tbuckley/cabot-search huggingface dataset:
Disruption of L-Histidine Decarboxylase Reduces Airway Eosinophilia but not Hyperresponsiveness
Authors: Akira Koarai, Masakazu Ichinose, Satsuki Ishigaki-Suzuki, Shunsuke Yamagata, Hisatoshi Sugiura, Eiko Sakurai, Yoko Makabe-Kobayashi, Atsuo Kuramasu, Takehiko Watanabe, Kunio Shirato, Toshio Hattori, Hiroshi Ohtsu
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Histamine has a variety of airway actions and is considered to be an important mediator in asthma. This study examined the role of endogenous histamine in allergic airway eosinophil recruitment and hyperresponsiveness using L-histidine decarboxylase gene knockout mice. Histamine levels of the airways in L-histidine decarboxylase knockout mice were largely diminished compared with wild-type mice. Inhalation challenge with ovalbumin (OVA) in OVA-sensitized wild-type mice caused eosinophil accumulation in the lung as well as airway hyperresponsiveness to methacholine 3 days after the challenge. The eosinophil recruitment was significantly reduced in the knockout mice. In the bone marrow, the proliferation of eosinophils was enhanced after OVA challenge in the wild-type mice; however, the proliferation was significantly reduced in the knockout mice. The induction of P-selectin in the lung after OVA challenge was also inhibited in the knockout mice. In contrast, airway hyperresponsiveness was not suppressed in the knockout mice. These results suggest that endogenous histamine is involved in the accumulation of eosinophils into the airways after allergic challenge, possibly acting in the bone marrow and producing P-selectin in the airways. Furthermore, allergen-induced airway hyperresponsiveness appeared to occur independently of airway eosinophilia in our present model.
271 MONITORING THE HEPATIC VENOUS PRESSURE GRADIENT IS USEFUL IN THE PREVENTION OF VARICEAL REBLEEDING AND IMPROVES SURVIVAL
Authors: A. Amorós, J.M. Palazón, L. Sempere, I. Mozas, M.D. Picó, J. Sánchez-Payá, F. Carnicer, S. Pascual, M. Pérez-Mateo
Journal: Journal of Hepatology (2008)
Impact of clinical and molecular predictors of benefit from erlotinib in advanced non-small cell lung cancer on cost-effectiveness
Authors: P. A. Bradbury, D. Tu, L. Seymour, R. Ng, L. Zhu, P. K. Isogai, N. Mittmann, W. K. Evans, F. A. Shepherd, N. B. Leighl
Journal: Journal of Clinical Oncology (2008)

6531 Background: Previously we have shown that the incremental cost effectiveness ratio (ICER) of erlotinib, in unselected patients with advanced non-small cell lung cancer (NSCLC) after chemotherapy failure, was $95,869 (2007 CAD), per life year gained (LYG), using original patient data from the NCIC CTG BR.21 trial of erlotinib versus placebo in advanced NSCLC. Here, we investigate the value of combining clinical and molecular predictors of outcome to identify more, and less cost- effective patient subgroups for treatment. Methods: Cost-effectiveness ranges of interest were identified a priori: group A ICER <$50,000/LYG, B $50,000- 75,000/LYG and C >$200,000/LYG CAD. Significant clinical and molecular predictors of outcome from the BR.21 trial were assessed to identify groups within these thresholds of cost-effectiveness, and to characterize patient characteristics of each group that had >50 patients. Due to small numbers, EGFR mutation status was not included. Results: The subgroup with lowest ICER ($22,564/LYG; n=52) consisted of patients with adenocarcinoma, never smoker status who had received one prior chemotherapy regimen. By contrast, past and present smokers with wild-type EGFR and K-ras gene mutation had the highest ICER for erlotinib treatment ($3,862,962/LYG; n=52). The presence of one of the following variables, never smoking status, high EGFR copy number or EGFR protein positive tumours (immunohistochemistry), predicted for lower ICERs in groups A and B, irrespective of histological subtype. Female gender was associated with higher ICERs in all three groups. Conclusions: Incorporation of molecular and clinical predictors into economic analyses has the potential to differentiate cost-effective versus cost-ineffective subgroups for treatment. We identified subsets of patients (e.g. smoking history, non-adenocarcinoma histology) who could be treated within a reasonable range of cost effectiveness. While subset analyses must be interpreted with caution, examining different methodological approaches in the economic analysis of novel agents is warranted and a parallel investigation using classification and regression tree methodology is underway. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Roche and OSIP Roche, Roche and OSIP
Provoked priapism in sickle cell anemia
Authors: Marcel E. Conrad, George M. Perrine, James C. Barton, John R. Durant
Journal: American Journal of Hematology (1980)

Two patients with sickle cell anemia are reported who developed relative impotence after repeated episodes of priapism. They learned that excessive ethanol ingestion produced an erection and utilized this mechanism to satisfy sexual partners. Hospitalization and transfusion therapy were required for repeated episodes of priapism. Extensive interviews were required in order to learn the sequence of events. This synergistic relationship between ethanol and priapism should be sought in patients with repeated hospitalizations for this complication of sickle cell anemia because it is preventable with appropriate counseling.
Lung function in patients with tracheobronchopathia osteochondroplastica
Authors: H Tukiainen, M Torkko, EO Terho
Journal: European Respiratory Journal (1988)

We have analysed the ventilatory function of seven patients with tracheobronchopathia osteochondroplastica. One patient showed reversible airflow obstruction meeting the criteria of bronchial asthma. Another two patients yielded reduced percentage forced expiratory volume (FEV%) and features of small airways obstruction. The patients' previous spirometric measurements also made the rough estimation of longitudinal changes in lung function possible during a follow-up period of 1-8 yrs (mean 4.2 yrs). Although most patients had suffered severe chest infections, no deterioration in spirometric parameters was found during the follow-up. These findings suggest that tracheobronchopathia osteochondroplastica usually has a benign course.
Depression and 18-Month Prognosis After Myocardial Infarction
Authors: Nancy Frasure-Smith, François Lespérance, Mario Talajic
Journal: Circulation (1995)

Background We previously reported that major depression in patients in the hospital after a myocardial infarction (MI) substantially increases the risk of mortality during the first 6 months. We examined the impact of depression over 18 months and present additional evidence concerning potential mechanisms linking depression and mortality. Methods and Results Two-hundred twenty-two patients responded to a modified version of the National Institute of Mental Health Diagnostic Interview Schedule (DIS) for a major depressive episode at approximately 7 days after MI. The Beck Depression Inventory (BDI), which measures depressive symptomatology, was also completed by 218 of the patients. All patients and/or families were contacted at 18 months to determine survival status. Thirty-five patients met the modified DIS criteria for major in-hospital depression after the MI. Sixty-eight had BDI scores ≥10, indicative of mild to moderate symptoms of depression. There were 21 deaths during the follow-up period, including 19 from cardiac causes. Seven of these deaths occurred among patients who met DIS criteria for depression, and 12 occurred among patients with elevated BDI scores. Multiple logistic regression analyses showed that both the DIS (odds ratio, 3.64; 95% confidence interval [CI], 1.32 to 10.05; P =.012) and elevated BDI scores (odds ratio, 7.82; 95% CI, 2.42 to 25.26; P =.0002) were significantly related to 18-month cardiac mortality. After we controlled for the other significant multivariate predictors of mortality in the data set (previous MI, Killip class, premature ventricular contractions [PVCs] of ≥10 per hour), the impact of the BDI score remained significant (adjusted odds ratio, 6.64; 95% CI, 1.76 to 25.09; P =.0026). In addition, the interaction of PVCs and BDI score marginally improved the model ( P =.094). The interaction showed that deaths were concentrated among depressed patients with PVCs of ≥10 per hour (odds ratio, 29.1; 95% CI, 6.97 to 122.07; P &lt;.00001). Conclusions Depression while in the hospital after an MI is a significant predictor of 18-month post-MI cardiac mortality. Depression also significantly improves a risk-stratification model based on traditional post-MI risks, including previous MI, Killip class, and PVCs. Furthermore, the risk associated with depression is greatest among patients with ≥10 PVCs per hour. This result is compatible with the literature suggesting an arrhythmic mechanism as the link between psychological factors and sudden cardiac death and underscores the importance of developing screening and treatment programs for post-MI depression.
Mobilizing monocytes to cross-present circulating viral antigen in chronic infection
Authors: Adam J. Gehring, Muzlifah Haniffa, Patrick T. Kennedy, Zi Zong Ho, Carolina Boni, Amanda Shin, Nasirah Banu, Adeline Chia, Seng Gee Lim, Carlo Ferrari, Florent Ginhoux, Antonio Bertoletti
Journal: Journal of Clinical Investigation (2013)

Selection of antigens for therapeutic vaccination against chronic viral infections is complicated by pathogen genetic variations. We tested whether antigens present during persistent viral infections could provide a personalized antigenic reservoir for therapeutic T cell expansion in humans. We focused our study on the HBV surface antigen (HBsAg), which is present in microgram quantities in the serum of chronic HBV patients. We demonstrated by quantitative fluorescent microscopy that, out of 6 professional APC populations in the circulation, only CD14 monocytes (MNs) retained an HBsAg depot. Using TCR-redirected CD8+ T cells specific for MHC-I-restricted HBV epitopes, we showed that, despite being constantly exposed to antigen, ex vivo-isolated APCs did not constitutively activate HBV-specific CD8+ T cells. However, differentiation of HBsAg+ CD14 MNs from chronic patients to MN-derived DCs (moDCs) induced cross-presentation of the intracellular reservoir of viral antigen. We exploited this mechanism to cross-present circulating viral antigen and showed that moDCs from chronically infected patients stimulated expansion of autologous HBV-specific T cells. Thus, these data demonstrate that circulating viral antigen produced during chronic infection can serve as a personalized antigenic reservoir to activate virus-specific T cells.
555 TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT (TIPS) AFTER LIVER TRANSPLANTATION (LT): VASCULAR COMPLICATIONS CONSTITUTE A GOOD INDICATION
Authors: M. Senzolo, G. Magini, A. Burroughs, R. Agazzi, M. Colledan, G. Zanus, G. Gaffuri, S. Fagiuoli
Journal: Journal of Hepatology (2011)
Implementation of guidelines for seasonal allergic rhinitis: a randomized controlled trial
Authors: J. Bousquet, V. J. Lund, P. Van Cauwenberge, C. Bremard‐Oury, N. Mounedji, M. T. Stevens, T. El‐Akkad
Journal: Allergy (2003)

Background: Allergic rhinitis is a common disease altering quality of life. Its treatment is well established and guidelines have been proposed. However, their efficacy has never been tested. The aim of the study was to validate the guidelines of the International Consensus on Rhinitis in the treatment of seasonal allergic rhinitis. Methods: A multicenter, multinational, open label, parallel, randomized study compared two therapeutic strategies in seasonal allergic rhinitis during a 3‐week treatment. General practitioners were randomized into two groups. In the first group of 224 patients, doctors followed guidelines from the International Consensus on Rhinitis. Depending on the severity of nasal and ocular symptoms defined using visual analogue scales, patients received ebastine (an oral antihistamine), triamcinolone acetonide (a topical corticosteroid) and/or ophthalmic nedocromil sodium (a topical ocular cromone). In the second group of 241 patients, general practitioners had a free choice of treatment. The primary efficacy end points were quality of life measured using the standardized rhinoconjunctivitis quality of life questionnaire (RQLQ) and the symptom‐medication scores assessed daily with an electronic dairy system. Results: Adjusted mean total symptom scores over 21 days were 4.93 in the guidelines strategy group compared with 7.48 in the free‐choice treatment group ( P = 0.0001). Mean total scores in the RQLQ decreased by 2.19 in the guidelines group compared with a decrease of 1.79 in the free‐choice treatment group ( P = 0.0001). At 21 days, the least square mean difference in improvement in overall scores for RQLQ in the guidelines group compared with the free‐choice treatment group was 0.53, which was greater than the minimal important difference. Conclusions: Patients with seasonal allergic rhinitis often present severe symptoms which are not well recognized or controlled by physicians using their own criteria of severity and treatment. Using a simple method for the evaluation of the severity and a simple therapeutic scheme based on International Guidelines, patients with seasonal allergic rhinitis presented a significant improvement by comparison with those receiving a non‐standardized treatment.
A potential role for inhibitors of XIAP in the treatment of NSCLC
Authors: S. Foster
Journal: Thorax (2010)

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer mortality worldwide. The pathogenesis of NSCLC involves the evasion of apoptosis. One way this is achieved is via the overexpression of inhibitor of apoptosis proteins (IAPs). Eight human IAPs have been identified, the best characterised and most …
Tofacitinib Facilitates the Expansion of Myeloid‐Derived Suppressor Cells and Ameliorates Arthritis in SKG Mice
Authors: Keisuke Nishimura, Jun Saegusa, Fumichika Matsuki, Kengo Akashi, Goichi Kageyama, Akio Morinobu
Journal: Arthritis & Rheumatology (2014)

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that have the ability to suppress T cell responses. The aim of this study was to evaluate the effects of the JAK inhibitor tofacitinib on MDSCs in a mouse model of rheumatoid arthritis. Arthritis was induced in SKG mice by zymosan A (ZyA) injection. MDSCs isolated from the bone marrow (BM) of donor SKG mice with arthritis were adoptively transferred to recipient mice with arthritis. In a separate experiment, tofacitinib was administered to arthritic SKG mice subcutaneously via osmotic pump, in some cases followed by injection of an anti-Gr-1 monoclonal antibody (mAb). BM cells from untreated mice were cultured for 5 days with granulocyte-macrophage colony-stimulating factor, with or without tofacitinib, and then analyzed by flow cytometry. The numbers of MDSCs and polymorphonuclear MDSCs (PMN-MDSCs) were significantly increased in the spleens of SKG mice following ZyA injection. Adoptive transfer of MDSCs to recipient arthritic mice reduced the severity of arthritis compared to that in untreated control mice. Treatment with tofacitinib also ameliorated the progression of arthritis in SKG mice and induced significantly higher numbers of MDSCs and PMN-MDSCs in the BM of these animals. Furthermore, administration of an anti-Gr-1 mAb reduced the antiarthritic effect of tofacitinib in SKG mice. In vitro, tofacitinib facilitated the differentiation of BM cells to MDSCs, and inhibited their differentiation to dendritic cells. Tofacitinib facilitates the expansion of MDSCs and ameliorates arthritis in SKG mice.
Invasion and metastasis in pancreatic cancer.
Authors: Shereen Keleg, Peter Büchler, Roman Ludwig, Markus W Büchler, Helmut Friess
Journal: Molecular Cancer (2003)

Pancreatic cancer remains a challenging disease with an overall cumulative 5-year survival rate below 1%. The process of cancer initiation, progression and metastasis is still not understood well. Invasion and tumor metastasis are closely related and both occur within a tumour-host microecology, where stroma and tumour cells exchange enzymes and cytokines that modify the local extracellular matrix, stimulate cell migration, and promote cell proliferation and tumor cell survival. During the last decade considerable progress has been made in understanding genetic alterations of genes involved in local and systemic tumor growth. The most important changes occur in genes which regulate cell cycle progression, extracellular matrix homeostasis and cell migration. Furthermore, there is growing evidence that epigenetic factors including angiogenesis and lymphangiogenesis may participate in the formation of tumor metastasis. In this review we highlight the most important genetic alterations involved in tumor invasion and metastasis and further outline the role of tumor angiogenesis and lymphangiogenesis in systemic tumor dissemination.
Structure-based Phylogenetic Analysis of Short-chain Alcohol Dehydrogenases and Reclassification of the 17beta-Hydroxysteroid Dehydrogenase Family
Authors: Rainer Breitling, Daniela Laubner, Jerzy Adamski
Journal: Molecular Biology and Evolution (2001)

Short-chain alcohol dehydrogenases (SCAD) constitute a large and diverse family of ancient origin. Several of its members play an important role in human physiology and disease, especially in the metabolism of steroid substrates (e.g., prostaglandins, estrogens, androgens, and corticosteroids). Their involvement in common human disorders such as endocrine-related cancer, osteoporosis, and Alzheimer disease makes them an important candidate for drug targets. Recent phylogenetic analysis of SCAD is incomplete and does not allow any conclusions on very ancient divergences or on a functional characterization of novel proteins within this complex family. We have developed a 3D structure-based approach to establish the deep-branching pattern within the SCAD family. In this approach, pairwise superpositions of X-ray structures were used to calculate similarity scores as an input for a tree-building algorithm. The resulting phylogeny was validated by comparison with the results of sequence-based algorithms and biochemical data. It was possible to use the 3D data as a template for the reliable determination of the phylogenetic position of novel proteins as a first step toward functional predictions. We were able to discern new patterns in the phylogenetic relationships of the SCAD family, including a basal dichotomy of the 17beta-hydroxysteroid dehydrogenases (17beta-HSDs). These data provide an important contribution toward the development of type-specific inhibitors for 17beta-HSDs for the treatment and prevention of disease. Our structure-based phylogenetic approach can also be applied to increase the reliability of evolutionary reconstructions in other large protein families.
EULAR international liaison activities
Authors: A D Woolf
Journal: Annals of the Rheumatic Diseases (2003)

For a variety of activities with the Bone and Joint Decade, WHO, and the European Community, liaison is being maintained to promote European rheumatology and EULAR.

Over 1200 organisations are now supporting the decade

Multidisciplinary national action networks (equivalent to combined scientific and social leagues) have now been established in 51 countries. National coordinators in a further 39 countries are trying to establish more national action networks. The networks work together to gain priority and to improve health care for musculoskeletal conditions.

Forty six governments have now endorsed the decade.

The WHO technical report on the “Burden of musculoskeletal conditions at the start of the new millennium” will be published this year. This provides data on the impact of the different major musculoskeletal …
Genome-wide association study of smoking behaviours in patients with COPD
Authors: M. Siedlinski, M. H. Cho, P. Bakke, A. Gulsvik, D. A. Lomas, W. Anderson, X. Kong, S. I. Rennard, T. H. Beaty, J. E. Hokanson, J. D. Crapo, E. K. Silverman
Journal: Thorax (2011)

<h3>Background</h3> Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease (COPD) and COPD severity. Previous genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) and a dopamine beta-hydroxylase (DBH) locus associated with smoking cessation in multiple populations. <h3>Objective</h3> To identify SNPs associated with lifetime average and current CPD, age at smoking initiation, and smoking cessation in patients with COPD. <h3>Methods</h3> GWAS were conducted in four independent cohorts encompassing 3441 ever-smoking patients with COPD (Global Initiative for Obstructive Lung Disease stage II or higher). Untyped SNPs were imputed using the HapMap (phase II) panel. Results from all cohorts were meta-analysed. <h3>Results</h3> Several SNPs near the HLA region on chromosome 6p21 and in an intergenic region on chromosome 2q21 showed associations with age at smoking initiation, both with the lowest p=2×10<sup>−7</sup>. No SNPs were associated with lifetime average CPD, current CPD or smoking cessation with p&lt;10<sup>−6</sup>. Nominally significant associations with candidate SNPs within cholinergic receptors, nicotinic, alpha 3/5 (<i>CHRNA3/CHRNA5</i>; eg, p=0.00011 for SNP rs1051730) and cytochrome P450, family 2, subfamily A, polypeptide 6 (<i>CYP2A6</i>; eg, p=2.78×10<sup>−5</sup> for a non-synonymous SNP rs1801272) regions were observed for lifetime average CPD, however only <i>CYP2A6</i> showed evidence of significant association with current CPD. A candidate SNP (rs3025343) in <i>DBH</i> was significantly (p=0.015) associated with smoking cessation. <h3>Conclusion</h3> The authors identified two candidate regions associated with age at smoking initiation in patients with COPD. Associations of <i>CHRNA3/CHRNA5</i> and <i>CYP2A6</i> loci with CPD and <i>DBH</i> with smoking cessation are also likely of importance in the smoking behaviours of patients with COPD.