Protein profiles in Tc1 mice implicate novel pathway perturbations in the Down syndrome brain

Tc1 mouse model of Down syndrome (DS) is functionally trisomic for ∼120 human chromosome 21 (HSA21) classical protein-coding genes. Tc1 mice display features relevant to the DS phenotype, including abnormalities in learning and memory and synaptic plasticity. To determine the molecular basis for the phenotypic features, the levels of 90 phosphorylation-specific and phosphorylation-independent proteins were measured by Reverse Phase Protein Arrays in hippocampus and cortex, and 64 in cerebellum, of Tc1 mice and littermate controls. Abnormal levels of proteins involved in MAP kinase, mTOR, GSK3B and neuregulin signaling were identified in trisomic mice. In addition, altered correlations among the levels of N-methyl-D-aspartate (NMDA) receptor subunits and the HSA21 proteins amyloid beta (A4) precursor protein (APP) and TIAM1, and between immediate early gene (IEG) proteins and the HSA21 protein superoxide dismutase-1 (SOD1) were found in the hippocampus of Tc1 mice, suggesting altered stoichiometry among these sets of functionally interacting proteins. Protein abnormalities in Tc1 mice were compared with the results of a similar analysis of Ts65Dn mice, a DS mouse model that is trisomic for orthologs of 50 genes trisomic in the Tc1 plus an additional 38 HSA21 orthologs. While there are similarities, abnormalities unique to the Tc1 include increased levels of the S100B calcium-binding protein, mTOR proteins RAPTOR and P70S6, the AMP-kinase catalytic subunit AMPKA, the IEG proteins FBJ murine osteosarcoma viral oncogene homolog (CFOS) and activity-regulated cytoskeleton-associated protein (ARC), and the neuregulin 1 receptor ERBB4. These data identify novel perturbations, relevant to neurological function and to some seen in Alzheimer's disease, that may occur in the DS brain, potentially contributing to phenotypic features and influencing drug responses

Fully-automated μMRI morphometric phenotyping of the Tc1 mouse model of Down Syndrome

We describe a fully automated pipeline for the morphometric phenotyping of mouse brains from μMRI data, and show its application to the Tc1 mouse model of Down syndrome, to identify new morphological phenotypes in the brain of this first transchromosomic animal carrying human chromosome 21. We incorporate an accessible approach for simultaneously scanning multiple ex vivo brains, requiring only a 3D-printed brain holder, and novel image processing steps for their separation and orientation. We employ clinically established multi-atlas techniques-superior to single-atlas methods-together with publicly-available atlas databases for automatic skull-stripping and tissue segmentation, providing high-quality, subject-specific tissue maps. We follow these steps with group-wise registration, structural parcellation and both Voxel- and Tensor-Based Morphometry-advantageous for their ability to highlight morphological differences without the laborious delineation of regions of interest. We show the application of freely available open-source software developed for clinical MRI analysis to mouse brain data: NiftySeg for segmentation and NiftyReg for registration, and discuss atlases and parameters suitable for the preclinical paradigm. We used this pipeline to compare 29 Tc1 brains with 26 wild-type littermate controls, imaged ex vivo at 9.4T. We show an unexpected increase in Tc1 total intracranial volume and, controlling for this, local volume and grey matter density reductions in the Tc1 brain compared to the wild-types, most prominently in the cerebellum, in agreement with human DS and previous histological findings

The impact of trained patient educators on musculoskeletal clinical skills attainment in pre-clerkship medical students

<p>Abstract</p> <p>Background</p> <p>Despite the high burden of musculoskeletal (MSK) diseases, few generalists are comfortable teaching MSK physical examination (PE) skills. Patient Partners^®in Arthritis (PP^®IA) is a standardized patient educator program that could potentially supplement current MSK PE teaching. This study aims to determine if differences exist in MSK PE skills between non-MSK specialist physician and PP^®IA taught students.</p> <p>Methods</p> <p>Pre-clerkship medical students attended 2-hour small group MSK PE teaching by either non-MSK specialist physician tutors or by PP^®IA. All students underwent an MSK OSCE and completed retrospective pre-post questionnaires regarding comfort with MSK PE and interest in MSK.</p> <p>Results</p> <p>83 students completed the OSCE (42 PP^®IA, 41 physician taught) and 82 completed the questionnaire (42 PP^®IA, 40 physician taught). There were no significant differences between groups in OSCE scores. For all questionnaire items, post-session ratings were significantly higher than pre-session ratings for both groups. In exploratory analysis PP^®IA students showed significantly greater improvement in 12 of 22 questions including three of five patient-centred learning questions.</p> <p>Conclusions</p> <p>PP^®IA MSK PE teaching is as good as non-MSK specialist physician tutor teaching when measured by a five station OSCE and provide an excellent complementary resource to address current deficits in MSK PE teaching.</p

Определение скорости перемещения деформаций растяжений в массиве при подземной выемке угля

Приведена швидкість переміщення деформацій в непорушеному масиві. Встановлено, що швидкість в породах середнього ступеня метаморфізму складає 15 м/добу. Середня швидкість переміщення деформацій в сланцях – 10 м/добу, в піщаниках – 15 м/добу. При повторній підробці швидкість переміщення деформацій складає 17 м/добу.Deformation’s speed travel in the virgin rock massif is given in this article. It has been determined that deformation’s speed in the rocks of medium-scale metamorphism was 15 meters over the entire circadian period. The average speed of deformation’s travel in the shale rocks is 10 meters over the entire circadian period and in the sandstone is 15 meters over the entire circadian period. During the recurring undermining the speed travel of deformations is 17 meters over the entire circadian period

Part 2: CT characterisation of pancreatic neoplasm: tumour mimics

There are numerous pancreatic and peripancreatic conditions that can mimic pancreatic neoplasms. Many of these can be confidently diagnosed on computed tomography (CT), while others will require further imaging. Knowledge of these tumour mimics is important to avoid misclassification of benign conditions as malignant and to avoid unnecessary surgery. Mimics can be grouped as parenchymal, vascular, biliary and peripancreatic. These are discussed and illustrated in this review

An Economic Evaluation of Home Management of Malaria in Uganda: An Interactive Markov Model

BACKGROUND: Home management of malaria (HMM), promoting presumptive treatment of febrile children in the community, is advocated to improve prompt appropriate treatment of malaria in Africa. The cost-effectiveness of HMM is likely to vary widely in different settings and with the antimalarial drugs used. However, no data on the cost-effectiveness of HMM programmes are available. METHODS/PRINCIPAL FINDINGS: A Markov model was constructed to estimate the cost-effectiveness of HMM as compared to conventional care for febrile illnesses in children without HMM. The model was populated with data from Uganda, but is designed to be interactive, allowing the user to adjust certain parameters, including the antimalarials distributed. The model calculates the cost per disability adjusted life year averted and presents the incremental cost-effectiveness ratio compared to a threshold value. Model output is stratified by level of malaria transmission and the probability that a child would receive appropriate care from a health facility, to indicate the circumstances in which HMM is likely to be cost-effective. The model output suggests that the cost-effectiveness of HMM varies with malaria transmission, the probability of appropriate care, and the drug distributed. Where transmission is high and the probability of appropriate care is limited, HMM is likely to be cost-effective from a provider perspective. Even with the most effective antimalarials, HMM remains an attractive intervention only in areas of high malaria transmission and in medium transmission areas with a lower probability of appropriate care. HMM is generally not cost-effective in low transmission areas, regardless of which antimalarial is distributed. Considering the analysis from the societal perspective decreases the attractiveness of HMM. CONCLUSION: Syndromic HMM for children with fever may be a useful strategy for higher transmission settings with limited health care and diagnosis, but is not appropriate for all settings. HMM may need to be tailored to specific settings, accounting for local malaria transmission intensity and availability of health services

Loss of protein kinase C delta alters mammary gland development and apoptosis

As apoptotic pathways are commonly deregulated in breast cancer, exploring how mammary gland cell death is regulated is critical for understanding human disease. We show that primary mammary epithelial cells from protein kinase C delta (PKCδ) −/− mice have a suppressed response to apoptotic agents in vitro. In the mammary gland in vivo, apoptosis is critical for ductal morphogenesis during puberty and involution following lactation. We have explored mammary gland development in the PKCδ −/− mouse during these two critical windows. Branching morphogenesis was altered in 4- to 6-week-old PKCδ −/− mice as indicated by reduced ductal branching; however, apoptosis and proliferation in the terminal end buds was unaltered. Conversely, activation of caspase-3 during involution was delayed in PKCδ −/− mice, but involution proceeded normally. The thymus also undergoes apoptosis in response to physiological signals. A dramatic suppression of caspase-3 activation was observed in the thymus of PKCδ −/− mice treated with irradiation, but not mice treated with dexamethasone, suggesting that there are both target- and tissue-dependent differences in the execution of apoptotic pathways in vivo. These findings highlight a role for PKCδ in both apoptotic and nonapoptotic processes in the mammary gland and underscore the redundancy of apoptotic pathways in vivo