tbuckley/cabot-search huggingface dataset:
Activation of Liver X Receptors Promotes Neuroprotection and Reduces Brain Inflammation in Experimental Stroke
Authors: Jesús R. Morales, Iván Ballesteros, José Manuel Deniz, Olivia Hurtado, José Vivancos, Florentino Nombela, Ignacio Lizasoain, Antonio Castrillo, María A. Moro
Journal: Circulation (2008)

Background— The liver X receptors (LXRs) belong to the nuclear receptor superfamily and act as transcriptional regulators of cholesterol metabolism in several tissues. Recent work also has identified LXRs as potent antiinflammatory molecules in macrophages and other immune cells. Combined changes in lipid and inflammatory profiles are likely mediating the protective role of LXRs in models of chronic injury like atherosclerosis. These beneficial actions, however, have not been illustrated in other models of acute injury such as stroke in which inflammation is an important pathophysiological feature. Methods and Results— We have studied LXR expression and function in the course of experimental stroke caused by permanent middle cerebral artery occlusion in rats and mice. Here, we show that administration of the synthetic LXR agonists GW3965 or TO901317 after the ischemic occlusion improves stroke outcome as shown by decreased infarct volume area and better neurological scores in rats. Neuroprotection observed with LXR agonists correlated with decreased expression of proinflammatory genes in the brain and with reduced nuclear factor-κB transcriptional activity. Loss of function studies using LXRα,β −/− mice demonstrated that the effect of LXR agonists is receptor specific. Interestingly, infarcted brain area and inflammatory signaling were significantly extended in LXRα,β −/− mice compared with control animals, indicating that endogenous LXR signaling mediates neuroprotection in this setting. Conclusion— This work highlights the transcriptional action of LXR as a protective pathway in brain injury and the potential use of LXR agonists as therapeutic agents in stroke.
A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis
Authors: Stephan Miehlke, Petr Hruz, Michael Vieth, Christian Bussmann, Ulrike von Arnim, Monther Bajbouj, Christoph Schlag, Ahmed Madisch, Christiane Fibbe, Henning Wittenburg, Hans Dieter Allescher, Max Reinshagen, Stefan Schubert, Jan Tack, Michaela Müller, Patrick Krummenerl, Joris Arts, Ralph Mueller, Karin Dilger, Roland Greinwald, Alex Straumann
Journal: Gut (2015)

OBJECTIVES: To evaluate genetic damage as the frequency of sister chromatid exchanges and micronuclei in lymphocytes of peripheral blood of operating room personnel exposed to waste anaesthetic gases. METHODS: Occupational exposure was measured with a direct reading instrument. Venous blood samples were drawn from 10 non-smokers working in the operating room and 10 non-smoking controls (matched by age, sex, and smoking habits). Lymphocytes were cultured separately over 72 hours for each assay with standard protocols. At the end of the culture time, the cells were harvested, stained, and coded for blind scoring. The exchanges of DNA material were evaluated by counting the number of sister chromatid exchanges in 30 metaphases per probe or by counting the frequency of micronuclei in 2000 binucleated cells. Also, the mitotic and proliferative indices were measured. RESULTS: The operating room personnel at the hospital were exposed to an 8 hour time weighted average of 12.8 ppm nitrous oxide and 5.3 ppm isoflurane. The mean (SD) frequency of sister chromatid exchanges was significantly higher (10.2 (1.9) v 7.4 (2.4)) in exposed workers than controls (p = 0.036) the proportion of micronuclei (micronuclei/500 binucleated cells) was also higher (8.7 (2.9) v 6.8 (2.5)), but was not significant (p = 0.10). CONCLUSION: Exposure even to trace concentrations of waste anaesthetic gases may cause dose-dependent genetic damage. Concerning the micronuclei test, no clastogenic potential could be detected after average chronic exposure to waste anaesthetic gas. However, an increased frequency of sister chromatid exchanges in human lymphocytes could be detected. Although the measured differences were low, they were comparable with smoking 11-20 cigarettes a day. Due to these findings, the increased proportion of micronuclei and rates of sister chromatid exchanges may be relevant long term and need further investigation.
Guidelines for the prevention and treatment of infection in patients with an absent or dysfunctional spleen
Journal: BMJ (1996)

Guidelines for the prevention and treatment ofinfection in patients with an absent or dysfunctional spleen Working Party of the British Committee for Standards in Haematology Clinical Haematology Task Force Overwhelming postsplenectomy infection should be preventable if simple precautions are taken.An ad hoc working party of the British Committee for Standards in Haematology has reviewed recom- mendations for patients without a spleen and drawn up a consensus.Members of the working party were selected for their personal expertise and to represent relevant professional bodies.The guidelines, which are set out below, include and extend the chief medical officer's 1994 update. Key guidelines* All splenectomised patients and those with functional hyposplenism should receive pneumococcal immunisation (A, B) * Documentation, communication, and re- immunisation require attention (A, B) * Patients not previously immunised should receive Haemophilus influenzae type b vaccine (A, B) * Meningococcal immunisation is not routinely recommended (B) * Influenza immunisation may be beneficial (B) * Lifelong prophylactic antibiotics are recom- mended (oral phenoxymethylpenicillin or an alternative) (A, B) * Asplenic patients are at risk of severe malaria (A) * Animal and tick bites may be dangerous (A) * Patients should be given a leaflet and a card to alert health professionals to their risk of over- whelming infection (A, B).* Patients developing infection despite mea- sures must be given a systemic antibiotic and urgently admitted to hospital (A, B) A=Based on published evidence.B=Expert opinion.
Secretion of lysosomal hydrolases by stimulated and nonstimulated macrophages.
Authors: J Schnyder, M Baggiolini
Journal: The Journal of Experimental Medicine (1978)

Peritoneal macrophages were obtained from untreated mice and from mice treated with thioglycollate medium (TA), proteose peptone medium (PP), or a suspension of streptococcus A cell wall material (SA). The biochemical and secretory properties of these cells in long term cultures (up to 2 wk) were compared. TA-elicited macrophages contained more protein, lactate dehydrogenase, lysosomal hydrolases, and in particular, more plasminogen activator than the other cells studied. All types of macrophages studied were found to release considerable amounts of lysosomal hydrolases (beta-glucuronidase, N-acetyl-beta-glucosaminidase, alpha-mannosidase, and acid phosphatase) into the medium. Release was independent of phagocytosis and must, therefore, be regarded as true secretion. In both elicited and nonelicited macrophages, the rates of lysosomal enzyme secretion were virtually identical in the presence and in the absence of serum, and they were not enhanced by increasing serum concentrations. Lysosomal enzyme secretion in macrophages appears to depend on protein synthesis, since it was blocked by low concentrations of cycloheximide which neither affected cell viability nor lowered the intracellular enzyme levels. The amounts of lysosomal hydrolases secreted were highest in TA-elicited macrophages. The rates of secretion of PP- or SA-elicited and of nonelicited macrophages were about one-fourth of that of the TA-elicited cells. This difference, although significant, is much smaller than that observed for the secretion of plasminogen activator which was 20-50 times higher in TA-elicited cells. Acid glycosidases were also found in the peritoneal lavage media used for cell harvesting from both treated and nontreated mice. This indicates that active secretion of lysosomal hydrolases may be an in vivo property of the macrophage.
Interpretation of occupational peak flow records: level of agreement between expert clinicians and Oasys-2
Authors: D R Baldwin
Journal: Thorax (2002)

Oasys-2 is a validated diagnostic aid for occupational asthma that interprets peak expiratory flow (PEF) records as well as generating summary plots. The system removes inconsistency in interpretation, which is important if there is limited agreement between experts. A study was undertaken to assess the level of agreement between expert clinicians interpreting serial PEF measurements in relation to work exposure and to compare the responses given by Oasys-2.35 PEF records from workers under investigation for suspected occupational asthma were available for review. Records included details of nature of work, intercurrent illness, drug therapy, predicted PEF, rest periods, and holidays. Simple plots of PEF and the Oasys-2 generated plots were available. Experts were advised that approximately 1 hour was available to review the records. They were asked to score each work-rest-work (WRW) period and each rest-work-rest (RWR) period for evidence of occupational effect. At the end of each record scores of 0-100% were given for evidence of "asthma" and "occupational effect" for the whole record. Kappa values were calculated for each scored period and for the opinions on the whole record. The scores were converted into four groups (0-25%, 26-50%, 51-75%, 76-100%) and two groups (0-50% and 51-100%) for analysis. This is relevant to scores produced by Oasys-2. Agreement between Oasys-2 scores and each expert was calculated.24 of 35 records were analysed by seven experts in the allotted time. For whole record occupational effect, median kappa values were 0.83 (range 0.56-0.94) for two groups and 0.62 (0.11-0.83) for four groups. For asthma, median kappa values were 0.58 (0-0.67) and 0.42 (0.15-0.70) for two and four groups respectively. For all WRW and RWR periods kappa values were 0.84 (0.42-0.94) and 0.70 (0.46-0.87) respectively. Agreement between Oasys-2 and individual experts showed a median kappa value of 0.75 (0.50-0.92) for two groups and 0.50 (0.39-0.70) for four groups. Kappa values for the median expert score v Oasys-2 were 0.75 for two groups and 0.67 for four groups. Agreement was poor for records with intermediate probability, as defined by Oasys-2.Considerable variation in agreement was seen in expert interpretation of occupational PEF records which may lead to inconsistencies in diagnosis of occupational asthma. There is a need for an objective scoring system which removes human variability, such as that provided by Oasys-2.
Evasion of a Single-Step, Chemotherapy-Induced Senescence in Breast Cancer Cells: Implications for Treatment Response
Authors: Lynne W. Elmore, Xu Di, Catherine Dumur, Shawn E. Holt, David A. Gewirtz
Journal: Clinical Cancer Research (2005)

Abstract Purpose: The purpose of this study is to define the mechanistic basis for recovery of proliferative capacity in breast tumor cells after chemotherapy. Here, we test the hypothesis that evasion of senescence confers resistance to chemotherapeutic drugs and ionizing radiation. Experimental Design: MCF-7 cells were treated with a single, clinically relevant dose (0.75-1.0 μmol/L) of Adriamycin. Two weeks following induction of senescence, clonal outgrowths were expanded and characterized in terms of senescence-associated β-galactosidase activity, gene expression profiles (Affymetrix U95 probe sets, Affymetrix, Santa Clara, CA) with confirmatory Western analyses, and telomerase activity following a second drug treatment. Levels of intracellular Adriamycin, as well as cross-resistance to other therapeutic agents, were also determined to define the resistance phenotype. Results: A senescence-resistant (SR) clone (clone 2) was identified that was largely refractory to both Adriamycin-induced and γ-irradiation–induced senescence. Clone 2 continued to proliferate and maintain high levels of telomerase activity following a second drug treatment, when treated parental cells expressed very low levels of telomerase and many positive cell cycle regulators. SR clone 2 also expressed substantially more cdc-2 than parental cells and undetectable levels of MDR1, showed an intact p53 checkpoint and only a modestly lower level of intracellular drug accumulation, while exhibiting cross-resistance to other topoisomerase inhibitors. Conclusions: SR clone 2 is intrinsically resistant to DNA damage–induced senescence perhaps through an ability to prevent down-regulation of cdc-2. Telomerase is a marker of proliferative recovery for breast cancer cells after chemotherapy exposure. Evasion or escape from a single-step, drug-induced senescence may represent a unique and previously unrecognized drug-resistance phenotype.
Efficient Deletion of Normal <i>Brca2</i>-Deficient Intestinal Epithelium by Poly(ADP-Ribose) Polymerase Inhibition Models Potential Prophylactic Therapy
Authors: Trevor Hay, Helen Jenkins, Owen J. Sansom, Niall M.B. Martin, Graeme C.M. Smith, Alan R. Clarke
Journal: Cancer Research (2005)

Abstract The genes encoding the BRCA1 and BRCA2 tumor suppressors are the most commonly mutated in human familial breast cancers. Both have separate roles in the maintenance of genomic stability through involvement in homologous recombination, an error-free process enabling cells to repair DNA double-strand breaks. We have previously shown that cre-mediated conditional deletion of Brca2 within the mouse small intestine sensitizes the tissue to DNA damage. Eventually, the tissue repopulates via stem cells in which recombination at the floxed Brca2 allele has not taken place. In this study, we have treated Brca2-deficient small intestine with a potent small-molecule inhibitor of poly(ADP-ribose) polymerase 1 (PARP1), an enzyme predominantly involved in the recognition of DNA single-strand breaks. Brca2 deficiency rendered otherwise normal cells exquisitely sensitive to PARP inhibition, resulting in very high levels of apoptosis as early as 6 hours after treatment, with evidence for repopulation of the tissue at 12 hours. Furthermore, the intestines of animals treated with serial injections of the inhibitor repopulated very rapidly in comparison with those from untreated mice. Our results represent the first in vivo demonstration that inhibition of PARP1 activity confers exquisite sensitivity to death in physiologically normal Brca2-deficient cells, suggesting that such a regimen may be extremely potent prophylactically in women heterozygous for the BRCA2 gene, as well as against established tumors lacking functional BRCA2.
721 THE VALUE OF INTRAHEPATIC HBV TDNA AND CCCDNA AT CESSATION NAS AS AN INDICATOR FOR RELAPSE IN THE CHB PATIENTS
Authors: N.J. Jiang, X.Y. Liang, W.W. Guo, H. Lu, H.M. Su, H.Z. Liu, D.H. Li, G.J. Hu, H.X. Huang, R. Xie, Q.M. Zhu
Journal: Journal of Hepatology (2011)
Improved Tumor Targeting With Radiolabeled, Recombinant, Single-Chain, Antigen-Binding Protein
Authors: S. M. Larson
Journal: JNCI Journal of the National Cancer Institute (1990)

"The imperial messenger sets out on his journey; a powerful, an indefatigable man, now pushing with his right arm, now with his left, he cleaves a way for himself through the throng; if he encounters resistance he points to his breast, where the symbol of the sun glitters; the way is made easier for him than it would be for any other man…"—Franz Kafka, "The Imperial Messenger."
Influence of Potassium Depletion on Myocardial Concentration of Tritiated Digoxin
Authors: KEITH E. COHN, ROBERT E. KLEIGER, DONALD C. HARRISON
Journal: Circulation Research (1967)

The influence of potassium deficiency on myocardial 3 H-digoxin concentration in the mouse was studied. Tritiated digoxin, 400 µg/kg, was injected intraperitoneally into mice, which were killed at varying time intervals, and the 3 H-digoxin was extracted. One-half of the mice were made potassium deficient by a diet free of potassium. In control animals, myocardial 3 H-digoxin was maximal by 30 min and declined through 24 hours. There was no significant difference between the myocardial 3 H-digoxin of the control and potassium-depleted groups at ½ 1, 2, 6, or 16 hours, but at 24 hours a significantly higher concentration of digoxin was present in the potassium-deficient mouse hearts (23.6 ± 5.2 mµg/g) than in the control group (3.1 ± 1.5 mµg/g). Potassium-depleted mice with total renal failure, produced by bilateral ligation of the renal pedicle, showed increased myocardial 3 H-digoxin levels at 20 hours as compared with mice with renal failure but without potassium deficiency. It is concluded that potassium deficiency may lead to increased concentrations of cardiac digoxin. The findings in the anuric animals suggest that diminished renal function produced by potassium depletion is not the sole mechanism of this retention of cardiac 3 H-digoxin.
Chronic Lymphocytic Leukemia: A Niche for Flavopiridol?
Authors: Jennifer R. Brown
Journal: Clinical Cancer Research (2005)

Cyclin-dependent kinases (cdks) are key regulators of orderly progression through the cell cycle and of RNA transcription. Inhibition of their activity in vitro can cause cell cycle arrest at the G1-S or G2-M boundaries ([1][1], [2][2]). Flavopiridol, a synthetic flavone related to a natural product
BASIC DETERMINANTS OF MYOCARDIAL HYPERTROPHY: A Review of Molecular Mechanisms
Authors: George Cooper
Journal: Annual Review of Medicine (1997)

▪ Abstract The essential cardiac response to a fixed increase in hemodynamic load is an increase in cardiac mass. If the load increase is neither too severe initially nor indefinitely progressive, cardiac stress is renormalized, and compensated hypertrophy ensues. But hypertrophic compensation is often abrogated by progressively abnormal contractile performance per unit mass of myocardium, even when function at the organ level is maintained by the mass increase itself. That is, even when hypertrophy is appropriate to the load imposed, and in a manner analogous to dystrophic growth of skeletal muscle, specific phenotypic changes occurring during this growth response render compensation imperfect such that congestive heart failure ensues. This fact, and the fact that the presence of deleterious phenotypic changes in hypertrophied myocardium is critically dependent on the type of hemodynamic load imposed, mandates that cardiac hypertrophy be understood on the most basic level as a growth process if early, definitive interventions to prevent congestive heart failure following pathological hemodynamic overloads are to be realized.
Reporting of results from network meta-analyses: methodological systematic review
Authors: A. Bafeta, L. Trinquart, R. Seror, P. Ravaud
Journal: BMJ (2014)

<b>Objective</b> To examine how the results of network meta-analyses are reported. <b>Design</b> Methodological systematic review of published reports of network meta-analyses. <b>Data sources</b> Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Medline, and Embase, searched from inception to 12 July 2012. <b>Study selection</b> All network meta-analyses comparing the clinical efficacy of three or more interventions in randomised controlled trials were included, excluding meta-analyses with an open loop network of three interventions. <b>Data extraction and synthesis</b> The reporting of the network and results was assessed. A composite outcome included the description of the network (number of interventions, direct comparisons, and randomised controlled trials and patients for each comparison) and the reporting of effect sizes derived from direct evidence, indirect evidence, and the network meta-analysis. <b>Results</b> 121 network meta-analyses (55 published in general journals; 48 funded by at least one private source) were included. The network and its geometry (network graph) were not reported in 100 (83%) articles. The effect sizes derived from direct evidence, indirect evidence, and the network meta-analysis were not reported in 48 (40%), 108 (89%), and 43 (36%) articles, respectively. In 52 reports that ranked interventions, 43 did not report the uncertainty in ranking. Overall, 119 (98%) reports of network meta-analyses did not give a description of the network or effect sizes from direct evidence, indirect evidence, and the network meta-analysis. This finding did not differ by journal type or funding source. <b>Conclusions</b> The results of network meta-analyses are heterogeneously reported. Development of reporting guidelines to assist authors in writing and readers in critically appraising reports of network meta-analyses is timely.
Utility of signs and symptoms of chronic cough in predicting specific cause in children
Authors: Julie Marchant, Ian Brent Masters, Simone Taylor, Anne Chang
Journal: Thorax (2006)

<b>Background:</b> Paediatricians rely on cough descriptors to direct them to the level of investigations needed for a child presenting with chronic cough, yet there is a lack of published data to support this approach. A study was undertaken to evaluate (1) whether historical cough pointers can predict which children have a specific cause for their cough and (2) the usefulness of chest radiography and spirometry as standard investigations in children with chronic cough. <b>Methods:</b> This was a prospective cohort study of children referred to a tertiary hospital with a cough lasting &gt;3 weeks between June 2002 and July 2004. All included children completed a detailed history and examination using a standardised data collection sheet and followed a pathway of investigation until a diagnosis was made. <b>Results:</b> In 100 consecutively recruited children of median age 2.8 years, the best predictor of specific cough observed was a moist cough at the time of consultation with an odds ratio (OR) of 9.34 (95% CI 3.49 to 25.03). Chest examination or chest radiographic abnormalities were also predictive with OR 3.60 (95% CI 1.31 to 9.90) and 3.16 (95% CI 1.32 to 7.62), respectively. The most significant historical pointer for predicting a specific cause of the cough was a parental history of moist cough (sensitivity 96%, specificity 26%, positive predictive value 74%). <b>Conclusions:</b> The most useful clinical marker in predicting specific cough is the presence of a daily moist cough. Both chest examination and chest radiographic abnormalities are also useful in predicting whether children have a specific cause of their cough.