Proof of concept, randomized, placebo-controlled study of the effect of simvastatin on the course of age-related macular degeneration

BACKGROUND: HMG Co-A reductase inhibitors are ubiquitous in our community yet their potential role in age-related macular degeneration (AMD) remains to be determined. METHODOLOGY/PRINCIPAL FINDINGS: OBJECTIVES: To evaluate the effect of simvastatin on AMD progression and the effect modification by polymorphism in apolipoprotein E (ApoE) and complement factor H (CFH) genes. DESIGN: A proof of concept double-masked randomized controlled study. PARTICIPANTS: 114 participants aged 53 to 91 years, with either bilateral intermediate AMD or unilateral non-advanced AMD (with advanced AMD in fellow eye), BCVA ≥ 20/60 in at least one eye, and a normal lipid profile. INTERVENTION: Simvastatin 40 mg/day or placebo, allocated 1:1. MAIN OUTCOME MEASURES: Progression of AMD either to advanced AMD or in severity of non-advanced AMD. Results. The cumulative AMD progression rates were 70% in the placebo and 54% in the simvastatin group. Intent to treat multivariable logistic regression analysis, adjusted for age, sex, smoking and baseline AMD severity, showed a significant 2-fold decrease in the risk of progression in the simvastatin group: OR 0.43 (0.18-0.99), p = 0.047. Post-hoc analysis stratified by baseline AMD severity showed no benefit from treatment in those who had advanced AMD in the fellow eye before enrolment: OR 0.97 (0.27-3.52), p = 0.96, after adjusting for age, sex and smoking. However, there was a significant reduction in the risk of progression in the bilateral intermediate AMD group compared to placebo [adjusted OR 0.23 (0.07-0.75), p = 0.015]. The most prominent effect was observed amongst those who had the CC (Y402H) at risk genotype of the CFH gene [OR 0.08 (0.02-0.45), p = 0.004]. No evidence of harm from simvastatin intervention was detected. CONCLUSION/SIGNIFICANCE: Simvastatin may slow progression of non-advanced AMD, especially for those with the at risk CFH genotype CC (Y402H). Further exploration of the potential use of statins for AMD, with emphasis on genetic subgroups, is warranted. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry (ANZCTR) ACTRN1260500032065

Early decrements in bone density after completion of neoadjuvant chemotherapy in pediatric bone sarcoma patients

<p>Abstract</p> <p>Background</p> <p>Bone mineral density (BMD) accrual during childhood and adolescence is important for attaining peak bone mass. BMD decrements have been reported in survivors of childhood bone sarcomas. However, little is known about the onset and development of bone loss during cancer treatment. The objective of this cross-sectional study was to evaluate BMD in newly diagnosed Ewing's and osteosarcoma patients by means of dual-energy x-ray absorptiometry (DXA) after completion of neoadjuvant chemotherapy.</p> <p>Methods</p> <p>DXA measurements of the lumbar spine (L2-4), both femora and calcanei were performed perioperatively in 46 children and adolescents (mean age: 14.3 years, range: 8.6-21.5 years). Mean <it>Z</it>-scores, areal BMD (g/cm²), calculated volumetric BMD (g/cm³) and bone mineral content (BMC, g) were determined.</p> <p>Results</p> <p>Lumbar spine mean Z-score was -0.14 (95% CI: -0.46 to 0.18), areal BMD was 1.016 g/cm²(95% CI: 0.950 to 1.082) and volumetric BMD was 0.330 g/cm³(95% CI: 0.314 to 0.347) which is comparable to healthy peers. For patients with a lower extremity tumor (n = 36), the difference between the affected and non-affected femoral neck was 12.1% (95% CI: -16.3 to -7.9) in areal BMD. The reduction of BMD was more pronounced in the calcaneus with a difference between the affected and contralateral side of 21.7% (95% CI: -29.3 to -14.0) for areal BMD. Furthermore, significant correlations for femoral and calcaneal DXA measurements were found with Spearman-rho coefficients ranging from ρ = 0.55 to ρ = 0.80.</p> <p>Conclusions</p> <p>The tumor disease located in the lower extremity in combination with offloading recommendations induced diminished BMD values, indicating local osteopenia conditions. However, the results revealed no significant decrements of lumbar spine BMD in pediatric sarcoma patients after completion of neoadjuvant chemotherapy. Nevertheless, it has to be taken into account that bone tumor patients may experience BMD decrements or secondary osteoporosis in later life. Furthermore, the peripheral assessment of BMD in the calcaneus via DXA is a feasible approach to quantify bone loss in the lower extremity in bone sarcoma patients and may serve as an alternative procedure, when the established assessment of femoral BMD is not practicable due to endoprosthetic replacements.</p

Heritability and Artificial Selection on Ambulatory Dispersal Distance in Tetranychus urticae: Effects of Density and Maternal Effects

Dispersal distance is understudied although the evolution of dispersal distance affects the distribution of genetic diversity through space. Using the two-spotted spider mite, Tetranychus urticae, we tested the conditions under which dispersal distance could evolve. To this aim, we performed artificial selection based on dispersal distance by choosing 40 individuals (out of 150) that settled furthest from the home patch (high dispersal, HDIS) and 40 individuals that remained close to the home patch (low dispersal, LDIS) with three replicates per treatment. We did not observe a response to selection nor a difference between treatments in life-history traits (fecundity, survival, longevity, and sex-ratio) after ten generations of selection. However, we show that heritability for dispersal distance depends on density. Heritability for dispersal distance was low and non-significant when using the same density as the artificial selection experiments while heritability becomes significant at a lower density. Furthermore, we show that maternal effects may have influenced the dispersal behaviour of the mites. Our results suggest primarily that selection did not work because high density and maternal effects induced phenotypic plasticity for dispersal distance. Density and maternal effects may affect the evolution of dispersal distance and should be incorporated into future theoretical and empirical studies

Connectivity of larval stages of sedentary marine communities between hard substrates and offshore structures in the North Sea

Man-made structures including rigs, pipelines, cables, renewable energy devices, and ship wrecks, offer hard substrate in the largely soft-sediment environment of the North Sea. These structures become colonised by sedentary organisms and non-migratory reef fish, and form local ecosystems that attract larger predators including seals, birds, and fish. It is possible that these structures form a system of interconnected reef environments through the planktonic dispersal of the pelagic stages of organisms by ocean currents. Changes to the overall arrangement of hard substrate areas through removal or addition of individual man-made structures will affect the interconnectivity and could impact on the ecosystem. Here, we assessed the connectivity of sectors with oil and gas structures, wind farms, wrecks, and natural hard substrate, using a model that simulates the drift of planktonic stages of seven organisms with sedentary adult stages associated with hard substrate, applied to the period 2001–2010. Connectivity was assessed using a classification system designed to address the function of sectors in the network. Results showed a relatively stable overall spatial distribution of sector function but with distinct variations between species and years. The results are discussed in the context of decommissioning of oil and gas infrastructure in the North Sea

Improved imputation accuracy of rare and low-frequency variants using population-specific high-coverage WGS-based imputation reference panel

Genetic imputation is a cost-efficient way to improve the power and resolution of genome-wide association (GWA) studies. Current publicly accessible imputation reference panels accurately predict genotypes for common variants with minor allele frequency (MAF) >= 5% and low-frequency variants (0.5Peer reviewe

Regularity Properties and Pathologies of Position-Space Renormalization-Group Transformations

We reconsider the conceptual foundations of the renormalization-group (RG) formalism, and prove some rigorous theorems on the regularity properties and possible pathologies of the RG map. Regarding regularity, we show that the RG map, defined on a suitable space of interactions (= formal Hamiltonians), is always single-valued and Lipschitz continuous on its domain of definition. This rules out a recently proposed scenario for the RG description of first-order phase transitions. On the pathological side, we make rigorous some arguments of Griffiths, Pearce and Israel, and prove in several cases that the renormalized measure is not a Gibbs measure for any reasonable interaction. This means that the RG map is ill-defined, and that the conventional RG description of first-order phase transitions is not universally valid. For decimation or Kadanoff transformations applied to the Ising model in dimension $d \ge 3$, these pathologies occur in a full neighborhood $\{ \beta > \beta_0 ,\, |h| < \epsilon(\beta) \}$ of the low-temperature part of the first-order phase-transition surface. For block-averaging transformations applied to the Ising model in dimension $d \ge 2$, the pathologies occur at low temperatures for arbitrary magnetic-field strength. Pathologies may also occur in the critical region for Ising models in dimension $d \ge 4$. We discuss in detail the distinction between Gibbsian and non-Gibbsian measures, and give a rather complete catalogue of the known examples. Finally, we discuss the heuristic and numerical evidence on RG pathologies in the light of our rigorous theorems.Comment: 273 pages including 14 figures, Postscript, See also ftp.scri.fsu.edu:hep-lat/papers/9210/9210032.ps.