Apolipoprotein E associated with reconstituted high-density lipoprotein-like particles is protected from aggregation.

Apolipoprotein E (APOE) genotype determines Alzheimer\u27s disease (AD) susceptibility, with the APOE ε4 allele being an established risk factor for late-onset AD. The ApoE lipidation status has been reported to impact amyloid-beta (Aβ) peptide metabolism. The details of how lipidation affects ApoE behavior remain to be elucidated. In this study, we prepared lipid-free and lipid-bound ApoE particles, mimicking the high-density lipoprotein particles found in vivo, for all three isoforms (ApoE2, ApoE3, and ApoE4) and biophysically characterized them. We find that lipid-free ApoE in solution has the tendency to aggregate in vitro in an isoform-dependent manner under near-physiological conditions and that aggregation is impeded by lipidation of ApoE

Biochemical characterization of New Delhi metallo-beta-lactamase variants reveals differences in protein stability

Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Rhodes Trust (UK); a Clarendon Scholarship; a St Hugh's College W. Louey Scholarship; the Biotechnology & Biological Sciences Research Council (BBSRC); a Royal Society Dorothy Hodgkin Research Fellowship; and the Medical Research Council (MRC)/Canadian Grant G1100135

In-vivo high resolution imaging of optic nerve head drusen using spectral-domain Optical Coherence Tomography

<p>Abstract</p> <p>Background</p> <p>Optic nerve head drusen (ONHD) are white calcareous deposits, seen either superficially on the optic nerve head or buried within it. Diagnosis of ONHD is made by one or more ways: clinical exam, autofluorescence, ultrasound of the optic nerve, CT scan and/or visual field examination. The present study describes features of ONHD based on another diagnostic modality, the spectral-domain OCT (Spectralis).</p> <p>Methods</p> <p>This is a retrospective case series of 5 patients with bilateral ONHD with a best-corrected visual acuity of 20/20 and no other posterior segment pathology. All the patients underwent fundus photography, fundus autofluorescence, B-scan ultrasonography, Spectralis OCT and Humphrey 30-2 threshold visual fields.</p> <p>Results</p> <p>All 5 patients had surface ONHD which were autofluorescent and echodense on B-scan ultrasonography. Spectralis OCT findings in the corresponding areas include 'scattered spots with high reflectivity' casting a shadow underneath. The reflectivity can be distinctly differentiated from the blood vessels on the optic nerve. Two patients had an arcuate scotoma on the Humphrey visual fields. No correlation was found between the changes on Spectralis OCT with that of visual field.</p> <p>Conclusions</p> <p>Spectralis OCT is another useful ancillary investigation in the diagnosis of ONHD and we describe the features in the present study.</p

Tracking family medicine graduates. Where do they go, what services do they provide and whom do they see?

<p>Abstract</p> <p>Background</p> <p>There are continued concerns over an adequate supply of family physicians (FPs) practicing in Canada. While most resource planning has focused on intake into postgraduate education, less information is available on what postgraduate medical training yields. We therefore undertook a study of Family Medicine (FM) graduates from the University of Toronto (U of T) to determine the type of information for physician resource planning that may come from tracking FM graduates using health administrative data. This study compared three cohorts of FM graduates over a 10 year period of time and it also compared FM graduates to all Ontario practicing FPs in 2005/06. The objectives for tracking the three cohorts of FM graduates were to: 1) describe where FM graduates practice in the province 2) examine the impact of a policy introduced to influence the distribution of new FM graduates in the province 3) describe the services provided by FM graduates and 4) compare workload measures. The objectives for the comparison of FM graduates to all practicing FPs in 2005/06 were to: 1) describe the patient population served by FM graduates, 2) compare workload of FM graduates to all practicing FPs.</p> <p>Methods</p> <p>The study cohort consisted of all U of T FM postgraduate trainees who started and completed their training between 1993 and 2003. This study was a descriptive record linkage study whereby postgraduate information for FM graduates was linked to provincial health administrative data. Comprehensiveness of care indicators and workload measures based on administrative data where determined for the study cohort.</p> <p>Results</p> <p>From 1993 to 2003 there were 857 University of Toronto FM graduates. While the majority of U of T FM graduates practice in Toronto or the surrounding Greater Toronto Area, there are FM graduates from U of T practicing in every region in Ontario, Canada. The proportion of FM graduates undertaking further emergency training had doubled from 3.6% to 7.8%. From 1993 to 2003, a higher proportion of the most recent FM graduates did hospital visits, emergency room care and a lower proportion undertook home visits. Male FM graduates appear to have had higher workloads compared with female FM graduates, though the difference between them was decreasing over time. A 1997 policy initiative to discount fees paid to new FPs practicing in areas deemed over supplied did result in a decrease in the proportion of FM graduates practicing in metropolitan areas.</p> <p>Conclusions</p> <p>We were able to profile the practices of FM graduates using existing and routinely collected population-based health administrative data. Further work tracking FM graduates could be helpful for physician resource forecasting and in examining the impact of policies on family medicine practice.</p

Validation of diffusion tensor MRI measurements of cardiac microstructure with structure tensor synchrotron radiation imaging.

Background Diffusion tensor imaging (DTI) is widely used to assess tissue microstructure non-invasively. Cardiac DTI enables inference of cell and sheetlet orientations, which are altered under pathological conditions. However, DTI is affected by many factors, therefore robust validation is critical. Existing histological validation is intrinsically flawed, since it requires further tissue processing leading to sample distortion, is routinely limited in field-of-view and requires reconstruction of three-dimensional volumes from two-dimensional images. In contrast, synchrotron radiation imaging (SRI) data enables imaging of the heart in 3D without further preparation following DTI. The objective of the study was to validate DTI measurements based on structure tensor analysis of SRI data. Methods One isolated, fixed rat heart was imaged ex vivo with DTI and X-ray phase contrast SRI, and reconstructed at 100 μm and 3.6 μm isotropic resolution respectively. Structure tensors were determined from the SRI data and registered to the DTI data. Results Excellent agreement in helix angles (HA) and transverse angles (TA) was observed between the DTI and structure tensor synchrotron radiation imaging (STSRI) data, where HADTI-STSRI = −1.4° ± 23.2° and TADTI-STSRI = −1.4° ± 35.0° (mean ± 1.96 standard deviation across all voxels in the left ventricle). STSRI confirmed that the primary eigenvector of the diffusion tensor corresponds with the cardiomyocyte long-axis across the whole myocardium. Conclusions We have used STSRI as a novel and high-resolution gold standard for the validation of DTI, allowing like-with-like comparison of three-dimensional tissue structures in the same intact heart free of distortion. This represents a critical step forward in independently verifying the structural basis and informing the interpretation of cardiac DTI data, thereby supporting the further development and adoption of DTI in structure-based electro-mechanical modelling and routine clinical applications

Operative versus non-operative management of pediatric medial epicondyle fractures: a systematic review

There is ongoing debate about the management of medial epicondyle fractures in the pediatric population. This systematic review evaluated non-operative versus operative treatment of medial epicondyle fractures in pediatric and adolescent patients over the last six decades. A systematic review of the available literature was performed. Frequency-weighted mean union times were used to compare union rates for closed versus open treatments. Moreover, functional outcomes and range-of-motion variables were correlated with varying treatment modalities. Any complications, including ulnar nerve symptoms, pain, instability, infection, and residual deformity, were cataloged. Fourteen studies, encompassing 498 patients, met the inclusion/exclusion criteria. There were 261 males and 132 female patients; the frequency-weighted average age was 11.93 years. The follow-up range was 6–216 months. Under the cumulative random effects model, the odds of union with operative fixation was 9.33 times the odds of union with non-operative treatment (P &lt; 0.0001). There was no significant difference between operative and non-operative treatments in terms of pain at final follow-up (P = 0.73) or ulnar nerve symptoms (P = 0.412). Operative treatment affords a significantly higher union rate over the non-operative management of medial epicondyle fractures. There was no difference in pain at final follow-up between operative and non-operative treatments. As surgical indications evolve, and the functional demands of pediatric patients increase, surgical fixation should be strongly considered to achieve stable fixation and bony union

Examining the validity and utility of two secondary sources of food environment data against street audits in England

Background: Secondary data containing the locations of food outlets is increasingly used in nutrition and obesity research and policy. However, evidence evaluating these data is limited. This study validates two sources of secondary food environment data: Ordnance Survey Points of Interest data (POI) and food hygiene data from the Food Standards Agency (FSA), against street audits in England and appraises the utility of these data. Methods: Audits were conducted across 52 Lower Super Output Areas in England. All streets within each Lower Super Output Area were covered to identify the name and street address of all food outlets therein. Audit-identified outlets were matched to outlets in the POI and FSA data to identify true positives (TP: outlets in both the audits and the POI/FSA data), false positives (FP: outlets in the POI/FSA data only) and false negatives (FN: outlets in the audits only). Agreement was assessed using positive predictive values (PPV: TP/(TP+FP)) and sensitivities (TP/(TP+FN)). Variations in sensitivities and PPVs across environment and outlet types were assessed using multi-level logistic regression. Proprietary classifications within the POI data were additionally used to classify outlets, and agreement between audit-derived and POI-derived classifications was assessed. Results: Street audits identified 1172 outlets, compared to 1100 and 1082 for POI and FSA respectively. PPVs were statistically significantly higher for FSA (0.91, CI: 0.89-0.93) than for POI (0.86, CI: 0.84-0.88). However, sensitivity values were not different between the two datasets. Sensitivity and PPVs varied across outlet types for both datasets. Without accounting for this, POI had statistically significantly better PPVs in rural and affluent areas. After accounting for variability across outlet types, FSA had statistically significantly better sensitivity in rural areas and worse sensitivity in rural middle affluence areas (relative to deprived). Audit-derived and POI-derived classifications exhibited substantial agreement (p < 0.001; Kappa = 0.66, CI: 0.63 - 0.70). Conclusions: POI and FSA data have good agreement with street audits; although both datasets had geographic biases which may need to be accounted for in analyses. Use of POI proprietary classifications is an accurate method for classifying outlets, providing time savings compared to manual classification of outlets

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

A Novel Role for MAPKAPK2 in Morphogenesis during Zebrafish Development

One of the earliest morphogenetic processes in the development of many animals is epiboly. In the zebrafish, epiboly ensues when the animally localized blastoderm cells spread, thin over, and enclose the vegetally localized yolk. Only a few factors are known to function in this fundamental process. We identified a maternal-effect mutant, betty boop (bbp), which displays a novel defect in epiboly, wherein the blastoderm margin constricts dramatically, precisely when half of the yolk cell is covered by the blastoderm, causing the yolk cell to burst. Whole-blastoderm transplants and mRNA microinjection rescue demonstrate that Bbp functions in the yolk cell to regulate epiboly. We positionally cloned the maternal-effect bbp mutant gene and identified it as the zebrafish homolog of the serine-threonine kinase Mitogen Activated Protein Kinase Activated Protein Kinase 2, or MAPKAPK2, which was not previously known to function in embryonic development. We show that the regulation of MAPKAPK2 is conserved and p38 MAP kinase functions upstream of MAPKAPK2 in regulating epiboly in the zebrafish embryo. Dramatic alterations in calcium dynamics, together with the massive marginal constrictive force observed in bbp mutants, indicate precocious constriction of an F-actin network within the yolk cell, which first forms at 50% epiboly and regulates epiboly progression. We show that MAPKAPK2 activity and its regulator p38 MAPK function in the yolk cell to regulate the process of epiboly, identifying a new pathway regulating this cell movement process. We postulate that a p38 MAPKAPK2 kinase cascade modulates the activity of F-actin at the yolk cell margin circumference allowing the gradual closure of the blastopore as epiboly progresses