tbuckley/cabot-search huggingface dataset:
Increased renal expression of nitric oxide synthase type III in cirrhotic rats with ascites
Authors: Marta Bosch-Marcé, Manuel Morales-Ruiz, Wladimiro Jiménez, Nuria Bordas, Manuel Solé, Josefa Ros, Ramón Deulofeu, Vicente Arroyo, Francisca Rivera, Juan Rodés
Journal: Hepatology (1998)

This article assesses the circulating levels of l -arginine, the renal response to l -arginine infusion, and the renal expression of inducible and constitutive nitric oxide synthase (NOS II and NOS III, respectively) in cirrhotic rats with ascites. Systemic and renal hemodynamics and renal function were measured in basal conditions and following two doses of l -arginine (5 and 10 mg · kg −1 · min for 40 minutes). Renal NOS II and III messenger RNA (mRNA) expression was evaluated in basal conditions by polymerase chain reaction and Northern blot, respectively. Renal NOS II and III protein expression was assessed by Western blot and immunohistochemistry. Plasma concentration of l -arginine was significantly lower in cirrhotic rats than in control rats (48 ± 11 vs. 86 ± 9 μmol/L, P &lt; .025). In both groups l -arginine infusion had no effect on systemic hemodynamics, but markedly increased renal perfusion. This effect was significantly more intense in cirrhotic rats. A very weak signal of similar intensity was found for NOS II mRNA in both groups of animals. However, no NOS II protein expression was detected. In contrast, higher NOS III mRNA abundance and protein expression, which was mainly located in the endothelial lining of the renal arterioles, were found in the kidney of cirrhotic animals. These results indicated increased renal expression of NOS III mRNA and protein, deficient circulating levels of l -arginine, and increased renal hemodynamic response to this amino acid in cirrhotic rats with ascites. Our results suggest that l -arginine supplementation at doses not affecting arterial pressure could have beneficial effects on renal perfusion in cirrhosis
In situ induction of dendritic cell–based T cell tolerance in humanized mice and nonhuman primates
Authors: Kyeong Cheon Jung, Chung-Gyu Park, Yoon Kyung Jeon, Hyo Jin Park, Young Larn Ban, Hye Sook Min, Eun Ji Kim, Ju Hyun Kim, Byung Hyun Kang, Seung Pyo Park, Youngmee Bae, Il-Hee Yoon, Yong-Hee Kim, Jae-Il Lee, Jung-Sik Kim, Jun-Seop Shin, Jaeseok Yang, Sung Joo Kim, Emily Rostlund, William A. Muller, Seong Hoe Park
Journal: The Journal of Experimental Medicine (2011)

Induction of antigen-specific T cell tolerance would aid treatment of diverse immunological disorders and help prevent allograft rejection and graft versus host disease. In this study, we establish a method of inducing antigen-specific T cell tolerance in situ in diabetic humanized mice and Rhesus monkeys receiving porcine islet xenografts. Antigen-specific T cell tolerance is induced by administration of an antibody ligating a particular epitope on ICAM-1 (intercellular adhesion molecule 1). Antibody-mediated ligation of ICAM-1 on dendritic cells (DCs) led to the arrest of DCs in a semimature stage in vitro and in vivo. Ablation of DCs from mice completely abrogated anti-ICAM-1-induced antigen-specific T cell tolerance. T cell responses to unrelated antigens remained unaffected. In situ induction of DC-mediated T cell tolerance using this method may represent a potent therapeutic tool for preventing graft rejection.
SOX2-RNAi attenuates S-phase entry and induces RhoA-dependent switch to protease-independent amoeboid migration in human glioma cells
Authors: Felix Oppel, Nadja Müller, Gabriele Schackert, Sandy Hendruschk, Daniel Martin, Kathrin D Geiger, Achim Temme
Journal: Molecular Cancer (2011)

Abstract Background SOX2, a high mobility group (HMG)-box containing transcription factor, is a key regulator during development of the nervous system and a persistent marker of neural stem cells. Recent studies suggested a role of SOX2 in tumor progression. In our previous work we detected SOX2 in glioma cells and glioblastoma specimens. Herein, we aim to explore the role of SOX2 for glioma malignancy in particular its role in cell proliferation and migration. Methods Retroviral shRNA-vectors were utilized to stably knockdown SOX2 in U343-MG and U373-MG cells. The resulting phenotype was investigated by Western blot, migration/invasion assays, RhoA G-LISA, time lapse video imaging, and orthotopic xenograft experiments. Results SOX2 depletion results in pleiotropic effects including attenuated cell proliferation caused by decreased levels of cyclinD1. Also an increased TCF/LEF-signaling and concomitant decrease in Oct4 and Nestin expression was noted. Furthermore, down-regulation of focal adhesion kinase (FAK) signaling and of downstream proteins such as HEF1/NEDD9, matrix metalloproteinases pro-MMP-1 and -2 impaired invasive proteolysis-dependent migration. Yet, cells with knockdown of SOX2 switched to a RhoA-dependent amoeboid-like migration mode which could be blocked by the ROCK inhibitor Y27632 downstream of RhoA-signaling. Orthotopic xenograft experiments revealed a higher tumorigenicity of U343-MG glioma cells transduced with shRNA targeting SOX2 which was characterized by increased dissemination of glioma cells. Conclusion Our findings suggest that SOX2 plays a role in the maintenance of a less differentiated glioma cell phenotype. In addition, the results indicate a critical role of SOX2 in adhesion and migration of malignant gliomas.
Diabetes in Urban African-Americans. IX. Provider Adherence to Management Protocols
Authors: Imad M El-Kebbi, David C Ziemer, Victoria C Musey, Daniel L Gallina, Annette M Bernard, Lawrence S Phillips
Journal: Diabetes Care (1997)

Staged diabetes management should permit glycemic goals to be attained in a timely manner, but the success of such an approach requires conformity by health care providers. To test performance, we analyzed the adherence of practitioners to a protocol for staged management of NIDDM patients.Records of patients treated at the Grady Memorial Hospital Diabetes Clinic were reviewed retrospectively over a 3-year period. For each patient, intensification of therapy was indicated if fasting plasma glucose was > 7.8 mmol/l and a prior HbA1c was > 7.0%. Protocols dictated a progression from dietary therapy alone to increasing dosages of sulfonylureas to increasing dosages of insulin. Patients were seen at bimonthly intervals.During the 3-year period, 1,051 patient visits met protocol criteria for intensification. Adherence to the protocol improved significantly in the 3rd year compared with the first 2 years (30, 31, and 47% adherence in the 1st, 2nd, and 3rd years, respectively). Patients treated with diet alone were significantly less likely to have their therapy intensified than patients on sulfonylureas or insulin (intensification rates 25, 41, and 47%, respectively). In the management of patients treated with diet alone, practitioners were reluctant to intensify therapy at early visits, but were more likely to do so later, 19% of patients beyond goal range at the 2-month visit were started on pharmacological therapy vs. 28% at the 4-month visit, and 39% at the 6-month visit (P < 0.01). In contrast, there was no significant difference in the frequency of therapy intensification between early and late visits for patients on sulfonylureas or insulin. Practitioners appeared to base the decision to intensify on the fasting plasma glucose level more than on the most recent HbA1c. Age did not appear to be a significant factor in the decision to intensify.Although staged management protocols constitute critical tools to achieve glycemic goals, the adherence of health care providers may be suboptimal. Special efforts may be needed to assure compliance.
A gain of function mutation in<i>TNFRSF11B</i>encoding osteoprotegerin causes osteoarthritis with chondrocalcinosis
Authors: Yolande F M Ramos, Steffan D Bos, Ruud van der Breggen, Margreet Kloppenburg, Kai Ye, Eric-Wubbo E M W Lameijer, Rob G H H Nelissen, P Eline Slagboom, Ingrid Meulenbelt
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objective</h3> To identify pathogenic mutations that reveal underlying biological mechanisms driving osteoarthritis (OA). <h3>Methods</h3> Exome sequencing was applied to two distant family members with dominantly inherited early onset primary OA at multiple joint sites with chondrocalcinosis (familial generalised osteoarthritis, FOA). Confirmation of mutations occurred by genotyping and linkage analyses across the extended family. The functional effect of the mutation was investigated by means of a cell-based assay. To explore generalisability, mRNA expression analysis of the relevant genes in the discovered pathway was explored in preserved and osteoarthritic articular cartilage of independent patients undergoing joint replacement surgery. <h3>Results</h3> We identified a heterozygous, probably damaging, read-through mutation (c.1205A=&gt;T; p.Stop402Leu) in <i>TNFRSF11B</i> encoding osteoprotegerin that is likely causal to the OA phenotype in the extended family. In a bone resorption assay, the mutant form of osteoprotegerin showed enhanced capacity to inhibit osteoclastogenesis and bone resorption. Expression analyses in preserved and affected articular cartilage of independent OA patients showed that upregulation of <i>TNFRSF11B</i> is a general phenomenon in the pathophysiological process. <h3>Conclusions</h3> Albeit that the role of the molecular pathway of osteoprotegerin has been studied in OA, we are the first to demonstrate that enhanced osteoprotegerin function could be a directly underlying cause. We advocate that agents counteracting the function of osteoprotegerin could comply with new therapeutic interventions of OA.
Angiotensin Receptor Neprilysin Inhibition Compared With Enalapril on the Risk of Clinical Progression in Surviving Patients With Heart Failure
Authors: Milton Packer, John J.V. McMurray, Akshay S. Desai, Jianjian Gong, Martin P. Lefkowitz, Adel R. Rizkala, Jean L. Rouleau, Victor C. Shi, Scott D. Solomon, Karl Swedberg, Michael Zile, Karl Andersen, Juan Luis Arango, J. Malcolm Arnold, Jan Bělohlávek, Michael Böhm, Sergey Boytsov, Lesley J. Burgess, Walter Cabrera, Carlos Calvo, Chen-Huan Chen, Andrej Dukat, Yan Carlos Duarte, Andrejs Erglis, Michael Fu, Efrain Gomez, Angel Gonzàlez-Medina, Albert A. Hagège, Jun Huang, Tzvetana Katova, Songsak Kiatchoosakun, Kee-Sik Kim, Ömer Kozan, Edmundo Bayram Llamas, Felipe Martinez, Bela Merkely, Iván Mendoza, Arend Mosterd, Marta Negrusz-Kawecka, Keijo Peuhkurinen, Felix J.A. Ramires, Jens Refsgaard, Arvo Rosenthal, Michele Senni, Antonio S. Sibulo, José Silva-Cardoso, Iain B. Squire, Randall C. Starling, John R. Teerlink, Johan Vanhaecke, Dragos Vinereanu, Raymond Ching-Chiew Wong
Journal: Circulation (2014)

Background— Clinical trials in heart failure have focused on the improvement in symptoms or decreases in the risk of death and other cardiovascular events. Little is known about the effect of drugs on the risk of clinical deterioration in surviving patients. Methods and Results— We compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensin-converting enzyme inhibitor enalapril (20 mg daily) in 8399 patients with heart failure and reduced ejection fraction in a double-blind trial. The analyses focused on prespecified measures of nonfatal clinical deterioration. In comparison with the enalapril group, fewer LCZ696-treated patients required intensification of medical treatment for heart failure (520 versus 604; hazard ratio, 0.84; 95% confidence interval, 0.74–0.94; P =0.003) or an emergency department visit for worsening heart failure (hazard ratio, 0.66; 95% confidence interval, 0.52–0.85; P =0.001). The patients in the LCZ696 group had 23% fewer hospitalizations for worsening heart failure (851 versus 1079; P &lt;0.001) and were less likely to require intensive care (768 versus 879; 18% rate reduction, P =0.005), to receive intravenous positive inotropic agents (31% risk reduction, P &lt;0.001), and to have implantation of a heart failure device or cardiac transplantation (22% risk reduction, P =0.07). The reduction in heart failure hospitalization with LCZ696 was evident within the first 30 days after randomization. Worsening of symptom scores in surviving patients was consistently more common in the enalapril group. LCZ696 led to an early and sustained reduction in biomarkers of myocardial wall stress and injury (N-terminal pro–B-type natriuretic peptide and troponin) versus enalapril. Conclusions— Angiotensin-neprilysin inhibition prevents the clinical progression of surviving patients with heart failure more effectively than angiotensin-converting enzyme inhibition. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01035255.
Conditional deletion reveals a cell-autonomous requirement of SLP-76 for thymocyte selection
Authors: Jonathan S. Maltzman, Lisa Kovoor, James L. Clements, Gary A. Koretzky
Journal: The Journal of Experimental Medicine (2005)

The SH2 domain containing leukocyte phosphoprotein of 76 kD (SLP-76) is critical for pre-TCR–mediated maturation to the CD4+CD8+ double positive (DP) stage in the thymus. The absolute block in SLP-76null mice at the CD4−CD8−CD44−CD25+ (double-negative 3, DN3) stage has hindered our understanding of the role of this adaptor in αβ TCR-mediated signal transduction in primary thymocytes and peripheral T lymphocytes. To evaluate the requirements for SLP-76 in these events, we used a cre-loxP approach to generate mice that conditionally delete SLP-76 after the DN3 checkpoint. These mice develop DP thymocytes that express the αβ TCR on the surface, but lack SLP-76 at the genomic DNA and protein levels. The DP compartment has reduced cellularity in young mice and fails to undergo positive selection to CD4+ or CD8+ single positive (SP) cells in vivo or activation-induced cell death in vitro. A small number of CD4+SP thymocytes are generated, but these cells fail to flux calcium in response to an αβ TCR-generated signal. Peripheral T cells are reduced in number, lack SLP-76 protein, and have an abnormal surface phenotype. These studies show for the first time that SLP-76 is required for signal transduction through the mature αβ TCR in primary cells of the T lineage.
Effect of a quadrivalent meningococcal ACWY glycoconjugate or a serogroup B meningococcal vaccine on meningococcal carriage: an observer-blind, phase 3 randomised clinical trial
Authors: Robert C Read, David Baxter, David R Chadwick, Saul N Faust, Adam Finn, Stephen B Gordon, Paul T Heath, David J M Lewis, Andrew J Pollard, David P J Turner, Rohit Bazaz, Amitava Ganguli, Tom Havelock, Keith R Neal, Ifeanyichukwu O Okike, Begonia Morales-Aza, Kamlesh Patel, Matthew D Snape, John Williams, Stefanie Gilchrist, Steve J Gray, Martin C J Maiden, Daniela Toneatto, Huajun Wang, Maggie McCarthy, Peter M Dull, Ray Borrow
Journal: The Lancet (2014)
ABO blood groups, secretor status, salivary protein, and serum and salivary immunoglobulin concentrations
Authors: J. G. Waissbluth, M. J. S. Langman
Journal: Gut (1971)

Serum and salivary protein and immunoglobulin concentrations have been measured in people of different ABO blood groups and secretor status. The results have confirmed that salivary protein concentrations vary markedly according to an individual's blood group tending to be particularly high in people of group A, but have failed to show any parallel variation in serum protein concentrations. No clear differences were detected in immunoglobulin concentrations, although salivary IgA concentrations tended to be slightly higher in ABH secretors than in non-secretors.
Chemotherapy Use, Outcomes, and Costs for Older Persons With Advanced Non–Small-Cell Lung Cancer: Evidence From Surveillance, Epidemiology and End Results–Medicare
Authors: Scott D. Ramsey, Nadia Howlader, Ruth D. Etzioni, Bonnie Donato
Journal: Journal of Clinical Oncology (2004)

There is limited published documentation regarding US community patterns of care for older patients with advanced non-small-cell lung cancer (NSCLC). Using the Surveillance, Epidemiology and End Results (SEER)-Medicare database, we examined community treatment patterns for advanced NSCLC, focusing on chemotherapy.Patients with locally advanced or metastatic (TNM system stages IIIb and IV) NSCLC diagnosed between January 1, 1994, and December 31, 1999, were stratified based on chemotherapy agents received during the first 3 months following diagnosis. Cox proportional hazards models were used to compare survival, controlling for age, sex, race, noncancer comorbidity, stage at diagnosis, SEER region, and receipt of cancer-related surgery or radiation therapy in the first 3 months following diagnosis. Lifetime medical costs were calculated for each group.14,875 patients met inclusion criteria: 7,411 (49.8%) stage III and 7,464 (50.2%) stage IV at diagnosis. Thirty-one percent received chemotherapy, 8% received surgery, and 53% received radiation therapy either as initial or adjuvant treatment. Persons > or = 75 years of age, females, African Americans, and those with more than one comorbidity were significantly less likely to receive chemotherapy (P < .01). Survival was inferior for those who did not receive a platinum-containing agent (P < .01). Lifetime costs were highest for those receiving platinum + taxane combinations, exceeding other regimens by more than $10,000 USD per patient.Chemotherapy prolongs survival in community settings, but is underutilized for persons with advanced NSCLC. Reasons for lower use in minorities and variation across regions deserve further study.
Measurement of Symptoms, Lung Hyperinflation, and Endurance during Exercise in Chronic Obstructive Pulmonary Disease
Authors: DENIS E. O'DONNELL, MIU LAM, KATHERINE A. WEBB
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

Changes in lung hyperinflation, dyspnea, and exercise endurance are important outcomes in assessing therapeutic responses in chronic obstructive pulmonary disease (COPD). Therefore, we studied the reproducibility of Borg dyspnea ratings, inspiratory capacity (IC; to monitor lung hyperinflation), and endurance time during constant-load symptom-limited cycle exercise in 29 patients with COPD (FEV1 = 40 ± 2% predicted; mean ± SEM). Responsiveness was also studied by determining the acute effects of nebulized 500 μ g ipratropium bromide (IB) or saline placebo (P) on these measurements. During each of four visits conducted over an 8-wk period, spirometry and exercise testing were performed before and 1 h after receiving IB or P (randomized, double-blinded). Highly reproducible measurements included: endurance time (intraclass correlation R = 0.77, p < 0.0001); Borg ratings and IC at rest, at a standardized exercise time (STD), and at peak exercise (R > 0.6, p < 0.0001); and slopes of Borg ratings over time, oxygen consumption (V˙ o 2), and ventilation (R > 0.6, p < 0.0001). Responsiveness was confirmed by finding a significant drug effect for: change ( Δ ) in endurance time (p = 0.0001); Δ BorgSTD and Δ Borg-time slopes (p < 0.05); and Δ IC at rest, at STD, and at peak exercise (p = 0.0001). With all completed visits, Δ BorgSTD correlated better with Δ ICSTD than any other resting or exercise parameter (n = 115, r = − 0.35, p < 0.001). We concluded that Borg dyspnea ratings, and measurements of IC and endurance time during submaximal cycle exercise testing are highly reproducible and responsive to change in severe COPD.
In vivo exposure to nitrogen dioxide (NO2) induces a decrease in calcitonin gene-related peptide (CGRP) and tachykinin immunoreactivity in guinea-pig peripheral airways
Authors: RE Lucchini, DR Springall, P Chitano, LM Fabbri, JM Polak, CE Mapp
Journal: European Respiratory Journal (1996)

The mammalian respiratory tract is densely innervated by sensory and autonomic fibres. Subsets of the nerves contain bioactive regulatory peptides, such as substance P, calcitonin gene-related peptide (CGRP), and neurokinins. The sensory nervous system responds to inhaled irritants, resulting in a release of neuropeptides and, thus, a decrease in the peptide immunoreactivity of the fibres. We examined the effects of inhaled nitrogen dioxide (NO2), a well-known indoor and outdoor air pollutant, on pulmonary sensory neuropeptides. Guinea-pigs were exposed for 4 h to 18 parts per million (ppm) NO2 or to air (n = 5 each). At the end of the exposure, they were killed with urethane and their lungs were fixed in 1% paraformaldehyde in phosphate-buffered saline. Cryostat sections were stained with antisera to an anatomical nerve marker, protein gene product (PGP) 9.5, and to CGRP and tachykinins, utilizing the avidin-biotinylated peroxidase method. In the noncartilaginous airways (diameter &lt; 250 microns) of NO2-exposed animals, less tachykinin- and CGRP-immunoreactive nerve fibres were found compared with controls. No change was seen in the total nerve fibre distribution (PGP 9.5). It is concluded that the peptidergic nerves of guinea-pig peripheral airways are a sensitive indicator of exposure to nitrogen dioxide.
Confidence intervals of evolutionary distances between sequences and comparison with usual approaches including the bootstrap method
Authors: G. Andrieu, G. Caraux, O. Gascuel
Journal: Molecular Biology and Evolution (1997)

Two methods are commonly employed for evaluating the extent of the uncertainty of evolutionary distances between sequences: either some estimator of the variance of the distance estimator, or the bootstrap method. However, both approaches can be misleading, particularly when the evolutionary distance is small. We propose using another statistical method which does not have the same defect: interval estimation. We show how confidence intervals may be constructed for the Jukes and Cantor (1969) and Kimura two-parameter (1980) estimators. We compare the exact confidence intervals thus obtained with the approximate intervals derived by the two previous methods, using artificial and biological data. The results show that the usual methods clearly underestimate the variability when the substitution rate is low and when sequences are short. Moreover, our analysis suggests that similar results may be expected for other evolutionary distance estimators.
Clinical outcomes of tigecycline in the treatment of critically ill patients with multidrug-resistant Acinetobactor baumannii infection
Authors: Jung Ar Shin, Hyung Jung Kim, Min Kwang Byun
Journal: European Respiratory Journal (2011)

Background:  Acinetobacter baumannii (A. baumannii) has emerged as a major cause of nosocomial pneumonia and sepsis in seriously ill patients. Multidrug-resistant A. baumannii (MRAB) is increasing in frequency, and the management of A. baumannii infections is consequently difficult. Therefore, tigecycline is considered the drug of choice for MRAB treatment. The aim of our study was to evaluate the microbiological eradication and clinical effectiveness of tigecycline against MRAB in seriously ill patients, including patients with ventilator-associated pneumonia (VAP).   Methods:  We conducted a retrospective study including patients with A. baumannii infections that were treated with tigecycline between April 1, 2009 and March 31, 2010. We treated 27 patients with tigecycline for MRAB infections.   Results:  The mean age of the patients was 66.2 years (44-83 years) and 20 (74.1%) patients were male. The median length of stay was 74.6 days (11-135 days). MRAB was eradicated from the site of infection in 23 cases (85.2%), however only 17 cases (63.0%) showed positive clinical responses. Overall, an inhospital mortality rate of 51.9% was observed and 4 cases of death were attributable to sepsis. The combination therapy group showed better clinical and microbial success rates than the monotherapy group.   Conclusions:  We observed successful microbial eradication rates, but clinical success rates were lower than previous studies.