tbuckley/cabot-search huggingface dataset:
Effectiveness of Treatments for Severe Sepsis
Authors: Ricard Ferrer, Antonio Artigas, David Suarez, Eduardo Palencia, Mitchell M. Levy, Angel Arenzana, Xose Luis Pérez, Josep-Maria Sirvent
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Several Surviving Sepsis Campaign Guidelines recommendations are reevaluated.To analyze the effectiveness of treatments recommended in the sepsis guidelines.In a prospective observational study, we studied all adult patients with severe sepsis from 77 intensive care units. We recorded compliance with four therapeutic goals (central venous pressure 8 mm Hg or greater for persistent hypotension despite fluid resuscitation and/or lactate greater than 36 mg/dl, central venous oxygen saturation 70% or greater for persistent hypotension despite fluid resuscitation and/or lactate greater than 36 mg/dl, blood glucose greater than or equal to the lower limit of normal but less than 150 mg/dl, and inspiratory plateau pressure less than 30 cm H(2)O for mechanically ventilated patients) and four treatments (early broad-spectrum antibiotics, fluid challenge in the event of hypotension and/or lactate greater than 36 mg/dl, low-dose steroids for septic shock, drotrecogin alfa [activated] for multiorgan failure). The primary outcome measure was hospital mortality. The effectiveness of each treatment was estimated using propensity scores.Of 2,796 patients, 41.6% died before hospital discharge. Treatments associated with lower hospital mortality were early broad-spectrum antibiotic treatment (treatment within 1 hour vs. no treatment within first 6 hours of diagnosis; odds ratio, 0.67; 95% confidence interval, 0.50-0.90; P = 0.008) and drotrecogin alfa (activated) (odds ratio, 0.59; 95% confidence interval, 0.41-0.84; P = 0.004). Fluid challenge and low-dose steroids showed no benefits.In severe sepsis, early administration of broad-spectrum antibiotics in all patients and administration of drotrecogin alfa (activated) in the most severe patients reduce mortality.
Protective Interventions to Prevent Aflatoxin-Induced Carcinogenesis in Developing Countries
Authors: John D. Groopman, Thomas W. Kensler, Christopher P. Wild
Journal: Annual Review of Public Health (2007)

The public health impact of aflatoxin exposure is pervasive in economically developing countries; consequently, we need to design intervention strategies for prevention that are practicable for these high-risk populations. The adverse health consequences of aflatoxins in populations are quite varied, eliciting acute effects, such as rapid death, and chronic outcomes, such as hepatocellular carcinoma. Furthermore, a number of epidemiological studies describe a variety of general adverse health effects associated with aflatoxin, such as impaired growth in children. Thus, the magnitude of the problem is disseminated across the entire spectrum of age, gender, and health status in the population. The aflatoxins multiplicatively increase the risk of liver cancer in people chronically infected with hepatitis B virus (HBV), which illustrates the deleterious impact that even low toxin levels in the diet can pose for human health. Thus other aflatoxin interactions, which likely contribute to the diesease burden, still remain to be identified. Therefore, many diverse and appropriate strategies for disease prevention are needed to decrease the incidence of aflatoxin carcinogenesis in developing countries.
EFFECT OF VARIOUS MODES OF ADMINISTRATION OF INSULIN ON THE HYPOGLYCEMIA IN PATIENTS UNDERGOING INSULIN SHOCK THERAPY
Authors: WALTER GOLDFARB
Journal: American Journal of Psychiatry (1943)

The production of hypoglycemic coma by the intravenous use of insulin required essentially the same amounts of insulin as the intramuscular route. The onset of coma occurred earlier after intravenous insulin injection. The administration of insulin in divided doses both intravenously and intramuscularly reduced the amounts required to produce hypoglycemic coma, and reduced the number of days required to produce the initial coma.
Growth factors and interleukin-6 across the lung circulation in pulmonary hypertension
Authors: N. Selimovic, C-H. Bergh, B. Andersson, E. Sakiniene, H. Carlsten, B. Rundqvist
Journal: European Respiratory Journal (2009)

The aim of our study was to assess the levels of growth factors and interleukin (IL)-6 across the pulmonary circulation in patients with pulmonary arterial hypertension (PAH) and correlate them with clinical and haemodynamic data and outcome. Simultaneous arterial and pulmonary arterial blood samples in patients with PAH (n = 44) and controls (n = 20) were obtained during right heart catheterisation. Vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF)-BB, transforming growth factor (TGF)-beta1 and IL-6 were measured using ELISA. Arterial median (interquartile range) values for VEGF, PDGF-BB, TGF-beta1 and IL-6 were significantly higher in patients (377 (218-588) versus 9.0 pg.mL(-1); 1,955 (1,371-2,519) versus 306 (131-502) pg.mL(-1); 26.42 (11.3-41.1) versus 7.0 (1.8-18.4) ng.mL(-1); and 3.98 (0.7-8.1) versus 0.7 pg.mL(-1), respectively; p<0.001 for all variables). There was a consistent step-up of VEGF, PDGF-BB and TGF-beta1 across the lungs in PAH patients (p<0.001, p = 0.002 and p<0.001, respectively), whereas in controls, arterial and pulmonary arterial serum levels of IL-6 and growth factors were similar (statistically nonsignificant). In multivariate analysis, increased IL-6 levels predicted mortality (hazard ratio 1.08 (95% confidence interval 1.02-1.15); p = 0.012). Our findings indicate increased release and/or decreased clearance of growth factors at the lung vascular level, which may contribute to vascular remodelling in PAH.
Tbx20 Interacts With Smads to Confine <i>Tbx2</i> Expression to the Atrioventricular Canal
Authors: Reena Singh, Thomas Horsthuis, Henner F. Farin, Thomas Grieskamp, Julia Norden, Marianne Petry, Vincent Wakker, Antoon F.M. Moorman, Vincent M. Christoffels, Andreas Kispert
Journal: Circulation Research (2009)

T-box transcription factors play critical roles in the coordinated formation of the working chambers and the atrioventricular canal (AVC). Tbx2 patterns embryonic myocardial cells to form the AVC and suppresses their differentiation into chamber myocardium. Tbx20-deficient embryos, which fail to form chambers, ectopically express Tbx2 throughout the entire heart tube, providing a potential mechanism for the function of Tbx20 in chamber differentiation.To identify the mechanism of Tbx2 suppression by Tbx20 and to investigate the involvement of Tbx2 in Tbx20-mediated chamber formation.We generated Tbx20 and Tbx2 single and double knockout embryos and observed that loss of Tbx2 did not rescue the Tbx20-deficient heart from failure to form chambers. However, Tbx20 is required to suppress Tbx2 in the developing chambers, a prerequisite to localize its strong differentiation-inhibiting activity to the AVC. We identified a bone morphogenetic protein (Bmp)/Smad-dependent Tbx2 enhancer conferring AVC-restricted expression and Tbx20-dependent chamber suppression of Tbx2 in vivo. Unexpectedly, we found in transfection and localization studies in vitro that both Tbx20 and mutant isoforms of Tbx20 unable to bind DNA attenuate Bmp/Smad-dependent activation of Tbx2 by binding Smad1 and Smad5 and sequestering them from Smad4.Our data suggest that Tbx20 directly interferes with Bmp/Smad signaling to suppress Tbx2 expression in the chambers, thereby confining Tbx2 expression to the prospective AVC region.
Intrapartum care of healthy women and their babies: summary of updated NICE guidance
Authors: V. Delgado Nunes, M. Gholitabar, J. M. Sims, S. Bewley
Journal: BMJ (2014)

#### The bottom line The care that a woman receives during labour has the potential to affect the woman herself, both physically and emotionally, and the health of her baby in the short and longer term. Good communication, support, and compassion from staff, as well as having her wishes respected, can help her feel in control of what is happening and help make birth a positive experience for the woman and her birth companion(s). About 700 000 women give birth in England and Wales each year. Most are healthy, have a straightforward pregnancy, go into labour spontaneously, and give birth to a single baby after 37 weeks of pregnancy. Uncertainty around consistent practice and the availability of new evidence necessitated an update of 2007 guidance from the National Institute for Health and Care Excellence (NICE) on intrapartum care.1 This article summarises the most recent recommendations from NICE on the care of healthy women who go into labour at term (37-41 weeks' gestation) (Clinical Guideline CG190).2 NICE recommendations are based on systematic reviews of the best available evidence and explicit consideration of cost effectiveness. When minimal evidence is available, recommendations are based on the Guideline Development Group's experience and opinion of what constitutes good practice. Evidence levels for the recommendations are given in italic in square brackets. ### Choosing the planned place of birth
Effects of beta-adrenergic receptor stimulation and blockade on rate-dependent atrioventricular nodal properties.
Authors: M Nayebpour, M Talajic, S Nattel
Journal: Circulation Research (1992)

Recent work has shown that alterations in the dynamic atrioventricular (AV) nodal response to changes in heart rate can significantly modify AV nodal function. The present study was designed to evaluate the nature and potential importance of sympathetic regulation of the rate-dependent properties of the AV node. Selective stimulation protocols and mathematical formulations were used to independently quantify AV nodal recovery, facilitation, and fatigue in 12 morphine-chloralose-anesthetized dogs. Vagal effects were prevented by bilateral vagal transection and intravenous atropine, and the sinus node was crushed to allow a broader range of pacing cycle lengths. In seven dogs with sympathetic nerves intact, beta-adrenergic receptor blockade increased the recovery time constant (tau rec) for the conduction of premature test beats from 47 +/- 2 (mean +/- SEM) msec (control) to 62 +/- 1 msec (p less than 0.001), whereas isoproterenol decreased tau rec to 38 +/- 1 msec (p less than 0.001). In addition, beta-blockade increased the maximum amount of rate-dependent AV nodal fatigue from 7 +/- 1 msec (at a cycle length of 198 +/- 9 msec [control]) to 17 +/- 2 msec (p less than 0.001). In five dogs with decentralized stellate ganglia, tau rec was decreased from 71 +/- 3 msec (control) to 57 +/- 4 msec and 48 +/- 2 msec (p less than 0.001 for each) by left stellate ganglion stimulation at 5 and 10 Hz, respectively. Maximum fatigue was similarly reduced from 16 +/- 1 msec (control) to 12 +/- 2 msec (p = NS) and 8 +/- 1 msec (p less than 0.01), respectively. Stellate ganglion stimulation, isoproterenol, and beta-blockade did not alter AV nodal facilitation. A mathematical model incorporating quantitative indexes of AV nodal function accurately accounted for tachycardia-dependent increases in the atrial-His activation interval, which were enhanced by beta-adrenergic receptor blockade and reduced by isoproterenol. Furthermore, this model showed that beta-adrenergic effects were increased by increasing heart rate, with the majority of the rate-dependent action being due to changes in the time course of AV nodal recovery. We conclude that beta-adrenergic receptor stimulation alters functional properties that govern the AV nodal response to changes in heart rate. These changes in functional properties alter the ability of the AV node to conduct impulses during tachycardia and, as such, could play a major role in the ability of sympathetic stimulation to promote and beta-adrenergic receptor blockade to prevent the occurrence of AV nodal reentrant arrhythmias.
The Effect of VEGF-Targeted Therapy on Biomarker Expression in Sequential Tissue from Patients with Metastatic Clear Cell Renal Cancer
Authors: Kevin Sharpe, Grant D. Stewart, Alan Mackay, Christophe Van Neste, Charlotte Rofe, Dan Berney, Irfan Kayani, Axel Bex, Elaine Wan, Fiach C. O'Mahony, Marie O'Donnell, Simon Chowdhury, Rukma Doshi, Colan Ho-Yen, Marco Gerlinger, Dawn Baker, Neil Smith, Barry Davies, Anju Sahdev, Ekaterini Boleti, Tim De Meyer, Wim Van Criekinge, Luis Beltran, Yong-Jie Lu, David J. Harrison, Andrew R. Reynolds, Tom Powles
Journal: Clinical Cancer Research (2013)

To investigate how biologically relevant markers change in response to antiangiogenic therapy in metastatic clear cell renal cancer (mRCC) and correlate these changes with outcome.The study used sequential tumor tissue and functional imaging (taken at baseline and 12-16 weeks) obtained from three similar phase II studies. All three studies investigated the role of VEGF tyrosine kinase inhibitors (TKI) before planned nephrectomy in untreated mRCC (n = 85). The effect of targeted therapy on ten biomarkers was measured from sequential tissue. Comparative genomic hybridization (CGH) array and DNA methylation profiling (MethylCap-seq) was performed in matched frozen pairs. Biomarker expression was correlated with early progression (progression as best response) and delayed progression (between 12-16 weeks).VEGF TKI treatment caused a significant reduction in vessel density (CD31), phospho-S6K expression, PDL-1 expression, and FOXP3 expression (P < 0.05 for each). It also caused a significant increase in cytoplasmic FGF-2, MET receptor expression in vessels, Fuhrman tumor grade, and Ki-67 (P < 0.05 for each). Higher levels of Ki-67 and CD31 were associated with delayed progression (P < 0.05). Multiple samples (n = 5) from the same tumor showed marked heterogeneity of tumor grade, which increased significantly with treatment. Array CGH showed extensive intrapatient variability, which did not occur in DNA methylation analysis.TKI treatment is associated with dynamic changes in relevant biomarkers, despite significant heterogeneity in chromosomal and protein, but not epigenetic expression. Changes to Ki-67 expression and tumor grade indicate that treatment is associated with an increase in the aggressive phenotype of the tumor.
The role of macrophage migration inhibitory factor in autoimmune liver disease
Authors: David N. Assis, Lin Leng, Xin Du, Clarence K. Zhang, Gerrit Grieb, Melanie Merk, Alvaro Baeza Garcia, Catherine McCrann, Julius Chapiro, Andreas Meinhardt, Yuka Mizue, David J. Nikolic-Paterson, Jürgen Bernhagen, Marshall M. Kaplan, Hongyu Zhao, James L. Boyer, Richard Bucala
Journal: Hepatology (2013)

The role of the cytokine, macrophage migration inhibitory factor (MIF), and its receptor, CD74, was assessed in autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC). Two MIF promoter polymorphisms, a functional -794 CATT5-8 microsatellite repeat (rs5844572) and a -173 G/C single-nucleotide polymorphism (rs755622), were analyzed in DNA samples from over 500 patients with AIH, PBC, and controls. We found a higher frequency of the proinflammatory and high-expression -794 CATT7 allele in AIH, compared to PBC, whereas lower frequency was found in PBC, compared to both AIH and healthy controls. MIF and soluble MIF receptor (CD74) were measured by enzyme-linked immunosorbent assay in 165 serum samples of AIH, PBC, and controls. Circulating serum and hepatic MIF expression was elevated in patients with AIH and PBC versus healthy controls. We also identified a truncated circulating form of the MIF receptor, CD74, that is released from hepatic stellate cells and that binds MIF, neutralizing its signal transduction activity. Significantly higher levels of CD74 were found in patients with PBC versus AIH and controls. These data suggest a distinct genetic and immunopathogenic basis for AIH and PBC at the MIF locus. Circulating MIF and MIF receptor profiles distinguish PBC from the more inflammatory phenotype of AIH and may play a role in pathogenesis and as biomarkers of these diseases.
Ubiquitin-dependent Degradation of p73 Is Inhibited by PML
Authors: Francesca Bernassola, Paolo Salomoni, Andrew Oberst, Charles J. Di Como, Michele Pagano, Gerry Melino, Pier Paolo Pandolfi
Journal: The Journal of Experimental Medicine (2004)

p73 has been identified recently as a structural and functional homologue of the tumor suppressor p53. Here, we report that p73 stability is directly regulated by the ubiquitin–proteasome pathway. Furthermore, we show that the promyelocytic leukemia (PML) protein modulates p73 half-life by inhibiting its degradation in a PML–nuclear body (NB)–dependent manner. p38 mitogen-activated protein kinase–mediated phosphorylation of p73 is required for p73 recruitment into the PML-NB and subsequent PML-dependent p73 stabilization. We find that p300-mediated acetylation of p73 protects it against ubiquitinylation and that PML regulates p73 stability by positively modulating its acetylation levels. As a result, PML potentiates p73 transcriptional and proapoptotic activities that are markedly impaired in Pml−/− primary cells. Our findings demonstrate that PML plays a crucial role in modulating p73 function, thus providing further insights on the molecular network for tumor suppression.
Iloprost inhibits neutrophil function in vitro and in vivo and limits experimental infarct size in canine heart.
Authors: P J Simpson, J Mickelson, J C Fantone, K P Gallagher, B R Lucchesi
Journal: Circulation Research (1987)

The prostacyclin analogue iloprost (ZK 36374) inhibits neutrophil activation in vitro, reduces neutrophil accumulation in inflammatory skin lesions, and reduces ultimate infarct size in an anesthetized open-chest canine model of regional ischemia and reperfusion. Iloprost (0.1-100 microM) inhibited the in vitro production of superoxide anion by canine neutrophils in a concentration-dependent manner. Iloprost (100 ng/kg/min i.v.) inhibited C5a-induced neutrophil migration into inflammatory skin lesions as assessed by the neutrophil-specific enzyme marker, myeloperoxidase. The myeloperoxidase activity determined 2 hours after the intradermal administration of C5a in each of the groups was control 13.3 +/- 1.8 units/g tissue (n = 12) and iloprost 6.5 +/- 0.9 units/g (n = 12), p less than 0.01. Iloprost was administered to anesthetized open-chest dogs (100 ng/kg/min) 10 minutes after left circumflex coronary artery (LCCA) occlusion and continued during the 90-minute occlusion period and the first 2 hours of reperfusion. Regional myocardial blood flow was similar between treatment groups at baseline, 5 minutes and 80 minutes after LCCA occlusion, and after 1 hour of reperfusion. Infarct size, assessed 6 hours after reperfusion, was reduced by iloprost treatment: 22.4 +/- 3.1% of the area at risk (n = 15) compared with 42.4 +/- 3.3% of control (n = 13), p less than 0.01. Iloprost treatment reduced the accumulation of neutrophils (measured by myeloperoxidase activity) in the ischemic myocardium at the interface between infarcted and noninfarcted tissue: control (n = 9) 9.0 +/- 1.8 units/g tissue, iloprost (n = 6) 2.0 +/- 0.4 units/g, p less than 0.01.(ABSTRACT TRUNCATED AT 250 WORDS)
Recent Intron Gain in Elongation Factor-1α of Colletid Bees (Hymenoptera: Colletidae)
Authors: Seán G. Brady, Bryan N. Danforth
Journal: Molecular Biology and Evolution (2004)

We discovered the presence of a unique spliceosomal intron in the F1 copy of elongation factor-1alpha (EF-1alpha) restricted to the bee family Colletidae (Hymenoptera: Apoidae). The intron ranges in size from 101 to 1044 bp and shows no positional sliding. Our data also demonstrate the complete absence of this intron from exemplars representing all other bee families, as well as from close hymenopteran relatives. A review of the literature finds that this intron is likewise absent from all other arthropods for which data are available. This provides unambiguous evidence for a relatively recent intron insertion event in the colletid common ancestor and, at least in this specific instance, lends support to the introns-late hypothesis. The comparative distribution of this novel intron also supports the monophyly of Colletidae and the exclusion of the Stenotritidae from this family, providing an example of the potential of some introns to act as robust markers of shared descent.
A gamma/delta cell receptor heterodimer induces the expression of CD4 and CD8 in thymocytes.
Authors: M Iwashima, M M Davis, Y H Chien
Journal: The Journal of Experimental Medicine (1991)

CD4 and CD8 have been useful surface markers for alpha/beta T cell maturation. In an alpha/beta T cell receptor (TCR) transgenic SCID mice system, it has been shown that alpha/beta TCR alone is sufficient to induce CD4 and CD8 surface expression on thymic T cells. Although the late embryonic thymic gamma/delta T cells are predominately single and double positive, it has not been clear if gamma/delta TCR has a similar capacity. In this study, we show that when transgenes encoding the earliest embryonic gamma/delta TCR are coexpressed with the SCID defect, the gamma/delta transgenes promote the appearance of both the CD4-8- and CD4+8+ T cells in the thymus. Furthermore, the expression of CD4 and CD8 does not require continuous surface gamma/delta TCR expression. These results indicate that gamma/delta TCR alone can promote the CD4/8 surface expression, and may suggest a role for gamma/delta T cells in initiating normal thymic ontogeny.
Lipoprotein oxidation as a mediator of atherogenesis: insights from pharmacological studies
Authors: A. Daugherty, S. E Roselaar
Journal: Cardiovascular Research (1995)

Journal Article Lipoprotein oxidation as a mediator of atherogenesis: insights from pharmacological studies Get access Alan Daugherty, Alan Daugherty * Cardiovascular Division (Box 8086), Department of Medicine, Washington University School of Medicine, 660 S Euclid, St Louis, MO 63110, USA *Correspondence to Dr Daugherty doco@imgate.wustl.edu Search for other works by this author on: Oxford Academic PubMed Google Scholar Simon E Roselaar Simon E Roselaar Cardiovascular Division (Box 8086), Department of Medicine, Washington University School of Medicine, 660 S Euclid, St Louis, MO 63110, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 29, Issue 3, March 1995, Pages 297–311, https://doi.org/10.1016/S0008-6363(96)88585-3 Published: 01 March 1995 Article history Received: 24 August 1994 Accepted: 03 October 1994 Published: 01 March 1995