tbuckley/cabot-search huggingface dataset:
Alveolar Extracellular 20S Proteasome in Patients with Acute Respiratory Distress Syndrome
Authors: Stephan Urs Sixt, Michael Adamzik, Daniel Spyrka, Boris Saul, Jan Hakenbeck, Jeremias Wohlschlaeger, Ulrich Costabel, Alexander Kloß, Jan Giesebrecht, Burkhardt Dahlmann, Jürgen Peters
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Rationale: Repair mechanisms resulting in alveolar protein degradation in acute respiratory distress syndrome (ARDS) are largely unknown.Objectives: To test whether the 20S proteasome is present and functional in the alveolar space in patients with ARDS.Methods: Proteasome antigenic concentration in bronchoalveolar lavage (BAL) supernatants was measured by ELISA in patients with ARDS (n = 64), acute lung injury (ALI) (n = 8), sarcoidosis (n = 13), and in healthy subjects (n = 8). Cleavage of specific fluorogenic substrates (±epoxomicin), I125 albumin degradation rate, and gel filtration were used to quantify and characterize proteasomal activity. The presence of proteasomes was confirmed independently by electron microscopic techniques.Measurements and Main Results: Proteasome concentrations in patients with ARDS were markedly increased (1,069 ± 1,194 ng/ml) in comparison to healthy subjects (60.8 ± 49.8; P < 0.001), ALI (154 ± 43; P = 0.006), and sarcoidosis (97.6 ± 42.2; P = 0.037). All fluorogenic substrates were hydrolyzed (Suc-LLVY-AMC, 3.6 ± 8.8 pkat/mg; BZ-VGR-AMC, 1.8 ± 3.1; Suc-LLE-AMC, 1 ± 1.7) by BAL supernatants of patients with ARDS, with inhibition by epoxomicin (P = 0.0001), and the majority of proteolytic activity was detected in BAL supernatant. Maximum hydrolyzing activity occurred at 660 kD and 20S proteasome was seen microscopically after purification and being released by pneumocytes type II. Proteasomal activity and albumin degradation rate in patients with ARDS were approximately 17-fold lower than in healthy subjects. Proteasomal activity in normal BAL was inhibited by BAL aliquots from patients with ARDS but not by denatured BAL, and returned to normal by purification.Conclusions: For the first time, we identified extracellular, biologically active 20S proteasome in the alveolar space of patients with ARDS in concentrations much higher than in normal subjects or in those with ALI.
Interaction of human beta 1 thyroid hormone receptor and its mutants with DNA and retinoid X receptor beta. T3 response element-dependent dominant negative potency.
Authors: C A Meier, C Parkison, A Chen, K Ashizawa, S C Meier-Heusler, P Muchmore, S Y Cheng, B D Weintraub
Journal: Journal of Clinical Investigation (1993)

Mutations in the human beta thyroid hormone receptor (h-TR beta) gene are associated with the syndrome of generalized resistance to thyroid hormone. We investigated the interaction of three h-TR beta 1 mutants representing different types of functional impairment (kindreds ED, OK, and PV) with different response elements for 3,3',5-triiodothyronine (T3) and with retinoid X receptor beta (RXR beta). The mutant receptors showed an increased tendency to form homodimers on a palindromic T3-response element (TREpal), a direct repeat (DR + 4), and an inverted palindrome (TRElap). On TRElap, wild type TR binding was decreased by T3, while the mutant receptors showed a variably decreased degree of dissociation from TRElap in response to T3. The extent of dissociation was proportional to their T3 binding affinities. RXR beta induced the formation of h-TR beta 1:RXR beta heterodimers equally well for mutants and the wild type h-TR beta 1 on these T3 response elements. However, the T3-dependent increase in heterodimerization with RXR beta was absent or reduced for the mutant TRs. Transient transfection studies indicated that the dominant negative potency was several-fold more pronounced on the TRElap as compared to TREpal or DR + 4. In CV-1 and HeLa cells, transfection of RXR beta could not reverse the dominant negative action. These results demonstrate that the binding of mutant h-TRs to DNA, as well as their dominant negative potency, are TRE dependent. In addition, competition for DNA binding, rather than for limiting amounts of RXR beta, is likely to mediate the dominant negative action.
Outbreak of Burkholderia cepacia bloodstream infections traced to the use of Ringer lactate solution as multiple-dose vial for catheter flushing, Phnom Penh, Cambodia
Authors: B. De Smet, C. Veng, L. Kruy, C. Kham, J. van Griensven, C. Peeters, S. Ieng, T. Phe, E. Vlieghe, P. Vandamme, J. Jacobs
Journal: Clinical Microbiology and Infection (2012)

The Burkholderia cepacia complex is a group of Gram-negative bacteria known as respiratory pathogens in cystic fibrosis patients, but also increasingly reported as a cause of healthcare associated infections. We describe an outbreak of B. cepacia bloodstream infections in a referral hospital in Phnom Penh, Cambodia. Over a 1.5-month period, blood cultures from eight adult patients grew B. cepacia. Bloodstream infection occurred after a median of 2.5 days of hospitalisation. Three patients died: 7, 10 and 17 days after blood cultures were sampled. As part of the outbreak investigation, patient files were reviewed and environmental sampling was performed. All patients had peripheral venous catheters that were flushed with Ringer lactate drawn from a 1 L bag, used as multiple-dose vial at the ward. Cultures of unopened Ringer lactate and disinfectants remained sterile but an in-use bag of Ringer lactate solution and the dispensing pin grew B. cepacia. The isolates from patients and flushing solution were identified as B. cepacia by recA gene sequence analysis, and random amplified polymorphic DNA typing confirmed clonal relatedness. The onset of the outbreak had coincided with the introduction of a dispensing pin with a screw fit that did not allow proper disinfection. Re-enforcement of aseptic procedures with sterile syringe and needle has ended the outbreak. Growth of B. cepacia should alert the possibility of healthcare associated infection also in tropical resource-limited settings. The use of multiple-dose vials should be avoided and newly introduced procedures should be assessed for infection control risks.
Peroxisome proliferator activated receptor in colonic epithelial cells protects against experimental inflammatory bowel disease
Authors: M Adachi
Journal: Gut (2005)

Peroxisome proliferator activated receptor gamma (PPARgamma) is expressed in epithelial cells, macrophage, and T and B lymphocytes. Ligand induced activation of PPARgamma was reported to attenuate colitis activity but it is not clear whether this protection is mediated by epithelial or leucocyte PPARgamma.Mice with targeted disruption of the PPARgamma gene in intestinal epithelial cells, generated using a villin-Cre transgene and floxed PPARgamma allele and designated PPARgamma(DeltaIEpC), were compared with littermate mice having only the PPARgamma floxed allele with no Cre transgene that expressed PPARgamma in the gut, designated PPARgamma(F/F). Colitis was induced by administering dextran sodium sulphate (DSS) and the two mouse lines compared for typical symptoms of disease and expression of inflammatory cytokines.PPARgamma(DeltaIEpC) mice displayed reduced expression of the PPARgamma target genes ADRP and FABP in the gut but were otherwise normal. Increased susceptibility to DSS induced colitis, as defined by body weight loss, colon length, diarrhoea, bleeding score, and altered histology, was found in PPARgamma(DeltaIEpC) mice in comparison with PPARgamma(F/F) mice. Interleukin (IL)-6, IL-1beta, and tumour necrosis factor alpha mRNA levels in colons of PPARgamma(DeltaIEpC) mice treated with DSS were higher than in similarly treated PPARgamma(F/F) mice. The PPARgamma ligand rosiglitazone decreased the severity of DSS induced colitis and suppressed cytokine production in both PPARgamma(F/F) and PPARgamma(DeltaIEpC) mice.These studies reveal that PPARgamma expressed in the colonic epithelium has an endogenous role in protection against DSS induced colitis and that rosiglitazone may act through a PPARgamma independent pathway to suppress inflammation.
Interleukin-4 and Its Alternatively Spliced Variant (IL-4 δ 2) in Patients with Atopic Asthma
Authors: GEOK TENG SEAH, PEI SONG GAO, JULIAN M. HOPKIN, GRAHAM A. W. ROOK
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

The interleukin-4 (IL-4) splice variant (IL-4 δ 2) is known to antagonize many biological activities of IL-4, and this challenges our understanding of the role of IL-4 in asthma. Studies that have used nonspecific antibodies, probes, and/or primers to quantify IL-4 in clinical samples would not have distinguished the expression of IL-4 from IL-4 δ 2. This is the first study to examine patients with chronic asthma and atopy for IL-4 δ 2 mRNA in their peripheral blood mononuclear cells without antigen stimulation, using a quantitative nested reverse-transcription polymerase chain reaction (RT-PCR) protocol. The median IL-4 mRNA copy number in cells from the patients with asthma was 2.8 logs higher than in a comparator group of patients with tuberculosis (p = 0.0005) and 4.5 logs higher (p = 0.0004) than in healthy control subjects. In contrast, IL-4 δ 2 expression in cells from patients with asthma was similar to that seen in cells from patients with tuberculosis. Hence, the median ratio of IL-4 to IL-4 δ 2 was 500-fold higher in the patients with asthma when compared with either patients with tuberculosis or healthy control subjects. The relative expression of IL-4 and IL-4 δ 2 may be a reason for the functional diversity of Th2 cells in different clinical conditions, and a hitherto unexplored mechanism for the pulmonary pathology in patients with atopic asthma.
Penetrance of Mutations in the Familial Wilms Tumor Gene FWT1
Authors: N. Rahman, L. Arbour, R. Houlston, C. Bonaiti-Pellie, F. Abidi, J. Tranchemontagne, D. Ford, S. Narod, K. Pritchard-Jones, W. D. Foulkes, C. Schwartz, M. R. Stratton
Journal: JNCI Journal of the National Cancer Institute (2000)
S90 Effectiveness of Voriconazole In the Treatment of Aspergillus fumigatus Associated Asthma
Authors: J Agbetile, M Bourne, A Fairs, B Hargadon, D Desai, C Broad, J Morley, P Bradding, C Brightling, R Green, P Haldar, C Pashley, I Pavord, A Wardlaw
Journal: Thorax (2013)

<h3>Background</h3> IgE sensitisation to <i>Aspergillus fumigatus</i> and a positive sputum fungal culture are common in refractory asthma. It is not clear whether these patients would benefit from anti-fungal treatment. <h3>Objectives</h3> To determine if a three-month course of voriconazole improved asthma related outcomes in people with asthma who are IgE sensitised to <i>A. fumigatus.</i> <h3>Methods</h3> Asthmatics IgE sensitised to <i>A fumigatus</i> with a history of at least two severe exacerbations in the previous twelve months were treated for three months with voriconazole two hundred milligrams twice daily, followed by observation for nine months, in a double blind, placebo controlled, randomised design. Primary outcomes were improvement in quality of life at the end of the treatment period and a reduction in the number of severe exacerbations over the twelve months of the study. <h3>Results</h3> 65 patients were randomised. 59 patients started treatment (32 voriconazole and 27 placebo) and were included in an intention to treat analysis. 56 patients took the full three months of medication. There was no significant difference in the number of severe exacerbations between the voriconazole and placebo groups (1.25 vs 1.52/patient/year; mean difference 0.27; 95% CI 0.24 to 0.31) respectively, quality of life (change in AQLQ 0.44 vs 0.35, mean difference between groups 0.08; 95% CI 0.07–0.09), or in any of our secondary outcome measures between the two groups. <h3>Conclusion</h3> We were unable to show a beneficial effect of three months treatment with voriconazole in people with moderate to severe asthma who were IgE sensitised to <i>A fumigatus</i> on either the rate of severe exacerbations, quality of life or other markers of asthma control. <h3>References</h3> Fairs A, Agbetile J, Hargadon B, Bourne M, Monteiro WR, Brightling CE, <i>et al</i>. IgE sensitisation to Aspergillus fumigatus is associated with reduced lung function in asthma. <i>Am J Respir Crit Care Med</i>. 2010;182(11):1362–8.
Impaired T Cell Death and Lupus-like Autoimmunity in T Cell–specific Adapter Protein–deficient Mice
Authors: Jorn Drappa, Lynn A. Kamen, Elena Chan, Maria Georgiev, Dalit Ashany, Francesc Marti, Philip D. King
Journal: The Journal of Experimental Medicine (2003)

T cell–specific adaptor protein (TSAd) is a T lineage–restricted signaling adaptor molecule that is thought to participate in the assembly of intracellular signaling complexes in T cells. Previous studies of TSAd-deficient mice have revealed a role for TSAd in the induction of T cell interleukin 2 secretion and proliferation. We now show that TSAd-deficient mice are susceptible to lupus-like autoimmune disease. On the nonautoimmune-prone C57BL/6 genetic background, TSAd deficiency results in hypergammaglobulinemia that affects all immunoglobulin (Ig)G subclasses. Older C57BL/6 TSAd-deficient mice (1 yr of age) accumulate large numbers of activated T and B cells in spleen, produce autoantibodies against a variety of self-targets including single stranded (ss) and double stranded (ds) DNA, and, in addition, develop glomerulonephritis. We further show that immunization of younger C57BL/6 TSAd-deficient mice (at age 2 mo) with pristane, a recognized nonspecific inflammatory trigger of lupus, results in more severe glomerulonephritis compared with C57BL/6 controls and the production of high titer ss and ds DNA antibodies of the IgG subclass that are not normally produced by C57BL/6 mice in this model. The development of autoimmunity in TSAd-deficient mice is associated with defective T cell death in vivo. These findings illustrate the role of TSAd as a critical regulator of T cell death whose absence promotes systemic autoimmunity.
The small GTPase Rap1b negatively regulates neutrophil chemotaxis and transcellular diapedesis by inhibiting Akt activation
Authors: Sachin Kumar, Juying Xu, Rupali Sani Kumar, Sribalaji Lakshmikanthan, Reuben Kapur, Matthew Kofron, Magdalena Chrzanowska-Wodnicka, Marie-Dominique Filippi
Journal: The Journal of Experimental Medicine (2014)

Neutrophils are the first line of cellular defense in response to infections and inflammatory injuries. However, neutrophil activation and accumulation into tissues trigger tissue damage due to release of a plethora of toxic oxidants and proteases, a cause of acute lung injury (ALI). Despite its clinical importance, the molecular regulation of neutrophil migration is poorly understood. The small GTPase Rap1b is generally viewed as a positive regulator of immune cell functions by controlling bidirectional integrin signaling. However, we found that Rap1b-deficient mice exhibited enhanced neutrophil recruitment to inflamed lungs and enhanced susceptibility to endotoxin shock. Unexpectedly, Rap1b deficiency promoted the transcellular route of diapedesis through endothelial cell. Increased transcellular migration of Rap1b-deficient neutrophils in vitro was selectively mediated by enhanced PI3K-Akt activation and invadopodia-like protrusions. Akt inhibition in vivo suppressed excessive Rap1b-deficient neutrophil migration and associated endotoxin shock. The inhibitory action of Rap1b on PI3K signaling may be mediated by activation of phosphatase SHP-1. Thus, this study reveals an unexpected role for Rap1b as a key suppressor of neutrophil migration and lung inflammation.
Apoptotic cells suppress mast cell inflammatory responses via the CD300a immunoreceptor
Authors: Chigusa Nakahashi-Oda, Satoko Tahara-Hanaoka, Masamichi Shoji, Yasushi Okoshi, Takako Nakano-Yokomizo, Nobuhiro Ohkohchi, Teruhito Yasui, Hitoshi Kikutani, Shin-ichiro Honda, Kazuko Shibuya, Shigekazu Nagata, Akira Shibuya
Journal: The Journal of Experimental Medicine (2012)

When a cell undergoes apoptosis, phosphatidylserine (PS) is exposed on the outer leaflet of the plasma membrane. PS acts as an “eat-me” signal to direct phagocytes expressing PS receptors to engulf the apoptotic cell. We recently reported that the immunoreceptor CD300a, which is expressed on myeloid cells, is a PS receptor. We show that CD300a does not facilitate macrophage phagocytosis of apoptotic cells. Instead, CD300a delivers an inhibitory signal in mast cells to suppress production of LPS-induced inflammatory cytokines and chemokines. After cecal ligation and puncture (CLP), when a large number of cells undergo apoptosis in the peritoneal cavity, CD300a-deficient peritoneal mast cells produced more chemoattractant and recruited more neutrophils than did wild-type (WT) mast cells. As a result, CD300a-deficient mice showed increased neutrophil recruitment and improved bacterial clearance in the peritoneal cavity, and survived longer than WT mice. Antibody blockade of CD300a–PS interactions improved bacterial clearance and extended survival of WT mice subjected to CLP. These results indicated that CD300a is a nonphagocytic PS receptor that regulates mast cell inflammatory responses to microbial infections.
Low Adiponectin Levels Predict Type 2 Diabetes in Mexican Children
Authors: Miguel Cruz, Rebeca García-Macedo, Yolanda García-Valerio, Margarita Gutiérrez, Rafael Medina-Navarro, Genoveva Duran, Niels Wacher, Jesús Kumate
Journal: Diabetes Care (2004)

HOMA, homeostasis model assessment; HOMA-IR, HOMA of insulin resistance
Medical Students’ Exposure to and Attitudes About Drug Company Interactions
Authors: Frederick S. Sierles, Amy C. Brodkey, Lynn M. Cleary, Frederick A. McCurdy, Matthew Mintz, Julia Frank, D. Joanne Lynn, Jason Chao, Bruce Z. Morgenstern, William Shore, John L. Woodard
Journal: JAMA (2005)

While exposure to and attitudes about drug company interactions among residents have been studied extensively, relatively little is known about relationships between drug companies and medical students.To measure third-year medical students' exposure to and attitudes about drug company interactions.In 2003, we distributed a 64-item anonymous survey to 1143 third-year students at 8 US medical schools, exploring their exposure and response to drug company interactions. The schools' characteristics included a wide spectrum of ownership types, National Institutes of Health funding, and geographic locations. In 2005, we conducted a national survey of student affairs deans to measure the prevalence of school-wide policies on drug company-medical student interactions.Monthly frequency of students' exposure to various activities and gifts during clerkships, and attitudes about receiving gifts.Overall response rate was 826/1143 (72.3%), with range among schools of 30.9%-90.7%. Mean exposure for each student was 1 gift or sponsored activity per week. Of respondents, 762/818 (93.2%) were asked or required by a physician to attend at least 1 sponsored lunch. Regarding attitudes, 556/808 (68.8%) believed gifts would not influence their practices and 464/804 (57.7%) believed gifts would not affect colleagues' practices. Of the students, 553/604 (80.3%) believed that they were entitled to gifts. Of 183 students who thought a gift valued at less than $50 was inappropriate, 158 (86.3%) had accepted one. The number of students who simultaneously believed that sponsored grand rounds are educationally helpful and are likely to be biased was 452/758 (59.6%). Students at 1 school who had attended a seminar about drug company-physician relationships were no more likely than the nonattending classmates to show skepticism. Of the respondents, 704/822 (85.6%) did not know if their school had a policy on these relationships. In a national survey of student affairs deans, among the 99 who knew their policy status, only 10 (10.1%) reported having school-wide policies about these interactions.Student experiences and attitudes suggest that as a group they are at risk for unrecognized influence by marketing efforts. Research should focus on evaluating methods to limit these experiences and affect the development of students' attitudes to ensure that physicians' decisions are based solely on helping each patient achieve the greatest possible benefit.
Effects of Randomization to Intensive Glucose Control on Adverse Events, Cardiovascular Disease, and Mortality in Older Versus Younger Adults in the ACCORD Trial
Authors: Michael E. Miller, Jeff D. Williamson, Hertzel C. Gerstein, Robert P. Byington, William C. Cushman, Henry N. Ginsberg, Walter T. Ambrosius, Laura Lovato, William B. Applegate
Journal: Diabetes Care (2013)

We explore the effect of randomized treatment, comparing intensive to standard glucose-lowering strategies on major cardiovascular outcomes, death, and severe adverse events in older versus younger participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.
Tumor Necrosis Factor Receptor 1 Gain-of-Function Mutation Aggravates Nonalcoholic Fatty Liver Disease but Does Not Cause Insulin Resistance in a Murine Model
Authors: Marcela Aparicio-Vergara, Pascal P.H. Hommelberg, Marijke Schreurs, Nanda Gruben, Rinke Stienstra, Ronit Shiri-Sverdlov, Niels J. Kloosterhuis, Alain de Bruin, Bart van de Sluis, Debby P.Y. Koonen, Marten H. Hofker
Journal: Hepatology (2012)

Ectodomain shedding of tumor necrosis factor receptor 1 (TNFR1) provides negative feedback to the inflammatory loop induced by TNFα. As the significance of this mechanism in obesity-associated pathologies is unclear, we aimed to unravel how much TNFR1 ectodomain shedding controls the development of nonalcoholic fatty liver disease (NAFLD), as well as its role in the development of insulin resistance. We used knockin mice expressing a mutated TNFR1 ectodomain (p55Δns), incapable of shedding and dampen the inflammatory response. Our data show that persistent TNFα signaling through this inability of TNFR1 ectodomain shedding contributes to chronic low-grade inflammation, which is confined to the liver. In spite of this, hepatic lipid levels were not affected by the nonshedding mutation in mice fed a chow diet, nor were they worse off following 12 weeks of high-fat diet (HFD) than controls (p55+/+) fed an HFD. We detected inflammatory infiltrates, hepatocellular necrosis, and apoptosis in livers of p55Δns/Δns mice fed an HFD, suggesting advanced progression of NAFLD toward nonalcoholic steatohepatitis (NASH). Indeed, fibrosis was present in p55Δns/Δns mice, but absent in wildtype mice, confirming that the p55Δns/Δns mice had a more severe NASH phenotype. Despite low-grade hepatic inflammation, insulin resistance was not observed in p55Δns/Δns mice fed a chow diet, and HFD-induced insulin resistance was no worse in p55Δns/Δns mice than p55+/+ mice. Conclusion: TNFR1 ectodomain shedding is not an essential feedback mechanism in preventing the development of hepatic steatosis or insulin resistance. It is, however, pivotal in attenuating the progression from “simple steatosis” towards a more serious phenotype with many NASH features. Targeting TNFR1 could therefore be beneficial in attenuating NASH.
Chromosomal localization, hematologic characterization, and iron metabolism of the hereditary erythroblastic anemia (hea) mutant mouse
Authors: Robert A. White, Steven G. McNulty, Shelly Roman, Uttam Garg, Eric Wirtz, Deanna Kohlbrecher, Ndona N. Nsumu, David Pinson, Roger Gaedigk, Krista Blackmore, Angela Copple, Sidrah Rasul, Masayo Watanabe, Koji Shimizu
Journal: Blood (2004)