tbuckley/cabot-search huggingface dataset:
Human Molecular Genetic and Functional Studies Identify <i>TRIM63</i> , Encoding Muscle RING Finger Protein 1, as a Novel Gene for Human Hypertrophic Cardiomyopathy
Authors: Suet Nee Chen, Grazyna Czernuszewicz, Yanli Tan, Raffaella Lombardi, Jianping Jin, James T. Willerson, Ali J. Marian
Journal: Circulation Research (2012)

Rationale: A delicate balance between protein synthesis and degradation maintains cardiac size and function. TRIM63 encoding Muscle RING Finger 1 (MuRF1) maintains muscle protein homeostasis by tagging the sarcomere proteins with ubiquitin for subsequent degradation by the ubiquitin-proteasome system (UPS). Objective: To determine the pathogenic role of TRIM63 in human hypertrophic cardiomyopathy (HCM). Methods and Results: Sequencing of TRIM63 gene in 302 HCM probands (250 white individuals) and 339 control subjects (262 white individuals) led to identification of 2 missense (p.A48V and p.I130M) and a deletion (p.Q247*) variants exclusively in the HCM probands. These 3 variants were absent in 751 additional control subjects screened by TaqMan assays. Likewise, rare variants were enriched in the white HCM population (11/250, 4.4% versus 3/262, 1.1%, respectively, P =0.024). Expression of the mutant TRIM63 was associated with mislocalization of TRIM63 to sarcomere Z disks, impaired auto-ubiquitination, reduced ubiquitination and UPS-mediated degradation of myosin heavy chain 6, cardiac myosin binding protein C, calcineurin (PPP3CB), and p-MTOR in adult cardiac myocytes. Induced expression of the mutant TRIM63 in the mouse heart was associated with cardiac hypertrophy, activation of the MTOR-S6K and calcineurin pathways, and expression of the hypertrophic markers, which were normalized on turning off expression of the mutant protein. Conclusions: TRIM63 mutations, identified in patients with HCM, impart loss-of-function effects on E3 ligase activity and are probably causal mutations in HCM. The findings implicate impaired protein degradation in the pathogenesis of HCM.
Phase I Study of the Humanized Antiepidermal Growth Factor Receptor Monoclonal Antibody EMD72000 in Patients With Advanced Solid Tumors That Express the Epidermal Growth Factor Receptor
Authors: Udo Vanhoefer, Mitra Tewes, Federico Rojo, Olaf Dirsch, Norbert Schleucher, Oliver Rosen, Joachim Tillner, Andreas Kovar, Ada H. Braun, Tanja Trarbach, Siegfried Seeber, Andreas Harstrick, José Baselga
Journal: Journal of Clinical Oncology (2003)

Purpose To investigate the safety and tolerability and to explore the pharmacokinetic and pharmacodynamic profile of the humanized antiepidermal growth factor receptor monoclonal antibody EMD72000 in patients with solid tumors that express epidermal growth factor receptor (EGFR). Patients and Methods This was a phase I dose-escalation trial of EMD72000 in patients with advanced, EGFR-positive, solid malignancies that were not amenable to any established chemotherapy or radiotherapy treatment. EMD72000 was administered weekly without routine premedication until disease progression or unacceptable toxicity. Results Twenty-two patients were treated with EMD72000 at five different dose levels (400 to 2,000 mg/wk). National Cancer Institute common toxicity criteria grade 3 headache and fever occurring after the first infusion were dose limiting at 2,000 mg/wk; thus, the maximum-tolerated dose was 1,600 mg/wk. No other severe side effects, especially no allergic reactions or diarrhea, were observed. Acneiform skin reaction was the most common toxicity, but it was mild, with grade 1 in 11 patients (50%) and grade 2 in three patients (14%). Pharmacokinetic analyses demonstrated a predictable pharmacokinetic profile for EMD72000 . Pharmacodynamic studies on serial skin biopsies revealed that EMD72000 effectively abrogated EGFR-mediated cell signaling (eg, reduced phosphorylation of EGFR and mitogen-activated protein kinase), with no alteration in total EGFR protein. Objective responses (23%; 95% CI, 8% to 45%) and disease stabilization (27%; 95% CI, 11% to 50%) were achieved at all dose levels, and responding patients received treatment for up to 18 months without cumulative toxicity. Conclusion Treatment with EMD72000 was well tolerated and showed evidence of activity in heavily pretreated patients with EGFR-expressing tumors. EMD72000 at the investigated doses significantly inhibited downstream EGFR-dependent processes.
Hepatitis C virus infection with peripheral neuropathy is not always associated with cryoglobulinaemia
Authors: O Lidove
Journal: Annals of the Rheumatic Diseases (2001)

<h3>OBJECTIVES</h3> To describe cases of peripheral neuropathy associated with chronic hepatitis C virus infection without mixed cryoglobulinaemia. <h3>METHODS</h3> Four cases of peripheral neuropathy associated with chronic hepatitis C virus infection with persistent negativity of mixed cryoglobulinaemia were found. <h3>RESULTS</h3> All patients had small increases of transaminase levels and a positive viraemia. Liver biopsy showed chronic active hepatitis in all but one case (Knodell 4–9, Metavir A0F0-A3F3). Neuromuscular biopsy showed axonal neuropathy associated with lymphoid infiltrates around small vessels in two cases. Rheumatoid factor was always negative and C4 complement level was always normal. In three patients, neuropathy improved with interferon α, interferon α + ursodesoxycholic acid, or steroids + plasma exchange. <h3>CONCLUSION</h3> Peripheral neuropathy may be associated with hepatitis C virus infection without mixed cryoglobulinaemia.
The sleep apnoea/hypopnoea syndrome depresses waking vagal tone independent of sympathetic activation
Authors: M.F. Hilton, M.J. Chappell, W.A. Bartlett, A. Malhotra, J.M. Beattie, R.M. Cayton
Journal: European Respiratory Journal (2001)

The modest daytime hypertension and sympathetic upregulation associated with the sleep apnoea/hypopnoea syndrome (SAHS), does not explain the relatively large increased risk of cardiac morbidity and mortality in the SAHS patients population. Therefore, efferent vagal and sympathetic activity was evaluated during wakefulness in SAHS subjects and matched healthy controls, in order to determine if vagal downregulation may play a role in the aetiology of cardiac disease in the SAHS. The awake autonomic nervous system function of 15 male subjects, with mild-to-moderate SAHS was compared to that of 14 healthy controls matched for age, body mass index, gender and blood pressure. All subjects were free from comorbidity. Vagal activity was estimated from measurements of heart rate variability high frequency power (HF) and sympathetic activity was measured from urine catecholamine excretion. The %HF power was significantly (p < 0.03) reduced in SAHS patients (10+/-1.6 (mean+/-SEM)) as compared to controls (17 +/- 3). In addition, HF power correlated with the apnoea/hypopnoea index in the SAHS subjects (R = -0.592, p = 0.02). There was no statistically significant difference in the daytime excretion of nonadrenaline between control (242 +/- 30 nmol x collection(-1)) and SAHS (316 +/- 46 nmol x collection(-1)) subjects (p = 0.38). In these sleep apnoea/hypopnoea syndrome patients there was limited evidence of increased waking levels of urine catecholamines. The principal component altering waking autonomic nervous system function, in the sleep apnoea/hypopnoea syndrome subjects, was a reduced daytime efferent vagal tone.
Cross-Sectional Volumetric Analysis of Brain Atrophy in Alcohol Dependence: Effects of Drinking History and Comorbid Substance Use Disorder
Authors: James M. Bjork, Steven J. Grant, Daniel W. Hommer
Journal: American Journal of Psychiatry (2003)

OBJECTIVE: The authors assessed whether individual differences in drinking history as well as lifetime incidence of comorbid cocaine or marijuana use disorder underlie differential patterns of brain atrophy in subjects with alcohol dependence. METHOD: Segmented magnetic resonance images were used to compare whole brain cerebral gray matter and white matter in 134 male subjects age 30–50 with alcohol dependence, either alone or with comorbid cocaine or marijuana use disorder. RESULTS: Across all subjects, drinking history variables correlated negatively with both gray matter and white matter after age was controlled. Alcohol-dependent subjects with no comorbid substance use disorder (N=51) showed a steeper negative correlation between age and the gray matter/white matter ratio than did alcohol-dependent subjects with a comorbid lifetime cocaine use disorder diagnosis (N=50). Alcohol-dependent subjects with comorbid cocaine use disorder tended to have a steeper negative correlation between age and white matter (adjusted for intracranial volume) than did alcohol-dependent subjects with no comorbid substance use disorder. After age and the greater estimated cumulative alcohol consumption of alcohol-dependent subjects with comorbid cocaine use disorder were controlled in a multiple regression analysis, however, comorbid cocaine use disorder did not account for any independent variance in any volumetric measure. CONCLUSIONS: Brain atrophy among subjects with alcohol dependence reflects individual differences in exposure to alcohol, and the data provide mixed evidence that comorbid cocaine use disorder may exacerbate white matter atrophy in alcoholism.
Interaction of α9β1 Integrin With Thrombospondin-1 Promotes Angiogenesis
Authors: Izabela Staniszewska, Shachi Zaveri, Luis Del Valle, Isabela Oliva, Vicki L. Rothman, Sidney E. Croul, David D. Roberts, Deane F. Mosher, George P. Tuszynski, Cezary Marcinkiewicz
Journal: Circulation Research (2007)

Thrombospondin-1 is a multifunctional protein interacting with several cell surface receptors including integrins. We found that it is a ligand for α9β1 integrin, and has an integrin binding site within its N-terminal domain (NoC1). Interaction of thrombospondin-1 and its recombinant NoC1 domain with α9β1 integrin was confirmed in ELISA and cell adhesion assays. Binding of NoC1 to cells expressing α9β1 integrin activated signaling proteins such as Erk1/2 and paxillin. Blocking of this integrin by monoclonal antibody and the met-leu-asp-disintegrin inhibited dermal human microvascular endothelial cell proliferation and NoC1-induced migration of these cells. Immunohistochemical studies revealed that α9β1 is expressed on microvascular endothelium in several organs including skin, lung, heart and brain. NoC1 induced neovascularization in an experimental quail chorioallantoic membrane system and Matrigel plug formation assay in mice. This proangiogenic activity of NoC1 in vivo was inhibited by α9β1 inhibitors. In summary, our results revealed that α9β1 integrin expressed on microvascular endothelial cells interacts with thrombospondin-1, and this interaction is involved in modulation of angiogenesis.
Pulsed dye laser vs. intense pulsed light for port-wine stains: a randomized side-by-side trial with blinded response evaluation
Authors: A. Faurschou, K. Togsverd-Bo, C. Zachariae, M. Haedersdal
Journal: British Journal of Dermatology (2008)

Pulsed dye lasers (PDLs) are considered the treatment of choice for port-wine stains (PWS). Studies have suggested broadband intense pulsed light (IPL) to be efficient as well. So far, no studies have directly compared the PDL with IPL in a randomized clinical trial.To compare efficacy and adverse events of PDL and IPL in an intraindividual randomized clinical trial.Twenty patients with PWS (face, trunk, extremities; pink, red and purple colours; skin types I-III) received one side-by-side treatment with PDL (V-beam Perfecta, 595 nm, 0.45-1.5 ms; Candela Laser Corporation, Wayland, MA, U.S.A.) and IPL (StarLux, Lux G prototype handpiece, 500-670 and 870-1400 nm, 5-10 ms; Palomar Medical Technologies, Burlington, MA, U.S.A.). Settings depended on the preoperative lesional colour. Treatment outcome was evaluated by blinded, clinical evaluations and by skin reflectance measurements.Both PDL and IPL lightened PWS. Median clinical improvements were significantly better for PDL (65%) than IPL (30%) (P = 0.0004). A higher proportion of patients obtained good or excellent clearance rates with the PDL (75%) compared with IPL (30%) (P = 0.0104). Skin reflectance also documented better results after PDL (33% lightening) than IPL (12% lightening) (P = 0.002). Eighteen of 20 patients preferred to receive continued treatments with PDL (P = 0.0004). No adverse events were observed with PDL or IPL.Both the specific PDL and IPL types of equipment used in this study lightened PWS and both were safe with no adverse events. However, the PDL conveyed the advantages of better efficacy and higher patient preference.
Canine scent detection in the diagnosis of lung cancer: revisiting a puzzling phenomenon
Authors: R. Ehmann, E. Boedeker, U. Friedrich, J. Sagert, J. Dippon, G. Friedel, T. Walles
Journal: European Respiratory Journal (2011)

Patient prognosis in lung cancer largely depends on early diagnosis. The exhaled breath of patients may represent the ideal specimen for future lung cancer screening. However, the clinical applicability of current diagnostic sensor technologies based on signal pattern analysis remains incalculable due to their inability to identify a clear target. To test the robustness of the presence of a so far unknown volatile organic compound in the breath of patients with lung cancer, sniffer dogs were applied. Exhalation samples of 220 volunteers (healthy individuals, confirmed lung cancer or chronic obstructive pulmonary disease (COPD)) were presented to sniffer dogs following a rigid scientific protocol. Patient history, drug administration and clinicopathological data were analysed to identify potential bias or confounders. Lung cancer was identified with an overall sensitivity of 71% and a specificity of 93%. Lung cancer detection was independent from COPD and the presence of tobacco smoke and food odours. Logistic regression identified two drugs as potential confounders. It must be assumed that a robust and specific volatile organic compound (or pattern) is present in the breath of patients with lung cancer. Additional research efforts are required to overcome the current technical limitations of electronic sensor technologies to engineer a clinically applicable screening tool.
A meta-analysis of impact exercise on postmenopausal bone loss: the case for mixed loading exercise programmes
Authors: M Martyn-St James, S Carroll
Journal: British Journal of Sports Medicine (2008)

Objectives: To assess the effects of differing impact exercise protocols on postmenopausal bone loss at the hip and spine. Design: Systematic review and meta-analysis. Data sources: Electronic bibliographic databases, key journals and reference lists of reviews and articles. Review methods: Two independent reviewers assessed controlled trials evaluating effects of impact exercise on lumbar spine, femoral neck and total hip bone mineral density (BMD) in postmenopausal women for inclusion. Heterogeneity amongst trials and publication bias were assessed. Trial quality assessment was also performed. Results: Impact protocols that included jogging mixed with walking and stair climbing, and protocols that incorporated impact exercise with high-magnitude loading (resistance exercises), were effective at lumbar spine (weighted mean difference (random effects) 0.025 g/cm 2 95% CI (0.004 to 0.046) and 0.016 g/cm 2 95% CI (0.005 to 0.027); p = 0.02 and p = 0.005 respectively), although heterogeneity was evident ( I 2 = 88% and I 2 = 73%, where I 2 measures the extent of inconsistency among the trials). Effects on femoral neck BMD following these types of protocols were significant (weighted mean difference (fixed effect) 0.022 g/cm 2 95% CI (0.014 to 0.030); p&lt;0.001 and 0.005 g/cm 2 95% CI (0.001 to 0.010); p = 0.03 respectively). High-impact only and odd-impact only protocols were ineffective in increasing BMD at any site. Conclusion: Mixed loading exercise programmes combining jogging with other low-impact loading activity and programmes mixing impact activity with high-magnitude exercise as resistance training appear effective in reducing postmenopausal bone loss at the hip and spine. Other forms of impact exercise appear less effective at preserving BMD in this population. However, diverse methodological and reporting discrepancies are evident in current published trials.
The Injury Fact Book
Authors: Joseph Greensher
Journal: JAMA (1992)

The second edition of<i>The Injury Fact Book</i>, while maintaining the structure of the first edition, updates knowledge and concepts on the injury problem in the United States. The inclusion of additional mortality data for the years 1980-1986 allows Susan Baker and team to compute and analyze more meaningful comparisons. In addition, chapters on sports and recreation, aviation, and large trucks have been added. Dr Baker has been at the forefront of change resulting in acceptance of injuries as the most serious public health problem facing developed societies. The result has been an increasing demand for action by the public, legislators, the media, and others who are influential in decision making. Choosing appropriately from varied strategies requires detailed information about products, people, and effective protection.<i>The Injury Fact Book</i>has been organized successfully to meet the need for broad detailed documentation presented so as to improve understanding of injuries and
Spatiotemporal spread of the 2014 outbreak of Ebola virus disease in Liberia and the effectiveness of non-pharmaceutical interventions: a computational modelling analysis
Authors: Stefano Merler, Marco Ajelli, Laura Fumanelli, Marcelo F C Gomes, Ana Pastore y Piontti, Luca Rossi, Dennis L Chao, Ira M Longini, M Elizabeth Halloran, Alessandro Vespignani
Journal: The Lancet Infectious Diseases (2015)
Embryonic endocrine pancreas and mature β cells acquire α and PP cell phenotypes upon Arx misexpression
Authors: Patrick Collombat, Jacob Hecksher-Sørensen, Jens Krull, Joachim Berger, Dietmar Riedel, Pedro L. Herrera, Palle Serup, Ahmed Mansouri
Journal: Journal of Clinical Investigation (2007)

Aristaless-related homeobox (Arx) was recently demonstrated to be involved in pancreatic α cell fate specification while simultaneously repressing the β and δ cell lineages. To establish whether Arx is not only necessary, but also sufficient to instruct the α cell fate in endocrine progenitors, we used a gain-of-function approach to generate mice conditionally misexpressing this factor. Mice with forced Arx expression in the embryonic pancreas or in developing islet cells developed a dramatic hyperglycemia and eventually died. Further analysis demonstrated a drastic loss of β and δ cells. Concurrently, a remarkable increase in the number of cells displaying α cell or, strikingly, pancreatic polypeptide (PP) cell features was observed. Notably, the ectopic expression of Arx induced in embryonic or adult β cells led to a loss of the β cell phenotype and a concomitant increase in a number of cells with α or PP cell characteristics. Combining quantitative real-time PCR and lineage-tracing experiments, we demonstrate that, in adult mice, the misexpression of Arx, rather than its overexpression, promotes a conversion of β cells into glucagon- or PP-producing cells in vivo. These results provide important insights into the complex mechanisms underlying proper pancreatic endocrine cell allocation and cell identity acquisition.
Simultaneous assessment of inflammation and epidermal proliferation in psoriatic plaques during long-term treatment with the vitamin D3 analogue MC903: modulations and interrelations
Authors: E. M. G. J. JONG, P. C. M. KERKHOF
Journal: British Journal of Dermatology (1991)

Journal Article Simultaneous assessment of inflammation and epidermal proliferation in psoriatic plaques during long‐term treatment with the vitamin D3 analogue MC903: modulations and interrelations Get access E. M. G. J. DE JONG, E. M. G. J. DE JONG Department of Dermatology, University of Nijmegen, The Netherlands Dr E. M. G. J. de Jong, Department of dermatology, University Hospital Nijmegen, Javastraat 104, 6524 MJ Nijmegen, The Netherlands. Search for other works by this author on: Oxford Academic Google Scholar P. C. M. VAN DE KERKHOF P. C. M. VAN DE KERKHOF Department of Dermatology, University of Nijmegen, The Netherlands Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 124, Issue 3, 1 March 1991, Pages 221–229, https://doi.org/10.1111/j.1365-2133.1991.tb00565.x Published: 01 March 1991
Autoantibodies from long-lived ‘memory’ plasma cells of NZB/W mice drive immune complex nephritis
Authors: Qingyu Cheng, Imtiaz M Mumtaz, Laleh Khodadadi, Andreas Radbruch, Bimba F Hoyer, Falk Hiepe
Journal: Annals of the Rheumatic Diseases (2013)

Objectives We have previously shown that both short- and long-lived plasma cells (PCs) significantly contribute to autoantibody production in NZB/W mice as a model of lupus nephritis. The aim of this study was to determine the role of autoreactive long-lived (memory) PCs refractory to immunosuppression and B cell depletion in the pathogenesis of systemic lupus erythematosus. Methods Splenic CD138+ antibody-secreting cells (ASCs) from &gt;6-month-old NZB/W mice with high titres of anti-dsDNA autoantibodies or from Balb/c mice 5 days after secondary immunisation with ovalbumin (OVA) were adoptively transferred to immunodeficient Rag1 −/− mice, in which the development of nephritis was investigated by measuring proteinuria. Total IgG and IgM as well as anti-dsDNA and anti-OVA antibody levels were followed up by ELISA. After 21 weeks the recipient mice were sacrificed so that PCs in spleen and bone marrow could be analysed using ELISPOT and flow cytometry and renal immunohistology performed. Results The adoptive transfer of NZB/W and anti-OVA ASCs resulted in the continuous generation of anti-dsDNA antibodies and anti-OVA antibodies, respectively, exclusively by long-lived PCs that had homed to the spleen and bone marrow of recipient Rag1 −/− mice. Rag1 −/− mice generating autoantibodies including anti-dsDNA had reduced survival, proteinuria and immune complex nephritis with C1q, C3, IgG and IgM deposits 21 weeks after transfer. Conclusions These findings demonstrate that autoantibodies exclusively secreted by long-lived (memory) PCs contribute to autoimmune pathology and should be considered as candidate targets for future therapeutic strategies.