tbuckley/cabot-search huggingface dataset:
Social regulation of gene expression in human leukocytes
Authors: Steve W Cole, Louise C Hawkley, Jesusa M Arevalo, Caroline Y Sung, Robert M Rose, John T Cacioppo
Journal: Genome biology (2007)

Abstract Background Social environmental influences on human health are well established in the epidemiology literature, but their functional genomic mechanisms are unclear. The present study analyzed genome-wide transcriptional activity in people who chronically experienced high versus low levels of subjective social isolation (loneliness) to assess alterations in the activity of transcription control pathways that might contribute to increased adverse health outcomes in social isolates. Results DNA microarray analysis identified 209 genes that were differentially expressed in circulating leukocytes from 14 high- versus low-lonely individuals, including up-regulation of genes involved in immune activation, transcription control, and cell proliferation, and down-regulation of genes supporting mature B lymphocyte function and type I interferon response. Promoter-based bioinformatic analyses showed under-expression of genes bearing anti-inflammatory glucocorticoid response elements (GREs; p = 0.032) and over-expression of genes bearing response elements for pro-inflammatory NF-κB/Rel transcription factors ( p = 0.011). This reciprocal shift in pro- and anti-inflammatory signaling was not attributable to differences in circulating cortisol levels, or to other demographic, psychological, or medical characteristics. Additional transcription control pathways showing differential activity in bioinformatic analyses included the CREB/ATF, JAK/STAT, IRF1, C/EBP, Oct, and GATA pathways. Conclusion These data provide the first indication that human genome-wide transcriptional activity is altered in association with a social epidemiological risk factor. Impaired transcription of glucocorticoid response genes and increased activity of pro-inflammatory transcription control pathways provide a functional genomic explanation for elevated risk of inflammatory disease in individuals who experience chronically high levels of subjective social isolation.
Outcomes of conduct problems in adolescence: 40 year follow-up of national cohort
Authors: I. Colman, J. Murray, R. A Abbott, B. Maughan, D. Kuh, T. J Croudace, P. B Jones
Journal: BMJ (2009)

The glucagon-like peptide-1 receptor (GLP-1R) is a class B G protein–coupled receptor and mainstay therapeutic target for the treatment of type 2 diabetes and obesity. Recent reports have highlighted how biased agonism at the GLP-1R affects sustained glucose-stimulated insulin secretion through avoidance of desensitization and downregulation. A number of GLP-1R agonists (GLP-1RAs) feature a fatty acid moiety to prolong their pharmacokinetics via increased albumin binding, but the potential for these chemical changes to influence GLP-1R function has rarely been investigated beyond potency assessments for cAMP. Here, we directly compare the prototypical GLP-1RA exendin-4 with its C-terminally acylated analog, exendin-4-C16. We examine relative propensities of each ligand to recruit and activate G proteins and <i>β</i>-arrestins, endocytic and postendocytic trafficking profiles, and interactions with model and cellular membranes in HEK293 and HEK293T cells. Both ligands had similar cAMP potency, but exendin-4-C16 showed ∼2.5-fold bias toward G protein recruitment and a ∼60% reduction in <i>β</i>-arrestin-2 recruitment efficacy compared with exendin-4, as well as reduced GLP-1R endocytosis and preferential targeting toward recycling pathways. These effects were associated with reduced movement of the GLP-1R extracellular domain measured using a conformational biosensor approach and a ∼70% increase in insulin secretion in INS-1 832/3 cells. Interactions with plasma membrane lipids were enhanced by the acyl chain. Exendin-4-C16 showed extensive albumin binding and was highly effective for lowering of blood glucose in mice over at least 72 hours. Our study highlights the importance of a broad approach to the evaluation of GLP-1RA pharmacology. <h3>SIGNIFICANCE STATEMENT</h3> Acylation is a common strategy to enhance the pharmacokinetics of peptide-based drugs. This work shows how acylation can also affect various other pharmacological parameters, including biased agonism, receptor trafficking, and interactions with the plasma membrane, which may be therapeutically important.
Tissue Transglutaminase and the Progression of Human Renal Scarring
Authors: Timothy S. Johnson, Ahmed F. El-Koraie, N. James Skill, Nahed M. Baddour, A. Meguid El Nahas, Melvin Njloma, Ahmed G. Adam, Martin Griffin
Journal: Journal of the American Society of Nephrology (2003)

ABSTRACT. Experimental renal scarring indicates that tissue transglutaminase (tTg) may be associated with the accumulation of extracellular matrix (ECM), both indirectly via TGF-β1 activation and directly by the formation of ε(γ-glutamyl) lysine dipeptide bonds within the ECM. The latter potentially accelerates deposition and confers the ECM with resistance to proteolytic digestion. Studied were 136 human renal biopsy samples from a range of chronic renal diseases (CRD) to determine changes in tTg and ε(γ-glutamyl) lysine crosslinking. Immunofluorescence for insoluble tTg showed a 14-fold increase in the kidneys of CRD patients (5.3 ± 0.5 <i>versus</i> 76 ± 54 mV/cm<sup>2</sup>), which was shown to be active by a similar 11-fold increase in the ε(γ-glutamyl) lysine crosslink (1.8 ± 0.2 <i>versus</i> 19.3 ± 14.2 mV/cm<sup>2</sup>). Correlations were obtained with renal function for tTg and crosslink. <i>In situ</i> hybridization for tTg mRNA showed that tubular epithelial cells were the major source of tTg; however, both mesangial and interstitial cells also contributed to elevated levels in CRD. This mRNA pattern was consistent with immunohistochemistry for soluble tTg. Changes in renal tTg and its product, the ε(γ-glutamyl) lysine crosslink, occur in progressive renal scarring in humans independently of the original etiology and in a similar manner to experimental models. tTg may therefore play a role in the pathogenesis of renal scarring and fibrosis in patients with CRD and can therefore be considered a potential therapeutic target. E-mail: T.Johnson@sheffield.ac.uk
Prevalence of<i>Staphylococcus aureus</i>carriage by young Malaysian footballers during indoor training
Authors: J L William, S Radu, S A Aziz, R A Rahim, Y K Cheah, A Liwan, S Lihan
Journal: British Journal of Sports Medicine (2004)

Research has shown that athletes are carriers of Staphylococcus aureus during physical activity.To estimate the mean total plate count of S aureus carried by footballers before and after training at an indoor venue.Forty Malay and 20 Indian students volunteered to participate. There was also a control group consisting of 40 Malay and 20 Indian students who were not active. The experimental group were active footballers who had played at school or club level. The subjects were healthy and free of skin infection. The experiment was divided into three sessions, with 20 subjects present at each. At each session, the subjects trained for one hour. Swabs were taken from the skin, nose, and ear before and after training. For the control group, swabs were taken only once from the skin, nose, and ear. The swabs were subjected to biochemical tests and then streaked and cultured aerobically in Baird Parker agar plates for 24 hours at 37 degrees C. Black colonies with a clear zone were presumed to be S aureus, and the mean total plate count of the colonies was estimated. Gram staining, catalase, coagulase slide, coagulase tube, acetoin production, o-nitrophenyl beta-D-galactopyranoside (ONPG), and mannitol fermentation tests were used to confirm the colonies as S aureus. A haemolysin test was conducted with human blood to confirm haemolytic activity.All subjects in the experimental group were carrying S aureus both before and after training. The estimated mean total counts of colonies from the skin, ear, and nose for the Malays before training were 33, 71, and 312 respectively. Counts after training were 21, 44, and 452 respectively. The results for the Indians were 72, 80, and 309 respectively before training and 55, 200, and 466 respectively after training. The positive results for Gram staining, catalase, coagulase slide, coagulase tube, acetoin production, ONPG, and mannitol fermentation tests were 100%, 96%, 95%, 95%, 93%, 93%, and 90% respectively. All subjects in the control group were also carrying S aureus.All of the players were carriers of S aureus during training. The decrease in total count from the skin for both races may be due to lysozyme activity lysing the bacterial cells. Contamination of the environment with these bacteria may have increased the estimated total plate count in the nose. The experimental group face a higher risk of infection because of lower immunity during training and higher rate of injuries compared with the control group.
Functional characterization of synthetic leukotriene B and its stereochemical isomers.
Authors: R A Lewis, E J Goetzl, J M Drazen, N A Soter, K F Austen, E J Corey
Journal: The Journal of Experimental Medicine (1981)

Leukotriene B (LTB), a potent lipid chemotactic factor for neutrophils, is 5S,12R-dihydroxy-6,14-cis,8,10-trans-eicosatetraenoic acid (Fig 1), based upon direct comparison of natural LTB with synthetic 5S,12R-dihydroxy-6,8,10,14-eicosatetraenoic acid (5,12-di-HETE) stereoisomers in three biological assays. Of the six synthetic stereoisomers evaluated, only the 5S,12R,6,14-cis,8,10-trans compound had chemotactic potency for human neutrophils in vitro that was comparable to that of natural LTB, with a concentration of 3 X 10(9-9) M eliciting a one-half maximum response. In contrast, the racemic mixture of 5R,12R- and 5S,12S-6,10-trans,8,14-cis, the racemic mixture of 5S,12R- and 5R,12S-6,10-trans,8,14-cis, the 5S,12R-6,8-trans,10,14-cis, the 5S,12R-6,8,10-trans,14-cis, and the 5S,12S-6,8,10-trans,14-cis stereoisomers required concentrations of 3 X 10(-7) to 1 X 10(-6) M to elicit comparable responses. Only natural LTB and its synthetic counterpart elicited a local neutrophil infiltration when injected into the skin of the rhesus monkey at 10 ng and 100 ng per site. Natural and synthetic LTB at a concentration of 3 X 10(-8) M each provoked an EC25 contractile response of guinea pig pulmonary parenchymal strips in vitro, whereas the other four tested stereoisomers of 5,12-di-HETE were inactive at this concentration. Structure-function analyses suggest that the neutrophil chemotactic activity depends critically upon the C-1 to C-12 domain, including the stereochemistry of the 6-,8-,and 10-olefinic bonds and the presence of both hydroxyl groups.
Prevalence of hardcore smoking in England, and associated attitudes and beliefs: cross sectional study
Authors: M. J Jarvis
Journal: BMJ (2003)

<h3>Abstract</h3> <b>Objective</b> To quantify the prevalence and characteristics of hardcore smokers in England. <b>Design</b> Cross sectional survey. <b>Setting</b> Interview in respondents9 household. <b>Participants</b> 7766 adult cigarette smokers. <b>Main outcome measures</b> Hardcore smoking defined by four criteria (less than a day without cigarettes in the past five years; no attempt to quit in the past year; no desire to quit; no intention to quit), all of which had to be satisfied. <b>Results</b> Some 16% of all smokers were categorised as hardcore. Hardcore smoking was associated with nicotine dependence, socioeconomic deprivation, and age, rising from 5% in young adults aged 16-24 to 30% in those aged ≥ 65 years. Hardcore smokers displayed distinctive attitudes towards and beliefs about smoking. In particular they were likely to deny that smoking affected their health or would do so in the future. Prevalence of hardcore smoking was almost four times higher than in California. <b>Conclusion</b> Hardcore smoking presents a serious challenge to public health efforts to reduce the prevalence of smoking, but the proportion of hardcore smokers does not necessarily increase as overall prevalence in a population declines. More hardcore smokers could be persuaded to quit, but this will require interventions that are targeted to the particular needs and perceptions of both socially disadvantaged and older smokers.
Macrophage-Mediated Natural Cytotoxicity of Dimethyl Sulfoxide-Treated Friend Erythroleukemia Cells&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: K H Hsu, H Friedman
Journal: JNCI Journal of the National Cancer Institute (1985)

Dimethyl sulfoxide (DMSO) treatment of the Friend erythroleukemia cell line GM 979 markedly increased its susceptibility to natural cytotoxicity by splenocytes from normal inbred DBA/2 mice. Cytotoxicity occurred with normal adherent spleen cells as well as dextran-elicited peritoneal exudate (PE) cells but not with resident PE cells. Susceptibility of the leukemia cells to natural cytotoxicity increased to maximum levels upon treatment with 210 mM DMSO for 2-3 days. The natural cytotoxicity assayed by the 51Cr release procedure was first detectable after 9 hours of incubation and reached maximum levels by 24-30 hours. Although both DMSO and n-butyric acid induced rapid erythroid cell differentiation of the GM 979 cells, and both resulted in increased hemoglobin synthesis, only DMSO treatment enhanced the susceptibility of the cells to natural cytotoxicity by normal splenocytes. Cell-free supernatants from adherent spleen cells cocultured with DMSO-treated GM 979 cells for 6-15 hours were markedly cytotoxic for cultures of other chromium-labeled DMSO-treated leukemia cells. Supernatants from cultured adherent spleen cells alone, or lysates of DMSO-treated leukemia cells, did not possess cytotoxic activity. Resident peritoneal macrophages also had no cytotoxic activity against DMSO-treated cells, and culture supernatants from resident PE cells, even after incubation with DMSO-treated target cells, failed to show significant levels of cytotoxicity. These results indicate that normal splenic adherent cells as well as elicited PE cells have the ability to lyse DMSO-treated leukemia cells.
Effect of nafamostat mesilate on pulmonary vascular injury induced by lipopolysaccharide in rats.
Authors: M Uchiba, K Okajima, K Murakami, H Okabe, K Takatsuki
Journal: American Journal of Respiratory and Critical Care Medicine (1997)

Nafamostat mesilate (NM) is a synthetic protease inhibitor that is capable of inhibiting the various coagulation factors such as factor VIIa and thrombin. To determine whether NM may also be useful in treating adult respiratory distress syndrome (ARDS) related in sepsis, we investigated the effect of NM on lipopolysaccharide (LPS)-induced pulmonary vascular injury in rats. The intraperitoneal administration of NM prevented the pulmonary vascular injury and coagulation abnormalities induced by LPS. DEGR-factor VIIa, a selective inhibitor of factor VIIa, prevented the coagulation abnormalities, but not the pulmonary vascular injury, induced by LPS. NM did not reduce LPS-induced increase in pulmonary accumulation of leukocytes. NM did not inhibit the increase in the plasma concentration of tumor necrosis factor-alpha (TNF-alpha) observed after administration of LPS. NM did not inhibit the function of activated neutrophils in vitro. Plasma values of total serum hemolytic complement (CH50) were markedly decreased after the administration of LPS. NM inhibited the LPS-induced decrease in plasma CH50 values. Findings suggest that NM may reduce the pulmonary vascular injury as well as the coagulation abnormalities induced by LPS. The former effect may be independent of the anticoagulant effect but dependent on the inhibitory effect of the activation of the complement system in rats administered LPS.
Ledipasvir‐sofosbuvir plus ribavirin for patients with genotype 1 hepatitis C virus previously treated in clinical trials of sofosbuvir regimens
Authors: David Wyles, Paul Pockros, Giuseppe Morelli, Ziad Younes, Evguenia Svarovskaia, Jenny C. Yang, Phillip S. Pang, Yanni Zhu, John G. McHutchison, Steven Flamm, Eric Lawitz
Journal: Hepatology (2015)

Patients who fail to achieve sustained virological response (SVR) after treatment with sofosbuvir (SOF) plus ribavirin (RBV) with or without pegylated interferon (Peg‐IFN) do not have established retreatment options. We conducted an open‐label trial to assess the efficacy and safety of ledipasvir (LDV)‐SOF plus RBV in patients with genotype 1 hepatitis C virus (HCV) who did not achieve SVR after treatment in phase II and III trials of SOF regimens. We enrolled 51 patients at 24 sites in the United States. All patients received the fixed‐dose combination tablet of LDV‐SOF once‐daily plus weight‐based RBV (1,000 or 1,200 mg/day) for 12 weeks. The efficacy endpoint was the proportion of patients with SVR 12 weeks after discontinuation of therapy (SVR12). Of the 51 patients enrolled, 25 (49%) had previously received SOF plus Peg‐IFN‐RBV, 20 (39%) had received SOF‐RBV, 5 (10%) had received SOF placebo plus Peg‐IFN‐RBV, and 1 (2%) received GS‐0938 monotherapy. Fourteen (27%) had compensated cirrhosis at baseline, and 47 (92%) had non‐CC interleukin‐28B genotypes. SVR12 was achieved by 50 of the 51 patients (98%) treated. Among the 45 patients who received SOF in earlier treatment, 44 (98%) achieved SVR12. The only patient who did not achieve SVR12 was a patient with genotype 3a HCV who had been incorrectly genotyped as 1a in the previous study. Given the high rates of SVR12, no differences among patient subgroups were discernible. Of 51 patients, 41 (80%) experienced at least one adverse event (AE), but most events were mild to moderate in severity. The most common AEs were fatigue, headache, and diarrhea. One patient discontinued treatment because of an unrelated AE (bipolar disorder). Conclusion : Twelve weeks of LDV‐SOF plus RBV was an effective and safe treatment for patients who have not achieved SVR with earlier regimens that included SOF. (H epatology 2015;61:1793–1797)
Epidermal antigens in lichen planus
Authors: E. ABELL, D. RAMNARAIN
Journal: British Journal of Dermatology (1975)

The loss of intercellular and basement membrane antigens has been associated with the development of epidermal cell dysplasia and neoplasia. The antigenic components of the epidermis have been investigated in lichen planus, lupus erythematosus and eczema, using pemphigoid and pemphigus sera by the indirect immunofluorescent staining method. In areas of active lichen planus there was extensive reduction or complete absence of basement membrane antigen. Intercellular antigen was preserved in lichen planus although in some damaged rete ridges it appeared to be reduced. Both these antigens were well preserved in lupus erythematosus and eczema. Loss of epithelial antigens is therefore not confined to the development of neoplasia.
Noninvasive ventilation and obstructive lung diseases
Authors: A. Cuvelier, J-F. Muir
Journal: European Respiratory Journal (2001)

The key role of noninvasive positive pressure ventilation (NPPV) is well documented in chronic obstructive pulmonary disease (COPD) patients with acute respiratory failure (ARF) since it may avoid endotrachal intubation in &gt;50% of cases when used as the initial treatment. However, currently only minimal data is available to assess usefulness of NPPV in COPD patients on a long-term basis. Even if such studies are difficult to manage, there is clearly a need for prospective studies comparing long-term oxygen therapy (LTOT) and NPPV in the most severe COPD in a large amount of patients and on a real long-term basis of several years. Two randomized prospective studies are being completed in Europe and the first preliminary results show that NPPV is associated with a reduction of hospitalization for chronic respiratory failure decompensation. The main beneficial effect of long-term mechanical ventilation in COPD patients with chronic respiratory failure implies a correction of nocturnal hypoventilation that could persist beyond the ventilation period because of a temporary improvement in carbon dioxide sensitivity that is often blunted in these patients. A synthesis from the literature suggest to consider NPPV for severe COPD patients who present with chronic hypoxia and hypercapnia and develop an unstable respiratory condition. Instability may be appreciated on a clinical basis and confirmed by a progressive worsening of arterial blood gas tensions, leading to frequent cardiorespiratory decompensations with ominous ARF episodes. NPPV should also be considered after an ARF episode successfully treated by noninvasive ventilation but with the impossibility to wean the patient from the ventilator. Thus, noninvasive positive pressure ventilation could be proposed as a preventive treatment in severe chronic obstructive pulmonary disease patients with unstable respiratory condition associated with fluctuating hypercapnia before, during and after an acute respiratory failure episode, avoiding the need for a tracheotomy. Adjunction of noninvasive ventilation to exercise rehabilitation is under evaluation.
Improving standards in flexible bronchoscopy for lung cancer
Authors: M.G. Slade, N.M. Rahman, A.E. Stanton, L. Curry, G.C. Slade, C.A. Clelland, F.V. Gleeson
Journal: European Respiratory Journal (2010)

Can the detection rate of flexible bronchoscopy for lung cancer be increased by a series of simple quality improvement measures? Bronchoscopy-associated clinical parameters were prospectively recorded between 2001 and 2007 in patients with suspected lung malignancy. The detection rate of bronchoscopy, diagnostic yield of each biopsy modality and the possible impact of different service-improvement measures were assessed. 746 bronchoscopies were performed in 704 patients. The detection rate of bronchoscopy for malignancy was 83.6%, and increased over time (67.3% detection rate in 2001 (95% CI 52.9–79.7), 89.7% detection rate in 2007 (95% CI 81.3–95.2); p&lt;0.001). Detection rate increased for bronchoscopically visible (75.0% in 2001 to 94.5% in 2007) and non-visible tumours (41.7% in 2001 to 81.2% in 2007; p&lt;0.001 for both analyses). Prior computed tomography availability was associated with a higher diagnostic yield that did not reach statistical significance. Logistic regression analysis identified tumour visibility, year of study, use of transbronchial needle aspiration and pathologist identity as independent predictors of a positive diagnosis. A significant increase in bronchoscopic detection rate for malignancy occurred in association with a number of simple improvement measures.