Lifelongα-tocopherol supplementation increases the median life span of C57BL/6 mice in the cold but has only minor effects on oxidative damage

The effects of dietary antioxidant supplementation on oxidative stress and life span are confused. We maintained C57BL/6 mice at 7 ± 2°C and supplemented their diet with α-tocopherol from 4 months of age. Supplementation significantly increased (p = 0.042) median life span by 15% (785 days, n = 44) relative to unsupplemented controls (682 days, n = 43) and also increased maximum life span (oldest 10%, p = 0.028). No sex or sex by treatment interaction effects were observed on life span, with treatment having no effect on resting or daily metabolic rate. Lymphocyte and hepatocyte oxidative DNA damage and hepatic lipid peroxidation were unaffected by supplementation, but hepatic oxidative DNA damage increased with age. Using a cDNA macroarray, genes associated with xenobiotic metabolism were significantly upregulated in the livers of female mice at 6 months of age (2 months supplementation). At 22 months of age (18 months supplementation) this response had largely abated, but various genes linked to the p21 signaling pathway were upregulated at this time. We suggest that α-tocopherol may initially be metabolized as a xenobiotic, potentially explaining why previous studies observe a life span extension generally when lifelong supplementation is initiated early in life. The absence of any significant effect on oxidative damage suggests that the life span extension observed was not mediated via any antioxidant properties of α-tocopherol. We propose that the life span extension observed following α-tocopherol supplementation may be mediated via upregulation of cytochrome p450 genes after 2 months of supplementation and/or upregulation of p21 signaling genes after 18 months of supplementation. However, these signaling pathways now require further investigation to establish their exact role in life span extension following α-tocopherol supplementation

Cost effectiveness of recombinant factor VIIa for treatment of intracerebral hemorrhage

<p>Abstract</p> <p>Background</p> <p>Phase I/II placebo-controlled clinical trials of recombinant Factor VIIa (rFVIIa) suggested that administration of rFVIIa within 4 hours after onset of intracerebral hemorrhage (ICH) is safe, limits ICH growth, and improves outcomes. We sought to determine the cost-effectiveness of rFVIIa for acute ICH treatment, using published Phase II data. We hypothesized that rFVIIa would have a low marginal cost-effectiveness ratio (mCER) given the poor neurologic outcomes after ICH with conventional management.</p> <p>Methods</p> <p>We performed an incremental cost-effectiveness analysis from the societal perspective, considering conventional management vs. 80 ug/kg rFVIIa treatment for acute ICH cases meeting Phase II inclusion criteria. The time frame for the analysis was 1. 25 years: data from the Phase II trial was used for 90 day outcomes and rFVIIa complications – arterial thromboembolic events (ATE). We assumed no substantial cost differences in care between the two strategies except: 1) cost of rFVIIa (for an 80 mcg/kg dose in an 80 kg patient, assumed cost of $6,408); 2) cost of ATE side effects from rFVIIa (which also decrease quality of life and increase the chance of death); and 3) differential monetary costs of outcomes and their impact on quality of life, including disposition (home vs. nursing home), and outpatient vs. inpatient rehabilitation. Sensitivity analyses were performed to explore uncertainty in parameter estimates, impact of rFVIIa cost, direct cost of neurologic outcomes, probability of ATE, and outcomes after ATE.</p> <p>Results</p> <p>In the "base case", treating ICH with rFVIIa dominates the usual care strategy by being more effective and less costly. rFVIIa maintained a mCER <$50,000/QALY over a wide range of sensitivity analyses. Sensitivity analyses showed that the cost of rFVIIa must exceed $14,500, or the frequency of ATE exceed 29$50,000/QALY. Varying the cost and/or reducing the utility of health states following ATE did not impact results.</p> <p>Conclusion</p> <p>Based on data from preliminary trials, treating selected ICH patients with rFVIIa results in lower cost and improved clinical outcomes. This potential cost-effectiveness must be considered in light of the Phase III trial results.</p

Preoperative transcatheter closure of congenital muscular ventricular septal defects.

BackgroundSurgical repair of muscular ventricular septal defects, particularly those associated with complex heart lesions carries a higher risk of reoperation and death than the repair of membranous defects. Closing a muscular defect through an incision in the systemic ventricle may cause late ventricular dysfunction. In a collaborative approach to this problem, we undertook preoperative transcatheter closure of muscular ventricular septal defects remote from the atrioventricular and semilunar valves, followed by the surgical repair of associated conditions.MethodsIn 12 patients selected jointly by a cardiologist and a cardiac surgeon, we attempted preoperative transcatheter umbrella closure of 21 defects. Half the patients had associated complex heart lesions; the others had had pulmonary-artery banding to reduce the amount of left-to-right shunting. Half had severe ventricular septal deficiency.ResultsAll 21 defects were successfully closed without major complications. Subsequent cardiac surgery for associated conditions in 11 of the 12 patients resulted in a mean pulmonary-to-systemic flow ratio of 1.1, indicating minimal residual left-to-right shunting; 1 patient awaited surgical repair. No deaths, reoperations, or late complications have occurred after a follow-up of 7 to 20 months.ConclusionsA collaborative approach using transcatheter closure followed by the surgical repair of associated cardiac lesions may decrease rates of operative mortality, reoperation, and left ventricular dysfunction in patients with muscular ventricular septal defects

Nernst branes from special geometry

We construct new black brane solutions in $U(1)$ gauged ${\cal N}=2$ supergravity with a general cubic prepotential, which have entropy density $s\sim T^{1/3}$ as $T \rightarrow 0$ and thus satisfy the Nernst Law. By using the real formulation of special geometry, we are able to obtain analytical solutions in closed form as functions of two parameters, the temperature $T$ and the chemical potential $\mu$. Our solutions interpolate between hyperscaling violating Lifshitz geometries with $(z,\theta)=(0,2)$ at the horizon and $(z,\theta)=(1,-1)$ at infinity. In the zero temperature limit, where the entropy density goes to zero, we recover the extremal Nernst branes of Barisch et al, and the parameters of the near horizon geometry change to $(z,\theta)=(3,1)$.Comment: 37 pages. v2: numerical pre-factors of scalar fields q_A corrected in Section 3. No changes to conclusions. References adde

Mobile phones in the diffusion of knowledge and persistence in inclusive human development in Sub-Saharan Africa

The success of inclusive development strategies in the post-2015 sustainable development agenda depends substantially on the adoption of common inclusive development policies among nations. Building on the relevance of a knowledge economy in the post-2015 development agenda, this study models the feasibility of common policies for inclusive human development in Sub-Saharan Africa (SSA). More specifically, we investigate the complementary role of knowledge diffusion in the inclusive benefits of mobile phone penetration in SSA from 2000 to 2012 by employing the Generalised Method of Moments. Knowledge diffusion variables include educational quality, innovation and Internet penetration. The main finding is that inclusive human development is persistently conditional on mobile phones in knowledge diffusion. Moreover, countries with low levels of inclusive human development are catching-up their counterparts with higher development. Policy implications are discussed with particular emphasis on how to leverage common knowledge economy initiatives for inclusive developmen

Rapid planetesimal formation in turbulent circumstellar discs

The initial stages of planet formation in circumstellar gas discs proceed via dust grains that collide and build up larger and larger bodies (Safronov 1969). How this process continues from metre-sized boulders to kilometre-scale planetesimals is a major unsolved problem (Dominik et al. 2007): boulders stick together poorly (Benz 2000), and spiral into the protostar in a few hundred orbits due to a head wind from the slower rotating gas (Weidenschilling 1977). Gravitational collapse of the solid component has been suggested to overcome this barrier (Safronov 1969, Goldreich & Ward 1973, Youdin & Shu 2002). Even low levels of turbulence, however, inhibit sedimentation of solids to a sufficiently dense midplane layer (Weidenschilling & Cuzzi 1993, Dominik et al. 2007), but turbulence must be present to explain observed gas accretion in protostellar discs (Hartmann 1998). Here we report the discovery of efficient gravitational collapse of boulders in locally overdense regions in the midplane. The boulders concentrate initially in transient high pressures in the turbulent gas (Johansen, Klahr, & Henning 2006), and these concentrations are augmented a further order of magnitude by a streaming instability (Youdin & Goodman 2005, Johansen, Henning, & Klahr 2006, Johansen & Youdin 2007) driven by the relative flow of gas and solids. We find that gravitationally bound clusters form with masses comparable to dwarf planets and containing a distribution of boulder sizes. Gravitational collapse happens much faster than radial drift, offering a possible path to planetesimal formation in accreting circumstellar discs.Comment: To appear in Nature (30 August 2007 issue). 18 pages (in referee mode), 3 figures. Supplementary Information can be found at 0708.389