tbuckley/cabot-search huggingface dataset:
Systemic Steroids in Severe Sepsis and Septic Shock
Authors: Gourang P. Patel, Robert A. Balk
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Despite more than 5 decades of study and debate, the role of corticosteroid treatment in patients with severe sepsis and septic shock remains controversial. Data support a beneficial effect on systemic blood pressure in patients with septic shock. However, the ability of corticosteroid therapy to improve mortality in patients with severe sepsis and septic shock remains controversial, with contradictory results from recent large multicenter clinical trials. Although it appears clear that high-dose corticosteroid treatment provides no benefit and possibly harm in septic patients, the experimental design flaws and biases of recent low-dose (physiologic) steroid treatment trials limit their ability to provide adequate answers to the important questions of which septic patients should be treated, how much steroid to give, and the optimum duration of treatment. Unfortunately, the answer to these important questions is not readily evident based on the current evidence or the application of metaanalysis to the available clinical data. This concise evidence-based review highlights the strengths and weaknesses of the current data to inform the practicing clinician as to which patients are likely to derive significant benefit from corticosteroid treatment, while we await more definitive guidance from future multicenter, prospective, randomized, controlled trials designed to better answer these important therapeutic questions.
Classic ischemic but not pharmacologic preconditioning is abrogated following genetic ablation of the TNFα gene
Authors: R Smith
Journal: Cardiovascular Research (2002)

Tumor necrosis factor alpha (TNFalpha) is known to mimic ischemic preconditioning (IP). However, it is not known whether TNFalpha-preconditioning is mediated by 'established' preconditioning signaling or via novel signaling cascades. Moreover, whether TNFalpha is required to induce the ischemic preconditioning phenotype has not been determined.To evaluate the role of TNFalpha, we determined the infarct-sparing effect of IP comparing TNFalpha null (TNFalpha-/-) and wild-type mice. The IP protocol included 4x5 min ischemia/reperfusion (I/R) prior to the index 35 min of global ischemia followed by 45 min of reperfusion in isolated perfused murine hearts. Infarct size was measured as a percentage of cardiac volume. To evoke particular signaling pathways numerous pharmacologic studies were performed.Following IP, infarct size was significantly reduced by 43% in wild-type mice. In contrast, infarct size was not attenuated by IP in the TNFalpha-/- group versus I/R controls (Infarct size-36+/-3%). Interestingly, pharmacologic preconditioning with adenosine (100 microM) and diazoxide (30 microM) mimicked IP in both the wild-type (infarct size-11+/-4% and 18+/-2%) and in TNFalpha-/- mice (infarct size-15+/-4% and 23+/-3%) versus respective I/R controls. Recombinant TNFalpha (0.5 ng/ml) administered for 7 min followed by a 10-min washout mimicked IP in wild-type mice but not in the TNFalpha deficient mouse hearts. The cardioprotective effects of IP, adenosine and TNFalpha were abolished by the co-administration of the putative mitochondrial K(ATP) blocker 5-hydroxydecanoate.We demonstrate that cardiac TNFalpha production is required for ischemic preconditioning-induced cardioprotection but not necessary in pharmacologic preconditioning with adenosine or diazoxide in TNFalpha-/- mice. Moreover, TNFalpha administration is sufficient to activate preconditioning in wild-type mice. Finally, as 5-hydroxydecanoate abrogates ischemic, adenosine and TNFalpha induced preconditioning, this suggests that diverse signaling pathways converge at the level of mitochondrial K(ATP) channel activation to mediate this cardioprotection.
Childhood Predictors of Adult Acute Insulin Response and Insulin Action
Authors: Marie S. Thearle, Joy C. Bunt, William C. Knowler, Jonathan Krakoff
Journal: Diabetes Care (2009)

OBJECTIVE Because declines in acute insulin response (AIR) and insulin action (M) predict development of type 2 diabetes, we sought to determine childhood factors that predict insulin action and AIR using longitudinal data from young Pima Indian adults with normal glucose regulation. RESEARCH DESIGN AND METHODS Predictors of adult M, measured by the euglycemic-hyperinsulinemic clamp, and AIR, measured after a 25-g glucose bolus, were assessed in 76 individuals from a set of childhood data (BMI, systolic blood pressure [sBP] and diastolic blood pressure, cholesterol, fasting and 2-h insulin, and glucose levels during an oral glucose tolerance test). RESULTS After adjustment for sex, adult percent body fat, adult and childhood age, childhood BMI, and sBP were negative and independent predictors of adult M. A 5 kg/m2 increase in childhood BMI was associated with a 7.4% decrease in adult insulin action (95% CI −12.7 to −1.8%, P = 0.01) and a 10-mmHg increase in childhood sBP with a 5.0% decrease in adult M (95% CI −8.4 to −1.4%, P = 0.007). After a similar adjustment with M as an additional covariate, childhood 2-h insulin was a positive predictor of adult AIR such that a 25% increase predicted a 7.3% increase in adult AIR (95% CI 1.5–13.5%, P = 0.014). CONCLUSIONS Childhood insulin response during an oral glucose challenge predicts adult AIR, indicating that β-cell capacity may be set early in life. Childhood measures related to adiposity predict adult insulin action, which may reflect common underlying mechanisms that may be amenable to modification through programs targeting prevention or treatment of childhood obesity.
Genetic polymorphisms of IL-23R and IL-17A and novel insights into their associations with inflammatory bowel disease
Authors: S. W. Kim, E. S. Kim, C. M. Moon, J. J. Park, T. I. Kim, W. H. Kim, J. H. Cheon
Journal: Gut (2011)

<h3>Background and Aims</h3> To identify the associations of genetic and epigenetic variations in <i>IL-23R</i> and <i>IL-17A</i> with inflammatory bowel diseases (IBD). <h3>Methods</h3> The promoter and exon regions of <i>IL-23R</i> and <i>IL-17A</i> were analysed in 727 subjects (201 Crohn9s disease, 268 ulcerative colitis and 258 healthy controls) using DNA sequencing and denaturing high performance liquid chromatography. Transcription factor binding affinity, <i>IL-17A</i> mRNA expression and methylation of the <i>IL-17A</i> promoter were evaluated in peripheral blood mononuclear cells (PBMC) and Jurkat cells. <h3>Results</h3> A case–control analysis showed that development of Crohn9s disease is associated with the <i>IL-23R</i> variant G149R (OR 0.32, 95% CI 0.15 to 0.68) and <i>IL-17A</i> variant IVS1+18G&gt;C (OR 10.65, 95% CI 1.32 to 85.89). Ulcerative colitis patients showed an association with <i>IL-23R</i> variants G149R (OR 0.41, 95% CI 0.21 to 0.76), IVS4+17C&gt;T (OR 2.89, 95% CI 1.20 to 6.96) and Q3H (OR 0.61, 95% CI 0.38 to 0.99), and <i>IL-17A</i> variants −737C&gt;T (OR 1.50, 95% CI 1.06 to 2.13), −197G&gt;A (OR 0.63, 95% CI 0.40 to 0.97) and IVS1+18 G&gt;C (OR 8.93, 95% CI 1.12 to 70.99). The −877G, −737T and −444A risk alleles of <i>IL-17A</i> displayed higher binding affinities with the transcription factor complex and higher expression levels of <i>IL-17A</i> transcripts. DNA hypomethylation of the <i>IL-17A</i> promoter was observed in PBMC from IBD patients with a significant inverse correlation between methylation extent of IVS1+17 and <i>IL-17A</i> mRNA level. Finally, Jurkat cells recovered <i>IL-17A</i> mRNA expression after exposure to demethylating agent. <h3>Conclusions</h3> The results provide insights into the genetic and epigenetic interactions in the IL-23R/IL-17 axis that are associated with elevated expression of IL-17 and IBD pathogenesis.
The Morphologic Spectrum of Halothane–Induced Hepatic Injury: Analysis of 77 Cases
Authors: Stanley B. Benjamin, Zachary D. Goodman, Kamal G. Ishak, Hyman J. Zimmerman, Nelson S. Irey
Journal: Hepatology (1985)

Hepatic histopathology and clinical-pathologic correlations were studied in 77 patients who met clinical criteria for halothane hepatotoxicity. They were divided into groups based on the type of surgery (minor or major) and outcome (nonfatal, biopsy group or fatal, autopsy group). The two nonfatal groups (minor surgery and major surgery) and the two fatal groups (minor surgery and major surgery) were comparable with regard to age, time of onset from exposure, peak aminotransferase values and peak bilirubin determinations. A spectrum of histologic patterns was identified in these patients. It ranged from panlobular and multifocal spotty necrosis resembling viral hepatitis through submassive confluent zonal necrosis to massive necrosis. Progression of severity of injury from spotty to massive necrosis was more closely related to multiple exposures to halothane (and especially repeated exposure within less than three months), than to the extensiveness of the associated surgical procedures.
Evolution of Closely Linked Gene Pairs in Vertebrate Genomes
Authors: E. Franck, T. Hulsen, M. A. Huynen, W. W. de Jong, N. H. Lubsen, O. Madsen
Journal: Molecular Biology and Evolution (2008)

The orientation of closely linked genes in mammalian genomes is not random: there are more head-to-head (h2h) gene pairs than expected. To understand the origin of this enrichment in h2h gene pairs, we have analyzed the phylogenetic distribution of gene pairs separated by less than 600 bp of intergenic DNA (gene duos). We show here that a lack of head-to-tail (h2t) gene duos is an even more distinctive characteristic of mammalian genomes, with the platypus genome as the only exception. In nonmammalian vertebrate and in nonvertebrate genomes, the frequency of h2h, h2t, and tail-to-tail (t2t) gene duos is close to random. In tetrapod genomes, the h2t and t2t gene duos are more likely to be part of a larger gene cluster of closely spaced genes than h2h gene duos; in fish and urochordate genomes, the reverse is seen. In human and mouse tissues, the expression profiles of gene duos were skewed toward positive coexpression, irrespective of orientation. The organization of orthologs of both members of about 40% of the human gene duos could be traced in other species, enabling a prediction of the organization at the branch points of gnathostomes, tetrapods, amniotes, and euarchontoglires. The accumulation of h2h gene duos started in tetrapods, whereas that of h2t and t2t gene duos only started in amniotes. The apparent lack of evolutionary conservation of h2t and t2t gene duos relative to that of h2h gene duos is thus a result of their relatively late origin in the lineage leading to mammals; we show that once they are formed h2t and t2t gene duos are as stable as h2h gene duos.
Increased risk of obstructive pulmonary disease in tunnel workers
Authors: B. Ulvestad
Journal: Thorax (2000)

<h3>BACKGROUND</h3> Tunnel workers are exposed to gases and particles from blasting and diesel exhausts. The aim of this study was to assess the occurrence of respiratory symptoms and airflow limitation in tunnel workers and to relate these findings to years of exposure. <h3>METHODS</h3> Two hundred and twelve tunnel workers and a reference group of 205 other heavy construction workers participated in a cross sectional investigation. Exposure measurements were carried out to demonstrate the difference in exposure between the two occupational groups. Spirometric tests and a questionnaire on respiratory symptoms and smoking habits were applied. Atopy was determined by a multiple radioallergosorbent test (RAST). Radiological signs of silicosis were evaluated. Respiratory symptoms and lung function were studied in relation to years of exposure and adjusted for smoking habits and atopy. <h3>RESULTS</h3> Compared with the reference subjects the tunnel workers had a significant decrease in forced vital capacity (FVC) % predicted and forced expiratory volume in one second (FEV<sub>1</sub>) % predicted when related to years of exposure. Adjusted FEV<sub>1</sub> decreased by 17 ml for each year of tunnel work exposure compared with 0.5 ml in outdoor heavy construction workers. The tunnel workers also reported significantly higher occurrence of respiratory symptoms. The prevalence of chronic obstructive pulmonary disease (COPD) was 14% in the tunnel workers compared with 8% in the reference subjects. <h3>CONCLUSION</h3> Exposure to dust and gases from diesel exhaust, blasting, drilling and rock transport in tunnel work enhances the risk for accelerated decline in FEV<sub>1</sub>, respiratory symptoms, and COPD in tunnel workers compared with other heavy construction workers.
Autohemolysis of Paroxysmal Nocturnal Hemoglobinuria (PNH) Erythrocytes. Effects of Controlled pH, Additives, and Heated Serum.
Authors: Delano Meriwether
Journal: Annals of Internal Medicine (1972)

Meeting Abstracts1 May 1972Autohemolysis of Paroxysmal Nocturnal Hemoglobinuria (PNH) Erythrocytes. Effects of Controlled pH, Additives, and Heated Serum.Delano Meriwether, M.D., Stanley P. Balcerzak, M.D., F.A.C.P.Delano Meriwether, M.D.Search for more papers by this author, Stanley P. Balcerzak, M.D., F.A.C.P.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-76-5-870_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptFactors influencing autohemolysis of paroxysmal nocturnal hemoglobinuria (PNH) RBCs were studied in vitro to further characterize the cell membrane lesion and the mechanism of hemolysis in this condition. Autohemolysis of naturally occurring PNH RBCs was measured under standard conditions of 48-hour incubation, in the absence and presence of various additives. Autohemolysis of washed PNH RBCs was also determined in vitro under controlled conditions of physiologic pH, temperature, and molarity, using barbital buffer and fresh serum. Finally, autohemolytic features of naturally occurring PNH RBCs were compared with those of artificially produced PNH RBCs, that is, normal RBCs treated with 0.3 M... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Boston, Mass., and Columbus, Ohio PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited ByThe Effects of Metabolic Inhibitors on the Autohaemolysis Test and its Relevance to the Mechanism of the Red Cell Lysis 1 May 1972Volume 76, Issue 5Page: 870-870KeywordsCell membranesHemoglobinLesionsTemperature Issue Published: 1 May 1972 PDF DownloadLoading ...
Prevalence of occupational asthma due to latex among hospital personnel.
Authors: O Vandenplas, J P Delwiche, G Evrard, P Aimont, X van der Brempt, J Jamart, L Delaunois
Journal: American Journal of Respiratory and Critical Care Medicine (1995)

Latex has been documented as causing immediate hypersensitivity reactions ranging from contact urticaria to severe anaphylaxis. Latex proteins may also act as airborne allergens causing rhinitis and asthma. The prevalence of occupational asthma due to latex gloves among health care workers is unknown. We surveyed the employees of a primary care hospital including nurses (n = 201), members of the cleaning staff (n = 50), and laboratory technologists (n = 38). In the initial part of the study, a questionnaire and skin-prick tests with latex and common inhalant allergens were administered to 273 of 289 (94%) members of the target population. Thirteen of the 273 subjects (4.7%; 95% CI: 2.6 to 8.1%) showed skin reactivity to latex. All latex-sensitive subjects reported glove-related urticaria, which was associated with rhinoconjunctivitis in 12 subjects and asthma in five subjects. No subject had a history suggestive of occupational asthma among those who had negative skin tests to latex. In the second part of the study, a histamine inhalation challenge was performed on 12 of 13 latex-sensitive subjects, including the five subjects with a history of occupational asthma. These 12 subjects demonstrated significant bronchial hyperresponsiveness. All underwent specific inhalation challenges with latex gloves in the laboratory. Seven subjects developed a significant bronchial response (four immediate and three dual reactions) to latex glove exposure. We conclude that occupational asthma due to latex occurred in 2.5% (95% CI: 1.0 to 5.2%) of hospital employees. Widespread use of latex gloves should therefore be considered a significant risk to the respiratory health of hospital employees.
Erratum to: Next-generation sequencing reveals novel differentially regulated mRNAs, lncRNAs, miRNAs, sdRNAs and a piRNA in pancreatic cancer
Authors: Sören Müller, Susanne Raulefs, Philipp Bruns, Fabian Afonso-Grunz, Anne Plötner, Rolf Thermann, Carsten Jäger, Anna Melissa Schlitter, Bo Kong, Ivonne Regel, W Kurt Roth, Björn Rotter, Klaus Hoffmeier, Günter Kahl, Ina Koch, Fabian J Theis, Jörg Kleeff, Peter Winter, Christoph W Michalski
Journal: Molecular Cancer (2015)

Previous studies identified microRNAs (miRNAs) and messenger RNAs with significantly different expression between normal pancreas and pancreatic cancer (PDAC) tissues. Due to technological limitations of microarrays and real-time PCR systems these studies focused on a fixed set of targets. Expression of other RNA classes such as long intergenic non-coding RNAs or sno-derived RNAs has rarely been examined in pancreatic cancer. Here, we analysed the coding and non-coding transcriptome of six PDAC and five control tissues using next-generation sequencing. Besides the confirmation of several deregulated mRNAs and miRNAs, miRNAs without previous implication in PDAC were detected: miR-802, miR-2114 or miR-561. SnoRNA-derived RNAs (e.g. sno-HBII-296B) and piR-017061, a piwi-interacting RNA, were found to be differentially expressed between PDAC and control tissues. In silico target analysis of miR-802 revealed potential binding sites in the 3′ UTR of TCF4, encoding a transcription factor that controls Wnt signalling genes. Overexpression of miR-802 in MiaPaCa pancreatic cancer cells reduced TCF4 protein levels. Using Massive Analysis of cDNA Ends (MACE) we identified differential expression of 43 lincRNAs, long intergenic non-coding RNAs, e.g. LINC00261 and LINC00152 as well as several natural antisense transcripts like HNF1A-AS1 and AFAP1-AS1. Differential expression was confirmed by qPCR on the mRNA/miRNA/lincRNA level and by immunohistochemistry on the protein level. Here, we report a novel lncRNA, sncRNA and mRNA signature of PDAC. In silico prediction of ncRNA targets allowed for assigning potential functions to differentially regulated RNAs.
Cost of care of patients with cystic fibrosis in The Netherlands in 1990-1.
Authors: M F Wildhagen, J B Verheij, J G Verzijl, H B Hilderink, L Kooij, T Tijmstra, L P ten Kate, J Gerritsen, W Bakker, J D Habbema, F Habbema
Journal: Thorax (1996)

BACKGROUND: Research on the cost of care of patients with cystic fibrosis is scarce. The aim of this study was to estimate the costs using age-specific medical consumption from real patient data. METHODS: The age-specific medical consumption of patients with cystic fibrosis in The Netherlands in 1991 was estimated from a survey of medical records and a patient questionnaire. A distinction was made between costs of hospital care, hospital and non-hospital medication, and home care. Costs per year were obtained by multiplying the yearly amount of care and the costs per unit. RESULTS: On average the annual cost of a patient with cystic fibrosis in 1991 was 10,908 pounds (hospital care 42%, medication 37%, home care 20%). The cost of care of cystic fibrosis in The Netherlands, with approximately 1000 patients, is estimated at 10.9 million pounds per year, which is 0.07% of the total health care budget. The cost of care of a patient up to the age of 35 is estimated at 614,587 pounds. When year-to-year survival is taken into account and future costs are discounted to the year of birth with a yearly discount rate of 5%, the cost of care of a patient with cystic fibrosis is estimated at 164,365 pounds for 1991. This estimate will be used in a prospective evaluation of screening for cystic fibrosis carriers. CONCLUSIONS: The cost of care of patients with cystic fibrosis estimated by age-specific medical consumption of real patients is higher than that estimated by non-age-specific medical consumption and/or expert opinions.
Hypoxia causes an abnormal contractile response in the atherosclerotic rabbit aorta. Implication of reduced nitric oxide and cGMP production.
Authors: S Simonet, J Porro de Bailliencourt, J J Descombes, P Mennecier, M Laubie, T J Verbeuren
Journal: Circulation Research (1993)

Both atherosclerotic lesions and hypoxia alter the contractile properties of the arterial wall and, in particular, may interfere with the relaxation mechanisms dependent or not on the endothelium. The present study was designed to test the effect of severe hypoxia on the contractile behavior of the atherosclerotic rabbit aorta. Segments of aortas obtained from control, cholesterol-fed, or Watanabe hereditary hyperlipidemic rabbits were mounted in organ chambers for isometric tension recording. A change of the bath PO2 from "normoxic" conditions (95% O2-5% CO2) to "hypoxic" conditions (95% N2-5% CO2) caused relaxation in the precontracted control aortas (by approximately 85%) but a transient contraction (approximately 20% of the maximal contraction obtained with 30 mM KCl) followed by a relaxation in the precontracted atherosclerotic aortas. Both types of responses were observed in aortas contracted with aggregating platelets, 5-hydroxytryptamine (5-HT), norepinephrine, endothelin, and prostaglandin F2 alpha. The hypoxic contractions in atherosclerosis were not dependent on the presence of an intact endothelium. They could not be antagonized by blockers of alpha-adrenoceptors, 5-HT2 receptors, histamine receptors, thromboxane receptors, and muscarinic cholinoreceptors. Inhibitors of cyclooxygenase, lipoxygenase, Na+, K(+)-ATPase, and free radical scavengers or an activator of endothelium-derived relaxing factor did not significantly affect the hypoxic contraction; the absence of effect of some inhibitors of protein synthesis seems to rule out the involvement of endothelin, angiotensin II, and bradykinin. The hypoxic contraction was not influenced by omission of Ca2+ from the medium or by inhibition of Ca2+ influx but was prevented by blockade of intracellular Ca2+. The inhibitor of nitric oxide synthase (nitro-L-arginine, 100 microM) and the guanylyl cyclase inhibitor (methylene blue, 10 microM) both enhanced the initial contractile responses to 5-HT to a similar extent as hypoxia and completely prevented the hypoxic contraction in the atherosclerotic tissues. The cyclic nucleotide analogues 8-bromo-cGMP and dibutyryl cAMP also inhibited the hypoxic contraction in the atherosclerotic aorta. The cGMP levels were markedly decreased and the cAMP levels were moderately decreased in the aortas of the cholesterol-fed rabbits as compared with the control aortas. Hypoxia further decreased cGMP but not the cAMP levels in atherosclerotic aortas with and without endothelium. Our data thus demonstrate the occurrence of an unusual vasoconstrictor response in atherosclerotic arteries; this constrictor response depends on the availability of intracellular Ca2+ and seems to be due to the further inhibition of an already impaired cGMP production.(ABSTRACT TRUNCATED AT 400 WORDS)