tbuckley/cabot-search huggingface dataset:
Interleukin 1 and TLR ligands give enhanced cytokine production by their interaction with HMGB1
Authors: H. Sigridur Hreggvidsdottir, H. Wahamaa, T. Ostberg, H. Schierbeck, A. Aveberger, L. Klevenvall, U. Andersson, H. Erlandsson Harris
Journal: Annals of the Rheumatic Diseases (2010)

The proinflammatory protein HMGB1 was recently identified as a mediator of rheumatoid arthritis (RA) and of other inflammatory diseases. This is demonstrated by extracellular HMGB1 expression both in experimental models of arthritis and in synovial biopsies from patients with RA. Furthermore, intra-articular injection of HMGB1 causes destructive synovitis in mice and HMGB1-targeted treatment ameliorates experimental arthritis. Recent data have indicated that HMGB1 alone does not have proinflammatory properties while complexes of HMGB1 and the TLR ligands CpG DNA and lipopolysaccharide …
Mechanism of syncope in patients with positive adenosine triphosphate tests
Authors: Paolo Donateo, Michele Brignole, Carlo Menozzi, Nicola Bottoni, Paolo Alboni, Maurizio Dinelli, Attilio Del Rosso, Francesco Croci, Daniele Oddone, Alberto Solano, Enrico Puggioni
Journal: Journal of the American College of Cardiology (2002)
HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies
Authors: Christian A. Fernandez, Colton Smith, Wenjian Yang, Mihir Daté, Donald Bashford, Eric Larsen, W. Paul Bowman, Chengcheng Liu, Laura B. Ramsey, Tamara Chang, Victoria Turner, Mignon L. Loh, Elizabeth A. Raetz, Naomi J. Winick, Stephen P. Hunger, William L. Carroll, Suna Onengut-Gumuscu, Wei-Min Chen, Patrick Concannon, Stephen S. Rich, Paul Scheet, Sima Jeha, Ching-Hon Pui, William E. Evans, Meenakshi Devidas, Mary V. Relling
Journal: Blood (2014)
Cardiac Troponin I Phosphorylation Increases the Rate of Cardiac Muscle Relaxation
Authors: Ren Zhang, Jiaju Zhao, Alan Mandveno, James D. Potter
Journal: Circulation Research (1995)

Abstract Cardiac troponin (Tn) I (CTnI), compared with skeletal TnI, contains extra amino acids (32 to 33) at its amino terminus, including two adjacent serine residues. These two serine residues are believed to be phosphorylated by protein kinase A (PKA) upon stimulation of the heart by β-agonists. In this study, we found that phosphorylation of a cardiac skinned muscle preparation by PKA, mainly at CTnI, results in a decrease in the Ca 2+ sensitivity of muscle contraction. The pCa 50 decreased by ≈0.27±0.06 pCa units upon phosphorylation. To study cardiac muscle relaxation, we used diazo-2, a photolabile Ca 2+ chelator with a low Ca 2+ affinity in its intact form that is converted to a high-affinity form after photolysis. We found that the rate of cardiac muscle relaxation increased from a time of half-relaxation (t 1/2 )=110±10 milliseconds to t 1/2 =70±8 milliseconds after CTnI phosphorylation. This result demonstrates that CTnI phosphorylation can be linked with the increased rate of muscle relaxation in a relatively intact muscle preparation. Since CTnI phosphorylation has been shown previously to affect the Ca 2+ affinity and Ca 2+ off-rate of CTnC in vitro, it is likely that the faster relaxation seen here reflects faster dissociation of Ca 2+ from cardiac TnC (CTnC). Model calculations show that increased dissociation of Ca 2+ from CTnC, coupled with the faster uptake of Ca 2+ by the sarcoplasmic reticulum stimulated by PKA phosphorylation of phospholamban, can account for the faster relaxation seen in the inotropic response of the heart to catecholamines.
Somatic deletion of the NF1 gene in a neurofibromatosis type 1-associated malignant melanoma demonstrated by digital PCR.
Authors: Albert Rübben, Birke Bausch, Arjen Nikkels
Journal: Molecular Cancer (2006)

Neurofibromatosis type 1 (NF1) is the most common hereditary neurocutaneous disorder and it is associated with an elevated risk for malignant tumors of tissues derived from neural crest cells. The NF1 gene is considered a tumor suppressor gene and inactivation of both copies can be found in NF1-associated benign and malignant tumors. Melanocytes also derive from neural crest cells but melanoma incidence is not markedly elevated in NF1. In this study we could analyze a typical superficial spreading melanoma of a 15-year-old boy with NF1 for loss of heterozygosity (LOH) within the NF1 gene. Neurofibromatosis in this patient was transmitted by the boy's farther who carried the mutation NF1 c. 5546 G/A. Melanoma cells were isolated from formalin-fixed tissue by liquid coverslip laser microdissection. In order to obtain statistically significant LOH data, digital PCR was performed at the intragenic microsatellite IVS27AC28 with DNA of approx. 3500 melanoma cells. Digital PCR detected 23 paternal alleles and one maternal allele. Statistical analysis by SPRT confirmed significance of the maternal allele loss. To our knowledge, this is the first molecular evidence of inactivation of both copies of the NF1 gene in a typical superficial spreading melanoma of a patient with NF1. The classical double-hit inactivation of the NF1 gene suggests that the NF1 genetic background promoted melanoma genesis in this patient.
Cost effectiveness of adding magnetic resonance imaging to the usual management of suspected scaphoid fractures
Authors: S Brooks, F M Cicuttini, S Lim, D Taylor, S L Stuckey, A E Wluka
Journal: British Journal of Sports Medicine (2005)

Objective: To determine the cost effectiveness of a magnetic resonance imaging scan (MRI) within 5 days of injury compared with the usual management of occult scaphoid fracture. Methods: All patients with suspected scaphoid fractures in five hospitals were invited to participate in a randomised controlled trial of usual treatment with or without an MRI scan. Healthcare costs were compared, and a cost effectiveness analysis of the use of MRI in this scenario was performed. Results: Twenty eight of the 37 patients identified were randomised: 17 in the control group, 11 in the MRI group. The groups were similar at baseline and follow up in terms of number of scaphoid fractures, other injuries, pain, and function. Of the patients without fracture, the MRI group had significantly fewer days immobilised: a median of 3.0 (interquartile range 3.0–3.0) v 10.0 (7–12) in the control group (p = 0.006). The MRI group used fewer healthcare units (median 3.0, interquartile range 2.0–4.25) than the control group (5.0, 3.0–6.5) (p = 0.03 for the difference). However, the median cost of health care in the MRI group ($594.35 AUD, $551.35–667.23) was slightly higher than in the control group ($428.15, $124.40–702.65) (p = 0.19 for the difference). The mean incremental cost effectiveness ratio derived from this simulation was that MRI costs $44.37 per day saved from unnecessary immobilisation (95% confidence interval $4.29 to $101.02). An illustrative willingness to pay was calculated using a combination of the trials measure of the subjects’ individual productivity losses and the average daily earnings. Conclusions: Use of MRI in the management of occult scaphoid fracture reduces the number of days of unnecessary immobilisation and use of healthcare units. Healthcare costs increased non-significantly in relation to the use of MRI in this setting. However, when productivity losses are considered, MRI may be considered cost effective, depending on the individual case.
The Early Effect of Medicare's Prospective Payment System on the Use of Medical Intensive Care Services in Three Community Hospitals
Authors: S A Mayer-Oakes, R K Oye, B Leake, R H Brook
Journal: JAMA (1988)

To assess the impact of Medicare's prospective payment system (PPS) on patient care and outcome from the medical intensive care unit (MICU), we reviewed the medical records of 400 MICU patients from three community hospitals: 200 patients were admitted before the PPS and 200 were admitted after the PPS. We sampled Medicare patients, aged 65 years and over, and non-Medicare comparison patients, aged 50 to 64 years, collecting data on case-mix, treatment intensity and discharge disposition, hospital and six-month mortality, length of stay, and number of intensive care unit beds. After the PPS, the number of intensive care unit beds decreased 31%, without changes in MICU patients' illness severity or treatment intensity. Hospital length of stay decreased 15% in the Medicare group and 43% in the comparison group. For both Medicare and comparison patients combined, MICU length of stay decreased 14% and patients after the PPS were less likely to be discharged to go home. There were no significant changes in in-hospital or six-month mortality. Thus, clinically meaningful decreases in length of stay among seriously ill patients did not result in a change in in-hospital or six-month mortality. (<i>JAMA</i>1988;260:3146-3149)
Deletion of Lys224 in regulatory domain 4 of Factor H reveals a novel pathomechanism for dense deposit disease (MPGN II)
Authors: C. Licht, S. Heinen, M. Józsi, I. Löschmann, R.E. Saunders, S.J. Perkins, R. Waldherr, C. Skerka, M. Kirschfink, B. Hoppe, P.F. Zipfel
Journal: Kidney International (2006)
Another look at active rehabilitation for slow-to-recover sport-related concussion in children and adolescents: further evidence to support its effectiveness
Authors: Isabelle Gagnon
Journal: British Journal of Sports Medicine (2013)

Objective To explore and impact of a previously developed active rehabilitation intervention for children who are slow-to-recover after concussion. Design Prospective repeated measures design. Setting The Montreal Children's Hospital Concussion Clinic. Participants Ten children (three girls and seven boys, mean age 14.4±1.3 years) participated in this study. Intervention Participants who were still symptomatic 4 weeks after the injury were involved in the active rehabilitation intervention (mean time since injury=47 days). It involves gradual, closely monitored light aerobic exercise, general coordination exercises, mental imagery, as well as reassurance and stress/anxiety reduction strategies. The program continued until complete symptom resolution at rest, at which time children and adolescents were eligible to resume the standard return to sports protocol. Main Outcome Measurements Primary outcome was evolution of post-concussion symptoms. Secondary outcomes included mood and energy level as well as balance and cognitive function. Those were assessed at initiation and at the end of the rehabilitation. Results Change in functioning was found in all domains assessed including Symptoms, Balance, Fatigue and Depressive Symptoms. Cognitive function was within normal limits at the initiation of the intervention and remained unchanged. Average duration of the intervention was 45 days (range 14–72 days). Conclusions Although no control group was used in this pilot study, children's functioning is improved after participation in the active rehabilitation intervention. Clinical Relevance The introduction of graded light intensity exercise in the post-acute period post-concussion is feasible and appears to have benefits on children's functioning. Acknowledgements Participants and their families, Trauma Programs of the Montreal Children's Hospital-McGill University Health Center, Fonds de la recherche du Québec-Santé; Réseau provincial de recherche en adaptation-réadaptation. Competing interests None.
Effect of chronic Giardia lamblia infection on epithelial transport and barrier function in human duodenum
Authors: H. Troeger, H.-J. Epple, T. Schneider, U. Wahnschaffe, R. Ullrich, G.-D. Burchard, T. Jelinek, M. Zeitz, M. Fromm, J.-D. Schulzke
Journal: Gut (2006)

<b>Background:</b><i>Giardia lamblia</i> causes infection of the small intestine, which leads to malabsorption and chronic diarrhoea. <b>Aim:</b> To characterise the inherent pathomechanisms of <i>G lamblia</i> infection. <b>Methods:</b> Duodenal biopsy specimens from 13 patients with chronic giardiasis and from controls were obtained endoscopically. Short-circuit current (I<sub>SC</sub>) and mannitol fluxes were measured in miniaturised Ussing chambers. Epithelial and subepithelial resistances were determined by impedance spectroscopy. Mucosal morphometry was performed and tight junction proteins were characterised by immunoblotting. Apoptotic ratio was determined by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling staining. <b>Results:</b> In giardiasis, mucosal surface area per unit serosa area was decreased to 75% (3%) of control, as a result of which epithelial resistance should increase. Instead, epithelial resistance of giardiasis biopsy specimens was decreased (19 (2) vs 25 (2) Ω cm<sup>2</sup>; p&lt;0.05) whereas mannitol flux was not significantly altered (140 (27) vs 105 (16) nmol/h/cm<sup>2</sup>). As structural correlate, reduced claudin 1 expression and increased epithelial apoptosis were detected. Furthermore, basal I<sub>SC</sub> increased from 191 (20) in control to 261 (12) µA/h/cm<sup>2</sup> in giardiasis. The bumetanide-sensitive portion of I<sub>SC</sub> in giardiasis was also increased (51 (5) vs 20 (9) µA/h/cm<sup>2</sup> in control; p&lt;0.05). Finally, phlorizin-sensitive Na<sup>+</sup>–glucose symport was reduced in patients with giardiasis (121 (9) vs 83 (14) µA/h/cm<sup>2</sup>). <b>Conclusions:</b><i>G lamblia</i> infection causes epithelial barrier dysfunction owing to down regulation of the tight junction protein claudin 1 and increased epithelial apoptoses. Na<sup>+</sup>-dependent d-glucose absorption is impaired and active electrogenic anion secretion is activated. Thus, the mechanisms of diarrhoea in human chronic giardiasis comprise leak flux, malabsorptive and secretory components.
Blood Pressure and Fasting Plasma Glucose Rather Than Metabolic Syndrome Predict Coronary Artery Calcium Progression
Authors: Caroline K. Kramer, Denise von Mühlen, Jorge L. Gross, Gail A. Laughlin, Elizabeth Barrett-Connor
Journal: Diabetes Care (2008)

To examine the association of the metabolic syndrome, defined by World Health Organization (WHO) and Adult Treatment Panel III (ATP-III) criteria, and its components with coronary artery calcium (CAC) progression.Participants were 338 older community-dwelling men and women without known heart disease who had measurements of heart disease risk factors and CAC at two clinic visits within an average interval of 4.5 years. Progression was defined as an increase in total CAC volume score > or =2.5 mm(3).At baseline, mean age was 67.6 years; metabolic syndrome was present in 15.1% by WHO criteria and in 11.8% by ATP-III criteria, and 5.3% met both criteria. Participants with WHO-defined metabolic syndrome had a greater change in total CAC volume score than those without (P = 0.001). There was no significant difference in CAC volume change by ATP-III-defined metabolic syndrome status (P = 0.69). Overall, 46.4% of participants were CAC progressors. In logistic regression analyses adjusted for age, sex, smoking status, and LDL cholesterol, neither WHO-nor ATP-III-defined metabolic syndrome predicted CAC progression. Among metabolic syndrome components, only hypertension was independently associated with CAC progression (odds ratio 2.11 [95% CI 1.33-3.3], P = 0.002). Fasting blood glucose (>100 mg/dl) was an independent predictor of CAC progression, but only for the 118 participants younger than age 65 years (2.3 [1.01-5.5], P = 0.04).In older adults without known heart disease, blood pressure levels and fasting plasma glucose were better independent determinants of CAC progression than metabolic syndrome itself.
General practice---time for a new definition
Authors: F. Olesen
Journal: BMJ (2000)

Editorial by Heath and others 

After some 30 years of medical development focusing largely on hospitals, organ specialisation, and high technology, the 1960s saw the revitalisation of general practice (in some countries known as family practice—see note at the end of the article), allowing this field of medicine to develop into a cornerstone of the healthcare system. At the end of the millennium academic general practice is now established in all developed countries. General practice is recognised as a special discipline and in many countries as a medical specialty equally important as and complementary to other specialties. Participation in specific training programmes has therefore become mandatory for anyone who wishes to become a specialist in this field.

The time has come to reflect on the education of general practitioners, which depends on the scientific content of general practice. A proper starting point is to consider the ideal content of the discipline as it would be described in a definition.

#### Summary points

It is time to create a new definition of general practice based on the ideal content of the specialty

Any new definition should describe the core content and function of general practice and should supplement the description of the medical discipline

It should also be universal, not country specific

It should provide a framework for teaching and training and describe where to find evidence to support science based work

A new proposed definition fulfils these criteria, emphasising the need for general practitioners to be able to take a biomedical, psychological, and social approach to patients and their problems

Many definitions of primary care and general practice have been proposed.1-5One of the most frequently quoted is the Leeuwenhorst definition from 1974: “The general practitioner is a licensed medical graduate who gives personal, primary and continuing care to individuals, families and …
Modernizing Device Regulation
Authors: Alan M Garber
Journal: New England Journal of Medicine (2010)

The Food and Drug Administration (FDA) is known for its rigor in regulating drugs, not devices. That may be about to change. In recent years, well-publicized device recalls and lawsuits have led to complaints that the FDA does not do enough to keep unsafe devices off the market. The failure of some devices, such as implantable defibrillators, could pose deadly risks.Fundamental differences between devices and drugs have important implications for FDA regulation. A typical device is an engineered product, rather than a chemical compound like a conventional drug or a biologic agent. The effects of a minor modification in . . .
Viral Infection of Transgenic Mice Expressing a Viral Protein in Oligodendrocytes Leads to Chronic Central Nervous System Autoimmune Disease
Authors: Claire F. Evans, Marc S. Horwitz, Monte V. Hobbs, Michael B.A. Oldstone
Journal: The Journal of Experimental Medicine (1996)

One hypothesis for the etiology of central nervous system (CNS) autoimmune disease is that infection by a virus sharing antigenic epitopes with CNS antigens (molecular mimicry) elicits a virus-specific immune response that also recognizes self-epitopes. To address this hypothesis, transgenic mice were generated that express the nucleoprotein or glycoprotein of lymphocytic choriomeningitis virus (LCMV) as self in oligodendrocytes. Intraperitoneal infection with LCMV strain Armstrong led to infection of tissues in the periphery but not the CNS, and the virus was cleared within 7–14 d. After clearance, a chronic inflammation of the CNS resulted, accompanied by upregulation of CNS expression of MHC class I and II molecules. A second LCMV infection led to enhanced CNS pathology, characterized by loss of myelin and clinical motor dysfunction. Disease enhancement also occurred after a second infection with unrelated viruses that cross-activated LCMV-specific memory T cells. These findings indicate that chronic CNS autoimmune disease may be induced by infection with a virus sharing epitopes with a protein expressed in oligodendrocytes and this disease may be enhanced by a second infection with the same or an unrelated virus. These results may explain the association of several different viruses with some human autoimmune diseases.
Haemomediastinum in a haemophiliac after minor trauma
Authors: S. K. M. Jivani, J. R. Mann
Journal: Thorax (1970)

Haemomediastinum is a very rare complication in haemophilia. Its occurrence after a minor chest injury in a boy aged 11 years is described. Complete recovery followed conservative treatment, which consisted of the correction of the coagulation defect with cryoprecipitate-AHG for 11 days, and a blood transfusion.
The proteosome inhibitor MG132 attenuates retinoic acid receptor trans-activation and enhances trans-repression of nuclear factor kappaB. Potential relevance to chemo-preventive interventions with retinoids.
Authors: Valentine B Andela, Randy N Rosier
Journal: Molecular Cancer (2004)

Nuclear factor kappa B (NFκB) is a pro-malignant transcription factor with reciprocal effects on pro-metastatic and anti-metastatic gene expression. Interestingly, NFκB blockade results in the reciprocal induction of retinoic acid receptors (RARs). Given the established property of RARs as negative regulators of malignant progression, we postulated that reciprocal interactions between NFκB and RARs constitute a signaling module in metastatic gene expression and malignant progression. Using Line 1 tumor cells as a model for signal regulation of metastatic gene expression, we investigated the reciprocal interactions between NFκB and RARs in response to the pan-RAR agonist, all-trans retinoic acid (at-RA) and the pan-RAR antagonist, AGN193109. At-RA [0.1–1 μM] dose-dependently activated RAR and coordinately trans-repressed NFκB, while AGN193109 [1–10 μM] dose-dependently antagonized the effects of at-RA. At-RA and AGN193109 reciprocally regulate pro-metastatic matrix metalloprotease 9 (MMP 9) and its endogenous inhibitor, the tissue inhibitor of metalloprotease 1 (TIMP 1), in a manner consistent with the putative roles of NFκB and RAR in malignant progression. Activation of RAR concurs with its ubiquitination and proteosomal degradation. Accordingly, the proteosome inhibitor, MG132 [5 μM], blocked RAR degradation, quelled RAR trans-activation and enhanced RAR trans-repression of NFκB. We conclude that reciprocal interactions between NFκB and RARs constitute a signaling module in metastatic gene expression and malignant progression and propose that the dissociative effect of proteosome inhibitors could be harnessed towards enhancing the anticancer activity of retinoids.
HIF-2α Enhances β-Catenin/TCF-Driven Transcription by Interacting with β-Catenin
Authors: Hyunsung Choi, Yang-Sook Chun, Tae-You Kim, Jong-Wan Park
Journal: Cancer Research (2010)

Abstract The tumor-promoting factors β-catenin and hypoxia-inducible factor (HIF) are often found to be coactivated in rapidly growing tumors. Recently, it was shown that HIF-1α negatively regulates Wnt/β-catenin signaling by sequestering β-catenin from β-catenin/T-cell factor (TCF). However, no investigation has been undertaken on the involvement of HIF-2α in β-catenin regulation. In this study, it was found that, like HIF-1α, HIF-2α interacts with β-catenin, but at a different site. Furthermore, HIF-2α was found to assemble with β-catenin/TCF and facilitate gene transcription. Mutational analyses revealed that transactivation domains of HIF-2α promote p300 coactivator recruitment by β-catenin. Furthermore, HIF-2α and β-catenin were found to associate in the nuclei of 786-0 renal cell carcinoma cells, and HIF-2α was found to be required for β-catenin activation in these cells and for their proliferation. These results suggest that this interaction contributes to the unrestrained growth of tumor cells containing coactivated HIF-2α and β-catenin. Interestingly, these actions of HIF-2α oppose those of HIF-1α on β-catenin and cell growth, and this suggests that HIF-1α/HIF-2α balance may importantly determine cell growth when hypoxia and Wnt stimulation coexist. Cancer Res; 70(24); 10101–11. ©2010 AACR.