tbuckley/cabot-search huggingface dataset:
Nitric Oxide Regulates Transforming Growth Factor-β Signaling in Endothelial Cells
Authors: Marta Saura, Carlos Zaragoza, Beatrice Herranz, Mercedes Griera, Luisa Diez-Marqués, Diego Rodriguez-Puyol, Manuel Rodriguez-Puyol
Journal: Circulation Research (2005)

Many forms of vascular disease are characterized by increased transforming growth factor (TGF)-beta1 expression and endothelial dysfunction. Smad proteins are a key step in TGF-beta-initiated signal transduction. We hypothesized that NO may regulate endothelial TGF-beta-dependent gene expression. We show that NO inhibits TGF-beta/Smad-regulated gene transactivation in a cGMP-dependent manner. NO effects were mimicked by a soluble analogue of cGMP. Inhibition of cGMP-dependent protein kinase 1 (PKG-1) or overexpression of dominant-negative PKG-1alpha suppressed NO/cGMP inhibition of TGF-beta-induced gene expression. Inversely, overexpression of PKG-1alpha catalytic subunit blocked TGF-beta-induced gene transactivation. Furthermore NO delayed and reduced phosphorylated Smad2/3 nuclear translocation, an effect mediated by PKG-1, whereas NG-nitro-L-arginine methyl ester augmented Smad phosphorylation and gene expression in response to TGF-beta. Aortas from endothelial NO synthase-deficient mice showed enhanced basal TGF-beta1 and collagen type I expression; endothelial cells from these animals showed increased Smad phosphorylation and transcriptional activity. Proteasome inhibitors prevented the inhibitory effect of NO on TGF-beta signaling. NO reduced the metabolic life of ectopically expressed Smad2 and enhanced its ubiquitination. Taken together, these results suggest that the endothelial NO/cGMP/PKG pathway interferes with TGF-beta/Smad2 signaling by directing the proteasomal degradation of activated Smad.
The Role of Health Care Systems in Increased Tobacco Cessation
Authors: Susan J. Curry, Paula A. Keller, C. Tracy Orleans, Michael C. Fiore
Journal: Annual Review of Public Health (2008)

Health care delivery systems are critical components of tobacco cessation efforts. This review summarizes recent evidence in support of the health care system recommendations in the 2000 U.S. Public Health Service Clinical Practice Guideline, Treating Tobacco Use and Dependence. Measurable progress in addressing tobacco use through the health care system is summarized, including accountabilities for addressing tobacco in national health care reporting systems, increases in reported advice to quit smoking from health care providers, and wider availability of insurance coverage for tobacco cessation treatments. Despite progress, significant gaps remain between what is possible and what is done by health care systems to impact tobacco cessation. A four-point public policy agenda is outlined to help close these gaps.
Calculation of Mercury’s Effects on Neurodevelopment
Authors: Philippe Grandjean, Celine Pichery, Martine Bellanger, Esben Budtz-Jørgensen
Journal: Environmental Health Perspectives (2012)

come from teaching and research institutions in France or abroad, or from public or private research centers.L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
Demonstration of Prosthetic Aortic Valve Dehiscence in a Patient With Noninfectious Aortitis by Multimodality Imaging
Authors: Hyun Jung Koo, Dong Hyun Yang, Joon-Won Kang, Kichang Han, Cheol Hyun Chung, Jae-Kwan Song, Inchul Lee, Tae-Hwan Lim
Journal: Circulation (2013)
Differential gene expression and cytokine production from neutrophils in asthma phenotypes
Authors: K. J. Baines, J. L. Simpson, N. A. Bowden, R. J. Scott, P. G. Gibson
Journal: European Respiratory Journal (2009)

Asthma is characterised into eosinophilic and non-eosinophilic phenotypes based on inflammatory cell patterns in airway secretions. Neutrophils are important in innate immunity, and are increased in the airways in non-eosinophilic asthma. The present study investigated the activity of neutrophils in asthma phenotypes. Participants with eosinophilic (n = 8) and non-eosinophilic asthma (n = 9) and healthy controls (n = 11) underwent sputum induction and blood collection. Neutrophils were isolated and cultured with or without lipopolysaccharide. Cytokines were measured by ELISA, and gene expression was analysed using a gene expression microarray and quantitative PCR. In non-eosinophilic asthma, blood neutrophils released significantly higher levels of interleukin-8 at rest. Cytokine gene expression and sputum neutrophil protein production did not differ between asthma subtypes. Microarrays demonstrated closely related expression profiles from participants with non-eosinophilic asthma that were significantly distinct from those in eosinophilic asthma. A total of 317 genes were significantly altered in resting neutrophils from participants with non-eosinophilic asthma versus eosinophilic asthma, including genes related to cell motility and regulation of apoptosis. Non-eosinophilic and eosinophilic asthma are associated with specific gene expression profiles, providing further evidence that these phenotypes of asthma involve different molecular mechanisms of disease pathogenesis at the systemic level. The mechanisms of non-eosinophilic asthma may involve enhancement of blood neutrophil chemotaxis and survival.
Multiple Enzymatic Defects in Mitochondria in Hematological Cells of Patients with Primary Sideroblastic Anemia
Authors: Yosuke Aoki
Journal: Journal of Clinical Investigation (1980)

Activities of mitochondrial enzymes in blood cells from 69 patients with primary sideroblastic anemia were determined to elucidate the pathogenesis of the disease. In erythroblasts of patients with primary acquired type the activities of both δ-aminolevulinic acid synthetase and mitochondrial serine protease were inevitably decreased. The susceptibility to the protease of apo-δ-aminolevulinic acid synthetase prepared from erythroblasts of patients with this type was within the normal range, in contrast to that of pyridoxine-responsive anemia. The activities of mitochondrial enzymes such as cytochrome oxidase, serine protease, and oligomycin-sensitive ATPase, except citrate synthetase, were usually decreased in mature granulocytes of the patients. Patients with hereditary sideroblastic anemia also had decreased δ-aminolevulinic acid synthetase activity in erythroblasts, and decreased serine protease activity in both erythroblasts and mature granulocytes. Mature granulocytes obtained from patients with pyridoxine-responsive anemia before therapy had decreased cytochrome oxidase activity, however, the activity increased to a normal level when the patients were in remission. The activities of other mitochondrial enzymes in mature granulocytes were within normal range in these patients before pyridoxine therapy. The activities of these mitochondrial enzymes in lymphocytes were within normal range in all groups of patients with primary sideroblastic anemia.
Blood pressure, stroke, and coronary heart disease
Authors: R Collins, R Peto, S MacMahon, J Godwin, N Qizilbash, R Collins, S MacMahon, P Hebert, K.A Eberlein, J.O Taylor, C.H Hennekens, N.H Fiebach, N Qizilbash, C.H Hennekens
Journal: The Lancet (1990)
Leveling the Playing Field: Bringing Development of Biomarkers and Molecular Diagnostics up to the Standards for Drug Development
Authors: George Poste, David P. Carbone, David R. Parkinson, Jaap Verweij, Stephen M. Hewitt, J. Milburn Jessup
Journal: Clinical Cancer Research (2012)

Abstract Molecular diagnostics are becoming increasingly important in clinical research to stratify or identify molecularly profiled patient cohorts for targeted therapies, to modify the dose of a therapeutic, and to assess early response to therapy or monitor patients. Molecular diagnostics can also be used to identify the pharmacogenetic risk of adverse drug reactions. The articles in this CCR Focus section on molecular diagnosis describe the development and use of markers to guide medical decisions regarding cancer patients. They define sources of preanalytic variability that need to be minimized, as well as the regulatory and financial challenges involved in developing diagnostics and integrating them into clinical practice. They also outline a National Cancer Institute program to assist diagnostic development. Molecular diagnostic clinical tests require rigor in their development and clinical validation, with sensitivity, specificity, and validity comparable to those required for the development of therapeutics. These diagnostics must be offered at a realistic cost that reflects both their clinical value and the costs associated with their development. When genome-sequencing technologies move into the clinic, they must be integrated with and traceable to current technology because they may identify more efficient and accurate approaches to drug development. In addition, regulators may define progressive drug approval for companion diagnostics that requires further evidence regarding efficacy and safety before full approval can be achieved. One way to accomplish this is to emphasize phase IV postmarketing, hypothesis-driven clinical trials with biological characterization that would permit an accurate definition of the association of low-prevalence gene alterations with toxicity or response in large cohorts. Clin Cancer Res; 18(6); 1515–23. ©2012 AACR.
Exocrine function of testis with germinal testicular tumour.
Authors: M A Jewett, J V Thachil, J F Harris
Journal: BMJ (1983)

Semen collected immediately before or soon after therapeutic unilateral orchidectomy from 86 men with germinal tumours of the testis was analysed. The mean sperm count was 65.6 +/- SEM 10.3 X 10(6) per ejaculate. This was significantly different from that in a control population, in whom the mean was 165.2 +/- 12.9 X 10(6) per ejaculate. The difference appeared to be due to a subpopulation of 32 patients with counts of 20 X 10(6) per ejaculate; the distribution of counts in the remaining patients was similar to that in the controls. The cause of this abnormality of exocrine function is unknown: it may either be due to the tumour or its treatment, or both, or, alternatively, it may predate the events of the malignant transformation, possibly even acting as an inducing or promoting factor.
Effect of Ischemic Preconditioning of the Myocardium on cAMP
Authors: Reena Sandhu, Usha Thomas, Roberto J. Diaz, Gregory J. Wilson
Journal: Circulation Research (1996)

Abstract Reduction of cAMP has been implicated in the protection of ischemic preconditioning (IP), but until now, this possibility has not been directly addressed. In this study, we found that in the in vivo rabbit heart, 10 to 30 minutes of sustained regional ischemia was accompanied by a nearly twofold rise in cAMP levels. This increase in cAMP was attenuated when sustained ischemia was preceded by IP induced with a single cycle of transient ischemia and reperfusion (TI/R) and prevented when ischemia was preceded by three cycles of TI/R. The mechanism of cAMP reduction by IP does not involve activation of protein kinase C (PKC), since the PKC inhibitor polymyxin B (24 mg/kg) did not raise cAMP levels during sustained ischemia in IP hearts. Furthermore, this effect is also not mediated by reduced responsiveness of the β-adrenergic effector pathway, since both nonischemic hearts and hearts subjected to three cycles of TI/R exhibited similar increases in cAMP in response to 5 μg/kg isoproterenol. However, propranolol (0.75 mg/kg) abolished the rise in cAMP levels observed during sustained ischemia in control hearts but did not reduce cAMP levels further in IP hearts. These data indicate that the ischemia-induced rise in cAMP levels in control hearts was mediated by activation of the β-adrenergic receptor. Taken together with data demonstrating that β-adrenergic responsiveness was not affected by IP, these data support the conclusion that the lack of elevation in cAMP levels observed during sustained ischemia in IP hearts is mediated by an attenuation of norepinephrine release. To examine whether the protection of IP against necrosis was mediated by the lack of elevation in cAMP levels, we determined whether the infarct size–limiting effect of IP could be blocked by NKH477, an activator of adenylyl cyclase. Four groups of rabbits were subjected to 30 minutes of in vivo regional ischemia and 90 minutes of reperfusion. Control hearts (n=10) had 53.6±5.5% infarction of the area at risk. IP with three cycles of transient ischemia limited infarct size to 3.2±1.3% (n=13, P &lt;.0001). NKH477 (45 μg/kg) increased average cAMP levels in IP hearts during sustained ischemia to levels similar to those in untreated control hearts. However, NKH477 did not block IP (50.2±7.7% of the area at risk was infarcted in the control+NKH477 group [n=10] versus 10.0±5.9% in the IP+NKH477 group [n=7], P &lt;.05). Therefore, we conclude that although IP lowers cAMP levels during sustained ischemia, this effect is not necessary for its protection against necrosis, since raising cAMP does not block this protection of IP.
In vivo fate mapping identifies pre-TCRα expression as an intra- and extrathymic, but not prethymic, marker of T lymphopoiesis
Authors: Hervé Luche, Tata Nageswara Rao, Suresh Kumar, Alpaslan Tasdogan, Franziska Beckel, Carmen Blum, Vera C. Martins, Hans-Reimer Rodewald, Hans Jörg Fehling
Journal: The Journal of Experimental Medicine (2013)

Expression of the pre–T cell receptor α (pTα) gene has been exploited in previous studies as a molecular marker to identify tiny cell populations in bone marrow (BM) and blood that were suggested to contain physiologically relevant thymus settling progenitors (TSPs). But to what extent these cells genuinely contribute to thymopoiesis has remained obscure. We have generated a novel pTαiCre knockin mouse line and performed lineage-tracing experiments to precisely quantitate the contribution of pTα-expressing progenitors to distinct differentiation pathways and to the genealogy of mature hematopoietic cells under physiological in vivo conditions. Using these mice in combination with fluorescent reporter strains, we observe highly consistent labeling patterns that identify pTα expression as a faithful molecular marker of T lineage commitment. Specifically, the fate of pTα-expressing progenitors was found to include all αβ and most γδ T cells but, in contrast to previous assumptions, to exclude B, NK, and thymic dendritic cells. Although we could detect small numbers of T cell progenitors with a history of pTα expression in BM and blood, our data clearly exclude these populations as physiologically important precursors of thymopoiesis and indicate that they instead belong to a pathway of T cell maturation previously defined as extrathymic.
PHOBIA AS A SYMPTOM IN HYPERTHYROIDISM
Authors: BERNARD J. FICARRA, RALPH A. NELSON
Journal: American Journal of Psychiatry (1947)

One hundred fifteen hyperthyroid patients were studied from a psychological viewpoint. The presence of phobias was discerned to be a presenting symptom. The majority of patients presenting phobias were women. Eight men were found to have this complaint. In almost all cases the combination of thyroidectomy and intensive psychotherapy resulted in a disappearance of the phobia. This survey argues for an adequate history-taking of patients suspected of possessing a phobia or presenting it as a major complaint. To label such persons as neurotics, neurasthenics or psychasthenics may be an injustice. Additional information, an adequate physical examination and laboratory studies should be made to rule out underlying thyroid disease. In the particular field of hyperthyroidism the close cooperation of the surgeon and a competent psychologist often reaps a worthy reward. This cooperation on many occasions has saved the neurotic patient from a needless thyroidectomy; even as the surgeon's scalpel has eliminated prolonged psychological treatment of patients with hyperthyroidism.
IHAE-Qol: Specific Health-Related Quality Of Life (HRQoL) Questionnaire In Hereditary Angioedema Due To C1 Inhibitor Deficiency (HAE-C1INH)
Authors: Nieves Prior, Eduardo Remor, Elia Pérez-Fernández, Carmen Gómez-Traseira, Magdalena Julia Caminoa, Francisco Gayá, Werner Aberer, Olga Melcina Barrera, Stephen D. Betschel, Laurence Bouillet, Anette Bygum, Henriette Farkas, Anete S. Grumach, Vesna Grivcheva-Panovska, Marcel Levi, Hilary Longhurst, Alejandro Malbran, Dumitru Moldovan, Gregor Porebski, Avner Reshef, Petra Staubach, Andrea Zanichelli, Yu-xiang Zhi, Teresa Caballero
Journal: Journal of Allergy and Clinical Immunology (2014)
Calcipotriol/betamethasone dipropionate ointment in mild-to-moderate paediatric psoriasis: long-term daily clinical practice data in a prospective cohort
Authors: M.J. van Geel, K. Mul, A.M. Oostveen, P.C.M. van de Kerkhof, E.M.G.J. de Jong, M.M.B. Seyger
Journal: British Journal of Dermatology (2014)

Background Psoriasis in children has a significant negative impact on the quality of life (QoL) and effective treatment can improve this. The two-compound ointment calcipotriol 50 μg g−1 and betamethasone dipropionate 0·5 mg g−1 is an effective treatment option for moderate-to-severe psoriasis in adults. Objectives To study prospectively the effectiveness and safety of calcipotriol/betamethasone dipropionate ointment in paediatric patients with mild-to-moderate plaque psoriasis in daily clinical practice and to investigate the influence on QoL. Methods Data were obtained from a prospective, longitudinal paediatric psoriasis registry, called Child-CAPTURE. Severity was assessed using the Psoriasis Area and Severity Index (PASI) and body surface area (BSA). The Children's Dermatology Life Quality Index (CDLQI) was used to assess QoL and visual analogue scores (VAS) for pain and itch were collected. For safety data the number of (serious) adverse events was recorded. Results Seventy-three patients (mean age 10·8 years, range 3–18) were treated for a median time of 35·0 weeks (range 1·0–176·0). At week 12, mean PASI decreased 15·4% (from 5·2 to 4·4), BSA barely changed, and median CDLQI decreased significantly from 5·5 to 4·0. VAS scores for pain and itch declined. At week 24, mean PASI decreased to 4·3 (17·3%). No related serious adverse events were observed. Conclusions In this daily clinical practice study in paediatric psoriasis, calcipotriol/betamethasone dipropionate ointment initially improved mild-to-moderate psoriasis and then maintained its effect. In addition, it improved QoL, with few adverse events.
Association of cathepsin B gene polymorphisms with tropical calcific pancreatitis
Authors: S Mahurkar
Journal: Gut (2006)

Tropical calcific pancreatitis (TCP) is a type of chronic pancreatitis unique to countries in the tropics. Mutations in pancreatic secretory trypsin inhibitor (SPINK1) rather than cationic trypsinogen (PRSS1) explain the disease in only 50% of TCP patients. As cathepsin B (CTSB) is known to activate cationic trypsinogen, we attempted to understand the role of CTSB mutations in TCP. Evidence of epistatic interaction was investigated with the previously associated N34S SPINK1 allele, a variant considered to be a modifier rather than a true susceptibility allele.We sequenced the coding region of CTSB gene in 51 TCP patients and 25 controls and further genotyped 89 patients and 130 controls from the same cohort for Leu26Val, C595T, T663C, and Ser53Gly polymorphisms. The positive findings observed in the earlier cohort were re-examined in an ethnically matched replication cohort comprising 166 patients and 175 controls. Appropriate statistical analyses were performed and Bonferroni correction for multiple testing was applied.We found a statistically significant association of the Val26 allele at Leu26Val polymorphism with an odds ratio (OR) of 2.15 (95% confidence interval (CI) 1.60-2.90 (p = 0.009)), after Bonferroni correction (corrected p value = 0.025). This significant association of Leu26Val with TCP was replicated in another cohort (OR 2.10 (95% CI 1.56-2.84); p = 0.013). Val26 allele also showed significantly higher frequency in N34S positive and N34S negative patients than in controls (p = 0.019 and 0.013, respectively). We also found significant differences in the mutant allele frequencies at Ser53Gly and C595T single nucleotide polymorphisms between N34S positive patients and controls (p = 0.008 and 0.001, respectively). Although haplotype analysis did not complement the results of allelic association, it did uncover a unique haplotype protective for TCP (p = 0.0035).Our study suggests for the first time that CTSB polymorphisms are associated with TCP. As PRSS1 mutations are absent in TCP and the N34S SPINK1 mutation is proposed to play a modifier role, these variants may be critical as a trigger for cationic trypsinogen activation.
Brain Imaging and Blood Biomarker Abnormalities in Children With Autosomal Dominant Alzheimer Disease
Authors: Yakeel T. Quiroz, Aaron P. Schultz, Kewei Chen, Hillary D. Protas, Michael Brickhouse, Adam S. Fleisher, Jessica B. Langbaum, Pradeep Thiyyagura, Anne M. Fagan, Aarti R. Shah, Martha Muniz, Joseph F. Arboleda-Velasquez, Claudia Munoz, Gloria Garcia, Natalia Acosta-Baena, Margarita Giraldo, Victoria Tirado, Dora L. Ramírez, Pierre N. Tariot, Bradford C. Dickerson, Reisa A. Sperling, Francisco Lopera, Eric M. Reiman
Journal: JAMA Neurology (2015)

Brain imaging and fluid biomarkers are characterized in children at risk for autosomal dominant Alzheimer disease (ADAD).To characterize and compare structural magnetic resonance imaging (MRI), resting-state and task-dependent functional MRI, and plasma amyloid-β (Aβ) measurements in presenilin 1 (PSEN1) E280A mutation-carrying and noncarrying children with ADAD.Cross-sectional measures of structural and functional MRI and plasma Aβ assays were assessed in 18 PSEN1 E280A carriers and 19 noncarriers aged 9 to 17 years from a Colombian kindred with ADAD. Recruitment and data collection for this study were conducted at the University of Antioquia and the Hospital Pablo Tobon Uribe in Medellín, Colombia, between August 2011 and June 2012.All participants had blood sampling, structural MRI, and functional MRI during associative memory encoding and resting-state and cognitive assessments. Outcome measures included plasma Aβ1-42 concentrations and Aβ1-42:Aβ1-40 ratios, memory encoding-dependent activation changes, resting-state connectivity, and regional gray matter volumes. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to AD.Similar to findings in adult mutation carriers, in the later preclinical and clinical stages of ADAD, mutation-carrying children were distinguished from control individuals by significantly higher plasma Aβ1-42 levels (mean [SD]: carriers, 18.8 [5.1] pg/mL and noncarriers, 13.1 [3.2] pg/mL; P < .001) and Aβ1-42:Aβ1-40 ratios (mean [SD]: carriers, 0.32 [0.06] and noncarriers, 0.21 [0.03]; P < .001), as well as less memory encoding task-related deactivation in parietal regions (eg, mean [SD] parameter estimates for the right precuneus were -0.590 [0.50] for noncarriers and -0.087 [0.38] for carriers; P < .005 uncorrected). Unlike carriers in the later stages, mutation-carrying children demonstrated increased functional connectivity of the posterior cingulate cortex with medial temporal lobe regions (mean [SD] parameter estimates were 0.038 [0.070] for noncarriers and 0.190 [0.057] for carriers), as well as greater gray matter volumes in temporal regions (eg, left parahippocampus; P < . 049, corrected for multiple comparisons).Children at genetic risk for ADAD have functional and structural brain changes and abnormal levels of plasma Aβ1-42. The extent to which the underlying brain changes are either neurodegenerative or developmental remains to be determined. This study provides additional information about the earliest known biomarker changes associated with ADAD.