tbuckley/cabot-search huggingface dataset:
Key Role for Clumping Factor B in Staphylococcus aureus Nasal Colonization of Humans
Authors: Heiman F. L Wertheim, Evelyn Walsh, Roos Choudhurry, Damian C Melles, Hélène A. M Boelens, Helen Miajlovic, Henri A Verbrugh, Timothy Foster, Alex van Belkum
Journal: PLoS Medicine (2008)

Background Staphylococcus aureus permanently colonizes the vestibulum nasi of one-fifth of the human population, which is a risk factor for autoinfection. The precise mechanisms whereby S. aureus colonizes the nose are still unknown. The staphylococcal cell-wall protein clumping factor B (ClfB) promotes adhesion to squamous epithelial cells in vitro and might be a physiologically relevant colonization factor. Methods and Findings We define the role of the staphylococcal cytokeratin-binding protein ClfB in the colonization process by artificial inoculation of human volunteers with a wild-type strain and its single locus ClfB knock-out mutant. The wild-type strain adhered to immobilized recombinant human cytokeratin 10 (CK10) in a dose-dependent manner, whereas the ClfB− mutant did not. The wild-type strain, when grown to the stationary phase in a poor growth medium, adhered better to CK10, than when the same strain was grown in a nutrient-rich environment. Nasal cultures show that the mutant strain is eliminated from the nares significantly faster than the wild-type strain, with a median of 3 ± 1 d versus 7 ± 4 d (p = 0.006). Furthermore, the wild-type strain was still present in the nares of 3/16 volunteers at the end of follow-up, and the mutant strain was not. Conclusions The human colonization model, in combination with in vitro data, shows that the ClfB protein is a major determinant of nasal-persistent S. aureus carriage and is a candidate target molecule for decolonization strategies.
Treatment of PD‐1−/− mice with amodiaquine and anti‐CTLA4 leads to liver injury similar to idiosyncratic liver injury in patients
Authors: Imir G. Metushi, M. Anthony Hayes, Jack Uetrecht
Journal: Hepatology (2014)

The mechanism of idiosyncratic drug-induced liver injury (IDILI) remains poorly understood, to a large degree because of the lack of a valid animal model. Recently, we reported an animal model in which treatment of female C57BL/6 mice with amodiaquine (AQ) resulted in mild liver injury with a delayed onset and resolution despite continued treatment. Such adaptation is a common outcome in the IDILI caused by drugs that can cause liver failure. We had hypothesized that most IDILI is immune-mediated and adaptation represents immune tolerance. In this study we found that AQ treatment of Cbl-b(-/-) and PD-1(-/-) mice, which have impaired immune tolerance, resulted in a slightly greater injury. Cotreatment of C57BL/6 with AQ and anti-CTLA4 also resulted in a greater increase in ALT than treatment with AQ alone; however, these mice also had an increase in T regulatory (Treg) cells and T helper cells expressing PD-1 and CTLA4. The increase in these cells implies the induction of immune tolerance, and the alanine aminotransferase (ALT) activity in these mice returned to normal despite continued treatment. Cotreatment of PD-1(-/-) mice with anti-CTLA4 antibody and AQ resulted in the greatest increase in ALT (200-300 U/L), and necroinflammatory responses characterized by portal infiltration of lymphocytes with interface hepatitis. The lymphocyte infiltration included T and B cells, and the CD8(+) T cells produced perforin and granzyme. In addition, the ALT activity in PD-1(-/-) mice cotreated with anti-CTLA4 antibody and AQ did not return to normal, as it had in other mice.We report here the first animal model of IDILI that is similar to the IDILI that occurs in humans, and it was accomplished by inhibiting immune tolerance.
Robustness of Late Lumen Loss in Discriminating Drug-Eluting Stents Across Variable Observational and Randomized Trials
Authors: Laura Mauri, E. John Orav, Susana C. Candia, Donald E. Cutlip, Richard E. Kuntz
Journal: Circulation (2005)

Background— Binary angiographic and clinical restenosis rates can vary widely between clinical studies, even for the same stent, influenced heavily by case-mix covariates that differ among observational and randomized trials intended to assess a given stent system. We hypothesized that mean in-stent late loss might be a more stable estimator of restenosis propensity across such studies. Methods and Results— In 46 trials of drug-eluting and bare-metal stenting, increasing mean late loss was associated with higher target lesion revascularization (TLR) rates ( P &lt;0.001). When the class of bare-metal stents was compared with the class of effective drug-eluting stents, late loss was more discriminating than TLR as measured by the high intraclass correlation coefficient (ρ) (late loss, ρ=0.71 versus TLR, ρ=0.22; 95% CI of difference=0.33, 0.65). When the individual drug-eluting stents and bare-metal stents were compared, late loss was a better discriminator than TLR (0.68 versus 0.19; 95% CI of difference=0.24, 0.60). Greater adjustments of study covariates are needed to stabilize assessments of TLR compared with late loss because of greater influence of reference vessel diameter on TLR than on in-stent late loss. Optimization of late loss with the use of a novel method of standardization according to diabetes prevalence and mean lesion length resulted in minor adjustments in late loss (&lt;0.08 mm for 90% of reported trials) and an ordered array of mean late loss values for the stent systems studied. Conclusions— Late loss is more reliable than restenosis rates for discriminating restenosis propensity between new drug-eluting stent platforms across studies and might be the optimum end point for evaluating drug-eluting stents in early, nonrandomized studies.
Plasma beta‐thromboglobulin values in thrombocytopenic patients with acute leukemia
Authors: Jack Kutti, Charles G. Zaroulis, Jolanta Kulpa, Lilian Reich, Bayard D. Clarkson, Robert A. Good
Journal: American Journal of Hematology (1980)

Abstract Plasma beta‐thromboglobulin (β‐TG) levels were measured in 14 healthy subjects and in 20 acute leukemia (AL) patients, newly diagnosed, with highly variable values for venous platelet counts. For healthy subjects the plasma β‐TG levels ranged 12–38 (mean 17) ng/ml. In this group of patients with AL, a highly significant positive correlation (P &lt; 0.001) between the values for plasma β‐TG and venous platelet count was present. During a thrombocytopenic period, the plasma β‐TG concentration was measured in nine of the AL patients immediately before and 10 to 12 hours after platelet transfusion therapy. Fourteen platelet transfusions were administered when the patient's highest temperature of the day was &lt;38.5° C, and 18 when the highest temperature of the day was &lt;38.5°C. The mean pretransfusion and post‐transfusion β‐TG values for the 14 platelet transfusions were 7 ± 2 and 20 ± 5 ng/ml, respectively. The corresponding means for the 18 transfusions given to febrile patients were 5 ± 2 ng/ml and 11 ± 2 ng/ml, respectively. Of the pretransfusion values, 11/14 and 14/18 were below the control range. We conclude that the plasma β‐TG values are considerably lower in thrombocytopenic patients than in subjects with normal platelet counts. Further work should provide reference values for plasma β‐TG over a wide range of venous platelet counts.
Common variants near MC4R are associated with fat mass, weight and risk of obesity
Authors: Ruth J F Loos, Cecilia M Lindgren, Shengxu Li, Eleanor Wheeler, Jing Hua Zhao, Inga Prokopenko, Michael Inouye, Rachel M Freathy, Antony P Attwood, Jacques S Beckmann, Sonja I Berndt, Sven Bergmann, Amanda J Bennett, Sheila A Bingham, Murielle Bochud, Morris Brown, Stéphane Cauchi, John M Connell, Cyrus Cooper, George Davey Smith, Ian Day, Christian Dina, Subhajyoti De, Emmanouil T Dermitzakis, Alex S F Doney, Katherine S Elliott, Paul Elliott, David M Evans, I Sadaf Farooqi, Philippe Froguel, Jilur Ghori, Christopher J Groves, Rhian Gwilliam, David Hadley, Alistair S Hall, Andrew T Hattersley, Johannes Hebebrand, Iris M Heid, Blanca Herrera, Anke Hinney, Sarah E Hunt, Marjo-Riitta Jarvelin, Toby Johnson, Jennifer D M Jolley, Fredrik Karpe, Andrew Keniry, Kay-Tee Khaw, Robert N Luben, Massimo Mangino, Jonathan Marchini, Wendy L McArdle, Ralph McGinnis, David Meyre, Patricia B Munroe, Andrew D Morris, Andrew R Ness, Matthew J Neville, Alexandra C Nica, Ken K Ong, Stephen O'Rahilly, Katharine R Owen, Colin N A Palmer, Konstantinos Papadakis, Simon Potter, Anneli Pouta, Lu Qi, Joshua C Randall, Nigel W Rayner, Susan M Ring, Manjinder S Sandhu, André Scherag, Matthew A Sims, Kijoung Song, Nicole Soranzo, Elizabeth K Speliotes, Holly E Syddall, Sarah A Teichmann, Nicholas J Timpson, Jonathan H Tobias, Manuela Uda, Carla I Ganz Vogel, Chris Wallace, Dawn M Waterworth, Michael N Weedon, Cristen J Willer, Vicki L Wraight, Xin Yuan, Eleftheria Zeggini, Joel N Hirschhorn, David P Strachan, Willem H Ouwehand, Mark J Caulfield, Nilesh J Samani, Timothy M Frayling, Peter Vollenweider, Gerard Waeber, Vincent Mooser, Panos Deloukas, Mark I McCarthy, Nicholas J Wareham, Inês Barroso
Journal: Nature Genetics (2008)
Health care reform — need for less emotion and more science
Authors: C. Ronald Kahn
Journal: Journal of Clinical Investigation (2009)

Compared with most European countries, Canada, and Japan, life expectancy in the US is shorter, and rates of infant mortality, maternal mortality, and adult mortality are higher (3).This occurs despite the fact that the US spends more of its gross domestic product per capita on health care than any country in the world. The physician's voice
THE PRODUCTION OF FEVER BY INFLUENZAL VIRUSES
Authors: Robert R. Wagner, Ivan L. Bennett, Virgil S. LeQuire
Journal: The Journal of Experimental Medicine (1949)

The intravenous injection of the PR8 strain of influenza A virus, the Lee strain of influenza B, and the "B" strain of Newcastle disease virus produces fever in rabbits. This phenomenon has been studied in relation to certain in vitro properties of these viruses. Saline suspensions of virus prepared by centrifugation or elution from chicken erythrocytes produced fever. Fluids from which most of the virus particles had been removed were non-pyrogenic. Exposure to temperatures which destroyed the infectivity of the virus for chick embryos did not prevent fever. However, heating sufficient to destroy the hemagglutinin also rendered virus non-pyrogenic. The injection of erythrocytes onto which virus had been adsorbed produced fever. Heated virus adsorbed onto erythrocytes, which failed to elute, produced no elevation of temperature, although heated virus alone was pyrogenic. Neutralization of virus with specific immune serum prevented fever. Antipyrine was capable of abolishing the febrile response to virus. Certain differences between the febrile response in rabbits to the injection of viruses and that following bacterial pyrogens were noted. The period between injection and beginning of temperature rise is longer with virus than with bacterial pyrogens. Relatively low temperatures inactivate the fever-producing capacity of viruses, whereas bacterial pyrogens withstand prolonged autoclaving, and the neutralization of viral fever by specific immune serum contrasts sharply with the failure of antibody to affect the response to bacterial pyrogens. Certain previous observations on the lymphopenia produced in rabbits by the injection of influenzal viruses were confirmed. The capacity of virus preparations to induce fever in rabbits closely parallels their capacity to induce lymphopenia. It was concluded that the fever-producing property of influenzal viruses is closely associated with the capacity to agglutinate erythrocytes.
Proteomic Profiling Identifies Dysregulated Pathways in Small Cell Lung Cancer and Novel Therapeutic Targets Including PARP1
Authors: Lauren Averett Byers, Jing Wang, Monique B. Nilsson, Junya Fujimoto, Pierre Saintigny, John Yordy, Uma Giri, Michael Peyton, You Hong Fan, Lixia Diao, Fatemeh Masrorpour, Li Shen, Wenbin Liu, Boris Duchemann, Praveen Tumula, Vikas Bhardwaj, James Welsh, Stephanie Weber, Bonnie S. Glisson, Neda Kalhor, Ignacio I. Wistuba, Luc Girard, Scott M. Lippman, Gordon B. Mills, Kevin R. Coombes, John N. Weinstein, John D. Minna, John V. Heymach
Journal: Cancer Discovery (2012)

Abstract Small cell lung cancer (SCLC) is an aggressive malignancy distinct from non–small cell lung cancer (NSCLC) in its metastatic potential and treatment response. Using an integrative proteomic and transcriptomic analysis, we investigated molecular differences contributing to the distinct clinical behavior of SCLCs and NSCLCs. SCLCs showed lower levels of several receptor tyrosine kinases and decreased activation of phosphoinositide 3-kinase (PI3K) and Ras/mitogen-activated protein (MAP)/extracellular signal–regulated kinase (ERK) kinase (MEK) pathways but significantly increased levels of E2F1-regulated factors including enhancer of zeste homolog 2 (EZH2), thymidylate synthase, apoptosis mediators, and DNA repair proteins. In addition, PARP1, a DNA repair protein and E2F1 co-activator, was highly expressed at the mRNA and protein levels in SCLCs. SCLC growth was inhibited by PARP1 and EZH2 knockdown. Furthermore, SCLC was significantly more sensitive to PARP inhibitors than were NSCLCs, and PARP inhibition downregulated key components of the DNA repair machinery and enhanced the efficacy of chemotherapy. Significance: SCLC is a highly lethal cancer with a 5-year survival rate of less than 10%. To date, no molecularly targeted agents have prolonged survival in patients with SCLCs. As a step toward identifying new targets, we systematically profiled SCLCs with a focus on therapeutically relevant signaling pathways. Our data reveal fundamental differences in the patterns of pathway activation in SCLCs and NSCLCs and identify several potential therapeutic targets for SCLCs, including PARP1 and EZH2. On the basis of these results, clinical studies evaluating PARP and EZH2 inhibition, together with chemotherapy or other agents, warrant further investigation. Cancer Discov; 2(9); 798–811. ©2012 AACR. Read the Commentary on this article by Rosell and Wannesson, p. 769. This article is highlighted in the In This Issue feature, p. 753.
Differential tumor necrosis factor alpha expression by astrocytes from experimental allergic encephalomyelitis-susceptible and -resistant rat strains.
Authors: I Y Chung, J G Norris, E N Benveniste
Journal: The Journal of Experimental Medicine (1991)

There is evidence that the cytokine tumor necrosis factor alpha (TNF-alpha) contributes to the pathogenesis of neurological autoimmune diseases such as multiple sclerosis (MS) and experimental allergic encephalomyelitis (EAE). TNF-alpha exerts damaging effects on oligodendrocytes, the myelin-producing cell of the central nervous system (CNS), and myelin itself. We have recently demonstrated TNF-alpha expression from astrocytes induced by lipopolysaccharide (LPS), interferon gamma (IFN-gamma), and interleukin 1 beta (IL-1 beta). Astrocytes secrete TNF-alpha in response to LPS alone, and can be primed by IFN-gamma to enhance LPS-induced TNF-alpha production. IFN-gamma and IL-1 beta, cytokines known to be present in the CNS during neurological disease states, do not induce TNF-alpha production alone, but act synergistically to stimulate astrocyte TNF-alpha expression. Inbred Lewis and Brown-Norway (BN) rats differ in genetic susceptibility to EAE, which is controlled in part by major histocompatibility complex (MHC) genes. We examined TNF-alpha gene expression by astrocytes derived from BN rats (resistant to EAE) and Lewis rats (highly susceptible). Astrocytes from BN rats express TNF-alpha mRNA and protein in response to LPS alone, yet IFN-gamma does not significantly enhance LPS-induced TNF-alpha expression, nor do they express appreciable TNF-alpha in response to the combined stimuli of IFN-gamma/IL-1 beta. In contrast, astrocytes from Lewis rats express low levels of TNF-alpha mRNA and protein in response to LPS, and are extremely responsive to the priming effect of IFN-gamma for subsequent TNF-alpha gene expression. Also, Lewis astrocytes produce TNF-alpha in response to IFN-gamma/IL-1 beta. The differential TNF-alpha production by astrocytes from BN and Lewis strains is not due to the suppressive effect of prostaglandins, because the addition of indomethacin does not alter the differential pattern of TNF-alpha expression. Furthermore, Lewis and BN astrocytes produce another cytokine, IL-6, in response to LPS, IFN-gamma, and IL-1 beta in a comparable fashion. Peritoneal macrophages and neonatal microglia from Lewis and BN rats are responsive to both LPS and IFN-gamma priming signals for subsequent TNF-alpha production, suggesting that differential TNF-alpha expression by the astrocyte is cell type specific. Taken together, these results suggest that differential TNF-alpha gene expression in response to LPS and IFN-gamma is strain and cell specific, and reflects both transcriptional and post-transcriptional control mechanisms.(ABSTRACT TRUNCATED AT 400 WORDS)
High-dose Dual Therapy Is Superior to Standard First-line or Rescue Therapy for Helicobacter pylori Infection
Authors: Jyh-Chin Yang, Chun-Jung Lin, Hong-Long Wang, Jin-De Chen, John Y. Kao, Chia-Tung Shun, Chien-Wei Lu, Bor-Ru Lin, Ming-Jium Shieh, Ming-Chu Chang, Yu-Ting Chang, Shu-Chen Wei, Lin-Chih Lin, Wen-Chun Yeh, Jen-Shin Kuo, Chien-Chih Tung, Yew-Loong Leong, Teh-Hong Wang, Jau-Min Wong
Journal: Clinical Gastroenterology and Hepatology (2014)
Evidence that the velocity of sarcomere shortening in single frog atrial cardiac cells is load dependent.
Authors: M Tarr, J W Trank, P Leiffer, N Shepherd
Journal: Circulation Research (1981)

Recent experiments using laser diffraction techniques to determine the time course and extent of sarcomere shortening in thin bundles of cardial tissue have given results which suggest that the velocity of sarcomere shortening in cardiac muscle is independent of the developed force (Nassar et al., 1974; Krueger and Pollack, 1975). However, the anatomical complexity of the intact tissue precludes a definite interpretation of the data, since the exact relationship between the force being borne by the total tissue to the force being borne by any observed group of sarcomeres is uncertain. The single frog atrial cell provides a simple cardiac preparation in which the relationship between sarcomere velocity and sarcomere force is well defined, since these cells are only 1-2 myofibrils wide. The purpose of the present investigation was to determine if sarcomere velocity in the single frog atrial cell is dependent on force by measuring the time course of sarcomere shortening in single cells under conditions in which the cell developed markedly different forces. The results presented in this paper give direct evidence that the velocity of sarcomere shortening in the single cardiac cell depends on the force being developed by the sarcomeres. Thus, cardiac sarcomeres have a type of force-velocity relationship, although the exact nature of this relationship could not be determined in these experiments.
Abstract 2358: Loss of Integrin Linked Kinase Produces an Arrhythmogenic Cardiomyopathy in Mice
Authors: Khai Le Quang, Ange Maguy, Francine Poulin, Louis Villeneuve, Jean-Claude Tardif, Stanley Nattel
Journal: Circulation (2009)

Background: Integrin-linked kinase (ILK) is a serine/threonine protein kinase with roles in signaling and molecular scaffolding of integrin-linked cell adhesion complexes. ILK mutation causes sever...
G-CSF/anti-G-CSF antibody complexes drive the potent recovery and expansion of CD11b+Gr-1+ myeloid cells without compromising CD8+ T cell immune responses
Authors: Mark P Rubinstein, Mohamed L Salem, Andrew L Doedens, Caitlin J Moore, Cody Chiuzan, Guillermo L Rivell, David J Cole, Ananda W Goldrath
Journal: Journal of Hematology & Oncology (2013)

Administration of recombinant G-CSF following cytoreductive therapy enhances the recovery of myeloid cells, minimizing the risk of opportunistic infection. Free G-CSF, however, is expensive, exhibits a short half-life, and has poor biological activity in vivo.We evaluated whether the biological activity of G-CSF could be improved by pre-association with anti-G-CSF mAb prior to injection into mice.We find that the efficacy of G-CSF therapy can be enhanced more than 100-fold by pre-association of G-CSF with an anti-G-CSF monoclonal antibody (mAb). Compared with G-CSF alone, administration of G-CSF/anti-G-CSF mAb complexes induced the potent expansion of CD11b+Gr-1+ myeloid cells in mice with or without concomitant cytoreductive treatment including radiation or chemotherapy. Despite driving the dramatic expansion of myeloid cells, in vivo antigen-specific CD8+ T cell immune responses were not compromised. Furthermore, injection of G-CSF/anti-G-CSF mAb complexes heightened protective immunity to bacterial infection. As a measure of clinical value, we also found that antibody complexes improved G-CSF biological activity much more significantly than pegylation.Our findings provide the first evidence that antibody cytokine complexes can effectively expand myeloid cells, and furthermore, that G-CSF/anti-G-CSF mAb complexes may provide an improved method for the administration of recombinant G-CSF.
The APOE −219G/T and +113G/C polymorphisms affect insulin resistance among Turks
Authors: Evrim Komurcu-Bayrak, Altan Onat, Berna Yuzbasiogullari, Nina Mononen, Reijo Laaksonen, Mika Kähönen, Gulay Hergenc, Terho Lehtimäki, Nihan Erginel-Unaltuna
Journal: Metabolism (2010)
Effects of Traditional and Western Environments on Prevalence of Type 2 Diabetes in Pima Indians in Mexico and the U.S.
Authors: Leslie O. Schulz, Peter H. Bennett, Eric Ravussin, Judith R. Kidd, Kenneth K. Kidd, Julian Esparza, Mauro E. Valencia
Journal: Diabetes Care (2006)

OBJECTIVE—Type 2 diabetes and obesity have genetic and environmental determinants. We studied the effects of different environments on these diseases in Pima Indians in Mexico and the U.S. RESEARCH DESIGN AND METHODS—Adult Pima-Indian and non-Pima populations in the Sierra Madre mountains of Mexico were examined using oral glucose tolerance tests and assessments for obesity, physical activity, and other risk factors. Results were compared with those from Pima Indians in Arizona. Both Pima populations were typed for DNA polymorphisms to establish their genetic similarity. RESULTS—The age- and sex-adjusted prevalence of type 2 diabetes in the Mexican Pima Indians (6.9%) was less than one-fifth that in the U.S. Pima Indians (38%) and similar to that of non-Pima Mexicans (2.6%). The prevalence of obesity was similar in the Mexican Pima Indians (7% in men and 20% in women) and non-Pima Mexicans (9% in men and 27% in women) but was much lower than in the U.S. Pima Indians. Levels of physical activity were much higher in both Mexican groups than in the U.S. Pima Indians. The two Pima groups share considerable genetic similarity relative to other Native Americans. CONCLUSIONS—The much lower prevalence of type 2 diabetes and obesity in the Pima Indians in Mexico than in the U.S. indicates that even in populations genetically prone to these conditions, their development is determined mostly by environmental circumstances, thereby suggesting that type 2 diabetes is largely preventable. This study provides compelling evidence that changes in lifestyle associated with Westernization play a major role in the global epidemic of type 2 diabetes.