tbuckley/cabot-search huggingface dataset:
Low Responsiveness to Clopidogrel Increases Risk among CKD Patients Undergoing Coronary Intervention
Authors: Patrik Htun, Suzanne Fateh-Moghadam, Christian Bischofs, Winston Banya, Karin Müller, Boris Bigalke, Konstantinos Stellos, Andreas E. May, Marcus Flather, Meinrad Gawaz, Tobias Geisler
Journal: Journal of the American Society of Nephrology (2011)

Patients with CKD are at higher risk for major events after percutaneous coronary intervention (PCI) compared with subjects with normal renal function. The aims of this study were to evaluate responsiveness to clopidogrel in patients with CKD and to examine the effect of antiplatelet drug response on post-PCI outcome. We retrospectively evaluated a consecutive cohort of 1567 patients with symptomatic coronary artery disease undergoing PCI, 648 (41%) of whom had stage 3 to 5 CKD. We assessed responsiveness to clopidogrel by ADP-induced platelet aggregation after oral administration of a 600-mg clopidogrel loading dose and 100 mg of aspirin. In a multivariate survival analysis that included 1335 (85%) of the cohort, stage 3 to 5 CKD and low response to clopidogrel were independent predictors of the primary end point (composite of myocardial infarction, ischemic stroke, and death within 1 year). In summary, a low response to clopidogrel might be an additional risk factor for the poorer outcomes in patients with stage 3 to 5 CKD compared with patients with better renal function.
Prophylactic antibiotics for the prevention of cellulitis (erysipelas) of the leg: results of the U.K. Dermatology Clinical Trials Network’s PATCH II trial
Journal: British Journal of Dermatology (2011)

Cellulitis (erysipelas) of the leg is a common, painful infection of the skin and underlying tissue. Repeat episodes are frequent, cause significant morbidity and result in high health service costs.To assess whether prophylactic antibiotics prescribed after an episode of cellulitis of the leg can prevent further episodes.Double-blind, randomized controlled trial including patients recently treated for an episode of leg cellulitis. Recruitment took place in 20 hospitals. Randomization was by computer-generated code, and treatments allocated by post from a central pharmacy. Participants were enrolled for a maximum of 3 years and received their randomized treatment for the first 6 months of this period.Participants (n=123) were randomized (31% of target due to slow recruitment). The majority (79%) had suffered one episode of cellulitis on entry into the study. The primary outcome of time to recurrence of cellulitis included all randomized participants and was blinded to treatment allocation. The hazard ratio (HR) showed that treatment with penicillin reduced the risk of recurrence by 47% [HR 0·53, 95% confidence interval (CI) 0·26-1·07, P=0·08]. In the penicillin V group 12/60 (20%) had a repeat episode compared with 21/63 (33%) in the placebo group. This equates to a number needed to treat (NNT) of eight participants in order to prevent one repeat episode of cellulitis [95% CI NNT(harm) 48 to ∞ to NNT(benefit) 3]. We found no difference between the two groups in the number of participants with oedema, ulceration or related adverse events.Although this trial was limited by slow recruitment, and the result failed to achieve statistical significance, it provides the best evidence available to date for the prevention of recurrence of this debilitating condition.
Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin
Authors: Karin Schwarz, Matias Simons, Jochen Reiser, Moin A. Saleem, Christian Faul, Wihelm Kriz, Andrey S. Shaw, Lawrence B. Holzman, Peter Mundel
Journal: Journal of Clinical Investigation (2001)

NPHS2 was recently identified as a gene whose mutations cause autosomal recessive steroid-resistant nephrotic syndrome. Its product, podocin, is a new member of the stomatin family, which consists of hairpin-like integral membrane proteins with intracellular NH2- and COOH-termini. Podocin is expressed in glomerular podocytes, but its subcellular distribution and interaction with other proteins are unknown. Here we show, by immunoelectron microscopy, that podocin localizes to the podocyte foot process membrane, at the insertion site of the slit diaphragm. Podocin accumulates in an oligomeric form in lipid rafts of the slit diaphragm. Moreover, GST pull-down experiments reveal that podocin associates via its COOH-terminal domain with CD2AP, a cytoplasmic binding partner of nephrin, and with nephrin itself. That podocin interacts with CD2AP and nephrin in vivo is shown by coimmunoprecipitation of these proteins from glomerular extracts. Furthermore, in vitro studies reveal direct interaction of podocin and CD2AP. Hence, as with the erythrocyte lipid raft protein stomatin, podocin is present in high-order oligomers and may serve a scaffolding function. We postulate that podocin serves in the structural organization of the slit diaphragm and the regulation of its filtration function.
NMR IN MULTIPLE SCLEROSIS AND CEREBRAL VASCULAR DISEASE
Authors: I.E.C. Ormerod, E.P.G.H. Du Boulay, M.M. Callanan, G. Johnson, S.J. Logsdail, I.S. Moseley, P. Rudge, R.C. Roberts, W.I. Mcdonald, A.M. Halliday, B.E. Kendall, D.G. Macmanus, M.A. Ron, K.J. Zilkha
Journal: The Lancet (1984)
Copying patients in is not as simple as it seems
Authors: B. McKinstry
Journal: BMJ (2008)

Richards advocates copying patients into all correspondence on the grounds of improving health literacy,1 but a sizeable minority of people in the UK have general literacy problems and are unlikely to benefit.2

As currently written, many letters from hospitals are difficult for patients to understand. My colleagues and I have had to explain to alarmed and bewildered patients who have received copies …
A Novel Murine Model of Severe Pulmonary Arterial Hypertension
Authors: Loredana Ciuclan, Olivier Bonneau, Martin Hussey, Nicholas Duggan, Alan M. Holmes, Robert Good, Rowan Stringer, Peter Jones, Nicholas W. Morrell, Gabor Jarai, Christoph Walker, John Westwick, Matthew Thomas
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

The complex pathologies associated with severe pulmonary arterial hypertension (PAH) in humans have been a challenge to reproduce in mice due to the subtle phenotype displayed to PAH stimuli.Here we aim to develop a novel murine model of PAH that recapitulates more of the pathologic processes, such as complex vascular remodeling and cardiac indices, that are not characteristic of alternative mouse models.Inhibition of vascular endothelial growth factor receptor (VEGFR) with SU5416 combined with 3 weeks of chronic hypoxia was investigated. Hemodynamics, cardiac function, histological assessment of pulmonary vasculature, and molecular pathway analysis gauged the extent of PAH pathology development.The combination of VEGFR inhibition with chronic hypoxia profoundly exacerbated all measures of PAH-like pathology when compared with hypoxia alone (> 45 mm Hg right ventricular pressure, > 0.35 right ventricular hypertrophy). The changes in pulmonary vascular remodeling in response to hypoxia were further enhanced on SU5416 treatment. Furthermore, hypoxia/SU5416 treatment steadily decreased cardiac output, indicating incipient heart failure. Molecular analysis showed a dysregulated transforming growth factor-β/bone morphogenetic protein/Smad axis in SU5416- and/or hypoxia-treated mice as well as augmented induction of IL-6 and Hif-1α levels. These changes were observed in accordance with up-regulation of Tph1 and Pdgfr gene transcripts as well as a rise in platelet-rich serotonin. Biomarker analysis in response to VEGFR inhibition and/or hypoxia revealed distinct signatures that correlate with cytokine profiles of patients with idiopathic PAH.These data describe a novel murine model of PAH, which displays many of the hallmarks of the human disease, thus opening new avenues of investigation to better understand PAH pathophysiology.
Results of ECFMG Examinations
Authors: G. Halsey Hunt
Journal: JAMA (1969)

This issue ofThe Journalcarries, for the first time, a tabulation showing the number of candidates from each medical school who took the examinations of the Educational Council for Foreign Medical Graduates in 1968, and the number who passed the medical portion of the examinations. Those who passed Medicine but failed the English Test are recorded as having passed, though they will not be eligible for ECFMG certification or for appointment to an approved internship or residency in the United States until they pass a future English test. It should be remembered that the ECFMG examination is made up of questions selected from the pool of questions maintained by the National Board of Medical Examiners, and that the examination is scored on the basis of the results that students in American and Canadian medical schools have obtained on these same questions in examinations of the National Board of Medical
Identifying the Social Support Needs of Young Cancer Patients in Japan
Authors: E. Nara, M. Yunokawa, K. Yonemori, C. Doutani, K. Shimizu, Y. Mimaki, N. Oomatsu, M. Komatsu, A. Hirakawa, C. Shimizu, Y. Fujiwara, K. Tamura
Journal: Annals of Oncology (2014)
Thinking Outside the Cleft to Understand Synaptic Activity: Contribution of the Cystine-Glutamate Antiporter (System x<sub>c</sub><sup>−</sup>) to Normal and Pathological Glutamatergic Signaling
Authors: Richard Bridges, Victoria Lutgen, Doug Lobner, David A. Baker
Journal: Pharmacological Reviews (2012)

System x<sub>c</sub><sup>−</sup> represents an intriguing target in attempts to understand the pathological states of the central nervous system. Also called a cystine-glutamate antiporter, system x<sub>c</sub><sup>−</sup> typically functions by exchanging one molecule of extracellular cystine for one molecule of intracellular glutamate. Nonvesicular glutamate released during cystine-glutamate exchange activates extrasynaptic glutamate receptors in a manner that shapes synaptic activity and plasticity. These findings contribute to the intriguing possibility that extracellular glutamate is regulated by a complex network of release and reuptake mechanisms, many of which are unique to glutamate and rarely depicted in models of excitatory signaling. Because system x<sub>c</sub><sup>−</sup> is often expressed on non-neuronal cells, the study of cystine-glutamate exchange may advance the emerging viewpoint that glia are active contributors to information processing in the brain. It is noteworthy that system x<sub>c</sub><sup>−</sup> is at the interface between excitatory signaling and oxidative stress, because the uptake of cystine that results from cystine-glutamate exchange is critical in maintaining the levels of glutathione, a critical antioxidant. As a result of these dual functions, system x<sub>c</sub><sup>−</sup> has been implicated in a wide array of central nervous system diseases ranging from addiction to neurodegenerative disorders to schizophrenia. In the current review, we briefly discuss the major cellular components that regulate glutamate homeostasis, including glutamate release by system x<sub>c</sub><sup>−</sup>. This is followed by an in-depth discussion of system x<sub>c</sub><sup>−</sup> as it relates to glutamate release, cystine transport, and glutathione synthesis. Finally, the role of system x<sub>c</sub><sup>−</sup> is surveyed across a number of psychiatric and neurodegenerative disorders.
Hepatocyte Growth Factor Activator Inhibitor Type 1 Regulates Epithelial to Mesenchymal Transition through Membrane-Bound Serine Proteinases
Authors: Haixia Cheng, Tsuyoshi Fukushima, Nobuyasu Takahashi, Hiroyuki Tanaka, Hiroaki Kataoka
Journal: Cancer Research (2009)

Abstract Hepatocyte growth factor activator inhibitor-1 (HAI-1), encoded by the serine protease inhibitor Kunitz type 1 (SPINT1) gene, is a membrane-associated proteinase inhibitor that potently inhibits a variety of serine proteinases, including those that are membrane bound. Although HAI-1/SPINT1 is widely expressed by epithelial cells and cancer cells, its functional role is still unclear, particularly in cancer. Here, we show that stable knockdown of HAI-1/SPINT1 in the human pancreatic cancer cell line SUIT-2 induces an elongated spindle-like morphology associated with accelerated invasion, thereby mimicking an epithelial to mesenchymal transition (EMT). We found that HAI-1/SPINT1 knockdown significantly reduced the expression of E-cadherin and was accompanied by up-regulation of Smad-interacting protein 1 (SIP1), an E-cadherin transcriptional repressor. In addition, matrix metalloproteinase-9 (MMP-9) was up-regulated. Similar results were obtained in the HLC-1 lung carcinoma cell line. Moreover, a metastatic variant of SUIT-2 (S2-CP8) that showed loss of E-cadherin expression also showed a significantly reduced level of HAI-1/SPINT1. Engineered overexpression of HAI-1/SPINT1 in S2-CP8 resulted in reversion of E-cadherin expression and SIP1 down-regulation, which accompanied reestablishment of epithelial morphology in culture. The EMT caused by HAI-1/SPINT1 knockdown seemed to be mediated, at least partly, by membrane-bound serine proteinases, matriptase/ST14 and TMPRSS4, as knockdown of matriptase/ST14 or TMPRSS4 in HAI-1/SPINT1 knockdown SUIT-2 cells and HLC-1 cells resulted in reversion of SIP1 and/or MMP-9 expression levels. We suggest that interactions between HAI-1/SPINT1 and membrane-bound serine proteinases contribute to transcriptional and functional changes involved in EMT in certain carcinoma cells. [Cancer Res 2009;69(5):1828–35]
Orofacial injuries and mouthguards: a study of the 1984 Wallabies.
Authors: P J Chapman
Journal: British Journal of Sports Medicine (1985)

As mouthguards provide protection of the teeth, jaws, adjacent soft tissues and also protect the brain against concussion following impacts to the mandible, the use of mouthguards in contact sports is strongly recommended. It is therefore essential to gauge regularly the use of mouthguards in the various contact sports at all levels of competition. Of the 30 members of the 1984 Australian Rugby Union Touring Team (the Wallabies), 80% wore mouthguards and of these, 75% believed that wearing mouthguards should be made compulsory for Rugby players. A comparison of these and other findings is made with previous studies in Rugby, and also with a similar study of the 1984 Great Britain Rugby League Touring Team.
Left Ventricular and Myocardial Function in Mice Expressing Constitutively Pseudophosphorylated Cardiac Troponin I
Authors: Jonathan A. Kirk, Guy A. MacGowan, Caroline Evans, Stephen H. Smith, Chad M. Warren, Ranganath Mamidi, Murali Chandra, Alexandre F.R. Stewart, R. John Solaro, Sanjeev G. Shroff
Journal: Circulation Research (2009)

Protein kinase (PK)C-induced phosphorylation of cardiac troponin (cTn)I has been shown to regulate cardiac contraction.Characterize functional effects of increased PKC-induced cTnI phosphorylation and identify underlying mechanisms using a transgenic mouse model (cTnI(PKC-P)) expressing mutant cTnI (S43E, S45E, T144E).Two-dimensional gel analysis showed 7.2+/-0.5% replacement of endogenous cTnI with the mutant form. Experiments included: mechanical measurements (perfused isolated hearts, isolated papillary muscles, and skinned fiber preparations), biochemical and molecular biological measurements, and a mathematical model-based analysis for integrative interpretation. Compared to wild-type mice, cTnI(PKC-P) mice exhibited negative inotropy in isolated hearts (14% decrease in peak developed pressure), papillary muscles (53% decrease in maximum developed force), and skinned fibers (14% decrease in maximally activated force, F(max)). Additionally, cTnI(PKC-P) mice exhibited slowed relaxation in both isolated hearts and intact papillary muscles. The cTnI(PKC-P) mice showed no differences in calcium sensitivity, cooperativity, steady-state force-MgATPase relationship, calcium transient (amplitude and relaxation), or baseline phosphorylation of other myofilamental proteins. The model-based analysis revealed that experimental observations in cTnI(PKC-P) mice could be reproduced by 2 simultaneous perturbations: a decrease in the rate of cross-bridge formation and an increase in calcium-independent persistence of the myofilament active state.A modest increase in PKC-induced cTnI phosphorylation ( approximately 7%) can significantly alter cardiac muscle contraction: negative inotropy via decreased cross-bridge formation and negative lusitropy via persistence of myofilament active state. Based on our data and data from the literature we speculate that effects of PKC-mediated cTnI phosphorylation are site-specific (S43/S45 versus T144).
Oxford handbook of rheumatology
Authors: D Humphries
Journal: British Journal of Sports Medicine (2008)

Edited by A Hakim, G Clunie, I Haq. . Published by Oxford University Press, UK, 2006, pp 606, £29.95 (softcover). ISBN 978-0-19-857135-3

For those who are looking for a one line review of the Oxford Handbook of Rheumatology : it is an excellent book, buy it.

For those who are looking for a slightly more comprehensive review, this book is another of the now extensive group of Oxford Handbooks. Subtitled The Essential Pocket Guide to Rheumatology , it runs to over 600 pages and you would need a fairly large pocket to put it in. For clinicians working in sport and exercise medicine, general practice and other fields of medicine where rheumatological …
Quantification of ultrasonic texture intra-heterogeneity via volumetric stochastic modeling for tissue characterization
Authors: Omar S. Al-Kadi, Daniel Y.F. Chung, Robert C. Carlisle, Constantin C. Coussios, J. Alison Noble
Journal: Medical Image Analysis (2014)

Intensity variations in image texture can provide powerful quantitative information about physical properties of biological tissue. However, tissue patterns can vary according to the utilized imaging system and are intrinsically correlated to the scale of analysis. In the case of ultrasound, the Nakagami distribution is a general model of the ultrasonic backscattering envelope under various scattering conditions and densities where it can be employed for characterizing image texture, but the subtle intra-heterogeneities within a given mass are difficult to capture via this model as it works at a single spatial scale. This paper proposes a locally adaptive 3D multi-resolution Nakagami-based fractal feature descriptor that extends Nakagami-based texture analysis to accommodate subtle speckle spatial frequency tissue intensity variability in volumetric scans. Local textural fractal descriptors - which are invariant to affine intensity changes - are extracted from volumetric patches at different spatial resolutions from voxel lattice-based generated shape and scale Nakagami parameters. Using ultrasound radio-frequency datasets we found that after applying an adaptive fractal decomposition label transfer approach on top of the generated Nakagami voxels, tissue characterization results were superior to the state of art. Experimental results on real 3D ultrasonic pre-clinical and clinical datasets suggest that describing tumor intra-heterogeneity via this descriptor may facilitate improved prediction of therapy response and disease characterization.
Translating Pharmacogenomics: Challenges on the Road to the Clinic
Authors: Jesse J Swen, Tom W Huizinga, Hans Gelderblom, Elisabeth G. E de Vries, Willem J. J Assendelft, Julia Kirchheiner, Henk-Jan Guchelaar
Journal: PLoS Medicine (2007)

Pharmacogenomics is one of the first clinical applications of the postgenomic era. It promises personalized medicine rather than the established "one size fits all" approach to drugs and dosages. The expected reduction in trial and error should ultimately lead to more efficient and safer drug therapy. In recent years, commercially available pharmacogenomic tests have been approved by the Food and Drug Administration (FDA), but their application in patient care remains very limited. More generally, the implementation of pharmacogenomics in routine clinical practice presents significant challenges. This article presents specific clinical examples of such challenges and discusses how obstacles to implementation of pharmacogenomic testing can be addressed.
Substance P Targets Sympathetic Control Neurons in the Paraventricular Nucleus
Authors: Matthew D. Womack, Richard Morris, Thomas C. Gent, Richard Barrett-Jolley
Journal: Circulation Research (2007)

The paraventricular nucleus (PVN) contains spinally-projecting neurons implicated in fine-tuning the cardiovascular system. In vivo activity of "presympathetic" parvocellular neurons is suppressed by tonic inhibition from GABA-ergic inputs, inhibition of which increases sympathetic pressor activity and heart rate. Targeting of this specific neuronal population could potentially limit elevations of heart rate and blood pressure associated with disease. Here we show, for the first time, that "presympathetic" PVN neurons are disinhibited by the neuropeptide substance P (SP) acting via tachykinin NK1 receptor inhibition of GABA(A) currents. Application of SP to the paraventricular nucleus of rats increases heart rate and blood pressure. In in vitro brain slice experiments, in the presence of GABA, 1 micromol/L SP increased action current frequency by a factor of 2.7+/-0.6 (n=5, P< or =0.05, ANOVA). Furthermore, 1 micromol/L SP inhibited GABA(A) currents by 70+/-8% (n=8, P< or =0.005 paired t test). These effects were abolished by NK1 antagonists, but not NK2 and NK3 antagonists. GABA(A) inhibition was not reproduced by NK2 or NK3 agonists. The inhibition of parvocellular GABA(A) currents by SP was also abolished by a protein kinase C (PKC) inhibitor peptide and mimicked by application of phorbol-12-myristate-13-acetate (PMA), implicating a PKC-dependent mechanism. Single-channel analysis indicates that SP acts through reduction of channel mean open-time (cmot): GABA(A) cmot being reduced by approximately 60% by SP (P< or =0.05 ANOVA, Bonferroni). These data suggest that tachykinins mediate their pressor activity by increasing the excitability of spinally-projecting neurons and identifies NK1 receptors as potential targets for therapeutic modulation of the cardiovascular system.
Blockade of canonical Wnt signalling ameliorates experimental dermal fibrosis
Authors: Christian Beyer, Helena Reichert, Hümeyra Akan, Tatjana Mallano, Amelie Schramm, Clara Dees, Katrin Palumbo-Zerr, Neng Yu Lin, Alfiya Distler, Kolja Gelse, John Varga, Oliver Distler, Georg Schett, Jörg H W Distler
Journal: Annals of the Rheumatic Diseases (2013)

Background and objectives Fibrosis is a major socioeconomic burden, but effective antifibrotic therapies are not available in the clinical routine. There is growing evidence for a central role of Wnt signalling in fibrotic diseases such as systemic sclerosis, and we therefore evaluated the translational potential of pharmacological Wnt inhibition in experimental dermal fibrosis. Methods We examined the antifibrotic effects of PKF118-310 and ICG-001, two novel inhibitors of downstream canonical Wnt signalling, in the models of prevention and treatment of bleomycin-induced dermal fibrosis as well as in experimental dermal fibrosis induced by adenoviral overexpression of a constitutively active transforming growth factor (TGF)-β receptor I. Results PKF118-310 and ICG-001 were well tolerated throughout all experiments. Both therapeutic approaches showed antifibrotic effects in preventing and reversing bleomycin-induced dermal fibrosis as measured by skin thickness, hydroxyproline content and myofibroblast counts. PKF118-310 and ICG-001 were effective in inhibiting TGF-β receptor I-driven fibrosis as assessed by the same outcome measures. Conclusions Blockade of canonical Wnt signalling by PKF118-310 and ICG-001 showed antifibrotic effects in different models of skin fibrosis. Both therapies were well tolerated. Although further experimental evidence for efficacy and tolerability is necessary, inhibition of canonical Wnt signalling is a promising treatment approach for fibrosis.