisional assembly of Rodinia. Neoproterozoic orogenic activity corresponds with theinferred development of convergent platemargin activity along the periphery of the supercontinent. In contrast in eastern North America, which lay within the internal parts of Rodinia, sedimentation did not commence until the mid-Neoproterozoic (ca. 760 Ma) during initial stages of supercontinent fragmentation. In the North Atlantic region, this time frame corresponds to a second pulse of extension represented by units such as the Dalradian Supergroup, which unconformably overlies the predeformed Moine succession

Palaeomagnetism and AR-40/AR-39 age determinations of the Ediacaran traps from the southwestern margin of the East European Craton, Ukraine : relevance to the Rodinia break-up

A palaeomagnetic study and age determinations have been performed on Ediacaran basalts from the northwestern Ukraine. Whole-rock ^sup 40^Ar/^sup 39^Ar age determination revealed plateau ages at 590-560 Ma and 393 Ma, the latter probably reflecting a resetting of the radiometric system. Palaeomagnetic poles have been calculated from five basalt flows, two of which (A poles) are considered reliable with ages that range from 580 to 560 Ma. Tentative poles (B poles), calculated from most probably primary magnetizations, have ages estimated at 580-545 Ma. Secondary magnetizations, possibly of late Ediacaran or Devonian age, have also been isolated (C poles). Based on the new poles, Baltica drifted together with Laurentia from an equatorial position at c. 750 Ma to occupy high southern latitude positions at c. 580 Ma. Baltica during that time period was joined to Laurentia in a similar relative position to that at 750 Ma. The two shields then split up from each other and from c. 550 Ma Baltica drifted at moderately high latitudes and rotated some 180° during the final opening of the Iapetus ocean. This reconstruction suggests that during the Ediacaran glaciation Baltica occupied high-latitude positions, which contradicts the high-obliquity model to explain low-latitude Neoproterozoic glaciationsValiderad; 2007; 20071023 (bajo

Palaeomagnetic configuration of continents during the Proterozoic

Palaeomagnetic data are used to study the configurations of continents during the Proterozoic. Applying stringent reliability criteria, the positions of the continents at 12 times in the 2.45- to 1.00-Ga period have been constructed. The continents lie predominantly in low to intermediate latitudes. The sedimentological indicators of palaeoclimate are generally consistent with the palaeomagnetic latitudes, with the exception of the Early Proterozoic, when low latitude glaciations took place on several continents. The Proterozoic continental configurations are generally in agreement with current geological models of the evolution of the continents. The data suggest that three large continental landmasses existed during the Proterozoic. The oldest one is the Neoarchaean Kenorland, which comprised at least Laurentia, Baltica, Australia and the Kalahari craton. The protracted breakup of Kenorland during the 2.45- to 2.10-Ga interval is manifested by mafic dykes and sedimentary rift-basins on many continents. The second 'supercontinental' landmass is Hudsonland (also known as Columbia). On the basis of purely palaeomagnetic data, this supercontinent consisted of Laurentia, Baltica, Ukraine, Amazonia and Australia and perhaps also Siberia, North China and Kalahari. Hudsonland existed from 1.83 to ca. 1.50-1.25 Ga. The youngest assembly is the Neoproterozoic supercontinent of Rodinia, which was formed by continent-continent collisions during similar to 1.10-1.00 Ga and which involved most of the continents. A new model for its assembly and configuration is presented, which suggests that multiple Grenvillian age collisions took place during 1.10-1.00 Ga. The configurations of Kenorland, Hudsonland and Rodinia depart from each other and also from the Pangaea assembly. The tectonic styles of their amalgamation are also different reflecting probable changes in sizes and thicknesses of the cratonic blocks as well as changes in the thermal conditions of the mantle through time. (C) 2003 Elsevier B.V. All rights reserved