Molecular diagnosis of multiple endocrine neoplasia type 2A

Objective. To identify by means of genetic analyses individuals who are at risk of developing medullary thyroid cancer that is a component of multiple endocrine neoplasia.Subjects. A three-generation kindred with clinically and biochemically diagnosed medUllary thyroid cancer.Method. Identification of a heterozygote mutation by nucleic acid sequencing and restriction analyses.Results. A heterozygote T → C (Cys → Arg) mutation at codon 618 in exon 10 of the RET proto-oncogene was identified in 4 family members who had previously been diagnosed with medullary thyroid cancer. The same mutation was also found in one of the proband's presymptomatic children who subsequently underwent a preemptive thyroidectomy. The genetic diagnosis was confirmed by histology. No mutations were detected in any other family members.Conclusion. Identification of heterozygote germline mutations in multiple endocrine neoplasia is direct, highly accurate and cost-effective. This study demonstrates that, appropriately used, molecular diagnosis can supersede conventional biochemical methods in the management of patients with inherited cancers

Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy

<p>Background: Statin therapy reduces the risk of occlusive vascular events, but uncertainty remains about potential effects on cancer. We sought to provide a detailed assessment of any effects on cancer of lowering LDL cholesterol (LDL-C) with a statin using individual patient records from 175,000 patients in 27 large-scale statin trials.</p> <p>Methods and Findings: Individual records of 134,537 participants in 22 randomised trials of statin versus control (median duration 4.8 years) and 39,612 participants in 5 trials of more intensive versus less intensive statin therapy (median duration 5.1 years) were obtained. Reducing LDL-C with a statin for about 5 years had no effect on newly diagnosed cancer or on death from such cancers in either the trials of statin versus control (cancer incidence: 3755 [1.4% per year [py]] versus 3738 [1.4% py], RR 1.00 [95% CI 0.96-1.05]; cancer mortality: 1365 [0.5% py] versus 1358 [0.5% py], RR 1.00 [95% CI 0.93–1.08]) or in the trials of more versus less statin (cancer incidence: 1466 [1.6% py] vs 1472 [1.6% py], RR 1.00 [95% CI 0.93–1.07]; cancer mortality: 447 [0.5% py] versus 481 [0.5% py], RR 0.93 [95% CI 0.82–1.06]). Moreover, there was no evidence of any effect of reducing LDL-C with statin therapy on cancer incidence or mortality at any of 23 individual categories of sites, with increasing years of treatment, for any individual statin, or in any given subgroup. In particular, among individuals with low baseline LDL-C (<2 mmol/L), there was no evidence that further LDL-C reduction (from about 1.7 to 1.3 mmol/L) increased cancer risk (381 [1.6% py] versus 408 [1.7% py]; RR 0.92 [99% CI 0.76–1.10]).</p> <p>Conclusions: In 27 randomised trials, a median of five years of statin therapy had no effect on the incidence of, or mortality from, any type of cancer (or the aggregate of all cancer).</p&gt

Primary care and health inequality : Difference-in-difference study comparing England and Ontario

BACKGROUND: It is not known whether equity-oriented primary care investment that seeks to scale up the delivery of effective care in disadvantaged communities can reduce health inequality within high-income settings that have pre-existing universal primary care systems. We provide some non-randomised controlled evidence by comparing health inequality trends between two similar jurisdictions-one of which implemented equity-oriented primary care investment in the mid-to-late 2000s as part of a cross-government strategy for reducing health inequality (England), and one which invested in primary care without any explicit equity objective (Ontario, Canada). METHODS: We analysed whole-population data on 32,482 neighbourhoods (with mean population size of approximately 1,500 people) in England, and 18,961 neighbourhoods (with mean population size of approximately 700 people) in Ontario. We examined trends in mortality amenable to healthcare by decile groups of neighbourhood deprivation within each jurisdiction. We used linear models to estimate absolute and relative gaps in amenable mortality between most and least deprived groups, considering the gradient between these extremes, and evaluated difference-in-difference comparisons between the two jurisdictions. RESULTS: Inequality trends were comparable in both jurisdictions from 2004-6 but diverged from 2007-11. Compared with Ontario, the absolute gap in amenable mortality in England fell between 2004-6 and 2007-11 by 19.8 per 100,000 population (95% CI: 4.8 to 34.9); and the relative gap in amenable mortality fell by 10 percentage points (95% CI: 1 to 19). The biggest divergence occurred in the most deprived decile group of neighbourhoods. DISCUSSION: In comparison to Ontario, England succeeded in reducing absolute socioeconomic gaps in mortality amenable to healthcare from 2007 to 2011, and preventing them from growing in relative terms. Equity-oriented primary care reform in England in the mid-to-late 2000s may have helped to reduce socioeconomic inequality in health, though other explanations for this divergence are possible and further research is needed on the specific causal mechanisms

Mitochondrial Dysfunction Increases Oxidative Stress and Decreases Chronological Life Span in Fission Yeast

Background: Oxidative stress is a probable cause of aging and associated diseases. Reactive oxygen species (ROS) originate mainly from endogenous sources, namely the mitochondria. Methodology/Principal Findings: We analyzed the effect of aerobic metabolism on oxidative damage in Schizosaccharomyces pombe by global mapping of those genes that are required for growth on both respiratory-proficient media and hydrogen-peroxide-containing fermentable media. Out of a collection of approximately 2700 haploid yeast deletion mutants, 51 were sensitive to both conditions and 19 of these were related to mitochondrial function. Twelve deletion mutants lacked components of the electron transport chain. The growth defects of these mutants can be alleviated by the addition of antioxidants, which points to intrinsic oxidative stress as the origin of the phenotypes observed. These respiration-deficient mutants display elevated steady-state levels of ROS, probably due to enhanced electron leakage from their defective transport chains, which compromises the viability of chronologically-aged cells. Conclusion/Significance: Individual mitochondrial dysfunctions have often been described as the cause of diseases or aging, and our global characterization emphasizes the primacy of oxidative stress in the etiology of such processes.This work was supported by Dirección General de Investigación of Spain Grant BFU2006-02610, and by the Spanish program Consolider-Ingenio 2010 Grant CSD 2007-0020 to E.H

Fault-controlled hydration of the upper mantle during continental rifting

Water and carbon are transferred from the ocean to the mantle in a process that alters mantle peridotite to create serpentinite and supports diverse ecosystems1. Serpentinized mantle rocks are found beneath the sea floor at slow- to ultraslow-spreading mid-ocean ridges1 and are thought to be present at about half the world’s rifted margins2, 3. Serpentinite is also inferred to exist in the downgoing plate at subduction zones4, where it may trigger arc magmatism or hydrate the deep Earth. Water is thought to reach the mantle via active faults3, 4. Here we show that serpentinization at the rifted continental margin offshore from western Spain was probably initiated when the whole crust cooled to become brittle and deformation was focused along large normal faults. We use seismic tomography to image the three-dimensional distribution of serpentinization in the mantle and find that the local volume of serpentinite beneath thinned, brittle crust is related to the amount of displacement along each fault. This implies that sea water reaches the mantle only when the faults are active. We estimate the fluid flux along the faults and find it is comparable to that inferred for mid-ocean ridge hydrothermal systems. We conclude that brittle processes in the crust may ultimately control the global flux of sea water into the Earth

The evolution of the terrestrial-terminating Irish Sea glacier during the last glaciation

Here we reconstruct the last advance to maximum limits and retreat of the Irish Sea Glacier (ISG), the only land‐terminating ice lobe of the western British Irish Ice Sheet. A series of reverse bedrock slopes rendered proglacial lakes endemic, forming time‐transgressive moraine‐ and bedrock‐dammed basins that evolved with ice marginal retreat. Combining, for the first time on glacial sediments, optically stimulated luminescence (OSL) bleaching profiles for cobbles with single grain and small aliquot OSL measurements on sands, has produced a coherent chronology from these heterogeneously bleached samples. This chronology constrains what is globally an early build‐up of ice during late Marine Isotope Stage 3 and Greenland Stadial (GS) 5, with ice margins reaching south Lancashire by 30 ± 1.2 ka, followed by a 120‐km advance at 28.3 ± 1.4 ka reaching its 26.5 ± 1.1 ka maximum extent during GS‐3. Early retreat during GS‐3 reflects piracy of ice sources shared with the Irish‐Sea Ice Stream (ISIS), starving the ISG. With ISG retreat, an opportunistic readvance of Welsh ice during GS‐2 rode over the ISG moraines occupying the space vacated, with ice margins oscillating within a substantial glacial over‐deepening. Our geomorphological chronosequence shows a glacial system forced by climate but mediated by piracy of ice sources shared with the ISIS, changing flow regimes and fronting environments

The deuteron: structure and form factors

A brief review of the history of the discovery of the deuteron in provided. The current status of both experiment and theory for the elastic electron scattering is then presented.Comment: 80 pages, 33 figures, submited to Advances in Nuclear Physic

Shotgun Proteomics Identifies Serum Fibronectin as a Candidate Diagnostic Biomarker for Inclusion in Future Multiplex Tests for Ectopic Pregnancy

Ectopic pregnancy (EP) is difficult to diagnose early and accurately. Women often present at emergency departments in early pregnancy with a 'pregnancy of unknown location' (PUL), and diagnosis and exclusion of EP is challenging due to a lack of reliable biomarkers. The objective of this study was to identify novel diagnostic biomarkers for EP. Shotgun proteomics, incorporating combinatorial-ligand library pre-fractionation, was used to interrogate pooled sera (n = 40) from women undergoing surgery for EP, termination of viable intrauterine pregnancy and management of non-viable intrauterine pregnancy. Western blot was used to validate results in individual sera. ELISAs were developed to interrogate sera from women with PUL (n = 120). Sera were collected at time of first symptomatic presentation and categorized according to pregnancy outcome. The main outcome measures were differences between groups and area under the receiver operating curve (ROC). Proteomics identified six biomarker candidates. Western blot detected significant differences in levels of two of these candidates. ELISA of sera from second cohort revealed that these differences were only significant for one of these candidates, fibronectin. ROC analysis of ability of fibronectin to discriminate EP from other pregnancy outcomes suggested that fibronectin has diagnostic potential (ROC 0.6439; 95% CI 0.5090 to 0.7788; P>0.05), becoming significant when 'ambiguous' medically managed PUL excluded from analysis (ROC 0.6538; 95% CI 0.5158 to 0.7918; P<0.05). Fibronectin may make a useful adjunct to future multiplex EP diagnostic tests

CsA can induce DNA double-strand breaks: implications for BMT regimens particularly for individuals with defective DNA repair

Several human disorders mutated in core components of the major DNA double-strand break (DSB) repair pathway, non-homologous end joining (NHEJ), have been described. Cell lines from these patients are characterized by sensitivity to DSB-inducing agents. DNA ligase IV syndrome (LIG4) patients specifically, for unknown reasons, respond particularly badly following treatment for malignancy or BMT. We report the first systematic evaluation of the response of LIG4 syndrome to compounds routinely employed for BMT conditioning. We found human pre-B lymphocytes, a key target population for BMT conditioning, when deficient for DNA ligase IV, unexpectedly exhibit significant sensitivity to CsA the principal prophylaxis for GVHD. Furthermore, we found that CsA treatment alone or in combination with BU and fludarabine resulted in increased levels of DSBs specifically in LIG4 syndrome cells compared to wild-type or Artemis-deficient cells. Our study shows that CsA can induce DSBs and that LIG4 syndrome patient's fail to adequately repair this damage. These DSBs likely arise as a consequence of DNA replication in the presence of CsA. This work has implications for BMT and GVHD management in general and specifically for LIG4 syndrome