tbuckley/cabot-search huggingface dataset:
THE DEPOSITION OF EXOGENOUS COPPER UNDER EXPERIMENTAL CONDITIONS WITH OBSERVATIONS ON ITS NEUROTOXIC AND NEPHROTOXIC PROPERTIES IN RELATION TO WILSON'S DISEASE
Authors: F. Stephen Vogel
Journal: The Journal of Experimental Medicine (1959)

Goldfish kept in water containing ionized copper and a detergent added with the aim of decreasing coagulation of the mucus on the gills, took in and retained this metal in their brains, livers, and kidneys, in concentrations comparable to those that occur naturally in Wilson's disease, as chemical assays disclosed. Histochemical studies made it clear that much copper had accumulated within the large neurons, principally in those of the telencephalon and anterior horn region of the spinal cord and in the tubular epithelial cells of the kidneys, the nuclei of the parenchymal cells of the liver, the sarcoplasm of the skeletal muscle, and in the epithelial covering of the gills. The intraneuronal deposition of copper was regularly associated after a time with conspicuous cytologic changes, notably contraction and hyperchromaticity of the nerve cells with tortuosity and fragmentation of the axis cylinders and lysis and loss of neurons. The accumulation of metal in the renal epithelium was frequently accompanied by necrosis and was regularly associated with hyperplasia and calcification of the epithelial cells of the larger renal tubules in all goldfish kept for prolonged periods in copper-rich water. The deposition of copper in the liver was not accompanied by consistent cytologic changes. The similarity of the cytologic alterations induced in the central nervous systems by copper and those that occur naturally in hepatolenticular degeneration in human beings provides evidence that copper itself plays an important role in the pathologic alterations of the brain in Wilson's disease.
ACCF/ASE/ACEP/ASNC/SCAI/SCCT/SCMR 2007 Appropriateness Criteria for Transthoracic and Transesophageal Echocardiography⁎⁎Developed in accordance with the principles and methodology outlined by ACCF: Patel MR, Spertus JA, Brindis RG, Hendel RC, Douglas PS, Peterson E, Wolk MJ, Allen JM, Raskin IE. ACCF proposed method for evaluating the appropriateness of cardiovascular imaging. J Am Coll Cardiol 2005;46:1606-13 (1).
Authors: Pamela S. Douglas, Bijoy Khandheria, Raymond F. Stainback, Neil J. Weissman, Ralph G. Brindis, Manesh R. Patel, Bijoy Khandheria, Joseph S. Alpert, David Fitzgerald, Paul Heidenreich, Edward T. Martin, Joseph V. Messer, Alan B. Miller, Michael H. Picard, Paolo Raggi, Kim D. Reed, John S. Rumsfeld, Anthony E. Steimle, Russ Tonkovic, Krishnaswami Vijayaraghavan, Neil J. Weissman, Susan Bok Yeon, Ralph G. Brindis, Pamela S. Douglas, Robert C. Hendel, Manesh R. Patel, Eric Peterson, Michael J. Wolk, Joseph M. Allen
Journal: Journal of the American College of Cardiology (2007)
Long-term effects on offspring of exposure of oocytes and embryos to chemical and physical agents
Authors: S. K. Walker
Journal: Human Reproduction Update (2000)

Central to this review is the knowledge that, in some livestock species, the environment in which fertilization and embryo development occurs influences not only preimplantation embryo development but also the phenotype of resulting offspring. This knowledge is based on in-vitro studies where the induced changes in the embryo can result in an array of developmental abnormalities after transfer including fetal overgrowth. Whilst such findings are of immediate relevance to assisted reproduction in the human, they also raise another equally important but less obvious issue. Can the in-vivo environments in which fertilization and embryo development normally occur be influenced by exogenous factors (either physical or chemical) in such a way that long-term development is adversely affected? In a global environment of increased use of synthetic chemicals and increased production of pollutants, it is an issue of growing relevance. This review examines technical information that is pertinent to these issues together with a brief assessment of some possible molecular mechanisms responsible for aberrant development. The review concludes with an assessment of the clinical significance of the findings.
Oxidative stress-mediated apoptosis of hepatocytes exposed to acute ethanol intoxication
Authors: I Kurose, H Higuchi, S Miura, H Saito, N Watanabe, R Hokari, M Hirokawa, M Takaishi, S Zeki, T Nakamura, H Ebinuma, S Kato, H Ishii
Journal: Hepatology (1997)

The present study was designed to investigate whether acute ethanol intoxication increases the production of active oxidants, and subsequently promotes apoptosis of hepatocytes. Hepatocytes were isolated from male Wistar rats, and cultured in the presence or absence of ethanol. The fluorescence in situ nick end labeling method and an enzyme-linked immunosorbent assay (ELISA) system to quantify fragmented DNA were used to estimate apoptotic change in hepatocytes. Nuclear morphological alterations and membrane barrier dysfunction of hepatocytes were assessed by staining with Hoechst 33342 and propidium iodide (PI). Intracellular glutathione level was determined as the fluorescence of monochlorobimane (MCLB), which forms conjugate with glutathione to become fluorescent. Ethanol (100 mmol/L) increased the amount of fragmented DNA and the number of apoptotic hepatocytes in vivo as well as in vitro. These ethanol-induced alterations in hepatocytes were attenuated by simultaneous incubation with either 4-methylpyrazole, an inhibitor of alcohol dehydrogenase, or dimethylthiourea, an intracellular oxidant scavenger. Diethyl maleic acid (DMA), a glutathione depletor, enhanced the induction of apoptotic change, and decreased membrane barrier function in ethanol-treated hepatocytes, whereas ethanol per se did not increase the number of PI-positive hepatocytes. Furthermore, combination of ethanol and DMA but not ethanol alone decreased the hepatocyte MCLB fluorescence. Taken together, the present study suggests that active oxidants produced during ethanol metabolism mediate fragmentation of DNA in hepatocytes, and that intracellular antioxidants such as glutathione play a critical role in the cytoprotective mechanisms of hepatocyte against lethal cell death, ie, apoptosis, induced by ethanol.
Hepatic lidocaine metabolism in chronic hepatitis C virus hepatitis with or without steatosis
Authors: Gloria Taliani, Franca Duca, Rosina Lecce, Donatella Livoli, Caterina Pasquazzi, Carlo De Bac, Andrea Fabbri, Giampaolo P. Bianchi, Guilio Marchesini
Journal: Hepatology (1995)
Antibodies with Dual Reactivity to Plasminogen and Complementary PR3 in PR3-ANCA Vasculitis
Authors: David J. Bautz, Gloria A. Preston, Sofia Lionaki, Peter Hewins, Alisa S. Wolberg, Jia Jin Yang, Susan L. Hogan, Hyunsook Chin, Stephan Moll, J. Charles Jennette, Ronald J. Falk
Journal: Journal of the American Society of Nephrology (2008)

Patients with inflammatory vascular disease caused by anti-neutrophil cytoplasmic autoantibodies (ANCA) can harbor antibodies not only to the autoantigen proteinase 3 (PR3) but also to complementary PR3 (cPR3(105-201)), a recombinant protein translated from the antisense strand of PR3 cDNA. The purpose of this study was to identify potential endogenous targets of anti-cPR3(105-201) antibodies. Patients' plasmapheresis material was tested for the presence of antigens reactive with affinity-purified rabbit and chicken anti-cPR3(105-201) polyclonal antibodies. Antigen-containing fractions were tested with patients' anti-cPR3(105-201) affinity-purified IgG, and putative protein targets were sequenced by mass spectrometry. Unexpectedly, plasminogen was identified as a target of anti-cPR3(105-201). Reactivity of affinity-purified antibodies from two patients was lost when plasminogen was converted to plasmin, indicating restricted specificity. Antiplasminogen antibodies from five patients bound plasminogen at a surface-exposed loop structure within the protease domain. This loop contains an amino acid motif that is also found in a portion of recombinant cPR3(105-201); site-directed mutagenesis of this sequence decreased antibody reactivity by 30%. Functionally, antiplasminogen antibodies delayed the conversion of plasminogen to plasmin and increased the dissolution time of fibrin clots. Serologically, antiplasminogen antibody levels were higher in PR3-ANCA patients (n = 72) than healthy control subjects (n = 63), myeloperoxidase-ANCA patients (n = 34), and patients with idiopathic thrombosis (n = 57; P = 0.001). Of the patients with PR3-ANCA, nine had documented deep venous thrombosis events, five of whom were positive for antiplasminogen antibodies. In summary, capitalizing on interactions with complementary proteins, specifically complementary PR3, this study identified plasminogen as a previously undescribed autoantigen in PR3-ANCA vasculitis.
TGFβ overrides HNF4α tumor suppressing activity through GSK3β inactivation: implication for hepatocellular carcinoma gene therapy
Authors: Angela Maria Cozzolino, Tonino Alonzi, Laura Santangelo, Carmine Mancone, Beatrice Conti, Corinna Steindler, Mariateresa Musone, Carla Cicchini, Marco Tripodi, Alessandra Marchetti
Journal: Journal of Hepatology (2012)
Association between Renal Insufficiency and Inducible Ischemia in Patients with Coronary Artery Disease
Authors: Joachim H. Ix, Michael G. Shlipak, Haiying H. Liu, Nelson B. Schiller, Mary A. Whooley
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Chronic renal insufficiency (CRI) is a predictor of stroke, cardiovascular, and all-cause mortality, but the mechanisms responsible for these associations are unclear. Whether CRI was associated with severity of coronary artery disease (CAD) as measured by exercise stress echocardiography among outpatients with stable CAD was evaluated. This study is a cross-sectional analysis of the Heart and Soul study, a prospective cohort of patients with known CAD. Renal function was assessed by 24-h urine collection, and CRI was defined as measured creatinine clearance ≤60 ml/min. Exercise stress echocardiography was used to identify inducible ischemia, defined as any wall motion abnormality seen at stress but not at rest. Logistic regression was used to evaluate the association of CRI with exercise-induced ischemia after adjustment for cardiovascular risk factors. Participants with CRI composed 97 (23%) of the 431 participants and were characterized by older age, worse CAD, lower ejection fraction, greater left ventricular mass and higher C-reactive protein values. The prevalence of exercise-induced ischemia was also substantially greater in the participants with CRI (42% versus 23%; odds ratio [OR], 2.3; 95% confidence interval [CI], 1.4 to 3.8; P < 0.001). This association was minimally changed by adjustment for traditional cardiovascular risk factors and coronary disease history (OR, 2.0; 95% CI, 1.3 to 3.3; P < 0.01) and remained strong even after adjustment for C-reactive protein (OR, 2.3; 95% CI, 1.0 to 5.1; P = 0.04). CRI is strongly associated with exercise-induced ischemia in patients with CAD. The greater severity of atherosclerotic disease observed in patients with CRI may in part explain the association of CRI with increased cardiovascular risk among individuals with CAD.
Effects of physical training in asthma: a systematic review
Authors: Felix S F Ram, Stewart M Robinson, Peter N Black
Journal: British Journal of Sports Medicine (2000)

Objectives —To assess the evidence for the effects of physical training on pulmonary function, symptoms, cardiopulmonary fitness, and quality of life in subjects with asthma. Methods —A search was conducted for randomised controlled trials of subjects with asthma undertaking physical training using the Cochrane Airways Group register of controlled clinical trials, Medline, Embase, Sportdiscus, Science citation index, and Current contents index. Studies were included in the review if the subjects had asthma, were 8 years of age or older, and had undertaken physical training for at least 20 minutes per session, twice a week, for a minimum of four weeks. The eligibility of trials for inclusion in the review and the quality of the trials were independently assessed by two reviewers. Results —Eight studies with a total of 226 subjects met the inclusion criteria for this review. Physical training had no effect on resting lung function but led to an improvement in cardiopulmonary fitness as measured by an increase in maximum oxygen uptake of 5.6 ml/kg/min (95% confidence interval 3.9 to 7.2). None of the studies measured quality of life. Conclusions —Physical training improves cardiopulmonary fitness without changing lung function. It is not clear if the improvement in fitness translates into a reduction in symptoms or an improvement in the quality of life. There is a need for further randomised controlled trials of the effects of physical training in the management of asthma.
REACTIONS OF NORMAL AND TUBERCULOUS ANIMALS TO TUBERCULO-PROTEIN AND TUBERCULO-PHOSPHATIDE
Authors: Kenneth C. Smithburn, Florence R. Sabin
Journal: The Journal of Experimental Medicine (1938)

Prior observations on the cellular reactions to tuberculo-phosphatide are confirmed and compared with reactions induced by this material in tuberculous animals. In the latter the response is accelerated and augmented and simulates the Koch phenomenon. Tuberculo-protein produces no macroscopic reaction in normal animals. The microscopic reaction of neutrophiles and monocytes regresses in less than a week. The same material in tuberculous animals causes a response characterized by more or less hemorrhage and necrosis, tissue degeneration, and infiltration of neutrophiles and monocytes. Late in the reaction there may be a few epithelioid cells and foreign body giant cells. Preparations of tuberculo-phosphatide which contain no tubercle bacilli, or only a few, induce the typical cellular response but do not induce hypersensitiveness to tuberculin. Repeated intradermal skin-test injections of tuberculo-protein MA-100 in normal guinea pigs may be followed by a mild hypersensitiveness to subsequent injections.
The natural history of chronic hepatitis B virus infection
Authors: Brian J. McMahon
Journal: Hepatology (2009)

Chronic hepatitis B virus (HBV) infection has a complicated course. Three phases are identified: an immune tolerant phase with high HBV DNA and normal alanine aminotransferase (ALT) levels associated with minimal liver disease; an immune active phase with high HBV DNA and elevated ALT levels with active liver inflammation; and an inactive phase with HBV DNA levels < 2000 IU/mL and normal ALT levels with minimal inflammation and fibrosis on liver biopsy. Affected persons can move progressively from one phase to the next and may revert backward. The primary adverse outcomes of chronic HBV infection are hepatocellular carcinoma (HCC) and cirrhosis. Published natural history studies were reviewed and ranked by the strength of evidence regarding the study design. Factors with the highest evidence of risk for development of HCC or cirrhosis from population-based prospective cohort studies include male sex, family history of HCC, HBV DNA level above 2000 IU/mL in persons above age 40, HBV genotypes C and F, and basal core promoter mutation. Those with the next highest level of evidence include aflatoxin exposure, and heavy alcohol and tobacco use. Improved methods to identify persons at highest risk of developing HCC or cirrhosis are needed to allow intervention earlier with antiviral therapy in appropriate patients. Future studies should include prospective follow-up of established population-based cohorts as well as new cohorts recruited from multiple centers stratified by HBV genotypes/subgenotypes and clinical phase to determine the incidence of the various HBV phases, HCC, and cirrhosis. Also, nested case-control studies assessing immunological and host genetic factors among persons with active and inactive disease phases, HCC, and cirrhosis could be conducted using these types of cohorts.
Sigh in Acute Respiratory Distress Syndrome
Authors: PAOLO PELOSI, PAOLO CADRINGHER, NICOLA BOTTINO, MAURO PANIGADA, FABIOLA CARRIERI, ELENA RIVA, ALFREDO LISSONI, LUCIANO GATTINONI
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Mechanical ventilation with plateau pressure lower than 35 cm H2O and high positive end-expiratory pressure (PEEP) has been recommended as lung protective strategy. Ten patients with ARDS (five from pulmonary [p] and five from extrapulmonary [exp] origin), underwent 2 h of lung protective strategy, 1 h of lung protective strategy with three consecutive sighs/min at 45 cm H2O plateau pressure, and 1 h of lung protective strategy. Total minute ventilation, PEEP (14.0 ± 2.2 cm H2O), inspiratory oxygen fraction, and mean airway pressure were kept constant. After 1 h of sigh we found that: (1) PaO2 increased (from 92.8 ± 18.6 to 137.6 ± 23.9 mm Hg, p < 0.01), venous admixture and PaCO2 decreased (from 38 ± 12 to 28 ± 14%, p < 0.01; and from 52.7 ± 19.4 to 49.1 ± 18.4 mm Hg, p < 0.05, respectively); (2) end-expiratory lung volume increased (from 1.49 ± 0.58 to 1.91 ± 0.67 L, p < 0.01), and was significantly correlated with the oxygenation (r = 0.82, p < 0.01) and lung elastance (r = 0.76, p < 0.01) improvement. Sigh was more effective in ARDSexp than in ARDSp. After 1 h of sigh interruption, all the physiologic variables returned to baseline. The derecruitment was correlated with PaCO2 (r = 0.86, p < 0.01). We conclude that: (1) lung protective strategy alone at the PEEP level used in this study may not provide full lung recruitment and best oxygenation; (2) application of sigh during lung protective strategy may improve recruitment and oxygenation.
Dual Inhibition of β-Adrenergic and Angiotensin II Receptors by a Single Antagonist
Authors: Liza Barki-Harrington, Louis M. Luttrell, Howard A. Rockman
Journal: Circulation (2003)

Background— Although the renin–angiotensin and the β-adrenergic systems are interrelated, a direct interaction between β-adrenergic receptors (βARs) and angiotensin II type 1 receptors (AT 1 Rs) has not been identified. Methods and Results— Here, we provide evidence for a functional and physiological interaction between 2 G protein–coupled receptors: the βAR and the AT 1 R. Selective blockade of βARs in mouse cardiomyocytes inhibits angiotensin-induced contractility with an IC 50 that is similar to its inhibition of isoproterenol-mediated contractility. Furthermore, administration of the angiotensin receptor blocker valsartan to intact mice results in a significant reduction in the maximal response to catecholamine-induced elevation of heart rate. The mechanism for this transinhibitory effect of β-blockers and angiotensin receptor blockers is through receptor–G protein uncoupling; ie, β-blockers interfere with AT 1 R-G q coupling, and valsartan interferes with βAR-G s coupling. Finally, we demonstrate that AT 1 Rs and βARs form constitutive complexes that are not affected by ligand stimulation. As a result of these interactions, a single receptor antagonist effectively blocks downstream signaling and trafficking of both receptors simultaneously. Conclusions— We show that direct interactions between βARs and AT 1 Rs may have profound consequences on the overall response to drugs that antagonize these receptors.
Exosomes in lungs of patients with sarcoidosis: a contributor to immune pathogenesis or just another by-product of heightened immune activity?
Authors: L.-P. Ho
Journal: Thorax (2010)

The concept that cells can directly communicate with, and influence the function of other cells by transfer of particulate complexes or cell surface proteins (eg, antigen-bound MHC-II, integrin, ATPase channels)1–3 rather than soluble factors like cytokines and chemokines has excited cell biologists for decades. Extensive efforts have been made to prove the existence of this phenomenon and understand the mechanisms by which cells (especially immune cells) transfer proteins between each other. There is now evidence for at least four ways that this transfer could occur4—proteolytic cleavage of the protein from one cell with attachment to another, formation of tubules between two cells, direct cell membrane fusion and transfer of enclosed membrane vesicle (figure 1). An exosome is an example of such a membrane vesicle and is significant in that it can contain the contents of both intracellular endosomes and proteins expressed …
Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (Trail) Is an Inhibitor of Autoimmune Inflammation and Cell Cycle Progression
Authors: Kaimei Song, Yiguang Chen, Rüdiger Göke, Andreas Wilmen, Cheryl Seidel, Alexandra Göke, Brendan Hilliard, Youhai Chen
Journal: The Journal of Experimental Medicine (2000)

The tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) induces apoptosis of tumor cells but not normal cells; its role in normal nontransformed tissues is unknown. We report here that chronic blockade of TRAIL in mice exacerbated autoimmune arthritis, and that intraarticular TRAIL gene transfer ameliorated the disease. In vivo, TRAIL blockade led to profound hyperproliferation of synovial cells and arthritogenic lymphocytes and heightened the production of cytokines and autoantibodies. In vitro, TRAIL inhibited DNA synthesis and prevented cell cycle progression of lymphocytes. Interestingly, TRAIL had no effect on apoptosis of inflammatory cells either in vivo or in vitro. Thus, unlike other members of the tumor necrosis factor superfamily, TRAIL is a prototype inhibitor protein that inhibits autoimmune inflammation by blocking cell cycle progression.
Systematic mapping of two component response regulators to gene targets in a model sulfate reducing bacterium
Authors: Lara Rajeev, Eric G Luning, Paramvir S Dehal, Morgan N Price, Adam P Arkin, Aindrila Mukhopadhyay
Journal: Genome biology (2011)

Abstract Background Two component regulatory systems are the primary form of signal transduction in bacteria. Although genomic binding sites have been determined for several eukaryotic and bacterial transcription factors, comprehensive identification of gene targets of two component response regulators remains challenging due to the lack of knowledge of the signals required for their activation. We focused our study on Desulfovibrio vulgaris Hildenborough, a sulfate reducing bacterium that encodes unusually diverse and largely uncharacterized two component signal transduction systems. Results We report the first systematic mapping of the genes regulated by all transcriptionally acting response regulators in a single bacterium. Our results enabled functional predictions for several response regulators and include key processes of carbon, nitrogen and energy metabolism, cell motility and biofilm formation, and responses to stresses such as nitrite, low potassium and phosphate starvation. Our study also led to the prediction of new genes and regulatory networks, which found corroboration in a compendium of transcriptome data available for D. vulgaris . For several regulators we predicted and experimentally verified the binding site motifs, most of which were discovered as part of this study. Conclusions The gene targets identified for the response regulators allowed strong functional predictions to be made for the corresponding two component systems. By tracking the D. vulgaris regulators and their motifs outside the Desulfovibrio spp. we provide testable hypotheses regarding the functions of orthologous regulators in other organisms. The in vitro array based method optimized here is generally applicable for the study of such systems in all organisms.