tbuckley/cabot-search huggingface dataset:
Effects of Cyclopropane and of Hypoxia on Transmembrane Potentials of Atrial, Ventricular and Purkinje Fibers
Authors: Larry D. Davis, John V. Temte, Phyllis R. Helmer, Quillian R. Murphy
Journal: Circulation Research (1966)

The effects of cyclopropane (6 to 8 vol% in Tyrode solution) and of hypoxia, on the transmembrane potentials of atrial, ventricular and Purkinje fibers of the dog heart, were studied. Action potentials were recorded during perfusion with solution equilibrated with 95% O 2 , and 5% CO 2 (control-Tyrode); during cyclopropane-Tyrode perfusion and during perfusion with solution in which nitrogen replaced cyclopropane (nitrogen-Tyrode). Changes in transmembrane potential observed during cyclopropane-Tyrode treatment were considered to be due to an action of cyclopropane only if they recovered or failed to appear during nitrogen-Tyrode perfusion. By interpretation on this basis it could not be determined that cyclopropane exerted an effect on atrial or ventricular fibers. In Purkinje fibers cyclopropane caused a significant increase in rate of repolarization during the plateau (phase 2) while the rate during the period of rapid repolarization (phase 3) decreased. The time required to repolarize to minus 60 millivolts was shortened significantly while the durations of the terminal phase of repolarization and of the total action potential were lengthened. A relative hypoxia averaging 300 mm Hg accelerated repolarization and reduced resting potential of atrial cells. Ventricular cells were affected similarly but only after two or more periods of hypoxia. Purkinje fibers were shown to be most resistant to this level of hypoxia.
Insulin-like growth factor-I and platelet-derived growth factor-BB induce directed migration of human arterial smooth muscle cells via signaling pathways that are distinct from those of proliferation.
Authors: K E Bornfeldt, E W Raines, T Nakano, L M Graves, E G Krebs, R Ross
Journal: Journal of Clinical Investigation (1994)

Directed migration or chemotaxis of arterial smooth muscle cells (SMC) contributes to intimal SMC accumulation, a key event in the development of atherosclerotic lesions and in restenosis after angioplasty. The present study compares and contrasts insulin-like growth factor I (IGF-I) and platelet-derived growth factor (PDGF-BB) as chemoattractants and mitogens for human arterial SMC. Compared with PDGF-BB, IGF-I is a weaker SMC mitogen. Thus, PDGF-BB, but not IGF-I, evokes a strong and rapid activation of mitogen-activated protein (MAP) kinase kinase and MAP kinase. However, IGF-I is a potent stimulator of directed migration of human arterial SMC, as measured in a Boyden chamber assay. The half-maximal concentration for migration is similar to the Kd for IGF-I receptor interaction. An IGF-I receptor-blocking antibody blocks the effects of IGF-I, IGF-II, and insulin, indicating that the effects are indeed mediated through the IGF-I receptor. The maximal effect of IGF-I on directed migration ranges between 50% and 100% of the effect of PDGF-BB, the strongest known chemoattractant for SMC. The ability of IGF-I and PDGF-BB to induce chemotaxis coincides with their ability to stimulate phosphatidylinositol turnover, diacylglycerol formation, and intracellular Ca2+ flux and suggests that these signaling pathways, but not activation of the MAP kinase cascade, are required for chemotaxis of human arterial SMC.
Intraepidermal leakage of plasma proteins after tape stripping of normal skin and uninvolved psoriatic skin
Authors: M. VERSCHOORE, C. KOWALEWSKI, M.JARZABEK CHORZHLSKA, B.A. BERNARD, Y.M. DARMON
Journal: British Journal of Dermatology (1990)

Following tape stripping of normal skin and uninvolved psoriatic skin, there was an early leakage of plasma proteins such as fibrinogen, fibronectin and immunoglobulins. This was accompanied by migration of mononuclear and polymorphonuclear cells into the epidermis. Both events appeared earlier, were more pronounced and lasted longer in psoriatic subjects than in controls.
Tumour necrosis factor gene polymorphisms are associated with COPD
Authors: M. R. Gingo, L. J. Silveira, Y. E. Miller, A. L. Friedlander, G. P. Cosgrove, E. D. Chan, L. A. Maier, R. P. Bowler
Journal: European Respiratory Journal (2008)

Tumour necrosis factor (TNF)-α has been shown to be an important factor in animal models of chronic obstructive pulmonary disease (COPD). However, human studies of <i>TNF</i> polymorphisms in COPD have been equivocal. Six <i>TNF</i> single nucleotide polymorphisms (-1031C/T, -863C/A, -857C/T, -237G/A, -308G/A and +487G/A) and their haplotypes were investigated in 423 Caucasian smokers (298 patients with spirometric evidence of COPD and 125 without airflow obstruction). The -308 minor allele (A) had a higher odds ratio (OR) of being associated with COPD in multivariate analysis (controlling for age, sex, pack-yrs; OR 1.9, 95% confidence interval (CI) 1.1–3.2) and was also associated with worse forced expiratory volume in one second/forced vital capacity. The -237 minor allele (A) had a lower OR of being associated with COPD (OR 0.40, 95% CI 0.19–0.86). In COPD patients, the -857 minor allele (T) had a lower OR of being associated with severe stages of COPD (Global Initiative for Obstructive Lung Disease stage III and IV <i>versus</i> stage I and II, OR 0.46, 95% CI 0.24–0.88). Other TNF single nucleotide polymorphisms were not associated with COPD but the -1031/-863 haplotype CC/TC had a lower OR in COPD patients <i>versus</i> smoking controls (OR 0.22, 95% CI 0.05–0.97). The present study adds further evidence that tumour necrosis factor genotypes play a role in susceptibility to cigarette smoke.
Exhaled Breath Condensate in Acute and Chronic Heart Failure: New Insights into the Role of Lung Injury and Barrier Dysfunction
Authors: Loukas K. Pappas, Georgios Giannopoulos, Stelios Loukides, Gerasimos Gavrielatos, Efrossini Athanasopoulou, Ioannis P. Alexanian, Dimitrios Farmakis, Ioanna Korovesi, Konstantinos P. Letsas, John T. Parissis, Spyridon Deftereos, Vlassis N. Pyrgakis, Anastasia Kotanidou, Dimitrios T. Kremastinos, Gerasimos S. Filippatos
Journal: American Journal of Respiratory and Critical Care Medicine (2014)
Dysfunction of Nucleus Accumbens-1 Activates Cellular Senescence and Inhibits Tumor Cell Proliferation and Oncogenesis
Authors: Yi Zhang, Yan Cheng, Xingcong Ren, Tsukasa Hori, Kathryn J. Huber-Keener, Li Zhang, Kai Lee Yap, David Liu, Lisa Shantz, Zheng-Hong Qin, Suping Zhang, Jianrong Wang, Hong-Gang Wang, Ie-Ming Shih, Jin-Ming Yang
Journal: Cancer Research (2012)

Abstract Nucleus accumbens-1 (NAC1), a nuclear factor belonging to the BTB/POZ gene family, has emerging roles in cancer. We report here that NAC1 acts as a negative regulator of cellular senescence in transformed and nontransformed cells, and dysfunction of NAC1 induces senescence and inhibits its oncogenic potential. We show that NAC1 deficiency markedly activates senescence and inhibits proliferation in tumor cells treated with sublethal doses of γ-irradiation. In mouse embryonic fibroblasts from NAC1 knockout mice, following infection with a Ras virus, NAC1−/− cells undergo significantly more senescence and are either nontransformed or less transformed in vitro and less tumorigenic in vivo when compared with NAC1+/+ cells. Furthermore, we show that the NAC1-caused senescence blunting is mediated by ΔNp63, which exerts its effect on senescence through p21, and that NAC1 activates transcription of ΔNp63 under stressful conditions. Our results not only reveal a previously unrecognized function of NAC1, the molecular pathway involved and its impact on pathogenesis of tumor initiation and development, but also identify a novel senescence regulator that may be exploited as a potential target for cancer prevention and treatment. Cancer Res; 72(16); 4262–75. ©2012 AACR.
The safety profile of a cationic lipid-mediated cystic fibrosis gene transfer agent following repeated monthly aerosol administration to sheep
Authors: Eric W.F.W. Alton, Alison Baker, Eilidh Baker, A. Christopher Boyd, Seng H. Cheng, Rebecca L. Coles, D. David S. Collie, Heather Davidson, Jane C. Davies, Deborah R. Gill, Catherine Gordon, Uta Griesenbach, Tracy Higgins, Stephen C. Hyde, J. Alastair Innes, Dominique McCormick, Michael McGovern, Gerry McLachlan, David J. Porteous, Ian Pringle, Ronald K. Scheule, Darren J. Shaw, Sionagh Smith, Stephanie G. Sumner-Jones, Peter Tennant, Christina Vrettou
Journal: Biomaterials (2013)
A population-based study of the usefulness of screening for neuroblastoma
Authors: William G Woods, Mendel Tuchman, Leslie L Robison, Mark Bernstein, Jean-Marie Leclerc, Linda C Brisson, Josee Brossard, Gerry Hill, Jonathan Shuster, Russell Luepker, Timothy Byrne, Sheila Weitzman, Greta Bunin, Bernard Lemieux
Journal: The Lancet (1996)
Sodium ingestion and the prevention of hyponatraemia during exercise
Authors: T Noakes
Journal: British Journal of Sports Medicine (2004)

The study of Twerenbold et al 1 is important for a number of reasons, not all of which may have been emphasised sufficiently by the authors.

Firstly, it confirms that a rate of fluid intake of 1000 ml/h is too high for a group of female runners running at ∼ 10 km/h and who would therefore complete a 42 km marathon in about 4.25 hours. As the athletes drank 4 litres and gained 2 kg during the trial, their average rate of weight loss (as opposed to sweat rate) was about 500 ml/h. As not all of the weight lost during exercise is sweat and as much as 1–3 kg of this weight loss may result from fuel and water losses that do not contribute to dehydration,2,3 the absolute maximum rate at which these athletes should have ingested fluid during exercise was probably even less than 500 ml/h. This is substantially less than the drinking guidelines of the American College of Sports Medicine4,5 and the Gatorade Sports Science Institute,6 which have promoted rates of fluid ingestion of up to 1200–1800 ml/h. As there is no evidence that gaining weight during exercise improves performance7,8 whereas there is good evidence that athletes who either lose no weight or who gain weight during exercise are increasingly likely to ( a ) have an impaired performance,7 ( b ) develop troubling gastrointestinal symptoms,7,8,9,10 or ( c ) finish the race with serum sodium concentrations below about 128 mmol/l causing hyponatraemic encephalopathy,11–13 it is not immediately clear why the authors chose such high rates of fluid intake in these athletes. Except, perhaps, if they wished to “prove” the value of sodium ingestion during exercise. I note, for example, that the study was funded by a commercial company …
IL‐30 (IL27p28) attenuates liver fibrosis through inducing NKG2D‐rae1 interaction between NKT and activated hepatic stellate cells in mice
Authors: Abhisek Mitra, Arun Satelli, Jun Yan, Xia Xueqing, Mihai Gagea, Christopher A. Hunter, Lopa Mishra, Shulin Li
Journal: Hepatology (2014)

Chronic hepatic diseases, such as cirrhosis, hepatocellular carcinoma, and virus-mediated immunopathogenic infections, affect billions of people worldwide. These diseases commonly initiate with fibrosis. Owing to the various side effects of antifibrotic therapy and the difficulty of diagnosing asymptomatic patients, suitable medication remains a major concern. To overcome this drawback, the use of cytokine-based sustained therapy might be a suitable alternative with minimal side effects. Here, we studied the therapeutic efficacy and potential mechanisms of interleukin (IL)−30 as antifibrosis therapy in murine liver fibrosis models. CCl4 or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) 0.1% (wt/wt) Purina 5015 Chow (LabDiet, St. Louis, MO) was fed for 3 weeks to induce liver fibrosis. Either control vector (pCtr) or pIL30 was injected hydrodynamically once per week. A significant decrease in collagen deposition and reduced expression of alpha-smooth muscle actin (α-SMA) protein indicated that IL-30-based gene therapy dramatically reduced bridging fibrosis that was induced by CCl4 or DDC. Immunophenotyping and knockout studies showed that IL-30 recruits natural-killer–like T (NKT) cells to the liver to remove activated hepatic stellate cells (HSCs) significantly and ameliorate liver fibrosis. Both flow cytometric and antibody-mediated neutralization studies showed that liver NKT cells up-regulate the natural killer group 2, member D (NKG2D) ligand and bind with the NKG2D ligand, retinoic acid early inducible 1 (Rae1), and positively activated HSCs to ameliorate liver fibrosis. Furthermore, adoptive transfer of liver NKT cells in T-cell-deficient mice showed reduction of fibrosis upon IL-30 administration. Conclusions: Highly target-specific liver NKT cells selectively remove activated HSCs through an NKG2D-Rae1 interaction to ameliorate liver fibrosis after IL-30 treatment. (Hepatology 2014;60:2026–2038)
Abciximab Suppresses the Rise in Levels of Circulating Inflammatory Markers After Percutaneous Coronary Revascularization
Authors: A.Michael Lincoff, Dean J. Kereiakes, Mary A. Mascelli, Lawrence I. Deckelbaum, Elliot S. Barnathan, Kamlesh K. Patel, Bart Frederick, Marian T. Nakada, Eric J. Topol
Journal: Circulation (2001)

Background — Previous investigators have shown that systemic markers of inflammation may be increased in patients with acute ischemic syndromes or after percutaneous coronary revascularization and that persistent elevation in these markers is predictive of excess risk of subsequent adverse cardiac events. By virtue of its cross-reactivity with the glycoprotein IIb/IIIa, avβ3, and αMβ2 receptors, abciximab may reduce inflammatory processes. Methods and Results — Assays for the inflammatory markers C-reactive protein, interleukin-6, and tumor necrosis factor-α were performed on serum samples obtained from 160 patients in a placebo-controlled, randomized trial of abciximab during angioplasty. Eighty patients each had received a placebo or abciximab bolus plus a 12-hour infusion. Serum samples were drawn at baseline (before revascularization), 24 to 48 hours after study drug administration, and 4 weeks after study drug administration. Between baseline and 24 to 48 hours, the increase in C-reactive protein was 32% less in patients receiving abciximab than placebo ( P =0.025); the rise in interleukin-6 levels was 76% less in the abciximab group ( P &lt;0.001); and the rise in tumor necrosis factor-α levels was 100% less with abciximab therapy ( P =0.112). By 4 weeks, most marker levels had returned to baseline, with no significant differences between placebo and abciximab groups. Conclusions — Systemic markers of inflammation increase in the first 24 to 48 hours after angioplasty, but the magnitude of that rise is diminished by periprocedural abciximab. Some of the long-term clinical benefit derived from this agent may be related to an anti-inflammatory effect.
Phase 0 Clinical Trial of the Poly (ADP-Ribose) Polymerase Inhibitor ABT-888 in Patients With Advanced Malignancies
Authors: Shivaani Kummar, Robert Kinders, Martin E. Gutierrez, Larry Rubinstein, Ralph E. Parchment, Lawrence R. Phillips, Jiuping Ji, Anne Monks, Jennifer A. Low, Alice Chen, Anthony J. Murgo, Jerry Collins, Seth M. Steinberg, Helen Eliopoulos, Vincent L. Giranda, Gary Gordon, Lee Helman, Robert Wiltrout, Joseph E. Tomaszewski, James H. Doroshow
Journal: Journal of Clinical Oncology (2009)

Purpose We conducted the first phase 0 clinical trial in oncology of a therapeutic agent under the Exploratory Investigational New Drug Guidance of the US Food and Drug Administration. It was a first-in-human study of the poly (ADP-ribose) polymerase (PARP) inhibitor ABT-888 in patients with advanced malignancies. Patients and Methods ABT-888 was administered as a single oral dose of 10, 25, or 50 mg to determine the dose range and time course over which ABT-888 inhibits PARP activity in tumor samples and peripheral blood mononuclear cells, and to evaluate ABT-888 pharmacokinetics. Blood samples and tumor biopsies were obtained pre- and postdrug administration for evaluation of PARP activity and pharmacokinetics. A novel statistical approach was developed and utilized to study pharmacodynamic modulation as the primary end point for trials of limited sample size. Results Thirteen patients with advanced malignancies received the study drug; nine patients underwent paired tumor biopsies. ABT-888 demonstrated good oral bioavailability and was well tolerated. Statistically significant inhibition of poly (ADP-ribose) levels was observed in tumor biopsies and peripheral blood mononuclear cells at the 25-mg and 50-mg dose levels. Conclusion Within 5 months of study activation, we obtained pivotal biochemical and pharmacokinetic data that have guided the design of subsequent phase I trials of ABT-888 in combination with DNA-damaging agents. In addition to accelerating the development of ABT-888, the rapid conclusion of this trial demonstrates the feasibility of conducting proof-of-principle phase 0 trials as part of an alternative paradigm for early drug development in oncology.
CHOLESTEROL EMBOLI: A Common Cause of Renal Failure
Authors: Donald G. Vidt, M.D
Journal: Annual Review of Medicine (1997)

▪ Abstract Cholesterol embolization (CE), usually occurring in males in their sixth or seventh decade of life, can affect multiple organ systems, including the kidney. Interventive diagnostic procedures and aortic surgery greatly increase the risk of CE. Rapid or insidious progression of renal failure in association with surgical or diagnostic radiologic procedures should suggest this diagnosis. Progressive renal insufficiency in older patients with generalized arterial disease should suggest ischemic nephropathy secondary to bilateral renal artery stenosis, renal CE, or both. Recent worsening of hypertension is characteristic of either diagnosis. A number of clinical conditions can simulate renal CE, and final differentiation may be possible only by renal biopsy. Aggressive, supportive management of renal CE is warranted because renal function may stabilize and, in a limited number of cases, may even improve.
Infiltrating cells, related cytokines and chemokine receptors in lesional skin of patients with dermatomyositis
Authors: M. Caproni, D. Torchia, C. Cardinali, W. Volpi, E. Del Bianco, A. D'Agata, P. Fabbri
Journal: British Journal of Dermatology (2004)

There have been only two reports on immunophenotypic characterization in the cutaneous lesions of dermatomyositis (DM) that emphasize the importance of the infiltrating CD4+ T lymphocytes.To characterize the immunophenotype of the cells that infiltrate the lesional skin of DM and to evaluate the possible T-helper (Th) polarization Th1/Th2 through detection of specific cytokines, chemokine receptors and markers of cellular activation.Skin biopsy specimens derived from pathognomonic lesions (Gottron's papules and Gottron's sign) of eight patients with DM were immunostained with a large panel of monoclonal antibodies to CD3, CD4, CD8, myeloperoxidase (MPO), eosinophil cationic protein, tryptase, CD40, CD40 ligand (CD40L), HLA-DR, interleukin (IL)-2, IL-4, IL-5, IL-13, interferon-gamma, tumour necrosis factor-alpha, receptor 3 for CXC chemokines (CXCR3) and receptor 3 for CC chemokines, using the alkaline phosphatase-antialkaline phosphatase method. Control specimens were obtained from five healthy subjects and from six patients with discoid lupus erythematosus.Activated CD4+ Th lymphocytes (HLA-DR+ CD40L+) were the principal infiltrating cells in the lesional skin of DM; the CD4/CD8 ratio was approximately 2.5. A mixed Th1/Th2 profile and higher Th1 cytokine production together with significant staining for CXCR3 were detected. Neutrophil granulocytes were the second most abundant population; eosinophil granulocytes were very poorly represented.Activated CD4+ T cells presumably mediate the main pathogenetic mechanisms in pathognomonic skin lesions. The interaction between CD40 and CD40L could be an important mechanism of cellular activation in cutaneous immune-mediated inflammation by induction of secretion of proinflammatory cytokines and chemokines. Neither Th1 nor Th2 clear polarization was found, although there was a slight Th1 prevalence. There was a significant quantity of MPO+ cells (neutrophil granulocytes) in the inflamed tissue, and they might have a role in sustaining the chronic inflammation.
Randomised study of three non-surgical treatments in mild to moderate obstructive sleep apnoea
Authors: B. Lam, K. Sam, W. Y. Mok, M. T. Cheung, D. Y. Fong, J. C. Lam, D. C. Lam, L. Y. Yam, M. S. lp
Journal: Thorax (2006)

<b>Background:</b> Patients with mild to moderate obstructive sleep apnoea (OSA) may be managed with different treatment options. This study compared the effectiveness of three commonly used non-surgical treatment modalities. <b>Methods:</b> Subjects with mild to moderate OSA were randomised to one of three treatment groups for 10 weeks: conservative measures (sleep hygiene) only, continuous positive airways pressure (CPAP) in addition to conservative measures or an oral appliance in addition to conservative measures. All overweight subjects were referred to a weight-reduction class. OSA was assessed by polysomnography. Blood pressure was recorded in the morning and evening in the sleep laboratory. Daytime sleepiness was assessed with the Epworth Sleepiness Scale. Health-related quality of life (HRQOL) was assessed with the 36-Item Short-Form Health Survey (SF-36) and Sleep Apnoea Quality of Life Index (SAQLI). <b>Results:</b> 101 subjects with a mean (SEM) apnoea–hypopnoea index (AHI) of 21.4 (1.1) were randomised to one of the three groups. The severity of sleep-disordered breathing was decreased in the CPAP and oral appliance groups compared with the conservative measures group, and the CPAP group was significantly better than the oral appliance group. Relief from sleepiness was significantly better in the CPAP group. CPAP was also better than the oral appliance or conservative measures in improving the "bodily pain" domain, and better than conservative measures in improving the "physical function" domain of SF-36. Both CPAP and the oral appliance were more effective than conservative measures in improving the SAQLI, although no difference was detected between the CPAP and oral appliance groups. CPAP and the oral appliance significantly lowered the morning diastolic blood pressure compared with baseline values, but there was no difference in the changes in blood pressure between the groups. There was also a linear relationship between the changes in AHI and body weight. <b>Conclusion:</b> CPAP produced the best improvement in terms of physiological, symptomatic and HRQOL measures, while the oral appliance was slightly less effective. Weight loss, if achieved, resulted in an improvement in sleep parameters, but weight control alone was not uniformly effective.
Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, open-label phase 2 trial
Authors: Mark Sulkowski, Christophe Hezode, Jan Gerstoft, John M Vierling, Josep Mallolas, Stanislas Pol, Marcelo Kugelmas, Abel Murillo, Nina Weis, Ronald Nahass, Oren Shibolet, Lawrence Serfaty, Marc Bourliere, Edwin DeJesus, Eli Zuckerman, Frank Dutko, Melissa Shaughnessy, Peggy Hwang, Anita Y M Howe, Janice Wahl, Michael Robertson, Eliav Barr, Barbara Haber
Journal: The Lancet (2014)