tbuckley/cabot-search huggingface dataset:
Cholestyramine Resin Therapy for Hypercholesteremia
Authors: Sami A. Hashim
Journal: JAMA (1965)

Cholestyramine resin, a bile-acid-sequestering agent, was administered to nine hypercholesteremic patients for periods of one month to four years. By promoting fecal excretion of bile acids, the resin appears to induce an increase in the rate of cholesterol conversion to bile acids in the liver, often resulting in a diminution of plasma cholesterol levels. During daily treatment with 13.3 gm of cholestyramine, eight of the subjects achieved mean serum total cholesterol levels that ranged from 80% to 50% of the average control values. The decreases were sustained for the duration of treatment. Two patients and one normal subject exhibited marked increases in fecal bile-acid excretion during resin administration, but neutral sterol output did not change consistently. The preparation produced occasional gastrointestinal discomfort; however, systemic side effects were not encountered.
Effect of fudosteine on mucin production
Authors: C. K. Rhee, C. M. Kang, M. B. You, H. K. Yoon, Y. K. Kim, K. H. Kim, H. S. Moon, S. H. Park, J. S. Song
Journal: European Respiratory Journal (2008)

Fudosteine is a novel mucoactive agent, although little is known about how fudosteine decreases mucin production. The present study examined the effects of fudosteine on MUC5AC mucin synthesis and cellular signalling. An animal model of lipopolysaccharide (LPS)-induced inflammation and a bronchial epithelial cell line model of tumour necrosis factor (TNF)-alpha-induced inflammation were used. Fudosteine was administered before stimulation with LPS or TNF-alpha. The MUC5AC mucin levels were assayed and the expression of the MUC5AC gene was measured. Western blotting was carried out for the detection of phosphorylated epidermal growth factor receptor (p-EGFR), phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) and phosphorylated extracellular signal-related kinase (p-ERK). MUC5AC mucin synthesis and the expression of the MUC5AC gene were increased by LPS in rats or TNF-alpha in NCI-H292 cells; these effects were inhibited by fudosteine treatment. After stimulation with LPS or TNF-alpha, the expression of p-EGFR, p-p38 MAPK and p-ERK were detected. Fudosteine treatment reduced the expression levels of p-p38 MAPK and p-ERK in vivo and of p-ERK in vitro. The present results suggest fudosteine inhibits MUC5AC mucin hypersecretion by reducing MUC5AC gene expression and the effects of fudosteine are associated with the inhibition of extracellular signal-related kinase and p38 mitogen-activated protein kinase in vivo and extracellular signal-related kinase in vitro.
TLR9 Differentiates Rapidly from Slowly Progressing Forms of Idiopathic Pulmonary Fibrosis
Authors: Glenda Trujillo, Alessia Meneghin, Kevin R. Flaherty, Lynette M. Sholl, Jeffrey L. Myers, Ella A. Kazerooni, Barry H. Gross, Sameer R. Oak, Ana Lucia Coelho, Holly Evanoff, Elizabeth Day, Galen B. Toews, Amrita D. Joshi, Matthew A. Schaller, Beatrice Waters, Gabor Jarai, John Westwick, Steven L. Kunkel, Fernando J. Martinez, Cory M. Hogaboam
Journal: Science Translational Medicine (2010)

Idiopathic pulmonary fibrosis is characterized by diffuse alveolar damage and severe fibrosis, resulting in a steady worsening of lung function and gas exchange. Because idiopathic pulmonary fibrosis is a generally progressive disorder with highly heterogeneous disease progression, we classified affected patients as either rapid or slow progressors over the first year of follow-up and then identified differences between the two groups to investigate the mechanism governing rapid progression. Previous work from our laboratory has demonstrated that Toll-like receptor 9 (TLR9), a pathogen recognition receptor that recognizes unmethylated CpG motifs in bacterial and viral DNA, promotes myofibroblast differentiation in lung fibroblasts cultured from biopsies of patients with idiopathic pulmonary fibrosis. Therefore, we hypothesized that TLR9 functions as both a sensor of pathogenic molecules and a profibrotic signal in rapidly progressive idiopathic pulmonary fibrosis. Indeed, TLR9 was present at higher concentrations in surgical lung biopsies from rapidly progressive patients than in tissue from slowly progressing patients. Moreover, fibroblasts from rapid progressors were more responsive to the TLR9 agonist, CpG DNA, than were fibroblasts from slowly progressing patients. Using a humanized severe combined immunodeficient mouse, we then demonstrated increased fibrosis in murine lungs receiving human lung fibroblasts from rapid progressors compared with mice receiving fibroblasts from slowly progressing patients. This fibrosis was exacerbated by intranasal CpG challenges. Furthermore, CpG induced the differentiation of blood monocytes into fibrocytes and the epithelial-to-mesenchymal transition of A549 lung epithelial cells. These data suggest that TLR9 may drive the pathogenesis of rapidly progressive idiopathic pulmonary fibrosis and may serve as a potential indicator for this subset of the disease.
Vehicle exhaust outside the home and onset of asthma among adults
Authors: L Modig, K Torén, C Janson, B Jarvholm, B Forsberg
Journal: European Respiratory Journal (2009)

Few studies have investigated the relationship between vehicle exhaust and the new onset of asthma among adults. The aim of the present prospective cohort study was to investigate the relationship between the cumulative incidence of asthma and onset of asthma among adults and vehicle exhaust concentrations at home. Participants from three Swedish cities included in the Respiratory Health in Northern Europe cohort constituted the study population. Exposure at each participant’s home was calculated using dispersion models. We also used &lt;50 m distance to nearest major road as a more simple indicator of exposure. The adjusted model included 3,609 participants, of which 107 were classified as onset cases and 55 as true incident cases of asthma. There was a positive association between asthma onset (odds ratio (OR) per 10 μg·m −3 1.46, 95% confidence interval (CI) 1.07–1.99) and incident asthma (OR per 10 μg·m −3 1.54, 95% CI 1.00–2.36) and the levels of nitrogen dioxide (NO 2 ), which remained statistically significant after adjusting for potential confounders. The relationship between asthma and NO 2 was not significantly modified by sex, hay fever or wheeze. The risk of developing asthma was also significantly related to living close to a major road. The current study suggests that elevated levels of vehicle exhaust outside the home increase the risk of onset and incident asthma among adults.
Abstract 19700: Recent Trends in Procedure Type, Morbidity and In-hospital Outcomes of Patients With Peripheral Artery Disease: Data From the Brazilian Public Health System
Authors: Bruno R Nascimento, Luisa C Brant, Maria Letícia L Lana, Eduardo L Lopes, Antônio Luiz P Ribeiro
Journal: Circulation (2014)

Introduction: The prevalence of peripheral artery disease (PAD) is rising worldwide, with a considerable impact on health care systems. We aimed to characterize the recent trends in surgical, percutaneous and clinical therapeutic procedures and in-hospital outcomes of PAD among all hospitalized patients in the Brazilian Public Health System between 2008 and 2012. Methods: Nationwide data of all hospitalizations in the Brazilian Public Health System (DataSUS) database in 2008, 2010, and 2012 were analyzed regarding the frequency of hospitalizations due to PAD (endovascular - EVR, surgical revascularizations - SR and clinical treatment - CT), length of hospital stay and in-hospital mortality and associated costs to the health system. Results: The number of hospitalizations related to PAD (EVR, SR and CT) remained stable from 2008 to 2012: 28,091 and 28,151 respectively, accounting for 0.25% and 0.24% of all in-hospital procedures. However, there was a significant change in the proportions of treatment modalities used in this period. In 2008: SR = 8,001 (29%), EVR = 3,207 (11%) and CT = 16,887 (60%); in 2010: SR = 7,999 (30%), EVR = 4,020 (15%) and CT: 14,849 (55%); and in 2012: SR = 7,882 (28%), EVR = 5,044 (18%) and CT = 15,225 (54%); p&lt;0.001. The results show a 57% increase in EVR, and a 9.8% decrease in CT in this period. Total costs raised 23%, from US$ 18.6 million in 2008 to R$ 22.9 million in 2012 (p&lt; 0.001), with a marked 92% increase in EVR costs (R$ 5.3 to 10.0 million), compared to SR (11%) and CT (30%). Global mean hospital days did not change from 2008 to 2012 (5.8 to 5.7 days), whereas it decreased for EVR (5.7 to 4.8, p&lt;0,001). Hospital mortality decreased from 2008 to 2012 for EVR (2.0 to 1.4%, p=0.048), increased for CT (5.1 to 5.8%, p=0.002) and remained stable for SR (8.5 to 8.8%, p=0.44). Overall mortality, however, increased from 6.2% in 2008 to 6.7% in 2012 (p=0.004). Conclusion: There is an increasing proportion of EVR for PAD in Brazil, with a concomitant increase in costs, mainly related to these procedures. Our administrative data-based analysis depicts the significant rise of overall PAD mortality in Brazil, especially in clinically treated patients, emphasizing the need of controlling PAD risk factors and promoting its early diagnosis and effective management.
Increased Gene Dosage of <i>Ube3a</i> Results in Autism Traits and Decreased Glutamate Synaptic Transmission in Mice
Authors: Stephen E. P. Smith, Yu-Dong Zhou, Guangping Zhang, Zhe Jin, David C. Stoppel, Matthew P. Anderson
Journal: Science Translational Medicine (2011)

People with autism spectrum disorder are characterized by impaired social interaction, reduced communication, and increased repetitive behaviors. The disorder has a substantial genetic component, and recent studies have revealed frequent genome copy number variations (CNVs) in some individuals. A common CNV that occurs in 1 to 3% of those with autism--maternal 15q11-13 duplication (dup15) and triplication (isodicentric extranumerary chromosome, idic15)--affects several genes that have been suggested to underlie autism behavioral traits. To test this, we tripled the dosage of one of these genes, the ubiquitin protein ligase Ube3a, which is expressed solely from the maternal allele in mature neurons, and reconstituted the three core autism traits in mice: defective social interaction, impaired communication, and increased repetitive stereotypic behavior. The penetrance of these autism traits depended on Ube3a gene copy number. In animals with increased Ube3a gene dosage, glutamatergic, but not GABAergic, synaptic transmission was suppressed as a result of reduced presynaptic release probability, synaptic glutamate concentration, and postsynaptic action potential coupling. These results suggest that Ube3a gene dosage may contribute to the autism traits of individuals with maternal 15q11-13 duplication and support the idea that increased E3A ubiquitin ligase gene dosage results in reduced excitatory synaptic transmission.
Diagnosis and management of juvenile idiopathic arthritis
Authors: F. H. M. Prince, M. H. Otten, L. W. A. v. Suijlekom-Smit
Journal: BMJ (2010)

#### Summary points

Juvenile idiopathic arthritis is the most common cause of chronic arthritis in childhood; a review of 34 epidemiological studies showed that 0.07-4.01 per 1000 children worldwide are affected.w1 It is characterised by joint inflammation that often leads to joint destruction with physical disability and chronic pain that affects daily life.1 During the past decade, increased understanding of the disease has improved treatment, particularly through earlier diagnosis and new treatments that help to prevent long term damage to joints. Earlier this year, the British Society for Paediatric and Adolescent Rheumatology published standards of care for children and young people with juvenile idiopathic arthritis, which outlined the importance of involving different disciplines within healthcare.2 We review recent advances in the diagnosis and management of juvenile idiopathic arthritis, focusing on evidence from randomised controlled trials, cohort studies, systematic reviews, and current guidelines.

#### Sources and selection criteria

As well as using our personal reference collections, we searched Medline, Embase, and Cochrane Central for clinical studies and reviews using the keywords “juvenile idiopathic arthritis”, “juvenile rheumatoid arthritis”, “juvenile chronic arthritis”, “diagnosis”, “treatment”, “therapy”, “non-steroidal anti-inflammatory drugs”, “corticosteroids”, “disease modifying antirheumatic drugs”, “biologicals”, and “biologics.” We also reviewed guidelines from the British Society …
H3F3A K27M mutations in thalamic gliomas from young adult patients
Authors: Koki Aihara, Akitake Mukasa, Kengo Gotoh, Kuniaki Saito, Genta Nagae, Shingo Tsuji, Kenji Tatsuno, Shogo Yamamoto, Shunsaku Takayanagi, Yoshitaka Narita, Soichiro Shibui, Hiroyuki Aburatani, Nobuhito Saito
Journal: Neuro-Oncology (2013)

Mutations in H3F3A, which encodes histone H3.3, commonly occur in pediatric glioblastoma. Additionally, H3F3A K27M substitutions occur in gliomas that arise at midline locations (eg, pons, thalamus, spine); moreover, this substitution occurs mainly in tumors in children and adolescents. Here, we sought to determine the association between H3F3A mutations and adult thalamic glioma. Genomic H3F3A was sequenced from 20 separate thalamic gliomas. Additionally, for 14 of the 20 gliomas, 639 genes—including cancer-related genes and chromatin-modifier genes—were sequenced, and the Infinium HumanMethylation450K BeadChip was used to examine DNA methylation across the genome. Of the 20 tumors, 18 were high-grade thalamic gliomas, and of these 18, 11 were from patients under 50 years of age (median age, 38 y; range, 17–46), and 7 were from patients over 50 years of age. The H3F3A K27M mutation was present in 10 of the 11 (91%) younger patients and absent from all 7 older patients. Additionally, H3F3A K27M was not detected in the 2 diffuse astrocytomas. Further sequencing revealed recurrent mutations in TP53, ATRX, NF1, and EGFR. Gliomas with H3F3A K27M from pediatric or young adult patients had similar, characteristic DNA methylation profiles. In contrast, thalamic gliomas with wild-type H3F3A had DNA methylation profiles similar to those of hemispheric glioblastomas. We found that high-grade thalamic gliomas from young adults, like those from children and adolescents, frequently had H3F3A K27M.
Toll-like receptor (TLR-7/9), MYOD88, TIR8, dependent and independent autoantigens
Authors: B. Marklein, Z. Konthur, T. Haupl, A. Cope, M. Shlomchik, G. Steiner, G. Burmester, K. Skriner
Journal: Annals of the Rheumatic Diseases (2010)

This study was conducted with sera from patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and arthritis and lupus-like disease animal models to identify innate immune system-dependent and -independent autoantigens.

Using protein filter technology (28000 human protein filter, RZPD, Berlin, Germany), the autoantigen profile (autoantigen fingerprint) of RA and SLE patients, mouse collagen and zymosan-induced arthritis, as well as collagen and pristan-induced arthritis in rats and TLR7, TLR9-deficient double-deficient and MyoD88 and Tir8-deficient mice …
p63, Sharp1, and HIFs: Master Regulators of Metastasis in Triple-Negative Breast Cancer
Authors: Stefano Piccolo, Elena Enzo, Marco Montagner
Journal: Cancer Research (2013)

Abstract Metastasis is the most significant cause of cancer-associated morbidity and mortality but remains poorly understood. Recent work revealed that metastasis of aggressive triple-negative breast cancers is suppressed by Sharp1, a factor that promotes degradation of hypoxia-inducible factors (HIF) and blunts HIF-induced malignant cell behavior. Cancer Res; 73(16); 4978–81. ©2013 AACR.
Influence of Viral Quasispecies on Effectiveness of Interferon Therapy in Chronic Hepatitis C Patients
Authors: Yoshiyuki Kanazawa, Norio Hayashi, Eiji Mita, Tiancheng Li, Hideki Hagiwara, Akinori Kasahara, Hideyuki Fusamoto, Takenobu Kamada
Journal: Hepatology (1994)

The quasispecies nature of hepatitis C virus genome distribution is most evident in hypervariable regions of the putative envelope 2 domain. Eight patients with chronic hepatitis C treated with interferon-alpha were studied as to heterogeneity of the hypervariable regions to clarify the implications of quasispecies. More than 10 recombinant clones generated from polymerase chain reaction-amplified products of the hypervariable regions were sequenced. The sets of clones derived from long-term responders before interferon therapy showed a significantly lower (p < 0.05) degree of sequence complexity of the hypervariable region 1 quasispecies than those from short-term ones or non-responders. The values of nucleotide diversity (the average number of nucleotide differences per site between two randomly chosen sequences) in hypervariable region 1 before interferon therapy were also significantly lower (p < 0.05) for long-term responders (mean, 2.31 x 10(-2)). In some cases, nucleotide diversity decreased remarkably during interferon therapy, whereas the values remained unchanged in other cases. In one interesting case, a short-term response was first noted with the nucleotide diversity decreasing from 13.98 x 10(-2) to 0.21 x 10(-2); namely, the diversity of the quasispecies was significantly reduced, and then a long-term response was observed after an additional course of interferon therapy. Thus, the degree of quasispecies' complexity and diversity of hypervariable region 1 was closely correlated with the responsiveness to interferon therapy in chronic hepatitis C patients, and thus may have some influence on interferon efficacy.
Increased upper airway cytokines and oxidative stress in severe obstructive sleep apnoea
Authors: R.J. Kimoff, Q. Hamid, M. Divangahi, S. Hussain, W. Bao, N. Naor, R.J. Payne, A. Ariyarajah, K. Mulrain, B.J. Petrof
Journal: European Respiratory Journal (2010)

Inflammation may contribute to upper airway pathophysiology in obstructive sleep apnoea (OSA). Our objective was to compare upper airway pro-inflammatory cytokine expression, oxidative stress and connective tissue deposition in severe (n = 25) versus mild (n = 17) OSA patients. Upper airway surgical specimens were separated by predominance of either mucosal or muscle tissue. Expression levels of interleukin (IL)-1α, IL-6, interferon-γ, RANTES (regulated on activation, normal T-cell expressed and secreted), transforming growth factor (TGF)-β and l -selectin were measured by ribonuclease protection assay. Oxidative stress was assessed via protein carbonyl group detection by immunoblotting. Histochemistry was employed for immunolocalisation of selected cytokines and connective tissue morphometry. In the severe OSA group, expression of IL-1α, IL-6 and TGF-β was significantly higher in mucosa-predominant tissues, whereas in muscle-predominant specimens, RANTES expression was greater in severe OSA. Increased protein carbonylation was observed in severe OSA within both mucosal and muscle compartments. Immunohistochemistry localised TGF-β to submucosal and perimuscular inflammatory cells, while IL-6 was primarily localised to myocytes. Consistent with the pro-fibrotic cytokine profile observed in mucosa-predominant tissue, morphometric analysis revealed greater submucosal and perimuscular connective tissue in severe OSA subjects. There is increased pro-inflammatory and pro-fibrotic cytokine expression, oxidative stress, and connective tissue deposition in upper airway tissues from severe versus mild OSA patients.
IL-4 and IL-13 augment cytokine- and CD40-induced RANTES production by human renal tubular epithelial cells in vitro.
Authors: J G Deckers, S De Haij, F J van der Woude, S W van der Kooij, M R Daha, C van Kooten
Journal: Journal of the American Society of Nephrology (1998)

Local production of cytokines by infiltrating monocytes/macrophages and Th1 and Th2 cells is of importance in renal allograft rejection. Activated Th1 cells can produce interleukin-2 (IL-2), interferon-gamma (IFN-gamma), and tumor necrosis factor (TNF), whereas Th2 cells produce IL-4 and IL-13, which inhibit Th1 cells. Furthermore, activated T cells express the costimulatory molecule CD40-ligand. During renal allograft rejection, the chemokine RANTES is detected in both infiltrating mononuclear cells and tubular epithelium. It has been shown previously that stimulation of proximal tubular epithelial cells (PTEC) with cytokines or CD40-ligand results in production of RANTES. The present study investigates the influence of Th1 and Th2 cytokines on RANTES production by activated PTEC. RANTES was not detectable in supernatants of human PTEC stimulated with IL-2, IL-4, IL-10, or IL-13 alone. Likewise, combination of these cytokines with IL-1 alpha, IFN-gamma, or TNF-alpha, respectively, did not result in detectable RANTES production. IL-2 and IL-10 had no significant effect on RANTES production by activated PTEC. IL-4 or IL-13 in combination with IL-1 alpha + IFN-gamma or IFN-gamma + TNF-alpha resulted in a two- to fourfold augmentation of RANTES production, ranging from 2.2 +/- 0.2 to 35 +/- 2 ng/ml in different cell lines. CD40-activated PTEC stimulated with IL-4 or IL-13 produced six to ten times more RANTES (ranging from 7.9 +/- 1.9 to 62 +/- 3.5 ng/ml in different cell lines) compared with CD40-activated cells alone. Because RANTES production is augmented by IL-4 and IL-13, this study suggests that during rejection, direct cellular contact between activated Th2 cells and tubular epithelial cells amplifies the local inflammatory reaction in the kidney.
Deciphering cellular states of innate tumor drug responses.
Authors: Esther Graudens, Virginie Boulanger, Cindy Mollard, Régine Mariage-Samson, Xavier Barlet, Guilaine Grémy, Christine Couillault, Malika Lajémi, Dominique Piatier-Tonneau, Patrick Zaborski, Eric Eveno, Charles Auffray, Sandrine Imbeaud
Journal: Genome biology (2006)

The molecular mechanisms underlying innate tumor drug resistance, a major obstacle to successful cancer therapy, remain poorly understood. In colorectal cancer (CRC), molecular studies have focused on drug-selected tumor cell lines or individual candidate genes using samples derived from patients already treated with drugs, so that very little data are available prior to drug treatment.Transcriptional profiles of clinical samples collected from CRC patients prior to their exposure to a combined chemotherapy of folinic acid, 5-fluorouracil and irinotecan were established using microarrays. Vigilant experimental design, power simulations and robust statistics were used to restrain the rates of false negative and false positive hybridizations, allowing successful discrimination between drug resistance and sensitivity states with restricted sampling. A list of 679 genes was established that intrinsically differentiates, for the first time prior to drug exposure, subsequently diagnosed chemo-sensitive and resistant patients. Independent biological validation performed through quantitative PCR confirmed the expression pattern on two additional patients. Careful annotation of interconnected functional networks provided a unique representation of the cellular states underlying drug responses.Molecular interaction networks are described that provide a solid foundation on which to anchor working hypotheses about mechanisms underlying in vivo innate tumor drug responses. These broad-spectrum cellular signatures represent a starting point from which by-pass chemotherapy schemes, targeting simultaneously several of the molecular mechanisms involved, may be developed for critical therapeutic intervention in CRC patients. The demonstrated power of this research strategy makes it generally applicable to other physiological and pathological situations.