tbuckley/cabot-search huggingface dataset:
Pathophysiology of Aortic Baroreceptors in Rabbits with Vitamin D Sclerosis and Hypertension
Authors: JENNIFER E. ANGELL-JAMES
Journal: Circulation Research (1974)

Calciferol (vitamin D 2 ) (50,000-100,000 IU) and calcium lactate (1 g) were added to the normal diet of 22 rabbits for 7-11 days. When mean arterial blood pressure had risen from a control value of 87.2 ± 3.7 mm Hg to an experimental value of 137.8 ± 5.7 mm Hg (11-145 weeks), the aortic arch of 9 of these rabbits was isolated and perfused with Krebs-Henseleit solution. The impulse activity in 75 aortic baroreceptor fibers from the left aortic nerve was studied during nonpulsatile perfusion at different pressures and was compared with the impulse activity in 29 fibers from 17 normal rabbits. The threshold pressures and the pressure at the point of inflection of the curves were lower in these fibers than they were with fibers from normal rabbits. The gradient of the curves relating baroreceptor impulse frequency to aortic pressure was depressed from a normal mean value of 1.19 impulses/sec mm Hg -1 to 0.61 impulses/sec mm Hg -1 ( P &lt; 0.001). A similar depression of the gradient was found in 7 baroreceptor fibers from the right aortic nerve. The change in the sensitivity of the baroreceptors was more closely related to the time interval after the calciferol treatment ( r =-0.95) than it was to the mean arterial blood pressure ( r = -0.76). The pressure-volume curves show that it was also related to the decreased distensibility of the aortic arch region. Histologically, the aortic arch region had extensive medial sclerosis with calcification.
Continuous positive airway pressure improves sleepiness but not calculated vascular risk in patients with minimally symptomatic obstructive sleep apnoea: the MOSAIC randomised controlled trial
Authors: Sonya Elizabeth Craig, Malcolm Kohler, Debby Nicoll, Daniel J Bratton, Andrew Nunn, Robert Davies, John Stradling
Journal: Thorax (2012)

Continuous positive airway pressure (CPAP) for symptomatic obstructive sleep apnoea (OSA) improves sleepiness and reduces vascular risk, but such treatment for the more prevalent, minimally symptomatic disease is contentious.This multicentre, randomised controlled, parallel, hospital-based trial across the UK and Canada, recruited 391 patients with confirmed OSA (oxygen desaturation index >7.5/h) but insufficient symptoms to warrant CPAP therapy. Patients were randomised to 6 months of auto-adjusting CPAP therapy, or standard care. Coprimary endpoints were change in Epworth Sleepiness Score (ESS) and predicted 5-year mortality using a cardiovascular risk score (components: age, sex, height, systolic blood pressure, smoking, diabetes, cholesterol, creatinine, left ventricular hypertrophy, previous myocardial infarction or stroke). Secondary endpoints included some of the individual components of the vascular risk score, objectively measured sleepiness and self-assessed health status.Of 391 patients randomised, 14 withdrew, 347 attended for their follow-up visit at 6 months within the predefined time window, of which 341 had complete ESS data (baseline mean 8.0, SD 4.3) and 310 had complete risk score data. 22% of patients in the CPAP group reported stopping treatment and overall median CPAP use was 2 : 39 h per night. CPAP significantly improved subjective daytime sleepiness (adjusted treatment effect on ESS -2.0 (95% CI -2.6 to -1.4), p<0.0001), objectively measured sleepiness and self-assessed health status. CPAP did not improve the 5-year calculated vascular risk or any of its components.In patients with minimally symptomatic OSA, CPAP can reduce subjective and objective daytime sleepiness, and improve self-assessed health status, but does not appear to improve calculated vascular risk.
Association between Phosphatidylinositol 3-Kinase Regulatory Subunit p85α <i>Met326Ile</i> Genetic Polymorphism and Colon Cancer Risk
Authors: Li Li, Sarah J. Plummer, Cheryl L. Thompson, Thomas C. Tucker, Graham Casey
Journal: Clinical Cancer Research (2008)

Abstract Purpose: The phosphatidylinositol 3-kinase signaling pathway is frequently activated in cancer. Emerging evidence supports the p85α regulatory subunit gene, PIK3R1, as a novel oncogene. Experimental Design: We examined the association of a functional missense polymorphism (Met326Ile) of PIK3R1 with colon cancer risk in a population-based case-control study of 421 incident cases and 483 controls. Results: In our base unconditional logistic regression model controlling for age, gender, and race, we observed a 47% increase in risk among those carrying one or two copies of the 326Ile variant (P = 0.01). Further adjustment for family history of colorectal cancer, body mass index, nonsteroidal anti-inflammatory drugs, smoking, alcohol consumption, and physical activity strengthened the association [odds ratio (OR), 1.73; 95% confidence interval (CI), 1.24-2.42, P = 0.001]. The association was more pronounced among those older than 64 years (OR, 2.10; 95% CI, 1.19-3.70, P = 0.01). Evaluation of the genotypes assuming an additive mode of inheritance showed a significant trend for gene-dose response, where compared with Met/Met, the OR estimates for Ile/Met and Ile/Ile were 1.68 (95% CI, 1.19-2.37) and 2.27 (95% CI, 0.98-5.29), respectively (P for trend = 0.001). Conclusions: This study is the first to describe a significant association between a germ line functional variant in PIK3R1 and cancer, providing new evidence supporting a role for PIK3R1 in the development of colon cancer.
Multiple Actions of Spinophilin Regulate Mu Opioid Receptor Function
Authors: Joanna J. Charlton, Patrick B. Allen, Kassi Psifogeorgou, Sumana Chakravarty, Ivone Gomes, Rachael L. Neve, Lakshmi A. Devi, Paul Greengard, Eric J. Nestler, Venetia Zachariou
Journal: Neuron (2008)
Host response to mechanical ventilation for viral respiratory tract infection
Authors: Marije P. Hennus, Riny Janssen, Jeroen L.A. Pennings, Hennie M. Hodemaekers, Debby Kruijsen, Nicolaas J. Jansen, Linde Meyaard, Adrianus J. van Vught, Louis J. Bont
Journal: European Respiratory Journal (2012)

Respiratory syncytial virus (RSV) bronchiolitis causes severe respiratory tract infection in infants, frequently necessitating mechanical ventilatory support. However, life-saving, mechanical ventilation aggravates lung inflammation. We set up a model to dissect the host molecular response to mechanical ventilation in RSV infection. Furthermore, the response to induced hypercapnic acidosis, reported to dampen the inflammatory response to mechanical ventilation in non-infectious models, was assessed. BALB/c mice were inoculated with RSV or mock-suspension and ventilated for 5 h on day 5 post inoculation. Mechanical ventilation of infected mice resulted in enhanced cellular influx and increased concentrations of pro-inflammatory cytokines in the bronchoalveolar space. Microarray analysis showed that enhanced inflammation was associated with a molecular signature of a stress response to mechanical ventilation with little effect on the virus-induced innate immune response. Hypercapnic acidosis during mechanical ventilation of infected mice did not change host transcript profiles. We conclude that mechanical ventilation during RSV infection adds a robust but distinct molecular stress response to virus-induced innate immunity activation, emphasising the importance of lung-protective mechanical ventilation strategies. Induced hypercapnic acidosis has no major effect on host transcription profiles during mechanical ventilation for RSV infection, suggesting that this is a safe approach to minimise ventilator-induced lung injury.
Rods in daylight act as relay cells for cone-driven horizontal cell–mediated surround inhibition
Authors: Tamas Szikra, Stuart Trenholm, Antonia Drinnenberg, Josephine Jüttner, Zoltan Raics, Karl Farrow, Martin Biel, Gautam Awatramani, Damon A Clark, José-Alain Sahel, Rava Azeredo da Silveira, Botond Roska
Journal: Nature Neuroscience (2014)
RNAi screen identifies UBE2D3 as a mediator of all-trans retinoic acid-induced cell growth arrest in human acute promyelocytic NB4 cells
Authors: Hidenori Hattori, Xueqing Zhang, Yonghui Jia, Kulandayan K. Subramanian, Hakryul Jo, Fabien Loison, Peter E. Newburger, Hongbo R. Luo
Journal: Blood (2007)
Expression of resistance to Friend virus-stimulated erythropoiesis in bone marrow chimeras containing Fv-2rr and Fv-2ss bone marrow.
Authors: J Silver, N Teich
Journal: The Journal of Experimental Medicine (1981)

Bone marrow chimeras were formed containing mixtures of DBA/2 (Fv-2ss, Hbbdd) and B10.D2 (Fv-2rr, Hbbss) bone marrow. When these mice were infected with the polycythemia-inducing strain of Friend virus, erythropoiesis was stimulated, but the proportion of B10.D2 hemoglobin fell rapidly and newly synthesized hemoglobin was essentially all of the DBA/2 type. The treatment of infected polycythemic chimeras with phenylhydrazine lowered the hematocrit and restored the synthesis of B10.D2 hemoglobin. These results imply that B10.D2 erythroid precursors are intrinsically resistant to Friend virus-stimulated erythropoiesis. The experiments also suggest that virus-stimulated erythropoiesis is not mediated by a factor or cell-cell interactions, unless such factors or interactions do not act across strain barriers.
Targeting of Macrophage Activity by Adenovirus-Mediated Intragraft Overexpression of TNFRp55-Ig, IL-12p40, and vIL-10 Ameliorates Adenovirus-Mediated Chronic Graft Injury, whereas Stimulation of Macrophages by Overexpression of IFN-γ Accelerates Chronic Graft Injury in a Rat Renal Allograft Model
Authors: Jun Yang, Anja Reutzel-Selke, Christoph Steier, Anke Jurisch, Stefan Gu[Combining Diaeresis]nter Tullius, Birgit Sawitzki, Jay Kolls, Hans-Dieter Volk, Thomas Ritter
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Adenovirus (Ad)–mediated gene transfer of immunoregulatory molecules prevents acute allograft rejection. It is here analyzed for the first time whether this approach may prevent the development of chronic renal allograft injury in rats. Renal allografts (F344→Lewis rat) were <i>ex vivo</i> transduced in group I with control Ad-construct, group II with three different therapeutic Ad-constructs expressing the immunoregulatory molecules vIL-10, TNFRp55-Ig, and IL-12p40, and group III with AdIFN-γ. Group IV served as untreated controls. Control grafts (IV) showed increasing proteinuria during the 24-wk follow-up. Chronic graft injury was accelerated by Ad-control (I) and even more by AdIFN-γ (III). All rats carrying the AdIFN-γ–transduced grafts died within 12 to 13 wk by advanced chronic renal failure associated with strong immune cell infiltration and immune gene expression. By contrast, the Ad-therapy group II showed less inflammation and improved graft histology and function if compared with the groups I and III. Moreover, significantly less infiltrating ED-1<sup>+</sup> macrophages and an improved histologic score even if compared with untreated controls (IV) was observed. However, after disappearance of therapeutic gene expression, group II showed increasing proteinuria probably as result of late T cell activation to the Ad-encoded proteins. <i>Ex vivo</i> transduction of allografts with Ad-control or even more AdIFN-γ expression promotes intragraft inflammation and chronic graft injury. Targeting macrophage activation by a cocktail of therapeutic genes improved the results. These data support the pathogenetic role of cytokines in chronic graft injury; however, they also show the limitations of the Ad-mediated gene transfer. E-mail: thomas.ritter@charite.de
AN EARLY EFFECT OF DIPHTHERIA TOXIN ON THE METABOLISM OF MAMMALIAN CELLS GROWING IN CULTURE
Authors: Iwao Kato, A. M. Pappenheimer
Journal: The Journal of Experimental Medicine (1960)

At concentrations of 0.1 Lf (0.25 microg.)/ml., or greater, diphtheria toxin produces an immediate decrease (40 +/- 5 per cent) in the steady-state level of incorporation of inorganic phosphate into ATP by cultures of normal human kidney cells growing at 37 degrees C. in the presence of glucose. The effect is readily reversible by specific antitoxin for a period of 30 minutes or more after adding toxin. Protein synthesis in these cells continues at a normal rate for 60 minutes after adding toxin and the toxin-treated cells are able to take up and concentrate potassium ions normally for at least 1 hour. Even high concentrations of toxin (5 Lf/ml. or more) fail to effect either protein synthesis or ATP formation by cultures of spleen cells from the mouse, an animal that is relatively resistant to the lethal action of the toxin. Of various inhibitors studied, antimycin A most closely resembles toxin in its action, both on protein synthesis and on ATP formation. Mouse cells are considerably more resistant to antimycin A than are human kidney cells. Human kidney cells treated with saturating doses of toxin continue to form RNA at a normal rate for about 1 hour, after which the rates of both P(i) (32) incorporation and of 6-C(14)-orotic acid incorporation into RNA sharply decline and continue at about 40 to 50 per cent their initial rate. At 37 degrees C., S(35)-methionine incorporation into cell protein ceases altogether 60 to 75 minutes after addition of a saturating dose of toxin. The effect of saturating doses of toxin on S(35)-methionine incorporation into human kidney cell protein at different temperatures, has been studied. It is concluded from the present studies that diphtheria toxin exerts a primary, reversible effect at the surface of susceptible cells where it inhibits cytochrome-linked phosphorylation concerned with transport of inorganic phosphate across the cell membrane.
Spi-1/PU.1 Oncogene Accelerates DNA Replication Fork Elongation and Promotes Genetic Instability in the Absence of DNA Breakage
Authors: Pauline Rimmelé, Jun Komatsu, Philippe Hupé, Christophe Roulin, Emmanuel Barillot, Marie Dutreix, Emmanuel Conseiller, Aaron Bensimon, Françoise Moreau-Gachelin, Christel Guillouf
Journal: Cancer Research (2010)

The multistage process of cancer formation is driven by the progressive acquisition of somatic mutations. Replication stress creates genomic instability in mammals. Using a well-defined multistep leukemia model driven by Spi-1/PU.1 overexpression in the mouse and Spi-1/PU.1-overexpressing human leukemic cells, we investigated the relationship between DNA replication and cancer progression. Here, using DNA molecular combing and flow cytometry methods, we show that Spi-1 increases the speed of replication by acting specifically on elongation rather than enhancing origin firing. This shortens the S-phase duration. Combining data from Spi-1 knockdown in murine cells with Spi-1 overexpression in human cells, we provide evidence that inappropriate Spi-1 expression is directly responsible for the replication alteration observed. Importantly, the acceleration of replication progression coincides with an increase in the frequency of genomic mutations without inducing DNA breakage. Thus, we propose that the hitherto unsuspected role for spi-1 oncogene in promoting replication elongation and genomic mutation promotes blastic progression during leukemic development.
Abstract 1556: α-mannosylceramide, a new NKT cell agonist, induces tumor immunity without anergy induction in NKT cells
Authors: Jessica O'Konek, Satomi Takao, Liat Izhak, Petr Illarinov, Gurdyal Besra, Jay Berzofsky, Masaki Terabe
Journal: Cancer Research (2012)

Abstract NKT cells are CD1d-restricted T cells recognizing lipid antigens. When NKT cells are activated with a prototypic antigen, α-galactosylceramide (α-GalCer), they induce strong tumor immunity. Strong preclinical evidence for α-GalCer's ability to induce tumor immunity through NKT cell-activation led to translation into therapy of cancer patients. However, so far minimal success has been achieved in patients. We reasoned that having an α-linked sugar moiety in the structure of α-GalCer can be a target for anti-α-linked galactose natural antibodies, which are a cause of acute xenograft rejection, and which might abrogate the biological activity of α-GalCer. After testing multiple glycosylceramides with potential agonistic activity for NKT cells, we discovered that α-mannosylceramide (α-ManCer) has strong activity to induce tumor immunity through a TNF-α- and NOS-dependent mechanism that is distinct from the IFN-γ dependent protection induced by α-GalCer. Another downside of α-GalCer treatment is induction of long-lasting anergy in activated NKT cells. Since we did not observe massive cytokine production with α-ManCer, in contrast to α-GalCer, we asked whether this new compound activates NKT cells without inducing long-lasting anergy in vivo. In contrast to α-GalCer, α-ManCer did not induce long-lasting anergy of activated NKT cells. This was correlated with the observation that α-ManCer induced only a short term expression of PD-1 on activated NKT cells, which has been reported to be responsible for α-GalCer-induced long-term anergy. Furthermore, while prior treatment with α-GalCer abrogated the protective effect of either α-GalCer or α-ManCer against CT26 colon carcinoma tumor challenge for at least two months, the pre-treatment with α-ManCer had no effect on the protection induced by either NKT cell agonist. Since α-ManCer can activate human NKT cells, this new NKT cell agonist may provide a better opportunity for NKT cell targeted immunotherapy in cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1556. doi:1538-7445.AM2012-1556
Fragile X syndrome. Improving understanding and diagnosis
Authors: C. T. Caskey
Journal: JAMA (1994)

Fragile X syndrome (Martin-Bell syndrome)<sup>1</sup>is the most common cause (one in 1500 males) of mental retardation from a single gene defect. The discovery of the fragile X mental retardation—1 (<i>FMR1</i>) gene and its mutation (CGG triplet repeat enlargement) in 1991<sup>1-4</sup>has prompted intensive molecular studies of both the gene function and the mechanism by which the triplet repeat further expands from generation to generation.<sup>5-8</sup>In this issue, the article by Warren and Nelson<sup>9</sup>summarizes the rapid increase in our molecular knowledge of the disease. In another article, Taylor et al<sup>10</sup>have retrospectively investigated female carriers of fragile X mutations for correlation of mental retardation syndrome with DNA-based methods of measuring the triplet repeat mutation. There is a great deal to be learned from both articles. See also pp 507 and 536. The physician is at a disadvantage in making a clinical diagnosis of fragile
US presidential candidates are urged to support open data campaign
Authors: I. Torjesen
Journal: BMJ (2015)

Campaigners for clinical trial transparency have written an open letter to all US presidential candidates urging them to declare support for the principles of open access to clinical trial data and to commit to making it a reality in the United States if elected.1

Clinical trials attempt to shed light on the potential harms and benefits of a treatment or a procedure, and their outcomes are …
Novel Pharmacophores of Connexin43 Based on the “RXP” Series of Cx43-Binding Peptides
Authors: Vandana Verma, Bjarne Due Larsen, Wanda Coombs, Xianming Lin, Gaelle Spagnol, Paul L. Sorgen, Steven M. Taffet, Mario Delmar
Journal: Circulation Research (2009)

Gap junction pharmacology is a nascent field. Previous studies have identified molecules that enhance intercellular communication, and may offer potential for innovative antiarrhythmic therapy. However, their specific molecular target(s) and mechanism(s) of action remain unknown. Previously, we identified a 34-aa peptide (RXP-E) that binds the carboxyl terminal domain of Cx43 (Cx43CT) and prevents cardiac gap junction closure and action potential propagation block. These results supported the feasibility of a peptide-based pharmacology to Cx43, but the structure of the core active element in RXP-E, an essential step for pharmacological development, remained undefined. Here, we used a combination of molecular modeling, surface plasmon resonance, nuclear magnetic resonance and patch-clamp strategies to define, for the first time, a unique ensemble of pharmacophores that bind Cx43CT and prevent closure of Cx43 channels. Two particular molecules are best representatives of this family: a cyclized heptapeptide (called CyRP-71) and a linear octapeptide of sequence RRNYRRNY. These 2 small compounds offer the first structural platform for the design of Cx43-interacting gap junction openers. Moreover, the structure of these compounds offers an imprint of a region of Cx43CT that is fundamental to gap junction channel function.
State Medicaid Coverage, ESRD Incidence, and Access to Care
Authors: Manjula Kurella-Tamura, Benjamin A. Goldstein, Yoshio N. Hall, Aya A. Mitani, Wolfgang C. Winkelmayer
Journal: Journal of the American Society of Nephrology (2014)

The proportion of low-income nonelderly adults covered by Medicaid varies widely by state. We sought to determine whether broader state Medicaid coverage, defined as the proportion of each state’s low-income nonelderly adult population covered by Medicaid, associates with lower state-level incidence of ESRD and greater access to care. The main outcomes were incidence of ESRD and five indicators of access to care. We identified 408,535 adults aged 20–64 years, who developed ESRD between January 1, 2001, and December 31, 2008. Medicaid coverage among low-income nonelderly adults ranged from 12.2% to 66.0% (median 32.5%). For each additional 10% of the low-income nonelderly population covered by Medicaid, there was a 1.8% (95% confidence interval, 1.0% to 2.6%) decrease in ESRD incidence. Among nonelderly adults with ESRD, gaps in access to care between those with private insurance and those with Medicaid were narrower in states with broader coverage. For a 50-year-old white woman, the access gap to the kidney transplant waiting list between Medicaid and private insurance decreased by 7.7 percentage points in high (>45%) versus low (<25%) Medicaid coverage states. Similarly, the access gap to transplantation decreased by 4.0 percentage points and the access gap to peritoneal dialysis decreased by 3.8 percentage points in high Medicaid coverage states. In conclusion, states with broader Medicaid coverage had a lower incidence of ESRD and smaller insurance-related access gaps.
From the Alcohol, Drug Abuse, and Mental Health Administration
Authors: Donald Ian Macdonald
Journal: JAMA (1986)

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