People of the British Isles: preliminary analysis of genotypes and surnames in a UK control population

There is a great deal of interest in fine scale population structure in the UK, both as a signature of historical immigration events and because of the effect population structure may have on disease association studies. Although population structure appears to have a minor impact on the current generation of genome-wide association studies, it is likely to play a significant part in the next generation of studies designed to search for rare variants. A powerful way of detecting such structure is to control and document carefully the provenance of the samples involved. Here we describe the collection of a cohort of rural UK samples (The People of the British Isles), aimed at providing a well-characterised UK control population that can be used as a resource by the research community as well as providing fine scale genetic information on the British population. So far, some 4,000 samples have been collected, the majority of which fit the criteria of coming from a rural area and having all four grandparents from approximately the same area. Analysis of the first 3,865 samples that have been geocoded indicates that 75% have a mean distance between grandparental places of birth of 37.3km, and that about 70% of grandparental places of birth can be classed as rural. Preliminary genotyping of 1,057 samples demonstrates the value of these samples for investigating fine scale population structure within the UK, and shows how this can be enhanced by the use of surnames

Problem formulation by medical students: an observation study

<p>Abstract</p> <p>Background</p> <p>Medical problems are often complex and ill-structured. In formulating the problem, one has to discriminate pertinent elements from irrelevant information in order to effectively find a solution. In this observation study, we describe how medical students formulate the problem of a complex case.</p> <p>Methods</p> <p>32 third year medical students were presented with a complex case of endocarditis. They were asked to synthesize the case and give the best formulation of the problem. They were then asked to provide a diagnosis. A subsequent group of 25 students were presented with the problem already formulated and were also asked for the diagnosis. We analyzed the student's problem formulations using the presence or absence of essential elements of the case, the use of higher-order concepts and the use of relations between concepts.</p> <p>Results</p> <p>12/32 students presented with the case made the correct diagnosis. Diagnostic accuracy was significantly associated with the use of higher-order concepts and relations between concepts. Establishing explicit relations was particularly important. Almost all students who missed the diagnosis could not elicit any relations between concepts but only reported factual observations. When presented with an already formulated problem, 19/25 students made the correct diagnosis. (p < 0.05)</p> <p>Conclusion</p> <p>When faced with a complex new case, students may not have the structured knowledge to recognize the nature of the problem. They have to build new schema or problem representation. Our observations suggest that this process involves using higher-order concepts and establishing new relations between concepts. The fact that students could recognize the disease when presented with a formulated problem but had more difficulty when presented with the original complex case indicates that knowledge of the clinical features may be necessary but not sufficient for problem formulation. Our hypothesis is that problem formulation represents a distinct ability.</p

Is the onset of disabling chronic conditions in later childhood associated with exposure to social disadvantage in earlier childhood? a prospective cohort study using the ONS Longitudinal Study for England and Wales

Background: The aetiology of disabling chronic conditions in childhood in high income countries is not fully understood, particularly the association with socio-economic status (SES). Very few studies have used longitudinal datasets to examine whether exposure to social disadvantage in early childhood increases the risk of developing chronic conditions in later childhood. Here we examine this association, and its temporal ordering, with onset of all-cause disabling chronic later childhood in children reported as free from disability in early childhood. Methods: The study comprised a prospective cohort study, using data from the Office for National Statistics Longitudinal Study (ONSLS) for England and Wales. The study sample included 52,839 children with complete data born between 1981–1991 with no disabling chronic condition/s in 1991. Index cases were children with disability recorded in 2001. Comparison cases were children with no recorded disability in 1991. A socio-economic disadvantage index (SDI) was constructed from data on social class, housing tenure and car/van access. Associations were explored with logistic regression modelling controlling sequentially for potentially confounding factors; age, gender, ethnicity and lone parenthood. Results: By 2001, 2049 (4%) had at least one disability. Socio-economic disadvantage, age, gender and lone parenthood but not ethnicity were significantly associated with onset of disabling chronic conditions. The SDI showed a finely graded association with onset of disabling chronic conditions in the index group (most disadvantaged OR 2·11 [CI 1·76 to 2·53]; disadvantaged in two domains OR 1·45 [CI 1·20 to 1·75]; disadvantaged in one domain OR 1·14 [CI 0·93 to 1·39] that was unaffected by age, gender and ethnicity and slightly attenuated by lone parenthood. Conclusion: To our knowledge, this is the first study to identify socio-economic disadvantage in earlier childhood as a predisposing factor for onset of all-cause disabling chronic conditions in later childhood. Temporal ordering and gradation of the response indicate socio-economic disadvantage may play a causal role. This suggests that targeting preventative efforts to reduce socio-economic disadvantage in early childhood is likely to be an important public health strategy to decease health inequalities in later childhood and early adulthood

Radio emission from Supernova Remnants

The explosion of a supernova releases almost instantaneously about 10^51 ergs of mechanic energy, changing irreversibly the physical and chemical properties of large regions in the galaxies. The stellar ejecta, the nebula resulting from the powerful shock waves, and sometimes a compact stellar remnant, constitute a supernova remnant (SNR). They can radiate their energy across the whole electromagnetic spectrum, but the great majority are radio sources. Almost 70 years after the first detection of radio emission coming from a SNR, great progress has been achieved in the comprehension of their physical characteristics and evolution. We review the present knowledge of different aspects of radio remnants, focusing on sources of the Milky Way and the Magellanic Clouds, where the SNRs can be spatially resolved. We present a brief overview of theoretical background, analyze morphology and polarization properties, and review and critical discuss different methods applied to determine the radio spectrum and distances. The consequences of the interaction between the SNR shocks and the surrounding medium are examined, including the question of whether SNRs can trigger the formation of new stars. Cases of multispectral comparison are presented. A section is devoted to reviewing recent results of radio SNRs in the Magellanic Clouds, with particular emphasis on the radio properties of SN 1987A, an ideal laboratory to investigate dynamical evolution of an SNR in near real time. The review concludes with a summary of issues on radio SNRs that deserve further study, and analyzing the prospects for future research with the latest generation radio telescopes.Comment: Revised version. 48 pages, 15 figure

Genetic variants in the KIF6 region and coronary event reduction from statin therapy

A single nucleotide polymorphism (SNP) in KIF6, a member of the KIF9 family of kinesins, is associated with differential coronary event reduction from statin therapy in four randomized controlled trials; this SNP (rs20455) is also associated with the risk for coronary heart disease (CHD) in multiple prospective studies. We investigated whether other common SNPs in the KIF6 region were associated with event reduction from statin therapy. Of the 170 SNPs in the KIF6 region investigated in the Cholesterol and Recurrent Events trial (CARE), 28 were associated with differential event reduction from statin therapy (Pinteraction < 0.1 in Caucasians, adjusted for age and sex) and were further investigated in the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI22) and West of Scotland Coronary Prevention Study (WOSCOPS). These analyses revealed that two SNPs (rs9462535 and rs9471077), in addition to rs20455, were associated with event reduction from statin therapy (Pinteraction < 0.1 in each of the three studies). The relative risk reduction ranged from 37 to 50% (P < 0.01) in carriers of the minor alleles of these SNPs and from −4 to 13% (P > 0.4) in non-carriers. These three SNPs are in high linkage disequilibrium with one another (r2 > 0.84). Functional studies of these variants may help to understand the role of KIF6 in the pathogenesis of CHD and differential response to statin therapy

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Wnt signaling and orthopedics, an overview

Wnt signaling is a ubiquitous system for intercellular communication, with multiple functions during development and in homeostasis of the body. It comprises several ligands, receptors, and inhibitors. Some molecules, such as sclerostin, appear to have bone-specific functions, and can be targeted by potential drugs. Now, ongoing clinical trials are testing these drugs as treatments for osteoporosis. Animal studies have also suggested that these drugs can accelerate fracture healing and implant fixation. This brief overview focuses on currently available information on the effects of manipulations of Wnt signaling on bone healing

Novel method for combined linkage and genome-wide association analysis finds evidence of distinct genetic architecture for two subtypes of autism

The Autism Genome Project has assembled two large datasets originally designed for linkage analysis and genome-wide association analysis, respectively: 1,069 multiplex families genotyped on the Affymetrix 10 K platform, and 1,129 autism trios genotyped on the Illumina 1 M platform. We set out to exploit this unique pair of resources by analyzing the combined data with a novel statistical method, based on the PPL statistical framework, simultaneously searching for linkage and association to loci involved in autism spectrum disorders (ASD). Our analysis also allowed for potential differences in genetic architecture for ASD in the presence or absence of lower IQ, an important clinical indicator of ASD subtypes. We found strong evidence of multiple linked loci; however, association evidence implicating specific genes was low even under the linkage peaks. Distinct loci were found in the lower IQ families, and these families showed stronger and more numerous linkage peaks, while the normal IQ group yielded the strongest association evidence. It appears that presence/absence of lower IQ (LIQ) demarcates more genetically homogeneous subgroups of ASD patients, with not just different sets of loci acting in the two groups, but possibly distinct genetic architecture between them, such that the LIQ group involves more major gene effects (amenable to linkage mapping), while the normal IQ group potentially involves more common alleles with lower penetrances. The possibility of distinct genetic architecture across subtypes of ASD has implications for further research and perhaps for research approaches to other complex disorders as well

The Formation and Stabilization of a Novel G-Quadruplex in the 5′-Flanking Region of the Relaxin Gene

It has been reported that binding of STAT3 protein to the 5′-flanking region of the relaxin gene may result in downregulation of the relaxin expression. There is a Guanine(G)-rich segment located in about 3.8 Kb upstream of the relaxin gene and very close to the STAT3's binding site. In our study, NMR spectroscopy revealed the formation of G-quadruplex by this G-rich strand, and the result was confirmed by ESI mass spectrometry and CD spectroscopy. The theoretical structure of RLX G-quadruplex was constructed and refined by molecular modeling. When this relaxin G-quadruplex was stabilized by berberine(ΔTm = 10°C), a natural alkaloid from a Chinese herb, the gene expression could be up-regulated in a dose-dependent manner which was proved by luciferase assay. This result is different from the general G-quadruplex function that inhibiting the telomere replication or down-regulating many oncogenes expression. Therefore, our study reported a novel G-quadruplex in the relaxin gene and complemented the regulation mechanism about gene expression by G-quadruplexes