tbuckley/cabot-search huggingface dataset:
Characteristics and Baseline Clinical Predictors of Future Fatal Versus Nonfatal Coronary Heart Disease Events in Older Adults
Authors: Camille A. Pearte, Curt D. Furberg, Ellen S. O’Meara, Bruce M. Psaty, Lewis Kuller, Neil R. Powe, Teri Manolio
Journal: Circulation (2006)

Although >80% of annual coronary heart disease (CHD) deaths occur in adults aged >65 years and the population is aging rapidly, CHD event fatality and its predictors in the elderly have not been well described.The first myocardial infarction (MI) or CHD death among the 5888 adults aged > or =65 years occurring during enrollment in the Cardiovascular Health Study during 1989-2001 was identified and adjudicated. Characteristics measured at examinations before the event were examined for associations with case fatality (death before hospitalization or hospital discharge) and for differences in predictors by demographics or clinical history. During a median follow-up of 8.2 years, 985 CHD events occurred, of which 30% were fatal. Case fatality decreased slightly over time, ranging from 28% to 30% per year in the early 1990s versus 23% by 2000-2001; with adjustment for age at MI and gender, there was a 6% lower odds of fatality with each successive year (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.90 to 0.98). Case fatality was similar by race and gender but higher with age and prior CHD (MI, angina, or revascularization). When considered alone, many subclinical disease measures, such as common carotid intima-media thickness, ankle-arm index, left ventricular mass by ECG, and a major ECG abnormality, and traditional risk factors, such as diabetes and hypertension, were associated with fatality. In multivariable analysis, independent predictors of fatality were prior congestive heart failure (OR, 3.20; 95% CI, 2.32 to 4.41), prior CHD rather than only history of MI (OR, 2.51; 95% CI, 1.84 to 3.43), diabetes (OR, 1.66; 95% CI, 1.10 to 2.31), and age (OR, 1.21 per 5 years; 95% CI, 1.07 to 1.37), adjusted for gender and each other. Prior congestive heart failure, regardless of left ventricular systolic function, age, gender, or prior CHD, conferred a > or =3-fold increased risk of fatality in almost all subgroups.Among community-dwelling older adults, CHD case fatality remains substantial, with easily identifiable risk factors that may be different from those that predict incident disease. In the elderly in whom the risk/benefit of therapies may be influenced by multiple competing comorbidities and care needs, risk stratification possibly may be improved further by focusing more aggressive care on specific patients, especially those with a history of congestive heart failure or prior CHD.
Dopamine-induced apoptosis in human melanocytes involves generation of reactive oxygen species
Authors: C-Y. Chu, Y-L. Liu, H-C. Chiu, S-H. Jee
Journal: British Journal of Dermatology (2006)

Previous studies have shown that significant increases in urinary and plasma levels of several monoamines and their metabolites characterize the onset of vitiligo and its progression. Recently, both epidermal keratinocytes and melanocytes were found to have the capacity for the biosynthesis of several catecholamines and serotonin. Some monoamines and their metabolites can induce apoptosis and cytotoxicity in neural cells. However, no previous report has investigated the potential role of these monoamines in inducing apoptosis or cytotoxicity in melanocytes.To study the effects of dopamine (DA), norepinephrine (NE), epinephrine (EP), and serotonin (5-HT) on melanocyte cytotoxicity and apoptosis.Primary cultures of normal human melanocytes established from the foreskins of normal individuals were treated with different concentrations of DA, NE, EP and 5-HT for 5 and 7 days. Cell viability was measured by the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay. Melanocyte apoptosis was evaluated by morphological examination and flow cytometric analysis. We also measured the generation of reactive oxygen species (ROS) after DA treatment.Among the four monoamines used in this study, only DA had an effect, dose-dependently decreasing the melanocyte viability at concentrations ranging from 0.01 to 100 micromol L(-1) (0.1 and 1 micromol L(-1), P < 0.05; 10 micromol L(-1), P < 0.01). In addition, DA-induced melanocyte apoptosis was evidenced by the increased percentage of sub-G1 cells from 7.71 +/- 0.28% (control) to 12.22 +/- 1.05% (0.1 micromol L(-1) DA) (P < 0.005), and treatment with the antioxidant N-acetylcysteine (NAC) reversed this apoptotic effect. DA treatment led to the generation of ROS, which could be prevented by pretreatment with NAC.DA can induce melanocyte apoptosis, which might be related to the generation of ROS. This novel effect might play an important role in the development or progression of vitiligo, which is currently viewed as a disease process closely related to melanocyte apoptosis.
Ca <sup>2+</sup> -Dependent Activation of Rho and Rho Kinase in Membrane Depolarization–Induced and Receptor Stimulation–Induced Vascular Smooth Muscle Contraction
Authors: Sotaro Sakurada, Noriko Takuwa, Naotoshi Sugimoto, Yu Wang, Minoru Seto, Yasuharu Sasaki, Yoh Takuwa
Journal: Circulation Research (2003)

Ca2+ sensitization of vascular smooth muscle (VSM) contraction involves Rho-dependent and Rho-kinase-dependent suppression of myosin phosphatase activity. We previously demonstrated that excitatory agonists in fact induce activation of RhoA in VSM. In this study, we demonstrate a novel Ca2+-dependent mechanism for activating RhoA in rabbit aortic VSM. High KCl-induced membrane depolarization as well as noradrenalin stimulation induced similar extents of sustained contraction in rabbit VSM. Both stimuli also induced similar extents of time-dependent, sustained increases in the amount of an active GTP-bound form of RhoA. Consistent with this, the Rho kinase inhibitors HA1077 and Y27632 inhibited both contraction and the 20-kDa myosin light chain phosphorylation induced by KCl as well as noradrenalin, with similar dose-response relations. Either removal of extracellular Ca2+ or the addition of a dihydropyridine Ca2+ channel antagonist totally abolished KCl-induced Rho stimulation and contraction. The calmodulin inhibitor W7 suppressed KCl-induced Rho activation and contraction. Ionomycin mimicked W7-sensitive Rho activation. The expression of dominant-negative N19RhoA suppressed Ca2+-induced Thr695 phosphorylation of the 110-kDa regulatory subunit of myosin phosphatase and phosphorylation of myosin light chain in VSM cells. Finally, either the combination of extracellular Ca2+ removal and depletion of the intracellular Ca2+ store or the addition of W7 greatly reduced noradrenalin-induced and the thromboxane A2 analogue-induced Rho stimulation and contraction. Taken together, these results indicate the existence of the thus-far unrecognized Ca2+-dependent Rho stimulation mechanism in VSM. Excitatory receptor agonists are suggested to use this pathway for simulating Rho.
Monocyte chemotactic protein-1 (MCP-1), -2, and -3 are chemotactic for human T lymphocytes.
Authors: D D Taub, P Proost, W J Murphy, M Anver, D L Longo, J van Damme, J J Oppenheim
Journal: Journal of Clinical Investigation (1995)

Monocyte chemotactic protein (MCP)-1, -2, and -3 all have been shown to induce monocyte/macrophage migration in vitro and MCP-1, also known as MCAF, chemoattracts basophils and mast cells. We report here that natural MCP-1 as well as synthetic preparations of MCP-2 and MCP-3 stimulate significant in vitro chemotaxis of human peripheral blood T lymphocytes. This MCP-induced migration was dose-dependent and directional, but not chemokinetic. Phenotypic analysis of the T cell population responsive to MCP-1, MCP-2, and MCP-3 demonstrates that both CD4+ and CD8+ T cells migrated in response to these chemokines. Similar results were observed using human CD4+ and CD8+ T cell clones. Neutralizing antisera to MCAF or MCP-2 abrogated T cell migration in response to MCP-1 and MCP-2, respectively, but not to RANTES. Subcutaneous administration of purified MCP-1 into the hind flanks of SCID mice engrafted with human peripheral blood lymphocytes (PBL) induced significant human CD3+ T cell infiltration into the site of injection at 4 h. These results demonstrate that MCP-1, MCP-2, and MCP-3 are inflammatory mediators that specifically stimulate the directional migration of T cells as well as monocytes and may play an important role in immune cell recruitment into sites of antigenic challenge.
Adiponectin-mediated modulation of hypertrophic signals in the heart
Authors: Rei Shibata, Noriyuki Ouchi, Masahiro Ito, Shinji Kihara, Ichiro Shiojima, David R Pimentel, Masahiro Kumada, Kaori Sato, Stephan Schiekofer, Koji Ohashi, Tohru Funahashi, Wilson S Colucci, Kenneth Walsh
Journal: Nature Medicine (2004)
β‐adrenergic receptor-mediated growth of human airway epithelial cell lines
Authors: K. Nishimura, J. Tamaoki, K. Isono, K. Aoshiba, A. Nagai
Journal: European Respiratory Journal (2002)

Abnormal growth of airway epithelium and the resultant thickening of airway walls may produce narrowing of airway calibre, thereby contributing to deterioration of bronchoconstriction in chronic obstructive pulmonary disease (COPD). β 2 ‐adrenergic agonists have been widely used for the treatment of COPD, but their effects on the growth of airway epithelial cells is unknown. Growth of three human airway epithelial cell lines was studied in vitro . Exposure to salbutamol in serum-free medium increased 3‐(4,5-dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium-bromide reduction and intracellular deoxyribonucleic acid (DNA) contents in 16-human bronchial epithelium (16-HBE) cells and NCI-H292 cells, but not in A549 cells. The growth-promoting effect of salbutamol in 16-HBE cells was equipotent to 10% foetal bovine serum and was inhibited by propranolol and a cyclic adenosine monophosphate (cAMP) antagonist, Rp-adenosine 3′,5′-cyclic monophosphorothioate triethylammonium salt (Rp-cAMPS). Likewise, forskolin and 8‐bromoadenosine 3′,5′-cyclic monophosphate (8‐Br-cAMP) caused cell growth and DNA synthesis. Western blot analysis showed that salbutamol, forskolin, and 8‐Br-cAMP each induced expression of the phosphorylated form of mitogen-activated protein (MAP) kinase, and that the salbutamol-induced phosphorylation was inhibited by propranolol, Rp-cAMPS, and the MAP kinase-kinase inhibitor PD98059. These results suggest that in certain airway epithelial cell lines stimulation of β 2 ‐adrenergic receptors and the consequent production of cyclic adenosine monophosphate may upregulate cell growth, probably through activation of the mitogen-activated protein kinase cascade.
Enhancement of human blood eosinophil cytotoxicity by semi-purified eosinophil colony-stimulating factor(s).
Authors: A J Dessein, M A Vadas, N A Nicola, D Metcalf, J R David
Journal: The Journal of Experimental Medicine (1982)

Purified human blood eosinophils, when incubated in human placental conditioned medium (a source of colony-stimulating factors) [CSF]) demonstrate an enhanced ability to damage antibody- or complement-coated schistosomula. This enhancement represents a 4- to 10-fold increase of eosinophil schistosomicidal ability and a 10-fold lowering of the threshold for antibody or complement required in the killing reaction. The activity that enhances eosinophil cytotoxicity and the eosinophil colony-stimulating activity in the placental conditioned medium are eluted in the same fraction (CSF-alpha) after chromatography on Sephadex G-100 and phenyl-Sepharose columns, suggesting that these two activities might be associated with the same molecule. CSF-alpha enhances the adherence step of the killing reaction: antibody-coated larvae were frequently found covered by several layers of eosinophils in tubes containing CSF-alpha. Such a degree of adherence was rarely seen in control tubes lacking CSF-alpha. This enhancement of the eosinophil adherence is detectable 45-60 min after addition of CSF-alpha to the culture. It is not affected by washing the cells after a short time of preincubation with CSF-alpha, and it occurs in the absence of protein synthesis, whereas colony-stimulating activity requires continuous protein synthesis and ceases when CSF is removed from the culture. Finally, CSF-alpha enhances the temperature-dependent reaction that insures the irreversibility of eosinophil attachment to schistosomula. These observations suggest that eosinopoietic factors could be responsible for some of the modified properties of blood eosinophils in eosinophilic individuals.
Why is ain't ought, or: Is <b><i>Homo sapiens</i></b> a rational humanist?
Authors: Oliver Vitouch
Journal: Behavioral and Brain Sciences (2004)

Although the critique of disputable norms is largely legitimate in the cognitive realm, the role of social norms is a different one. Darley, Zimbardo, Milgram, and CNN have compellingly demonstrated that humans are not always humane. But the very cognitive ability to distinguish between “is” and “ought” shows that there is behavioral plasticity, and space for education, inoculation, and learning.
HIF-1-mediated up-regulation of cardiotrophin-1 is involved in the survival response of cardiomyocytes to hypoxia
Authors: Pablo A. Robador, Gorka San José, Cristina Rodríguez, Anna Guadall, María U. Moreno, Javier Beaumont, Ana Fortuño, Javier Díez, José Martínez-González, Guillermo Zalba
Journal: Cardiovascular Research (2011)

AimsCardiotrophin-1 (CT-1) is a cytokine of the interleukin-6 superfamily which is up-regulated in cardiac diseases, in part via hypoxia-dependent mechanisms. However, no evidence for a direct regulation of CT-1 gene (CTF1) promoter by hypoxia inducible factor-1 (HIF-1) has been provided.
Cardiac Origins of the Postural Orthostatic Tachycardia Syndrome
Authors: Qi Fu, Tiffany B. VanGundy, M. Melyn Galbreath, Shigeki Shibata, Manish Jain, Jeffrey L. Hastings, Paul S. Bhella, Benjamin D. Levine
Journal: Journal of the American College of Cardiology (2010)
Gender-Related Differences in Acute Aortic Dissection
Authors: Christoph A. Nienaber, Rossella Fattori, Rajendra H. Mehta, Barbara M. Richartz, Arturo Evangelista, Michael Petzsch, Jeanna V. Cooper, James L. Januzzi, Hüseyin Ince, Udo Sechtem, Eduardo Bossone, Jianming Fang, Dean E. Smith, Eric M. Isselbacher, Linda A. Pape, Kim A. Eagle
Journal: Circulation (2004)

Background— Few data exist on gender-related differences in clinical presentation, diagnostic findings, management, and outcomes in acute aortic dissection (AAD). Methods and Results— Accordingly, we evaluated 1078 patients enrolled in the International Registry of Acute Aortic Dissection (IRAD) to assess differences in clinical features, management, and in-hospital outcomes between men and women. Of the patients enrolled in IRAD (32.1%) with AAD, 346 were women. Although less frequently affected by AAD (32.1% of AAD), women were significantly older and had more often presented later than men ( P =0.008); symptoms of coma/altered mental status were more common, whereas pulse deficit was less common. Diagnostic imaging suggestive of rupture, ie, periaortic hematoma, and pleural or pericardial effusion were more commonly observed in women. In-hospital complications of hypotension and tamponade occurred with greater frequency in women, resulting in higher in-hospital mortality compared with men. After adjustment for age and hypertension, women with aortic dissection die more frequently than men (OR, 1.4, P =0.04), predominantly in the 66- to 75-year age group. Moreover, surgical outcome was worse in women than men ( P =0.013); type A dissection in women was associated with a higher surgical mortality of 32% versus 22% in men despite similar delay, surgical technique, and hemodynamics. Conclusions— Our analysis provides insights into gender-related differences in AAD with regard to clinical characteristics, management, and outcomes; important diagnostic and therapeutic implications may help shed light on aortic dissection in women to improve their outcomes.
Percutaneous Repair or Surgery for Mitral Regurgitation
Authors: Ted Feldman, Elyse Foster, Donald D. Glower, Saibal Kar, Michael J. Rinaldi, Peter S. Fail, Richard W. Smalling, Robert Siegel, Geoffrey A. Rose, Eric Engeron, Catalin Loghin, Alfredo Trento, Eric R. Skipper, Tommy Fudge, George V. Letsou, Joseph M. Massaro, Laura Mauri
Journal: New England Journal of Medicine (2011)

Mitral-valve repair can be accomplished with an investigational procedure that involves the percutaneous implantation of a clip that grasps and approximates the edges of the mitral leaflets at the origin of the regurgitant jet.We randomly assigned 279 patients with moderately severe or severe (grade 3+ or 4+) mitral regurgitation in a 2:1 ratio to undergo either percutaneous repair or conventional surgery for repair or replacement of the mitral valve. The primary composite end point for efficacy was freedom from death, from surgery for mitral-valve dysfunction, and from grade 3+ or 4+ mitral regurgitation at 12 months. The primary safety end point was a composite of major adverse events within 30 days.At 12 months, the rates of the primary end point for efficacy were 55% in the percutaneous-repair group and 73% in the surgery group (P=0.007). The respective rates of the components of the primary end point were as follows: death, 6% in each group; surgery for mitral-valve dysfunction, 20% versus 2%; and grade 3+ or 4+ mitral regurgitation, 21% versus 20%. Major adverse events occurred in 15% of patients in the percutaneous-repair group and 48% of patients in the surgery group at 30 days (P<0.001). At 12 months, both groups had improved left ventricular size, New York Heart Association functional class, and quality-of-life measures, as compared with baseline.Although percutaneous repair was less effective at reducing mitral regurgitation than conventional surgery, the procedure was associated with superior safety and similar improvements in clinical outcomes. (Funded by Abbott Vascular; EVEREST II ClinicalTrials.gov number, NCT00209274.).
Acidic Sphingomyelinase (ASM) Is Necessary for Fas-induced GD3 Ganglioside Accumulation and Efficient Apoptosis of Lymphoid Cells
Authors: Ruggero De Maria, Maria Rita Rippo, Edward H. Schuchman, Roberto Testi
Journal: The Journal of Experimental Medicine (1998)

Ceramides deriving from sphingomyelin hydrolysis are important mediators of apoptotic signals originating from Fas (APO-1/CD95). However, definitive evidence for the role played by individual sphingomyelinases is still lacking. We have analyzed lymphoblastoid cell lines derived from patients affected by Niemann Pick disease (NPD), an autosomal recessive disorder caused by loss-of-function mutations within the acidic sphingomyelinase (ASM) gene. NPD lymphoblasts, which display normal neutral sphingomyelinase activity, fail to activate ASM in response to Fas cross-linking, unlike normal lymphoblasts. NPD lymphoblasts also fail to accumulate GD3 ganglioside, a downstream mediator of ceramide-induced cell death (De Maria, R., L. Lenti, F. Malisan, F. D'Agostino, B. Tomassini, A. Zeuner, M.R. Rippo, R. Testi. 1997. Science. 277:1652-1655), and display a substantially inefficient apoptosis after Fas cross-linking. Inefficient apoptosis is due to lack of ASM activity, because proximal signaling from Fas in NPD lymphoblasts is not impaired and apoptosis can be efficiently triggered by passing the ASM defect with exogenous ceramides. Moreover, mannose receptor-mediated transfer of ASM into NPD lymphoblasts rescues their ability to transiently activate ASM, accumulate GD3, and rapidly undergo apoptosis after Fas cross-linking. These results provide definitive genetic evidence for the role of ASM in the progression of apoptotic signals originating from Fas.
THE ARTHUS PHENOMENON
Authors: Leo M. Davidoff, Beatrice Carrier Seegal, David Seegal
Journal: The Journal of Experimental Medicine (1932)

1. Sixteen out of seventeen rabbits actively sensitized to various antigens by repeated cerebral and intravenous injections showed upon intracerebral reinjection of the same antigen local anaphylactic inflammation of the brain at the site of inoculation. 2. Six out of twenty rabbits actively sensitized to either horse serum or egg albumen by extracerebral injections, showed, upon introduction of the homologous antigen into the cerebrum, local anaphylactic inflammation at the site of inoculation. 3. The pathological picture of the Arthus phenomenon in the brain of the rabbit resembled that seen in the skin, after allowing for differences in the fundamental structure of the tissues involved. 4. None of the control animals exhibited lesions comparable to those found in the experimental animals. A few controls showed slight hemorrhages due to mechanical injury of blood vessels. 5. Clinical symptoms of varying degrees of severity, often leading to the death of the rabbit were observed in the sensitized animals. These symptoms were referable to the site of injection.
The Th17-Defining Transcription Factor RORγt Promotes Glomerulonephritis
Authors: Oliver M. Steinmetz, Shaun A. Summers, Poh-Yi Gan, Timothy Semple, Stephen R. Holdsworth, A. Richard Kitching
Journal: Journal of the American Society of Nephrology (2010)

Although Th17 responses may contribute to the pathogenesis of glomerulonephritis, whether the key transcription factor in Th17 cell development, RORγt, also promotes glomerulonephritis is unknown. Here, we induced crescentic glomerulonephritis in wild-type and RORγt-deficient (RORγt(-/-)) mice. RORγt(-/-) mice were protected from disease, with reduced histologic and functional injury and decreased leukocyte infiltration. Because RORγt(-/-) mice lack lymph nodes, which may influence the development of nephritis, we performed cell-transfer studies. We reconstituted Rag1(-/-) mice, which lack adaptive immunity but otherwise have normal architecture of the lymphatic system, with splenocytes from naïve wild-type or RORγt(-/-) mice. Mice receiving wild-type splenocytes exhibited high mortality from renal failure after induction of nephritis whereas mice receiving RORγt(-/-) cells were protected. To determine the effect of RORγt deficiency specifically in T helper cells, we isolated naïve CD4(+) T cells from wild-type and RORγt(-/-) mice and transferred them into Rag1(-/-) animals. Recipients of wild-type CD4(+) T cells developed severe glomerulonephritis whereas recipients of RORγt(-/-) cells developed less severe disease. To exclude effects of altered regulatory T cell (Treg) development caused by RORγt deficiency, we transferred naïve CD4(+) T cells depleted of Tregs into Rag1(-/-) mice. Recipients of wild-type, Treg-depleted, CD4(+) T cells developed severe glomerulonephritis whereas recipients of RORγt(-/-), Treg-depleted CD4(+) T cells did not. Taken together, this study demonstrates that RORγt promotes the development of crescentic glomerulonephritis by directing nephritogenic Th17 responses.