tbuckley/cabot-search huggingface dataset:
Effects of intensive multiple risk factor reduction on coronary atherosclerosis and clinical cardiac events in men and women with coronary artery disease. The Stanford Coronary Risk Intervention Project (SCRIP).
Authors: W L Haskell, E L Alderman, J M Fair, D J Maron, S F Mackey, H R Superko, P T Williams, I M Johnstone, M A Champagne, R M Krauss
Journal: Circulation (1994)

BACKGROUND Recent clinical trials have shown that modification of plasma lipoprotein concentrations can favorably alter progression of coronary atherosclerosis, but no data exist on the effects of a comprehensive program of risk reduction involving both changes in lifestyle and medications. This study tested the hypothesis that intensive multiple risk factor reduction over 4 years would significantly reduce the rate of progression of atherosclerosis in the coronary arteries of men and women compared with subjects randomly assigned to the usual care of their physician. METHODS AND RESULTS Three hundred men (n = 259) and women (n = 41) (mean age, 56 +/- 7.4 years) with angiographically defined coronary atherosclerosis were randomly assigned to usual care (n = 155) or multifactor risk reduction (n = 145). Patients assigned to risk reduction were provided individualized programs involving a low-fat and -cholesterol diet, exercise, weight loss, smoking cessation, and medications to favorably alter lipoprotein profiles. Computer-assisted quantitative coronary arteriography was performed at baseline and after 4 years. The main angiographic outcome was the rate of change in the minimal diameter of diseased segments. All subjects underwent medical and risk factor evaluations at baseline and yearly for 4 years, and reasons for all hospitalizations and deaths were documented. Of the 300 subjects randomized, 274 (91.3%) completed a follow-up arteriogram, and 246 (82%) had comparative measurements of segments with visible disease at baseline and follow-up. Intensive risk reduction resulted in highly significant improvements in various risk factors, including low-density lipoprotein cholesterol and apolipoprotein B (both, 22%), high-density lipoprotein cholesterol (+12%), plasma triglycerides (-20%), body weight (-4%), exercise capacity (+20%), and intake of dietary fat (-24%) and cholesterol (-40%) compared with relatively small changes in the usual-care group. No change was observed in lipoprotein(a) in either group. The risk-reduction group showed a rate of narrowing of diseased coronary artery segments that was 47% less than that for subjects in the usual-care group (change in minimal diameter, -0.024 +/- 0.066 mm/y versus -0.045 +/- 0.073 mm/y; P &lt; .02, two-tailed). Three deaths occurred in each group. There were 25 hospitalizations in the risk-reduction group initiated by clinical cardiac events compared with 44 in the usual-care group (rate ratio, 0.61; P = .05; 95% confidence interval, 0.4 to 0.9). CONCLUSIONS Intensive multifactor risk reduction conducted over 4 years favorably altered the rate of luminal narrowing in coronary arteries of men and women with coronary artery disease and decreased hospitalizations for clinical cardiac events.
N-acetylcysteine reduces the size and activity of von Willebrand factor in human plasma and mice
Authors: Junmei Chen, Adili Reheman, Francisca C. Gushiken, Leticia Nolasco, Xiaoyun Fu, Joel L. Moake, Heyu Ni, José A. López
Journal: Journal of Clinical Investigation (2011)

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease characterized by systemic microvascular thrombosis caused by adhesion of platelets to ultra-large vWF (ULVWF) multimers. These multimers accumulate because of a deficiency of the processing enzyme ADAMTS13. vWF protein forms long multimers from homodimers that first form through C-terminal disulfide bonds and then join through their N termini by further disulfide bonding. N-acetylcysteine (NAC) is an FDA-approved drug that has long been used to treat chronic obstructive lung disease and acetaminophen toxicity and is known to function in the former disorder by reducing mucin multimers. Here, we examined whether NAC could reduce vWF multimers, which polymerize in a manner similar to mucins. In vitro, NAC reduced soluble plasma-type vWF multimers in a concentration-dependent manner and rapidly degraded ULVWF multimer strings extruded from activated ECs. The effect was preceded by reduction of the intrachain disulfide bond encompassing the platelet-binding A1 domain. NAC also inhibited vWF-dependent platelet aggregation and collagen binding. Injection of NAC into ADAMTS13-deficient mice led to the rapid resolution of thrombi produced by ionophore treatment of the mesenteric venules and reduced plasma vWF multimers. These results suggest that NAC may be a rapid and effective treatment for patients with TTP.
Prognostic Factors in Cirrhosis Identified by Cox's Regression Model
Authors: Poul Schlichting, Erik Christensen, Per K. Andersen, Lis Fauerholdt, Erik Juhl, Hemming Poulsen, Niels Tygstrup
Journal: Hepatology (1983)

In a controlled clinical trial in 488 patients with chronic liver disease treated with prednisone or placebo, survival data were analyzed using Cox's proportional hazards model. A total of 162 variables were screened separately for prognostic and/or therapeutic effect by log-rank analyses, whereby 46 clinical, biochemical, serological, and histological variables were isolated. Another five variables traditionally found to be important in patients with liver disease were included. After extensively checking the assumptions of the model, the 51 variables were, by a step-wise procedure, reduced to a final model. It comprised, besides a treatment indicator, 12 variables with significant (p &lt; 0.05) prognostic or therapeutic effect. The following eight variables had a significant prognostic effect: sex, age, prothrombin, acetylcholinesterase, eosinophil leucocytes in liver parenchyma, liver cell necrosis, inflammation in liver connective tissue, and efferent veins in parenchymal nodules. A prognostic index based on the final model is formed allowing calculation of 5 years survival probability. The usefulness of the prognostic index was tested by a cross-validation method, and no statistical significant difference was found between the estimated and observed survivorship functions.
Lymphocyte called home: β2-adreneric neurotransmission confines T cells to lymph nodes to suppress inflammation
Authors: Kevin J. Tracey
Journal: The Journal of Experimental Medicine (2014)

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Insight from Kevin Tracey



The immune and nervous systems sense changes in the environment, mobilize host responses, and establish memories of threatening events. In this issue, an important study by [Nakai et al.][2] using experimental models of T cell inflammation shows that
Elevated expression of the metabolic regulator receptor-interacting protein 140 results in cardiac hypertrophy and impaired cardiac function
Authors: Asmaà Fritah, Jennifer H. Steel, Donna Nichol, Nadeene Parker, Sharron Williams, Anthony Price, Leena Strauss, Timothy A. Ryder, Margaret A. Mobberley, Matti Poutanen, Malcolm Parker, Roger White
Journal: Cardiovascular Research (2010)

Receptor-interacting protein 140 (RIP140) is a ligand-dependent cofactor for nuclear receptors that regulate networks of genes involved in cellular processes, including metabolism. An important role for RIP140 in metabolic control has been identified in RIP140 null mice, whose phenotypes include derepression of genes involved in energy mobilization or catabolism in adipocytes and a switch to more oxidative fibres in skeletal muscle. We hypothesized that ubiquitous expression of RIP140 would suppress metabolic processes, leading to defects in development or cellular function. The primary effect of exogenous expression of RIP140 mRNA (real-time PCR) and protein (western blotting) in transgenic mice is impaired postnatal heart function. There was rapid onset of cardiac hypertrophy and ventricular fibrosis, detected microscopically, in male RIP140 transgenic mice from 4 weeks of age, resulting in 25% mortality by 5 months. RIP140 exogenous expression in the heart leads to decreased mitochondria state III and state IV membrane potential and oxygen consumption. Quantitative PCR showed more than 50% reduced expression of genes involved in mitochondrial activity and fatty acid metabolism, including mitochondrial transcription factor A, cytochrome oxidase VIIa, cytochrome XII, CD36, medium-chain acyl dehydrogenase, and fatty acid transport protein, many of which are known targets for nuclear receptors, including peroxisome proliferator-activated receptors PPARα and PPARδ and oestrogen-related receptors ERRα and ERRγ. This study demonstrates that RIP140 is an important cofactor in postnatal cardiac function and that inhibition of the action of RIP140 may provide a model system to investigate specific interventions designed to prevent or delay the onset of cardiac disease.
Is There a Link Between Components of Health-Related Functioning and Incident Impaired Glucose Metabolism and Type 2 Diabetes?
Authors: Robyn J. Tapp, Adrienne O'Neil, Jonathan E. Shaw, Paul Z. Zimmet, Brian F. Oldenburg
Journal: Diabetes Care (2009)

OBJECTIVE To determine the longitudinal association of components of health-related functioning (HRF) with incident impaired glucose metabolism and type 2 diabetes. RESEARCH DESIGN AND METHODS The Australian Diabetes Obesity and Lifestyle (AusDiab) study is a national, longitudinal study of adults aged ≥25 years from 42 randomly selected areas of Australia. Diabetes status was defined using the World Health Organization criteria, and HRF was assessed using the SF-36 questionnaire in 1999–2000 and 2004–2005. RESULTS Incident impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and newly diagnosed type 2 diabetes were associated with increased bodily pain at baseline compared with those with normal glucose tolerance (NGT) (IFG P = 0.005, IGT P &amp;lt; 0.004, and newly diagnosed type 2 diabetes P = 0.005), after adjustment. In addition, those with incident IGT and newly diagnosed type 2 diabetes had significantly reduced physical functioning, general health, mental health, and vitality at baseline compared with those with NGT. After we controlled for factors associated with incident diabetes, those in the lowest quartile of the physical component summary scale at baseline had at least a 50% higher risk of progression to impaired glucose metabolism and diabetes 5 years later. CONCLUSIONS These findings show that incident IFG, IGT, and newly diagnosed type 2 diabetes are associated with reduced HRF independent of cardiovascular disease and that this is evident before the onset of these conditions. If future health promotion campaigns are to effectively target those at high risk of developing diabetes, an understanding of the process of declining health before onset of the disease is essential.
Polyarteritis nodosa with pulmonary vasculitis.
Authors: J Nick, R Tuder, R May, J Fisher
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

Although early postmortem series reported pulmonary involvement as a relatively common manifestation of polyarteritis nodosa (PAN), using the modern classification of PAN pulmonary involvement is very uncommon. A 62-yr-old male with well-documented classic PAN was found to have an arteritis of medium-sized muscular pulmonary arteries. The patient subsequently demonstrated a complete response to treatment. Of the few reported cases of PAN with pulmonary manifestations, the majority are autopsy series and the vascular lesion involves the bronchial arteries. There are no case reports of patients with pulmonary involvement of PAN who responded successfully to treatment. This case is the first description of a premortum diagnosis of pulmonary arteritis in PAN in which the patient had a response to treatment.
Heparin use in continuous renal replacement procedures
Authors: J van de Wetering, R G Westendorp, J G van der Hoeven, B Stolk, J D Feuth, P C Chang
Journal: Journal of the American Society of Nephrology (1996)

Heparin is the most widely used anticoagulant in continuous renal replacement procedures but little is known about the balance between filter coagulation and patient hemorrhage during treatment. Filter survival and hemorrhagic complications during 240 filter periods in 78 critically ill patients, treated with continuous arteriovenous hemofiltration and hemodiafiltration, were studied for this article. The crude incidence of filter coagulation was 17.7 +/- 2.5 (mean +/- SE) per 1000 h at an activated partial thromboplastin time (APTT) of 15 to 35 s, as determined in systemic blood samples. The incidence of filter coagulation gradually decreased to 9.0 +/- 2.7 per 1000 h at an APTT of 45 to 55 s (P = 0.031). The crude incidence of patient hemorrhage was 2.9 +/- 1.0 per 1000 h at an APTT of 15 to 35 s and increased almost threefold to 7.4 +/- 2.4 per 1000 h when the APTT was 45 to 55 s (P = 0.009). There was no difference in filter survival between treatment with hemofiltration only and hemodiafiltration. Mean survival of acrylonitrile filters (33.8 +/- 4.3) was significantly lower compared with the survival of polyamide filters (104.1 +/- 14.4 h, P = 0.003). After adjustment for the type of the filter, mean arterial blood pressure, and platelet count, the risk for filter coagulation decreased 25% (relative risk, 0.77; 95% confidence interval [CI], 0.62 to 0.96) for every 10-s increase in APTT. At the same time, the risk for patient hemorrhage increased 50% (relative risk, 1.57; 95% CI, 1.43 to 1.72). The occurrence of filter coagulation or hemorrhages were not correlated with the administered dose of heparin. Concurrent use of coumarin derivatives had a positive effect on filter survival, without increasing the overall incidence of hemorrhages. It was concluded that the systemic APTT is a good predictor of the risk for filter coagulation and patient hemorrhage. Safety and efficacy of heparin therapy seems optimal at an APTT between 35 and 45 s.
Intrathecal Baclofen for Spasticity in Cerebral Palsy
Authors: A. Leland Albright
Journal: JAMA (1991)

Seventeen patients with congenital spastic cerebral palsy and six patients with other forms of spasticity were injected intrathecally with doses of placebo or baclofen, 25 micrograms, 50 micrograms, or 100 micrograms, in a randomized, double-blind manner. Muscle tone in the upper and lower extremities was assessed by Ashworth scores both before the injections and every 2 hours afterward for 8 hours. Function of the upper extremities was evaluated before the injections and 4 hours afterward. Muscle tone in the lower extremities was significantly decreased within 2 hours after baclofen injection and remained lower than baseline 8 hours afterward. Upper extremity tone and function were not significantly affected by these single doses. Confusion and drowsiness occurred in two of the youngest children in the study after the 50-micrograms dose, but cleared within 2 hours. Our findings indicate that intrathecal baclofen reduces spasticity in children with cerebral palsy, as it does in adults with spasticity of spinal origin.
Cyclosporine Withdrawal from a Mycophenolate Mofetil–Containing Immunosuppressive Regimen
Authors: Daniel Abramowicz, Maria del Carmen Rial, Stefan Vitko, Domingo del Castillo, Derek Manas, Mieczyslaw Lao, Nesrin Gafner, Peter Wijngaard
Journal: Journal of the American Society of Nephrology (2005)

Maintenance immunosuppression with cyclosporine (CsA) is associated with nephrotoxicity, hyperlipidemia, and hypertension. This long-term study (core study + 4 yr of follow-up) investigated the long-term efficacy and safety of CsA withdrawal from a mycophenolate mofetil (MMF)-based regimen. Seventy-seven patients were maintained on CsA, MMF, and steroids (CsA-MMF group), and 74 were given a CsA-free regimen of MMF and steroids (MMF group). Serum creatinine and creatinine clearance were measured at 6-month intervals. Patient and graft survival, acute rejection episodes, malignancies, BP, and lipid profile were also recorded. At 5 yr, patient and graft survival was 93 and 88%, respectively, for the MMF group and 95 and 92%, respectively, for the CsA-MMF group. During follow-up, seven MMF patients experienced acute rejection episodes compared with one CsA-MMF patient (P = 0.0283). Nine grafts were lost to chronic rejection in the MMF group versus three in the CsA-MMF group. No demographic or immunologic characteristics were associated with acute or chronic rejection in the MMF group, but the doses of both MMF and steroids decreased significantly between 1 and 5 yr. The MMF group showed a trend toward improved creatinine clearance (67.4 versus 61.7 ml/min; P = 0.0500). Withdrawal of CsA from an MMF-containing immunosuppressive regimen resulted in an increased risk for acute rejection episodes and graft loss as a result of rejection throughout the 5-yr study period. The creatinine clearance-confirmed improvement in renal function observed at year 1 was maintained at 5 yr BP and cholesterol levels were well controlled in both groups.
Multiple Dopamine Functions at Different Time Courses
Authors: Wolfram Schultz
Journal: Annual Review of Neuroscience (2007)

Many lesion studies report an amazing variety of deficits in behavioral functions that cannot possibly be encoded in great detail by the relatively small number of midbrain dopamine neurons. Although hoping to unravel a single dopamine function underlying these phenomena, electrophysiological and neurochemical studies still give a confusing, mutually exclusive, and partly contradictory account of dopamine's role in behavior. However, the speed of observed phasic dopamine changes varies several thousand fold, which offers a means to differentiate the behavioral relationships according to their time courses. Thus dopamine is involved in mediating the reactivity of the organism to the environment at different time scales, from fast impulse responses related to reward via slower changes with uncertainty, punishment, and possibly movement to the tonic enabling of postsynaptic motor, cognitive, and motivational systems deficient in Parkinson's disease.
Loss of Inhibitory Interneurons in the Dorsal Spinal Cord and Elevated Itch in Bhlhb5 Mutant Mice
Authors: Sarah E. Ross, Alan R. Mardinly, Alejandra E. McCord, Jonathan Zurawski, Sonia Cohen, Cynthia Jung, Linda Hu, Stephanie I. Mok, Anar Shah, Erin M. Savner, Christos Tolias, Roman Corfas, Suzhen Chen, Perrine Inquimbert, Yi Xu, Roderick R. McInnes, Frank L. Rice, Gabriel Corfas, Qiufu Ma, Clifford J. Woolf, Michael E. Greenberg
Journal: Neuron (2010)
Management of acute anterior shoulder dislocation
Authors: Benan Dala-Ali, Marta Penna, Jamie McConnell, Ivor Vanhegan, Carlos Cobiella
Journal: British Journal of Sports Medicine (2012)

Shoulder dislocation is the most common large joint dislocation in the body. Recent advances in radiological imaging and shoulder surgery have shown the potential dangers of traditional reduction techniques such as the Kocher's and the Hippocratic methods, which are still advocated by many textbooks. Many non-specialists continue to use these techniques, unaware of their potential risks. This article reviews the clinical and radiographic presentation of dislocation; some common reduction techniques; their risks and success rate; analgesia methods to facilitate the reduction; and postreduction management. Many textbooks advocate methods that have been superceded by safer alternatives. Trainees should learn better and safer relocation methods backed up by the current evidence available.
Bruce Auld David Gershon Berry James William Birch Jill Hargreaves Joseph Jacobs John Ivor Pulsford James Harold William Rodgers George Herbert Ashby Simmons Gita Stephen John Low Steven Henry Winsley-Stolz
Authors: J. Auld, E. M Berry, A. El-Sobky, K. El-Sobky, D M Nolan, E G G Roberts, J. Chalmers, R. Rodgers, S. Robertson, D. Price, P. Knight, A. Fraser, B. Hoffbrand
Journal: BMJ (2001)

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Tumor Rejection by Disturbing Tumor Stroma Cell Interactions
Authors: Sabrina Ibe, Zhihai Qin, Thomas Schüler, Susanne Preiss, Thomas Blankenstein
Journal: The Journal of Experimental Medicine (2001)

The stroma of solid tumors is a complex network of different cell types. We analyzed stroma cell interactions in two tumor models during cyclophosphamide (Cy)-induced tumor rejection. In growing tumors, tumor infiltrating macrophages (TIMs) produced interleukin (IL)-10. Beginning 6 h after Cy-treatment T cells in the tumor were inactivated and TIMs switched to interferon (IFN)-γ production. Both, IL-10 production before and IFN-γ production after Cy-treatment by TIMs required T cells. With the same kinetics as TIMs started to produce IFN-γ the tumor vasculature was destroyed which required IFN-γ receptor expression on host but not tumor cells. These events preceded hemorrhagic necrosis and residual tumor cell elimination by T cells. Together, T cells regulate the function of TIMs and tumor rejection can be induced by disturbing the stroma network.
Chewing the fat on natural killer T cell development
Authors: Dale I. Godfrey, Malcolm J. McConville, Daniel G. Pellicci
Journal: The Journal of Experimental Medicine (2006)

Natural killer T cells (NKT cells) are selected in the thymus by self-glycolipid antigens presented by CD1d molecules. It is currently thought that one specific component of the lysosomal processing pathway, which leads to the production of isoglobotrihexosylceramide (iGb3), is essential for normal NKT cell development. New evidence now shows that NKT cell development can be disrupted by a diverse range of mutations that interfere with different elements of the lysosomal processing and degradation of glycolipids. This suggests that lysosomal storage diseases (LSDs) in general, rather than one specific defect, can disrupt CD1d antigen presentation, leading to impaired development of NKT cells.
Cryptogenic fibrosing alveolitis and the fibrosing alveolitis of systemic sclerosis: morphological differences on computed tomographic scans
Authors: T. Y. Chan, D. M. Hansell, M. B. Rubens, R. M. du Bois, A. U. Wells
Journal: Thorax (1997)

Slow, non-twitch muscles are widespread in lower vertebrates and invertebrates and are often assumed to be primarily involved in posture or slow motor patterns. However, in several preparations, including some well known invertebrate “model” preparations, slow muscles are driven by rapid, rhythmic inputs. The response of slow muscles to such inputs is little understood. We are investigating this issue with a slow stomatogastric muscle (cpv1b) driven by a relatively rapid, rhythmic neural pattern. A simple model suggests that as cycle period decreases, slow muscle contractions show increasing intercontraction temporal summation and at steady state consist of phasic contractions overlying a tonic contracture. We identify five components of these contractions: total, average, tonic, and phasic amplitudes, and percent phasic (phasic amplitude divided by total amplitude). cpv1b muscle contractions induced by spontaneous rhythmic neural input<i>in vitro</i> consist of phasic and tonic components. Nerve stimulation at varying cycle periods and constant duty cycle shows that a tonic component is always present, and at short periods the muscle transforms rhythmic input into almost completely tonic output. Varying spike frequency, spike number, and cycle period show that frequency codes total, average, and tonic amplitudes, number codes phasic amplitude, and period codes percent phasic. These data suggest that tonic contraction may be a property of slow muscles driven by rapid, rhythmic input, and in these cases it is necessary to identify the various contraction components and their neural coding. Furthermore, the parameters that code these components are interdependent, and control of slow muscle contraction is thus likely complex.