tbuckley/cabot-search huggingface dataset:
Adjunctive dexamethasone in bacterial meningitis: a meta-analysis of individual patient data
Authors: Diederik van de Beek, Jeremy J Farrar, Jan de Gans, Nguyen Thi Hoang Mai, Elizabeth M Molyneux, Heikki Peltola, Tim E Peto, Irmeli Roine, Mathew Scarborough, Constance Schultsz, Guy E Thwaites, Phung Quoc Tuan, AH Zwinderman
Journal: The Lancet Neurology (2010)

BackgroundDexamethasone improves outcome for some patients with bacterial meningitis, but not others. We aimed to identify which patients are most likely to benefit from dexamethasone treatment.MethodsWe did a meta-analysis of individual patient data from the randomised, double-blind, placebo-controlled trials of dexamethasone for bacterial meningitis in patients of all ages for which raw data were available. The pre-determined outcome measures were death at the time of first follow-up, death or severe neurological sequelae at 1 month follow-up, death or any neurological sequelae at first follow-up, and death or severe bilateral hearing loss at first follow-up. Combined odds ratios (ORs) and tests for heterogeneity were calculated using conventional Mantel-Haenszel statistics. We also did exploratory analysis of hearing loss among survivors and other exploratory subgroup analyses by use of logistic regression.FindingsData from 2029 patients from five trials were included in the analysis (833 [41·0%] aged <15 years). HIV infection was confirmed or likely in 580 (28·6%) patients and bacterial meningitis was confirmed in 1639 (80·8%). Dexamethasone was not associated with a significant reduction in death (270 of 1019 [26·5%] on dexamethasone vs 275 of 1010 [27·2%] on placebo; OR 0·97, 95% CI 0·79–1·19), death or severe neurological sequelae or bilateral severe deafness (42·3% vs 44·3%; 0·92, 0·76–1·11), death or any neurological sequelae or any hearing loss (54·2% vs 57·4%; 0·89, 0·74–1·07), or death or severe bilateral hearing loss (36·4% vs 38·9%; 0·89, 0·73–1·69). However, dexamethasone seemed to reduce hearing loss among survivors (24·1% vs 29·5%; 0·77, 0·60–0·99, p=0·04). Dexamethasone had no effect in any of the prespecified subgroups, including specific causative organisms, pre-dexamethasone antibiotic treatment, HIV status, or age. Pooling of the mortality data with those of all other published trials did not significantly change the results.InterpretationAdjunctive dexamethasone in the treatment of acute bacterial meningitis does not seem to significantly reduce death or neurological disability. There were no significant treatment effects in any of the prespecified subgroups. The benefit of adjunctive dexamethasone for all or any subgroup of patients with bacterial meningitis thus remains unproven.FundingWellcome Trust UK.
Studies of acid aerosols in six cities and in a new multi-city investigation: design issues.
Authors: F E Speizer
Journal: Environmental Health Perspectives (1989)

Techniques for measuring acid aerosols in the ambient environment have been developed only recently. As part of the on-going Harvard Study on the Health Effects of Sulfur Dioxide and Respirable Particulates, we have developed monitoring equipment for acidic particles that can be used in multiple field settings. Preliminary data suggest that these strong acid aerosol measurements may correlate with respiratory symptoms more closely than similar measurements of particulate matter less than 15 microns in size. These results have led to the beginning of a U.S.-Canadian cooperative study to assess the chronic effects of acid aerosols on the health of North American children. Communities are being selected on the basis of anticipated levels of H2SO4 in ambient air along with predicted levels of ozone and nitrates. Each community will undergo a 1-year period of every other day, 24-hr monitoring with newly developed monitoring equipment that will allow for quantification of H+ ion concentrations, as well as for specific measures of ozone and acid fractions. At the end of the 1-year period, while measurements are still being made, approximately 600 children aged 7 to 11 in each of up to 24 communities will be assessed with standardized questionnaires completed by parents, and pulmonary function will be measured in the children while in school. By estimating chronic exposure from the year-long measurement of acid aerosols and consideration of specific criteria for selecting communities to study, we hope to minimize potential confounding to allow us to assess the chronic impact of strong acid in the atmosphere on the respiratory health of these children.
Gal-Gal pyelonephritis Escherichia coli pili linear immunogenic and antigenic epitopes.
Authors: M A Schmidt, P O'Hanley, G K Schoolnik
Journal: The Journal of Experimental Medicine (1985)

The linear immunogenic and antigenic structure of E. coli Gal-Gal pili from the recombinant strain HU 849 was investigated with nine synthetic peptides corresponding to regions of the pilus sequence predicted to contain hydrophilic beta-turns. Five peptides, as bovine serum albumin conjugates, were found by anti-HU 849 pilus serum and were thus designated "immunogenic epitopes." Peptides corresponding to R 25-38, R 38-50, and R 48-61 (which jointly comprise the single intramolecular disulfide loop), and R 103-116, were bound in low titer. A prominent immunogenic epitope was specified by a peptide corresponding to R 65-75. Four peptides, as thyroglobulin conjugates, elicited antisera in rabbits that bound intact HU 849 pili. These were designated "antigenic epitopes." Two prominent antigenic epitopes were localized to peptides corresponding to R 5-12 and R 93-104, whereas peptides corresponding to R 65-75 and R 119-131 represented two minor antigenic epitopes. None of the peptide antisera bound Gal-Gal pili from heterologous strains except anti-R 93-104 and anti-R 5-12. In 8 of the 10 Gal-Gal-binding pyelonephritis isolates tested, anti-R 5-12 detected a protein with an apparent molecular weight of 18,000 co-migrating with several Gal-Gal pili. Anti-R 93-104 detected a corresponding protein in 4 of 8 fecal and 7 of 12 pyelonephritis Gal-Gal-binding isolates; however, it also bound apparently unrelated proteins of higher molecular weight.
Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: Relationship with the development of renal impairment and mortality
Authors: Miguel Navasa, Antonio Follo, Xavier Filella, Wladimiro Jiménez, Anna Francitorra, Ramón Planas, Antoni Rimola, Vicente Arroyo, Joan Rodés
Journal: Hepatology (1998)

Spontaneous bacterial peritonitis (SBP) is associated with an important production of inflammatory mediators. However, it is unknown whether there is a relationship between the abdominal production of these mediators and the development of renal impairment, one of the most important prognostic parameters in spontaneous bacterial peritonitis. We studied 52 cirrhotic patients at diagnosis and resolution of the infection, by measuring endotoxin, tumor necrosis factor (TNF), and interleukin-6 (IL-6) levels in plasma and ascitic fluid. Thirteen patients (25%) developed renal impairment. Patients developing renal impairment showed significantly higher plasma and ascitic fluid cytokine levels at diagnosis of infection than patients who did not (plasma TNF-alpha: 96.0+/-38.7 vs. 39.1+/-3.6 pg/mL, P=.0209; ascitic fluid TNF-alpha: 474.5+/-118.1 vs. 160.8+/-42.7 pg/mL, P=.0173; plasma IL-6: 6,635+/-2,897 vs. 458+/-109 pg/mL, P=.0004; ascitic fluid IL-6: 182,559+/-47,328 vs. 39,250+/-10,803 pg/mL, P=.0001). Independent predictors of development of renal impairment at diagnosis were: renal failure (blood urea nitrogen > 30 mg/dL or serum creatinine > 1.5 mg/dL) (P < .001), IL-6 levels in ascitic fluid (P < .001), and mean arterial pressure (P < .05). Ten of the 13 (77%) patients who developed renal impairment died during hospitalization, but only 2 of the 39 (5%) patients who did not (P=.0001). In addition, renal failure at diagnosis of the infection was the only independent predictor of hospital mortality (P < .001). In conclusion, the inflammatory response to the infection may be an important mechanism of renal impairment and the associated mortality in SBP.
Cytokine knockouts in reproduction: the use of gene ablation to dissect roles of cytokines in reproductive biology
Authors: Wendy V. Ingman, Rebecca L. Jones
Journal: Human Reproduction Update (2007)

Cytokines play many diverse and important roles in reproductive biology, and dissecting the complex interactions between these proteins and the different reproductive organs is a difficult task. One approach is to use gene ablation, or 'knockout', to analyse the effect of deletion of a single cytokine on mouse reproductive function. This review summarizes the essential roles of cytokines in reproductive biology that have been revealed by gene knockout studies, including development and regulation of the hypothalamo-pituitary-gondal axis, ovarian folliculogenesis, implantation and immune system modulation during pregnancy. However, successful utilization of this approach must consider the caveats associated with gene ablation studies, e.g. embryonic lethality, systemic effects of cytokine ablation on local reproductive processes and the limited exposure to pathogens in mice housed in laboratory conditions. New sophisticated technology that temporally or spatially regulates gene ablation can overcome some of these limitations. Discoveries on the roles of cytokines in reproductive function uncovered by gene ablation studies can now be applied to improve in vitro fertilization for infertile couples and in the development of contraceptive therapies.
Chlamydia Inhibits Interferon γ–inducible Major Histocompatibility Complex Class II Expression by Degradation of Upstream Stimulatory Factor 1
Authors: Guangming Zhong, Tao Fan, Li Liu
Journal: The Journal of Experimental Medicine (1999)

We report that chlamydiae, which are obligate intracellular bacterial pathogens, can inhibit interferon (IFN)-gamma-inducible major histocompatibility complex (MHC) class II expression. However, the IFN-gamma-induced IFN regulatory factor-1 (IRF-1) and intercellular adhesion molecule 1 (ICAM-1) expression is not affected, suggesting that chlamydia may selectively target the IFN-gamma signaling pathways required for MHC class II expression. Chlamydial inhibition of MHC class II expression is correlated with degradation of upstream stimulatory factor (USF)-1, a constitutively and ubiquitously expressed transcription factor required for IFN-gamma induction of class II transactivator (CIITA) but not of IRF-1 and ICAM-1. CIITA is an obligate mediator of IFN-gamma-inducible MHC class II expression. Thus, diminished CIITA expression as a result of USF-1 degradation may account for the suppression of the IFN-gamma-inducible MHC class II in chlamydia-infected cells. These results reveal a novel immune evasion strategy used by the intracellular bacterial pathogen chlamydia that improves our understanding of the molecular basis of pathogenesis.
Human mesenchymal stem cells as a two-edged sword in hepatic regenerative medicine: engraftment and hepatocyte differentiation versus profibrogenic potential
Authors: L V. di Bonzo, I Ferrero, C Cravanzola, K Mareschi, D Rustichell, E Novo, F Sanavio, S Cannito, E Zamara, M Bertero, A Davit, S Francica, F Novelli, S Colombatto, F Fagioli, M Parola
Journal: Gut (2007)

<h3>Background and aim:</h3> Mesenchymal stem cells from bone marrow (MSCs) may have the potential to differentiate <i>in vitro</i> and <i>in vivo</i> into hepatocytes. We investigated whether transplanted human MSCs (hMSCs) may engraft the liver of non-obese diabetic severe combined immuno-deficient (NOD/SCID) mice and differentiate into cells of hepatic lineage. <h3>Methods:</h3> <i>Ex vivo</i> expanded, highly purified and functionally active hMSCs from bone marrow were transplanted (caudal vein) in sublethally irradiated NOD/SCID mice that were either exposed or not to acute liver injury or submitted to a protocol of chronic injury (single or chronic intraperitoneal injection of CCl<sub>4</sub>, respectively). Chimeric livers were analysed for expression of human transcripts and antigens. <h3>Results:</h3> Liver engraftment of cells of human origin was very low in normal and acutely injured NOD/SCID mice with significantly higher numbers found in chronically injured livers. However, hepatocellular differentiation was relatively rare, limited to a low number of cells (ranging from less than 0.1% to 0.23%) as confirmed by very low or not detectable levels of human transcripts for α-fetoprotein, CK18, CK19 and albumin in either normal or injured livers. Finally, a significant number of cells of human origin exhibited a myofibroblast-like morphology. <h3>Conclusions:</h3> Transplanted hMSCs have the potential to migrate into normal and injured liver parenchyma, particularly under conditions of chronic injury, but differentiation into hepatocyte-like cells is a rare event and pro-fibrogenic potential of hMSC transplant should be not under-evaluated.
Enhancers of Adeno-associated Virus AAV2 Transduction via High Throughput siRNA Screening
Authors: Alexis J Wallen, Gregory A Barker, David E Fein, Huiyan Jing, Scott L Diamond
Journal: Molecular Therapy (2011)

Intracellular barriers to adeno-associated virus (AAV) transduction may limit gene delivery. We screened a short interfering RNA (siRNA) library targeting 5,520 genes to help identify pathways that modulate AAV transduction of human endothelium. In replicate screening, 50 pools (three siRNAs per gene) resulted in greater than eightfold reporter gene expression enhancement. Single siRNA confirmation tests demonstrated that at least one siRNA from each of the top 10 pools provided greater than twofold enhancement. Several siRNAs when used together resulted in additive effects and two of the most potent siRNA sequences were enhancers in cultured airway epithelium. However, enhanced transduction was not correlated with mRNA knockdown by quantitative real time PCR, indicating an off-target mechanism. In fact, four of the five most potent siRNAs contained a consensus hexamer region 5'-UGUUUC-3' at positions 2-7 of the antisense strand. The point mutation U4A within this region (but not mutations at positions 1 or 14) disrupted transduction enhancement, indicating a microRNA (miRNA)-like mechanism. Transcription profiling indicated that the hexamer also resulted in perturbation of the interferon pathway via reduced interferon-induced protein 44-like (IFI44L), interferon-inducible myxovirus resistance 1 (MX1), and interferon-induced protein with tetratricopeptide repeats (IFIT5) mRNAs. Direct interferon (α, β, and ω) receptor 2 (IFNAR2) knockdown resulted in greater than twofold transduction enhancement. In addition to providing insight into AAV biology and enhanced transduction, the results demonstrate certain beneficial siRNA off-target effects.
Analysis of thymic endogenous retroviral expression in murine lupus. Genetic and immune studies.
Authors: A M Krieg, A D Steinberg
Journal: Journal of Clinical Investigation (1990)

Inbred mouse genomes contain two subclasses of proviruses related to mink cell focus-forming (MCF) retroviruses: polytropic (Pmv), and modified polytropic (Mpmv). To determine whether one of these subclasses is associated with murine lupus, oligonucleotide probes specific for Pmv or Mpmv sequences were used in Northern analyses. Thymus 8.4 kb Mpmv RNA was expressed in five of five lupus-prone strains and crosses and this expression was not affected by genes that retard or accelerate development of lupus. Two of four leukemia-prone strains expressed low levels of such thymic transcripts, but none of 11 control strains did. 8.4 kb Mpmv RNA expression was not induced in thymuses of control mice by the lpr/lpr or gld/gld genotypes (which cause polyclonal immune activation) nor by treatment with mitogens. In contrast to Mpmv, thymic 8.4 kb Pmv expression was poorly associated with autoimmunity: it was easily detected in nearly all strains, and was increased by polyclonal activation in control mice. These studies indicate that the organ-specific thymic 8.4 kb Mpmv expression (a) is characteristic of several genetic backgrounds which predispose to murine lupus, (b) precedes and does not correlate with disease development, (c) is not due to polyclonal activation, and (d) is regulated independently of 8.4 kb Pmv expression.
Phase I/II Trial of Erlotinib and Temozolomide With Radiation Therapy in the Treatment of Newly Diagnosed Glioblastoma Multiforme: North Central Cancer Treatment Group Study N0177
Authors: Paul D. Brown, Sunil Krishnan, Jann N. Sarkaria, Wenting Wu, Kurt A. Jaeckle, Joon H. Uhm, Francois J. Geoffroy, Robert Arusell, Gaspar Kitange, Robert B. Jenkins, John W. Kugler, Roscoe F. Morton, Kendrith M. Rowland, Paul Mischel, William H. Yong, Bernd W. Scheithauer, David Schiff, Caterina Giannini, Jan C. Buckner
Journal: Journal of Clinical Oncology (2008)

Purpose Epidermal growth factor receptor (EGFR) amplification in glioblastoma multiforme (GBM) is a common occurrence and is associated with treatment resistance. Erlotinib, a selective EGFR inhibitor, was combined with temozolomide (TMZ) and radiotherapy (RT) in a phase I/II trial. Patients and Methods Adults not taking enzyme-inducing anticonvulsants after resection or biopsy of GBM were treated with erlotinib (150 mg daily) until progression. Erlotinib was delivered alone for 1 week, then concurrently with TMZ (75 mg mg/m 2 daily) and RT (60 Gy), and finally, concurrently with up to six cycles of adjuvant TMZ (200 mg/m 2 daily for 5 days every 28 days). The primary end point was survival at 1 year. Results Ninety-seven eligible patients were accrued with a median follow-up time of 22.2 months. By definition, the primary end point was successfully met with a median survival time of 15.3 months. However, there was no sign of benefit in overall survival when comparing N0177 with the RT/TMZ arm of the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial 26981/22981 (recursive partitioning analysis [RPA] class III, 19 v 21 months; RPA class IV, 16 v 16 months; RPA class V, 8 v 10 months, respectively). Presence of diarrhea, rash, and EGFRvIII, p53, phosphatase and tensin homolog (PTEN), combination EGFR and PTEN, and EGFR amplification status were not predictive (P &gt; .05) of survival. Conclusion Although the primary end point was successfully met using nitrosourea-based (pre-TMZ) chemotherapy era historic controls, there was no sign of benefit compared with TMZ era controls. Analyses of molecular subsets did not reveal cohorts of patients sensitive to erlotinib. TMZ chemotherapy combined with RT resulted in improved outcomes compared with historical controls who received nitrosourea-based chemotherapies.
Mechanism of TNFα-induced IL-1α, IL-1β and IL-6 expression in human cardiac fibroblasts: Effects of statins and thiazolidinediones
Authors: N TURNER, R MUGHAL, P WARBURTON, D OREGAN, S BALL, K PORTER
Journal: Cardiovascular Research (2007)

Journal Article Mechanism of TNFα-induced IL-1α, IL-1β and IL-6 expression in human cardiac fibroblasts: Effects of statins and thiazolidinediones Get access Neil A. Turner, Neil A. Turner * aAcademic Unit of Cardiovascular Medicine, Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds LS2 9JT, UK *Corresponding author. Tel.: +44 113 3435890; fax: +44 113 3434803. [email protected] Search for other works by this author on: Oxford Academic PubMed Google Scholar Romana S. Mughal, Romana S. Mughal aAcademic Unit of Cardiovascular Medicine, Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds LS2 9JT, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Philip Warburton, Philip Warburton aAcademic Unit of Cardiovascular Medicine, Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds LS2 9JT, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar David J. O'Regan, David J. O'Regan bDepartment of Cardiac Surgery, The Yorkshire Heart Centre, Leeds General Infirmary, Leeds LS1 3EX, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Stephen G. Ball, Stephen G. Ball aAcademic Unit of Cardiovascular Medicine, Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds LS2 9JT, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Karen E. Porter Karen E. Porter aAcademic Unit of Cardiovascular Medicine, Leeds Institute of Genetics, Health and Therapeutics (LIGHT), University of Leeds, Leeds LS2 9JT, UK Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 76, Issue 1, October 2007, Pages 81–90, https://doi.org/10.1016/j.cardiores.2007.06.003 Published: 01 October 2007 Article history Received: 29 November 2006 Revision requested: 04 June 2007 Accepted: 06 June 2007 Published: 01 October 2007
Effect of Pregnancy on Adverse Outcomes After General Surgery
Authors: Hunter B. Moore, Elizabeth Juarez-Colunga, Michael Bronsert, Karl E. Hammermeister, William G. Henderson, Ernest E. Moore, Robert A. Meguid
Journal: JAMA Surgery (2015)

The literature regarding the occurrence of adverse outcomes following nonobstetric surgery in pregnant compared with nonpregnant women has conflicting findings. Those differing conclusions may be the result of inadequate adjustment for differences between pregnant and nonpregnant women. It remains unclear whether pregnancy is a risk factor for postoperative morbidity and mortality of the woman after general surgery.To compare the risk of postoperative complications in pregnant vs nonpregnant women undergoing similar general surgical procedures.In this retrospective cohort study, data were obtained from the American College of Surgeons' National Surgical Quality Improvement Program participant user file from January 1, 2006, to December 31, 2011. Propensity-matched females based on 63 preoperative characteristics were matched 1:1 with nonpregnant women undergoing the same operations by general surgeons. Operations performed between January 1, 2006, and December 31, 2011, were analyzed for postoperative adverse events occurring within 30 days of surgery.Rates of 30-day postoperative mortality, overall morbidity, and 21 individual postoperative complications were compared.The unmatched cohorts included 2764 pregnant women (50.5% underwent emergency surgery) and 516,705 nonpregnant women (13.2% underwent emergency surgery) undergoing general surgery. After propensity matching, there were no meaningful differences in all 63 preoperative characteristics between 2539 pregnant and 2539 nonpregnant patients (all standardized differences, <0.1). The 30-day mortality rates were similar (0.4% in pregnant women vs 0.3% in nonpregnant women; P = .82), and the rate of overall morbidity was also not significantly different between pregnant vs nonpregnant patients (6.6% vs 7.4%; P = .30).There was no significant difference in overall morbidity or 30-day mortality rates in pregnant and nonpregnant propensity-matched women undergoing similar general surgical operations. General surgery appears to be as safe for pregnant women as it is for nonpregnant women.