Lower Limb Metaphyseal Bone Is Lost in Men with Coeliac Disease and Does Not Relate to Parathyroid Status

Aims. To investigate regional lower limb bone density and associations with weight, PTH, and bone breakdown in coeliac men. Methods. From whole body DXA scans bone mineral density (BMD) was measured in 28 coeliac men, in the lower limb (subdivided into 6 regions, 3 being metaphyseal (mainly trabecular) and 2 diaphyseal (mainly cortical)). BMD at femoral neck (FN) and lumbar spine L2–4, body weight, height, serum calcium, alkaline phosphatase, parathyroid hormone (PTH), and urinary calcium and NTx/Cr, a measure of bone breakdown, were also measured. Age matched healthy men provided values for BMD calculation of z and T scores and for biochemical measurements. Results. Low BMD z scores were found at metaphyseal regions in the leg (p<0.001) and in the FN (p<0.05). The distal metaphyseal region BMD in the leg was lower than spine or FN (p<0.05). PTH, urinary calcium/creatinine, and urinary NTx/Cr were similar to controls. Both metaphyseal and diaphyseal BMD z scores were associated with body weight (p<0.02), but not with either PTH or urinary NTx/Cr. Conclusions. Low BMD lower limb regions comprising mostly trabecular bone occur early in CD and in the absence of elevated PTH or increased bone resorption. Low BMD is associated with low body weight

Views of junior doctors about whether their medical school prepared them well for work: questionnaire surveys

<p>Abstract</p> <p>Background</p> <p>The transition from medical student to junior doctor in postgraduate training is a critical stage in career progression. We report junior doctors' views about the extent to which their medical school prepared them for their work in clinical practice.</p> <p>Methods</p> <p>Postal questionnaires were used to survey the medical graduates of 1999, 2000, 2002 and 2005, from all UK medical schools, one year after graduation, and graduates of 2000, 2002 and 2005 three years after graduation. Summary statistics, chi-squared tests, and binary logistic regression were used to analyse the results. The main outcome measure was the level of agreement that medical school had prepared the responder well for work.</p> <p>Results</p> <p>Response rate was 63.7% (11610/18216) in year one and 60.2% (8427/13997) in year three. One year after graduation, 36.3% (95% CI: 34.6, 38.0) of 1999/2000 graduates, 50.3% (48.5, 52.2) of 2002 graduates, and 58.2% (56.5, 59.9) of 2005 graduates agreed their medical school had prepared them well. Conversely, in year three agreement fell from 48.9% (47.1, 50.7) to 38.0% (36.0, 40.0) to 28.0% (26.2, 29.7). Combining cohorts at year one, percentages who agreed that they had been well prepared ranged from 82% (95% CI: 79-87) at the medical school with the highest level of agreement to 30% (25-35) at the lowest. At year three the range was 70% to 27%. Ethnicity and sex were partial predictors of doctors' level of agreement; following adjustment for them, substantial differences between schools remained. In years one and three, 30% and 34% of doctors specified that feeling unprepared had been a serious or medium-sized problem for them (only 3% in each year regarded it as serious).</p> <p>Conclusions</p> <p>The vast knowledge base of clinical practice makes full preparation impossible. Our statement about feeling prepared is simple yet discriminating and identified some substantial differences between medical schools. Medical schools need feedback from graduates about elements of training that could be improved.</p

Accuracy of advanced versus strictly conventional 12-lead ECG for detection and screening of coronary artery disease, left ventricular hypertrophy and left ventricular systolic dysfunction

<p>Abstract</p> <p>Background</p> <p>Resting conventional 12-lead ECG has low sensitivity for detection of coronary artery disease (CAD) and left ventricular hypertrophy (LVH) and low positive predictive value (PPV) for prediction of left ventricular systolic dysfunction (LVSD). We hypothesized that a ~5-min resting 12-lead <it>advanced </it>ECG test ("A-ECG") that combined results from both the advanced and conventional ECG could more accurately screen for these conditions than strictly conventional ECG.</p> <p>Methods</p> <p>Results from nearly every conventional and advanced resting ECG parameter known from the literature to have diagnostic or predictive value were first retrospectively evaluated in 418 healthy controls and 290 patients with imaging-proven CAD, LVH and/or LVSD. Each ECG parameter was examined for potential inclusion within multi-parameter A-ECG scores derived from multivariate regression models that were designed to optimally screen for disease in general or LVSD in particular. The performance of the best retrospectively-validated A-ECG scores was then compared against that of optimized pooled criteria from the strictly conventional ECG in a test set of 315 additional individuals.</p> <p>Results</p> <p>Compared to optimized pooled criteria from the strictly conventional ECG, a 7-parameter A-ECG score validated in the training set increased the sensitivity of resting ECG for identifying disease in the test set from 78% (72-84%) to 92% (88-96%) (P < 0.0001) while also increasing specificity from 85% (77-91%) to 94% (88-98%) (P < 0.05). In diseased patients, another 5-parameter A-ECG score increased the PPV of ECG for LVSD from 53% (41-65%) to 92% (78-98%) (P < 0.0001) without compromising related negative predictive value.</p> <p>Conclusion</p> <p>Resting 12-lead A-ECG scoring is more accurate than strictly conventional ECG in screening for CAD, LVH and LVSD.</p

The Extended Cleavage Specificity of Human Thrombin

Thrombin is one of the most extensively studied of all proteases. Its central role in the coagulation cascade as well as several other areas has been thoroughly documented. Despite this, its consensus cleavage site has never been determined in detail. Here we have determined its extended substrate recognition profile using phage-display technology. The consensus recognition sequence was identified as, P2-Pro, P1-Arg, P1′-Ser/Ala/Gly/Thr, P2′-not acidic and P3′-Arg. Our analysis also identifies an important role for a P3′-arginine in thrombin substrates lacking a P2-proline. In order to study kinetics of this cooperative or additive effect we developed a system for insertion of various pre-selected cleavable sequences in a linker region between two thioredoxin molecules. Using this system we show that mutations of P2-Pro and P3′-Arg lead to an approximate 20-fold and 14-fold reduction, respectively in the rate of cleavage. Mutating both Pro and Arg results in a drop in cleavage of 200–400 times, which highlights the importance of these two positions for maximal substrate cleavage. Interestingly, no natural substrates display the obtained consensus sequence but represent sequences that show only 1–30% of the optimal cleavage rate for thrombin. This clearly indicates that maximal cleavage, excluding the help of exosite interactions, is not always desired, which may instead cause problems with dysregulated coagulation. It is likely exosite cooperativity has a central role in determining the specificity and rate of cleavage of many of these in vivo substrates. Major effects on cleavage efficiency were also observed for residues as far away as 4 amino acids from the cleavage site. Insertion of an aspartic acid in position P4 resulted in a drop in cleavage by a factor of almost 20 times

The Magnitude of Global Marine Species Diversity

Background: The question of how many marine species exist is important because it provides a metric for how much we do and do not know about life in the oceans. We have compiled the first register of the marine species of the world and used this baseline to estimate how many more species, partitioned among all major eukaryotic groups, may be discovered. Results: There are ∼226,000 eukaryotic marine species described. More species were described in the past decade (∼20,000) than in any previous one. The number of authors describing new species has been increasing at a faster rate than the number of new species described in the past six decades. We report that there are ∼170,000 synonyms, that 58,000–72,000 species are collected but not yet described, and that 482,000–741,000 more species have yet to be sampled. Molecular methods may add tens of thousands of cryptic species. Thus, there may be 0.7–1.0 million marine species. Past rates of description of new species indicate there may be 0.5 ± 0.2 million marine species. On average 37% (median 31%) of species in over 100 recent field studies around the world might be new to science. Conclusions: Currently, between one-third and two-thirds of marine species may be undescribed, and previous estimates of there being well over one million marine species appear highly unlikely. More species than ever before are being described annually by an increasing number of authors. If the current trend continues, most species will be discovered this century

Empirical Legal Studies Before 1940: A Bibliographic Essay

The modern empirical legal studies movement has well-known antecedents in the law and society and law and economics traditions of the latter half of the 20th century. Less well known is the body of empirical research on legal phenomena from the period prior to World War II. This paper is an extensive bibliographic essay that surveys the English language empirical legal research from approximately 1940 and earlier. The essay is arranged around the themes in the research: criminal justice, civil justice (general studies of civil litigation, auto accident litigation and compensation, divorce, small claims, jurisdiction and procedure, civil juries), debt and bankruptcy, banking, appellate courts, legal needs, legal profession (including legal education), and judicial staffing and selection. Accompanying the essay is an extensive bibliography of research articles, books, and reports

Neurotransmitter Detection Using Corona Phase Molecular Recognition on Fluorescent Single-Walled Carbon Nanotube Sensors

ABSTRACT: Temporal and spatial changes in neurotransmitter concentrations are central to information processing in neural networks. Therefore, biosensors for neurotransmitters are essential tools for neuroscience. In this work, we applied a new technique, corona phase molecular recognition (CoPhMoRe), to identify adsorbed polymer phases on fluorescent single-walled carbon nanotubes (SWCNTs) that allow for the selective detection of specific neurotransmitters, including dopamine. We functionalized and suspended SWCNTs with a library of different polymers (n = 30) containing phospholipids, nucleic acids, and amphiphilic polymers to study how neurotransmitters modulate the resulting band gap, near-infrared (nIR) fluorescence of the SWCNT. We identified several corona phases that enable the selective detection of neurotransmitters. Catecholamines such as dopamine increased the fluorescence of specific single-stranded DNA- and RNA-wrapped SWCNTs by 58−80 % upon addition of 100 μM dopamine depending on the SWCNT chirality (n,m). In solution, the limit of detection was 11 nM [Kd = 433 nM for (GT)15 DNA-wrapped SWCNTs]. Mechanistic studies revealed that this turn-on response is due to an increase in fluorescence quantum yield and not covalent modification of the SWCNT or scavenging o

Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis

Multifactorial mechanisms underlying late-onset Alzheimer's disease (LOAD) are poorly characterized from an integrative perspective. Here spatiotemporal alterations in brain amyloid-β deposition, metabolism, vascular, functional activity at rest, structural properties, cognitive integrity and peripheral proteins levels are characterized in relation to LOAD progression. We analyse over 7,700 brain images and tens of plasma and cerebrospinal fluid biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Through a multifactorial data-driven analysis, we obtain dynamic LOAD–abnormality indices for all biomarkers, and a tentative temporal ordering of disease progression. Imaging results suggest that intra-brain vascular dysregulation is an early pathological event during disease development. Cognitive decline is noticeable from initial LOAD stages, suggesting early memory deficit associated with the primary disease factors. High abnormality levels are also observed for specific proteins associated with the vascular system's integrity. Although still subjected to the sensitivity of the algorithms and biomarkers employed, our results might contribute to the development of preventive therapeutic interventions