tbuckley/cabot-search huggingface dataset:
Increased serum levels and tissue expression of matrix metalloproteinase-12 in patients with systemic sclerosis: correlation with severity of skin and pulmonary fibrosis and vascular damage
Authors: Mirko Manetti, Serena Guiducci, Eloisa Romano, Silvia Bellando-Randone, Maria Letizia Conforti, Lidia Ibba-Manneschi, Marco Matucci-Cerinic
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objective</h3> To determine serum concentrations and tissue expression of matrix metalloproteinase-12 (MMP-12) and their correlation with clinical features in patients with systemic sclerosis (SSc). <h3>Methods</h3> Serum MMP-12 levels from 72 patients with SSc and 42 healthy volunteers were examined by ELISA. Immunohistochemical expression of MMP-12 was analysed in skin biopsies from 20 patients with SSc and 13 healthy subjects and lung biopsies from three patients with SSc-related interstitial lung disease (ILD) and five controls. <h3>Results</h3> Circulating levels of MMP-12 were significantly increased in patients with SSc compared with healthy controls. Serum MMP-12 levels were significantly higher in both patients with limited cutaneous SSc and those with diffuse cutaneous SSc than in healthy controls, and correlated positively with the extent of skin involvement. MMP-12 levels were raised in SSc patients with ILD compared with patients without ILD, and correlated with severity of lung restriction. Increased serum levels of MMP-12 were also associated with the presence of digital ulcers and severity of nailfold capillary abnormalities. In contrast to almost undetectable MMP-12 expression in healthy skin, MMP-12 was strongly expressed in keratinocytes, dermal endothelial cells, fibroblasts/myofibroblasts and inflammatory cells in the skin of patients with SSc. Affected lung tissue from patients with SSc-related ILD showed strong MMP-12 expression in capillary vessels, inflammatory cells, alveolar macrophages and fibroblasts in the thickened alveolar septa, while faint expression was observed in normal lung tissue. <h3>Conclusions</h3> MMP-12 levels are increased in patients with SSc and are associated with severity of skin and pulmonary fibrosis and peripheral vascular damage.
Ptf1a, a bHLH Transcriptional Gene, Defines GABAergic Neuronal Fates in Cerebellum
Authors: Mikio Hoshino, Shoko Nakamura, Kiyoshi Mori, Takeshi Kawauchi, Mami Terao, Yoshiaki V. Nishimura, Akihisa Fukuda, Toshimitsu Fuse, Naoki Matsuo, Masaki Sone, Masahiko Watanabe, Haruhiko Bito, Toshio Terashima, Christopher V.E. Wright, Yoshiya Kawaguchi, Kazuwa Nakao, Yo-ichi Nabeshima
Journal: Neuron (2005)
Myocardial infarction in rats. Infarct size, myocyte hypertrophy, and capillary growth.
Authors: P Anversa, C Beghi, Y Kikkawa, G Olivetti
Journal: Circulation Research (1986)

To determine the compensatory reserve capacity of the ventricular myocardium following infarction, the left coronary artery in rats was ligated, and the animals were killed 40 days later. Infarcts affecting an average 23% of the left ventricle were characterized by a 27% hypertrophic growth of the remaining myocardium that produced a complete replacement of the necrotic tissue. In contrast, infarcts with an average 50% loss of mass resulted in 83% expansion of the spared myocardium that was inadequate for a complete restoration of ventricular tissue. Myocyte hypertrophy was 26% and 78% in small and large infarcts, respectively. Cellular hypertrophy in both cases involved significant increases in myocyte transverse area and myocyte length. After large infarcts, there was an 18% reduction in capillary surface and a 16% increase in the diffusion distance. Corresponding values for small infarcts were -10% and 9%. These alterations combined with the deficient reconstitution of myocardial mass following large infarcts resulted in 25%, 29%, and 30% deficits in the absolute amounts of capillary lumen, surface, and length per ventricle respectively. Even with small infarcts, a deficit was seen in capillary luminal surface (-16%), and length (-19%). In conclusion, we have demonstrated that cardiac hypertrophy following myocardial infarction is consistent with cellular shape changes characteristic of a combination of concentric and eccentric hypertrophic growth. However, cardiac muscle cells appear to be unable to compensate for the loss of mass induced by a 50% infarct. The inadequate adaptation of the capillary vasculature in the infarcted hearts suggests that the injured ventricle is more vulnerable to additional ischemic episodes.
A 68-Year-Old Man With COPD Contemplating Colon Cancer Surgery
Authors: Gerald W. Smetana
Journal: JAMA (2007)

Mr A is a 68-year-old man with a history of melena who was found to have a mass in his colon that was suspicious for possible malignancy. His 75-pack-year smoking history has resulted in a chronic daily cough and the diagnosis of chronic obstructive pulmonary disease. On physical examination, he has wheezes, decreased breath sounds, and a prolonged expiratory phase; his forced expiratory volume in the first second (FEV1) is 1.34 L (47% predicted). Mr A needs surgery for potentially curative treatment for presumed colon cancer, but he is understandably worried about the effect of his lung disease on his surgical risk. In particular, he is worried that he may not be able to be weaned off the ventilator after surgery. This discussion reviews the important patient- and procedure-related risk factors for pulmonary complications after surgery, the role of preoperative testing, and the evidence supporting strategies to reduce the risk of pulmonary complications as they apply to Mr A.
Nitric oxide signaling comes of age: 20 years and thriving
Authors: S LAMAS, C LOWENSTEIN, T MICHEL
Journal: Cardiovascular Research (2007)

The lyrics of a famous tango state that “twenty years time is just nothing”. While this impression may broadly apply to different circumstances, such might not be the case for nitric oxide (NO). In the year 1987 two seminal contributions coming from independent laboratories [1,2] established the identity of the elusive endothelial derived relaxing factor reported by Bob Furchgott seven years earlier [3]. These laboratories showed that the chemical nature of “endothelium-derived relaxing factor” (EDRF) was identical to NO. The idea that NO could act as an activator of soluble guanylate cyclase had been proposed even earlier [4]. These four papers, together with the demonstration of l-arginine as substrate for the generation of NO [5], defined a pathway in endothelial cells which is now considered classical: the l-arginine-NO-cGMP pathway. Of importance, a considerable amount of information had already accumulated almost at the same time and had arrived at the same conclusions in non-vascular cells such as macrophages (see [6] for review). For the past twenty years, we have both witnessed and participated in an explosion of knowledge in the NO field, leading to the comprehension of the physiological and pathophysiological roles of NO in several organs and tissues, among which the cardiovascular system is “primus inter pares”.

This Spotlight Issue is devoted to classical and non-classical targets of NO signaling in the cardiovascular system. One of the most cogent analyses of NO signaling in pathways independent from cGMP was published in 1992, in which Loscalzo and colleagues proposed that S -nitrosylation of albumin could represent an effective mechanism to deliver NO at distal sites [7]. Studies from the laboratories of Stamler, Loscalzo and others opened a new perspective related to the potential modification of protein function by S -nitros(yl)ation [8]. In this current … 

* Corresponding author. Centro de Investigaciones Biologicas-CSIC, Ramiro de Maeztu 9, Madrid, 28040, Spain. Tel.: +34 91 837 3112x4302, +34 64 941 8799 (mobile); fax: +34 91 536 0432. slamas{at}cib.csic.es
Regulation of RANTES and ICAM-1 expression in murine mesangial cells.
Authors: J A Satriano, B Banas, B Luckow, P Nelson, D O Schlondorff
Journal: Journal of the American Society of Nephrology (1997)

Chemokines and adhesion molecules play a pivotal role in leukocyte infiltration during tissue injury. RANTES (regulated upon activation, normal T cell expressed and secreted) is a monocyte chemoattractant that induces the expression of CD11/CD18 integrins on leukocytes for which intercellular adhesion molecule-1 (ICAM-1) is the ligand. Both RANTES and ICAM-1 can be expressed by mesangial cells (MC) in culture and in glomeruli during immune injury. In this study, the role of reactive oxygen species (ROS) in the activation of RANTES and ICAM-1 in murine MC was examined. Tumor necrosis factor alpha (TNF-alpha) and aggregated immunoglobulin (aggr. Ig) G, which enhance ROS formation in MC, increased mRNA transcripts of both RANTES and ICAM-1. Thiol-containing free-radical scavengers N-acetyl cysteine, dimethyl- and tetramethylthiourea, or pyrrolidinedithiocarbamate abrogated the increase in mRNA for RANTES and ICAM-1 in response to TNF-alpha or IgG. Hydroxy-methoxy acetophenone, an inhibitor of NADPH-dependent oxidase, also attenuated RANTES and ICAM-1 in response to TNF-alpha or IgG. ROS generated by addition of xanthine oxidase and hypoxanthine induced RANTES and ICAM-1 expression, whereas hydrogen peroxide caused no response. Because cAMP can interfere with gene activation in MC, the effects of 8-Br-cAMP, forskolin, and prostaglandin E2 on mRNA levels were examined for RANTES and ICAM-1. These agents attenuated the response to IgG aggregates and also to superoxide generation. Finally, the effect of glucocorticoids, which are frequently used in glomerular immune injury, was examined. Dexamethasone decreased mRNA for both RANTES and ICAM-1 after stimulation with aggr. IgG or TNF-alpha. Both forskolin and dexamethasone also reduced the amount of RANTES protein secreted by MC in response to aggr. IgG. Only dexamethasone decreased RANTES secretion in response to TNF-alpha stimulation. The inhibitory effects of cAMP and dexamethasone may explain the beneficial effects of cAMP mimetics, such as prostaglandin E2 and glucocorticoid administration on glomerular inflammatory processes.
Low lipoprotein (a) levels during acute viral hepatitis
Authors: H C Geiss, M M Ritter, W O Richter, P Schwandt, R Zachoval
Journal: Hepatology (1996)

High serum concentrations of lipoprotein (a) [Lp(a)] are considered a risk factor for premature atherosclerosis. Besides apolipoprotein B–100, Lp(a) consists of apolipoprotein (a) [apo(a)], which shows a remarkable size polymorphism. The serum concentration of Lp(a) is considerably influenced by this apo(a) phenotype. Because Lp(a) is synthesized in the liver, we wondered whether and to what extent Lp(a) levels might be affected by acute liver disease. We compared Lp(a) serum concentrations in 74 patients (54% male, 46% female; mean age, 46 years) with acute viral hepatitis (32, 28, and 14 with hepatitis A, B, and C, respectively) with those in 404 healthy controls (57% men, 43% women; mean age, 47 years). In addition, the intraindividual course of Lp(a) concentration during and after acute hepatitis was followed in a subgroup of 23 patients (15, 6, and 2 with hepatitis A, B, and C, respectively). During acute hepatitis, median Lp(a) concentrations in the patient group were significantly diminished compared with controls (7 vs. 17 mg/dL; P &lt; .0001, Mann–Whitney test). Any bias by an unequal isoform distribution was excluded because there was no significant difference in the isoform distribution between patients and controls ( P &gt; .10, chi2 test). Furthermore, the decrease in Lp(a) concentration during acute hepatitis was independent of the molecular weight of the apo(a) isoform. Longitudinally observed patients showed a marked increase in Lp(a) concentration during convalescence (7 to 32 mg/dL; P &lt; .0001, Wilcoxon test). Our results show that acute hepatitis is associated with decreased Lp(a) serum levels. Further studies are needed to evaluate whether Lp(a) serum concentration might be clinically useful as a parameter of liver function.
Inhibition of Cancer Cell Invasion by Cannabinoids via Increased Expression of Tissue Inhibitor of Matrix Metalloproteinases-1
Authors: Robert Ramer, Burkhard Hinz
Journal: JNCI Journal of the National Cancer Institute (2007)

Cannabinoids, in addition to having palliative benefits in cancer therapy, have been associated with anticarcinogenic effects. Although the antiproliferative activities of cannabinoids have been intensively investigated, little is known about their effects on tumor invasion.Matrigel-coated and uncoated Boyden chambers were used to quantify invasiveness and migration, respectively, of human cervical cancer (HeLa) cells that had been treated with cannabinoids (the stable anandamide analog R(+)-methanandamide [MA] and the phytocannabinoid delta9-tetrahydrocannabinol [THC]) in the presence or absence of antagonists of the CB1 or CB2 cannabinoid receptors or of transient receptor potential vanilloid 1 (TRPV1) or inhibitors of p38 or p42/44 mitogen-activated protein kinase (MAPK) pathways. Reverse transcriptase-polymerase chain reaction (RT-PCR) and immunoblotting were used to assess the influence of cannabinoids on the expression of matrix metalloproteinases (MMPs) and endogenous tissue inhibitors of MMPs (TIMPs). The role of TIMP-1 in the anti-invasive action of cannabinoids was analyzed by transfecting HeLa, human cervical carcinoma (C33A), or human lung carcinoma cells (A549) cells with siRNA targeting TIMP-1. All statistical tests were two-sided.Without modifying migration, MA and THC caused a time- and concentration-dependent suppression of HeLa cell invasion through Matrigel that was accompanied by increased expression of TIMP-1. At the lowest concentrations tested, MA (0.1 microM) and THC (0.01 microM) led to a decrease in invasion (normalized to that observed with vehicle-treated cells) of 61.5% (95% CI = 38.7% to 84.3%, P < .001) and 68.1% (95% CI = 31.5% to 104.8%, P = .0039), respectively. The stimulation of TIMP-1 expression and suppression of cell invasion were reversed by pretreatment of cells with antagonists to CB1 or CB2 receptors, with inhibitors of MAPKs, or, in the case of MA, with an antagonist to TRPV1. Knockdown of cannabinoid-induced TIMP-1 expression by siRNA led to a reversal of the cannabinoid-elicited decrease in tumor cell invasiveness in HeLa, A549, and C33A cells.Increased expression of TIMP-1 mediates an anti-invasive effect of cannabinoids. Cannabinoids may therefore offer a therapeutic option in the treatment of highly invasive cancers.
Selective Constraints in Conserved Folded RNAs of Drosophilid and Hominid Genomes
Authors: R. Piskol, W. Stephan
Journal: Molecular Biology and Evolution (2010)

Small noncoding RNAs as well as folded RNA structures in genic regions are crucial for many cellular processes. They are involved in posttranscriptional gene regulation (microRNAs), RNA modification (small nucleolar RNAs), regulation of splicing, correct localization of proteins, and many other processes. In most cases, a distinct secondary structure of the molecule is necessary for its correct function. Hence, selection should act to retain the structure of the molecule, although the underlying sequence is allowed to vary. Here, we present the first genome-wide estimates of selective constraints in folded RNA molecules in the nuclear genomes of drosophilids and hominids. In comparison to putatively neutrally evolving sites, we observe substantially reduced rates of substitutions at paired and unpaired sites of folded molecules. We estimated evolutionary constraints to be in the ranges of (0.974,0.991) and (0.895,1.000) for paired nucleotides in drosophilids and hominids, respectively. These values are significantly higher than for constraints at nonsynonymous sites of protein-coding genes in both genera. Nonetheless, valleys of only moderately reduced fitness (s≈10 − 4) are sufficient to generate the observed fraction of nucleotide changes that are removed by purifying selection. In addition, a comparison of selective coefficients between drosophilids and hominids revealed significantly higher constraints in drosophilids, which can be attributed to the difference in long-term effective population size between these two groups of species. This difference is particularly apparent at the independently evolving (unpaired) sites.
Complement-mediated Defect in Clearance and Sequestration of Sensitized, Autologous Erythrocytes in Rodent Malaria
Authors: Michael G. Pappas, Ruth S. Nussenzweig, Victor Nussenzweig, Hannah Lustig Shear
Journal: Journal of Clinical Investigation (1981)

We investigated the ability of malaria-infected and normal mice to clear particulate immune complexes consisting of autologous erythrocytes sensitized with either IgG or complement.
Glucose Intolerance in Pregnancy and Future Risk of Pre-Diabetes or Diabetes
Authors: Ravi Retnakaran, Ying Qi, Mathew Sermer, Philip W Connelly, Anthony J.G. Hanley, Bernard Zinman
Journal: Diabetes Care (2008)

OBJECTIVE—The purpose of this study was to test the hypothesis that any degree of abnormal glucose homeostasis detected on antepartum screening for gestational diabetes mellitus (GDM) should be associated with an increased risk of postpartum pre-diabetes or diabetes. RESEARCH DESIGN AND METHODS—In this prospective cohort study, 487 women underwent 1) antepartum GDM screening by a glucose challenge test (GCT) and a diagnostic oral glucose tolerance test (OGTT) and 2) postpartum metabolic characterization by OGTT at 3 months after delivery. Four baseline glucose tolerance groups were defined on the basis of the antepartum GCT/OGTT: 1) GDM (n = 137); 2) gestational impaired glucose tolerance (GIGT) (n = 91); 3) abnormal GCT with normal glucose tolerance on an OGTT (abnormal GCT NGT) (n = 166); and 4) normal GCT with NGT on an OGTT (normal GCT NGT) (n = 93). RESULTS—The prevalence of postpartum glucose intolerance (pre-diabetes or diabetes) increased across the groups from normal GCT NGT (3.2%) to abnormal GCT NGT (10.2%) to GIGT (16.5%) to GDM (32.8%) (Ptrend &amp;lt; 0.0001). On logistic regression analysis, all three categories of abnormal glucose homeostasis in pregnancy independently predicted postpartum glucose intolerance: abnormal GCT NGT odds ratio (OR) 3.6 (95% CI 1.01–12.9); GIGT OR 5.7 (1.6–21.1); and GDM OR 14.3 (4.2–49.1). Furthermore, both in pregnancy and at 3 months postpartum, insulin sensitivity (ISOGTT) and pancreatic β-cell function (insulinogenic index/homeostasis model assessment of insulin resistance) progressively decreased across the groups from normal GCT NGT to abnormal GCT NGT to GIGT to GDM (all Ptrend &amp;lt; 0.0001). CONCLUSIONS—Any degree of abnormal glucose homeostasis in pregnancy independently predicts an increased risk of glucose intolerance postpartum.
Identification of HLA-A2–restricted CD8+ Cytotoxic T Cell Responses in Primary Biliary Cirrhosis
Authors: Hiroto Kita, Zhe-Xiong Lian, Judy Van de Water, Xiao-Song He, Shuji Matsumura, Marshall Kaplan, Velimir Luketic, Ross L. Coppel, Aftab A. Ansari, M. Eric Gershwin
Journal: The Journal of Experimental Medicine (2002)

Primary biliary cirrhosis (PBC) is characterized by an intense biliary inflammatory CD4(+) and CD8(+) T cell response. Very limited information on autoantigen-specific cytotoxic T lymphocyte (CTL) responses is available compared with autoreactive CD4(+) T cell responses. Using peripheral blood mononuclear cells (PBMCs) from PBC, we identified an HLA-A2-restricted CTL epitope of the E2 component of pyruvate dehydrogenase (PDC-E2), the immunodominant mitochondrial autoantigen. This peptide, amino acids 159-167 of PDC-E2, induces specific MHC class I-restricted CD8(+) CTL lines from 10/12 HLA-A2(+) PBC patients, but not controls, after in vitro stimulation with antigen-pulsed dendritic cells (DCs). PDC-E2-specific CTLs could also be generated by pulsing DCs with full-length recombinant PDC-E2 protein. Furthermore, using soluble PDC-E2 complexed with either PDC-E2-specific human monoclonal antibody or affinity-purified autoantibodies against PDC-E2, the generation of PDC-E2-specific CTLs, occurred at 100-fold and 10-fold less concentration, respectively, compared with soluble antigen alone. Collectively, these data demonstrate that autoantibody, helper, and CTL epitopes all contain a shared peptide sequence. The finding that autoantigen-immune complexes can not only cross-present but also that presentation of the autoantigen is of a higher relative efficiency, for the first time defines a unique role for autoantibodies in the pathogenesis of an autoimmune disease.
Non-contraceptive benefits of hormonal and intrauterine reversible contraceptive methods
Authors: Luis Bahamondes, M Valeria Bahamondes, Lee P Shulman
Journal: Human Reproduction Update (2015)

Most contraceptive methods present benefits beyond contraception; however, despite a large body of evidence, many healthcare professionals (HCPs), users and potential users are unaware of those benefits. This review evaluates the evidence for non-contraceptive benefits of hormonal and non-hormonal contraceptive methods. We searched the medical publications in PubMed, POPLINE, CENTRAL, EMBASE and LILACS for relevant articles, on non-contraceptive benefits of the use of hormonal and intrauterine reversible contraceptive methods, which were published in English between 1980 and July 2014. Articles were identified using the following search terms: 'contraceptive methods', 'benefits', 'cancer', 'anaemia', 'heavy menstrual bleeding (HMB)', 'endometrial hyperplasia', 'endometriosis' and 'leiomyoma'. We identified, through the literature search, evidence that some combined oral contraceptives have benefits in controlling HMB and anaemia, reducing the rate of endometrial, ovarian and colorectal cancer and ectopic pregnancy as well as alleviating symptoms of premenstrual dysphoric disorder. Furthermore, the use of the levonorgestrel-releasing intrauterine system also controls HMB and anaemia and endometrial hyperplasia and cancer, reduces rates of endometrial polyps in users of tamoxifen and alleviates pain associated with endometriosis and adenomyosis. Depot medroxyprogesterone acetate controls crises of pain associated with sickle cell disease and endometriosis. Users of the etonogestrel-releasing contraceptive implant have the benefits of a reduction of pain associated with endometriosis, and users of the copper intrauterine device have reduced rates of endometrial and cervical cancer. Despite the high contraceptive effectiveness of many hormonal and intrauterine reversible contraceptive methods, many HCPs, users and potential users are concerned mainly about side effects and safety of both hormonal and non-hormonal contraceptive methods, and there is scarce information about the many benefits that these methods offer beyond contraception.
Community based programmes can help to manage tuberculosis more effectively
Authors: R. de Soldenhoff
Journal: BMJ (1998)

EDITOR—In many low income countries the cure rates achieved by tuberculosis field programmes (for sputum smear positive cases) exceed the 85% target set by the World Health Organisation.1 However, the decision to favour outpatient rather than hospital treatment of tuberculosis in many such countries has been influenced by several factors not mentioned in Squire and Wilkinson's editorial2 that were only alluded to in the two accompanying papers. 3 4

Programmes to control tuberculosis are often the responsibility …