tbuckley/cabot-search huggingface dataset:
Dysfunction of the beta- and alpha-adrenergic systems in a model of congestive heart failure. The pacing-overdrive dog.
Authors: A Calderone, M Bouvier, K Li, C Juneau, J de Champlain, J L Rouleau
Journal: Circulation Research (1991)

The functional integrity of the beta- and alpha-adrenergic stimulatory pathways in a rapid ventricular pacing model of congestive heart failure in dogs was investigated; normal dogs served as controls. Total beta-adrenergic receptor density was 35% lower (p less than 0.01) in the pacing-overdrive dogs, and the beta-adrenergic receptor-mediated stimulation of adenylate cyclase (Vmax) was found to be 68% and 72% lower (p less than 0.01) in the left and right ventricles of the paced dogs. In addition, the basal adenylate cyclase activity was found to be 56% and 68% lower (p less than 0.01) in the left and right ventricles of the failing heart. Similarly, the Vmax of 5'-guanylylimidodiphosphate (GppNHp) and forskolin stimulation of adenylate cyclase activity was significantly lower, 70% and 55%, respectively (p less than 0.01), in both ventricles of the paced dogs. However, although the concentration yielding half-maximal velocity for beta-agonist and GppNHp stimulation of adenylate cyclase was similar in both groups, that for forskolin stimulation of the enzyme was significantly increased (p less than 0.01). Pertussis toxin-mediated ADP-ribosylation of membranes from control and failing hearts revealed a significant decrease in the inhibitory guanine nucleotide binding protein content (48 +/- 9%, p less than 0.01) in the hearts of the paced dogs. Moreover, although the pertussis toxin treatment increased the basal and the forskolin-stimulated adenylate cyclase activity in both normal and failing heart membranes, the adenylate cyclase activity remained significantly depressed in the failing heart after pertussis toxin treatment (p less than 0.01). Consistent with the depressed adenylate cyclase activity, mechanical studies on isolated papillary muscles and trabeculae revealed a decrease in baseline total tension (from 7.0 +/- 0.7 to 3.8 +/- 0.4 g/mm2, p less than 0.01) and dT/dt (from 26 +/- 8 to 13 +/- 1 g/mm2/sec, p less than 0.01) in the pacing-overdrive model. Tension generation and dT/dt observed in the paced dogs in response to increasing concentrations of forskolin demonstrated a rightward shift in the dose-response curve and a decrease in maximal forskolin stimulation (p less than 0.01). Similarly, maximal tension and dT/dt in the presence of isoproterenol was significantly lower than in the normal dogs (p less than 0.01). The decrease in beta-adrenergic responsiveness was accompanied by a decrease and rightward shift in alpha 1-adrenergic responsiveness (increase in tension was 1.1 +/- 0.1 g/mm2 in paced dogs versus 2.1 +/- 0.1 g/mm2 in controls, p less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)
Estimates of Sodium and Potassium Intake
Authors: MELVIN J. FREGLY
Journal: Annals of Internal Medicine (1983)

Attempts have been made to estimate both the discretionary (consumer-controlled) and nondiscretionary (commercially controlled or naturally occurring) daily intakes of NaCl. These studies suggest that the average American has a total (discretionary plus nondiscretionary) daily intake of NaCl ranging from 10 to 14.5 g, with about one third occurring naturally in food, one third added during food processing, and one third added by the consumer. Males consume more NaCl than females and intakes of both sexes decline with age. Sodium chloride ingested with grain and cereal products and meat comprise about 50% of the daily nondiscretionary NaCl intake. Additional amounts of sodium are ingested daily in drinking water and with drugs, but their contribution is difficult to determine. Total daily nondiscretionary intake of potassium is less well studied and is estimated to be in the range of 4 to 11 g/person.
Parallel Rate Heterogeneity in Chloroplast and Mitochondrial Genomes of Brazil Nut Trees (Lecythidaceae) Is Consistent with Lineage Effects
Authors: D. F. Soria-Hernanz, J. M. Braverman, M. B. Hamilton
Journal: Molecular Biology and Evolution (2008)

We investigated whether relative rates of divergence were correlated between the mitochondrial and chloroplast genomes as expected under lineage effects or were genome specific as expected with locus-specific effects. Five mitochondrial noncoding regions (nad1B_C, nad4exon1_2, nad7exon2_3, nad7exon3_4, and rps14-cob) for 21 samples from Lecythidaceae were sequenced. Three chloroplast regions (rpl20-5′rps12, trnS-trnG, and psbA-trnH) were sequenced to expand the taxa in an existing data set. Absolute rates of nucleotide and insertion and deletion (indel) changes were 13 times faster in the chloroplast genome than in the mitochondrial genome. Similar indel length frequency distributions for both organelles suggested that common mechanisms were responsible for generating indels. Molecular clock tests applied to phylogenetic trees estimated from mitochondrial and chloroplast sequences revealed global rate heterogeneity of nucleotide substitution. Maximum likelihood and Tajima's 1D relative rate tests show that Lecythis zabucajo exhibited a rate acceleration for both the mitochondrial and chloroplast sequences. Whereas Eschweilera romeu-cardosoi showed a significant rate slowdown for chloroplast sequences, the mitochondrial sequences for 3 Eschweilera taxa showed evidence for a rate slowdown only when compared with L. zabucajo. Significant rate heterogeneity was also observed for indel changes in the mitochondrial genome but not for the chloroplast. The lack of mitochondrial nucleotide changes for some taxa as well as chloroplast indel homoplasy may have limited the power of relative rate tests to detect rate variation. Relative ratio tests consistently indicated rate proportionality among branch lengths between the mitochondrial and chloroplast phylogenetic trees. The relative ratio tests showed that taxa possessing rate heterogeneity had parallel relative divergence rates in both mitochondrial and chloroplast sequences as expected under lineage effects. A neutral replication–dependent model of rate heterogeneity for both nucleotide and indel changes provides a simple explanation for common patterns of rate heterogeneity across the 2 organelle genomes in Lecythidaceae. The lineage effects observed here were uncoupled from annual/perennial habit because all the species from this study are perennial.
Can Self-Rated Health Scores Be Used for Risk Prediction in Patients With Type 2 Diabetes?
Authors: Alison J. Hayes, Philip M. Clarke, Paul G. Glasziou, R. John Simes, Paul L. Drury, Anthony C. Keech
Journal: Diabetes Care (2008)

To investigate whether self-rated health profiles compiled using the EuroQol group's visual analog scale (EQ VAS) are independent predictors of vascular events and major complications in people with type 2 diabetes after controlling for standard clinical risk factors.The study is based on 7,348 individuals with a mean follow-up of 2.4 years after completing the EQ-5D questionnaire. We used Cox proportional hazards modeling to estimate hazard ratios associated with EQ VAS scores after controlling for baseline covariates: age, sex, smoking status, diabetes duration, A1C, systolic blood pressure, BMI, plasma lipids, and prior clinical history.A 10-point higher EQ VAS score was associated with a 6% (95% CI 1-11) lower risk of vascular events and a 22% (95% CI 15-28) lower risk of diabetes complications.Self-rated health profiles compiled using the EQ VAS provide valuable information on patient risk in addition to that determined from clinical risk factors alone.
A Ca++ activated serine protease (LOPAP) could be responsible for the haemorrhagic syndrome caused by the caterpillar Lonomia obliqua
Authors: CV Reis, EMA Kelen, SHP Farsky, FCV Portaro, CAM Sampaio, BL Fernandes, ACM Camargo, AM Chudzinski-Tavassi
Journal: The Lancet (1999)
Risk factors for the development of Haemophilus influenzae pneumonia in hospitalized adults
Authors: B Barreiro, J Dorca, L Esteban, E Prats, JM Escriba, R Verdaguer, F Gudiol, F Manresa
Journal: European Respiratory Journal (1995)

Potential risk factors for developing Haemophilus influenzae nosocomial pneumonia have not been sufficiently studied. We wanted to investigate the incidence and risk factors for the development of Haemophilus influenzae pneumonia in the hospital by means of a multivariate analysis. A total of 468 cases of nosocomial pneumonia were observed during the study period, 317 (68%) of which were aetiologically diagnosed by means of highly reliable methods, and H. influenzae was isolated in 57 of them. Fifty of the 57 episodes of H. influenzae pneumonia occurred in mechanically-ventilated patients. Underlying diseases were: medical in 12 cases, surgical in 15 cases, and traumatological in 22. Variables associated with Haemophilus influenzae nosocomial pneumonia in intubated patients after the univariate analysis were: "period between admission and pneumonia 2-7 days" and "no previous antibiotics". A multivariate analysis demonstrated that the variables "no previous antibiotics" and "coma on admission" were risk factors for H. influenzae pneumonia. In nonintubated patients, no risk factors were found for H. influenzae pneumonia compared with other nosocomial pneumonia. We conclude that H. influenzae was involved in 57 out of 317 (18%) of nosocomial pneumonia registered in our institution, and the majority of patients (50 out of 57) were mechanically-ventilated. In this particular subgroup, coma of the patient on admission to hospital and absence of antibiotic treatment prior to developing pneumonia constitute two definite risk factors for developing H. influenzae nosocomial pneumonia.
IL-7 Receptor Signals Inhibit Expression of Transcription Factors TCF-1, LEF-1, and RORγt
Authors: Qing Yu, Batu Erman, Jung-Hyun Park, Lionel Feigenbaum, Alfred Singer
Journal: The Journal of Experimental Medicine (2004)

Intrathymic T cell development depends on signals transduced by both T cell receptor and cytokine receptors. Early CD4(-)CD8(-) (double negative) thymocytes require interleukin (IL)-7 receptor (IL-7R) signals for survival and proliferation, but IL-7R signals are normally extinguished by the immature single positive (ISP) stage of thymocyte development. We now demonstrate that IL-7R signals inhibit expression of transcription factors TCF-1, LEF-1, and RORgammat that are required for the ISP to double positive (DP) transition in the thymus. In addition, we demonstrate that IL-7R signals also inhibit TCF-1 and LEF-1 expression in mature peripheral T cells. Thus, the present work has identified several important downstream target genes of IL-7R signaling in T cells and thymocytes that provide a molecular mechanism for the inhibitory influence of IL-7R signaling on DP thymocyte development. We conclude that IL-7R signals down-regulate transcription factors required for the ISP to DP transition and so must be terminated by the ISP stage of thymocyte development.
Cardiac Transplantation
Authors: John Speer Schroeder
Journal: JAMA (1987)

JANUARY 1988 will mark the 20th anniversary of the performance of the first human cardiac transplant in the United States by Dr Norman Shumway, following nearly a decade of laboratory work developing and validating the technique involved. During these 20 years cardiac transplantation has evolved from what was initially considered a radical and experimental form of therapy to one that is currently viewed in most of the world as a valid form of advanced therapy for end-stage heart disease. The initial flurry of enthusiasm for this newsworthy procedure in 1968 quickly subsided when it became evident that the complexities of postoperative treatment went far beyond those of ordinary cardiac surgery and, although the surgical mortality rate was low, patient survival rates were initially measured in terms of days or months. The introduction during the ensuing years of a variety of improvements in immunosuppressive monitoring and treatment led to improving survival
NO in Exhaled Air of Asthmatic Children Is Reduced by the Leukotriene Receptor Antagonist Montelukast
Authors: HANS BISGAARD, LOTTE LOLAND, JACOB ANH ØJ
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Nitric oxide in exhaled air (Feno) is increased in asthmatic children, probably reflecting aspects of airway inflammation. We have studied the effect of the leukotriene receptor antagonist (LTRA) montelukast on Feno with a view to elucidate potential anti-inflammatory properties of LTRAs. Twenty-six asthmatic children 6 to 15 yr of age completed a double-blind crossover trial of 2 wk of treatment with 5 mg montelukast once daily versus placebo. Feno was measured during single-breath exhalation at a constant flow rate of 0.1 to 0.13 L/s against a resistance of 10 kPa/L/s. Eleven children were receiving maintenance treatment with inhaled steroids during the study (mean daily dose, 273 μ g), whereas the other 15 used only inhaled β2-agonists as required. The within-subject coefficient of variation of Feno over a 2-wk interval for the 26 children was 38%. Feno was significantly reduced by 20% after the 2-wk treatment with montelukast as compared with placebo as well as compared with baseline. This effect occurred rapidly with a 15% fall in Feno within 2 d. The effect of montelukast on Feno was independent of concurrent steroid treatment. The effect on Feno is probably not caused by bronchodilatation since Feno increased significantly after inhalation of terbutaline. In conclusion, Feno in asthmatic children was significantly decreased from montelukast, which corroborates anti- inflammatory properties of LTRA.
B cell–intrinsic TLR signals amplify but are not required for humoral immunity
Authors: Almut Meyer-Bahlburg, Socheath Khim, David J. Rawlings
Journal: The Journal of Experimental Medicine (2007)

Although innate signals driven by Toll-like receptors (TLRs) play a crucial role in T-dependent immune responses and serological memory, the precise cellular and time-dependent requirements for such signals remain poorly defined. To directly address the role for B cell–intrinsic TLR signals in these events, we compared the TLR response profile of germinal center (GC) versus naive mature B cell subsets. TLR responsiveness was markedly up-regulated during the GC reaction, and this change correlated with altered expression of the key adaptors MyD88, Mal, and IRAK-M. To assess the role for B cell–intrinsic signals in vivo, we transferred MyD88 wild-type or knockout B cells into B cell–deficient μMT mice and immunized recipient animals with 4-hydroxy-3-nitrophenylacetyl (NP) chicken gamma globulin. All recipients exhibited similar increases in NP-specific antibody titers during primary, secondary, and long-term memory responses. The addition of lipopolysaccharide to the immunogen enhanced B cell-intrinsic, MyD88-dependent NP-specific immunoglobulin (Ig)M production, whereas NP-specific IgG increased independently of TLR signaling in B cells. Our data demonstrate that B cell–intrinsic TLR responses are up-regulated during the GC reaction, and that this change significantly promotes antigen-specific IgM production in association with TLR ligands. However, B cell–intrinsic TLR signals are not required for antibody production or maintenance.
Progress in the Treatment of Metastatic Pancreatic Cancer and the Search for Next Opportunities
Authors: Andrew H. Ko
Journal: Journal of Clinical Oncology (2015)

A growing number of therapeutic options are now available for patients with metastatic pancreatic cancer, informed by positive results from recently completed phase III clinical trials. These have led to modest, if not necessarily transformative, improvements in clinical outcomes. Although the standard of care for metastatic disease remains cytotoxic therapy, a variety of novel therapeutic approaches are currently under active investigation, several of which have already demonstrated encouraging results in phase I/II studies. The following three broad categories (with significant overlap among them) are highlighted here: stromal-depleting agents, immunotherapies, and signal transduction inhibitors. The mechanistic rationale, limitations, and promise of each of these strategies specific to pancreatic cancer are discussed, as are the aspects of this disease and this patient population that pose ongoing challenges in terms of both therapeutic management and biomarker-driven trial design.
Lung Involvement During Follow-Up of 12 patients with Agammaglobulinemia
Authors: E.G. Marins, M.B. Dorna, E.M.G. Carnide, A.C. Pastorino, A.B.F. Fomin, A.P.B.M. Castro, C.M.A. Jacob
Journal: Journal of Allergy and Clinical Immunology (2006)
Efficacy of B-Cell–Targeted Therapy with Rituximab in Patients with Rheumatoid Arthritis
Authors: Jonathan C.W. Edwards, Leszek Szczepański, Jacek Szechiński, Anna Filipowicz-Sosnowska, Paul Emery, David R. Close, Randall M. Stevens, Tim Shaw
Journal: New England Journal of Medicine (2004)

An open-label study indicated that selective depletion of B cells with the use of rituximab led to sustained clinical improvements for patients with rheumatoid arthritis. To confirm these observations, we conducted a randomized, double-blind, controlled study.We randomly assigned 161 patients who had active rheumatoid arthritis despite treatment with methotrexate to receive one of four treatments: oral methotrexate (> or =10 mg per week) (control); rituximab (1000 mg on days 1 and 15); rituximab plus cyclophosphamide (750 mg on days 3 and 17); or rituximab plus methotrexate. Responses defined according to the criteria of the American College of Rheumatology (ACR) and the European League against Rheumatism (EULAR) were assessed at week 24 (primary analyses) and week 48 (exploratory analyses).At week 24, the proportion of patients with 50 percent improvement in disease symptoms according to the ACR criteria, the primary end point, was significantly greater with the rituximab-methotrexate combination (43 percent, P=0.005) and the rituximab-cyclophosphamide combination (41 percent, P=0.005) than with methotrexate alone (13 percent). In all groups treated with rituximab, a significantly higher proportion of patients had a 20 percent improvement in disease symptoms according to the ACR criteria (65 to 76 percent vs. 38 percent, P< or =0.025) or had EULAR responses (83 to 85 percent vs. 50 percent, P< or =0.004). All ACR responses were maintained at week 48 in the rituximab-methotrexate group. The majority of adverse events occurred with the first rituximab infusion: at 24 weeks, serious infections occurred in one patient (2.5 percent) in the control group and in four patients (3.3 percent) in the rituximab groups. Peripheral-blood immunoglobulin concentrations remained within normal ranges.In patients with active rheumatoid arthritis despite methotrexate treatment, a single course of two infusions of rituximab, alone or in combination with either cyclophosphamide or continued methotrexate, provided significant improvement in disease symptoms at both weeks 24 and 48.
Advancing the functional utility of PAR-CLIP by quantifying background binding to mRNAs and lncRNAs
Authors: Matthew B Friedersdorf, Jack D Keene
Journal: Genome biology (2014)

Abstract Background Sequence specific RNA binding proteins are important regulators of gene expression. Several related crosslinking-based, high-throughput sequencing methods, including PAR-CLIP, have recently been developed to determine direct binding sites of global protein-RNA interactions. However, no studies have quantitatively addressed the contribution of background binding to datasets produced by these methods. Results We measured non-specific RNA background in PAR-CLIP data, demonstrating that covalently crosslinked background binding is common, reproducible and apparently universal among laboratories. We show that quantitative determination of background is essential for identifying targets of most RNA-binding proteins and can substantially improve motif analysis. We also demonstrate that by applying background correction to an RNA binding protein of unknown binding specificity, Caprin1, we can identify a previously unrecognized RNA recognition element not otherwise apparent in a PAR-CLIP study. Conclusions Empirical background measurements of global RNA-protein crosslinking are a necessary addendum to other experimental controls, such as performing replicates, because covalently crosslinked background signals are reproducible and otherwise unavoidable. Recognizing and quantifying the contribution of background extends the utility of PAR-CLIP and can improve mechanistic understanding of protein-RNA specificity, protein-RNA affinity and protein-RNA association dynamics.
The Cancer/Testis Antigen Melanoma-Associated Antigen-A3/A6 Is a Novel Target of Fibroblast Growth Factor Receptor 2-IIIb through Histone H3 Modifications in Thyroid Cancer
Authors: Tetsuo Kondo, Xuegong Zhu, Sylvia L. Asa, Shereen Ezzat
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Fibroblast growth factor (FGF) signals play fundamental roles in development and tumorigenesis. Thyroid cancer is an example of a tumor with nonoverlapping genetic mutations that up-regulate mitogen-activated protein kinase. We reported recently that FGF receptor 2 (FGFR2) is down-regulated through extensive DNA promoter methylation in thyroid cancer. Reexpression of the FGFR2-IIIb isoform impedes signaling upstream of the BRAF/mitogen-activated protein kinase pathway to interrupt tumor progression. In this analysis, we examined a novel target of FGFR2-IIIb signaling, melanoma-associated antigen-A3 and A6 (MAGE-A3/6). Experimental Design: cDNA microarray analysis was done on human WRO thyroid cancer cells transfected with FGFR2-IIIb or empty vector. Identified gene target was confirmed by reverse transcription-PCR and Western blotting. Gene regulation was examined by treatment of WRO cells with the methylation inhibitor 5′-azacytidine followed by methylation-specific PCR and reverse transcription-PCR and by chromatin immunoprecipitation. Results: Gene expression profiling identified the cancer/testis antigen MAGE-A3/6 as a novel target of FGFR2-IIIb signaling. MAGE-A3/6 regulation was mediated through DNA methylation and chromatin modifications. In particular, FGF7/FGFR2-IIIb activation resulted in histone 3 methylation and deacetylation associated with the MAGE-A3/6 promoter to down-regulate gene expression. Conclusions: These data unmask a complex repertoire of epigenetically controlled signals that govern FGFR2-IIIb and MAGE-A3/6 expression. Our findings provide insights into the interrelationship between novel tumor markers that may also represent overlapping therapeutic targets.