tbuckley/cabot-search huggingface dataset:
Syndecan 4 Regulation of the Development of Autoimmune Arthritis in Mice by Modulating B Cell Migration and Germinal Center Formation
Authors: Tsutomu Endo, Koyu Ito, Junko Morimoto, Masashi Kanayama, Daichi Ota, Masahiro Ikesue, Shigeyuki Kon, Daisuke Takahashi, Tomohiro Onodera, Norimasa Iwasaki, Toshimitsu Uede
Journal: Arthritis & Rheumatology (2015)

Objective Syndecan 4 has been implicated as a critical mediator of inflammatory responses because of its functions as a coreceptor and reservoir for growth factors and chemokines. Although syndecan 4 is known to be expressed on B cells, its role in immune responses remains unclear. The purpose of this study was to investigate the contribution of syndecan 4 to the development of immune arthritis in murine models. Methods The clinical severity of 3 immunopathologically distinct models, collagen‐induced arthritis (CIA), antigen‐induced arthritis (AIA), and collagen antibody–induced arthritis (CAIA), was evaluated in wild‐type (WT) mice and in syndecan 4–deficient (Sdc4 –/– ) mice. Germinal center (GC) formation, B cell profiles, humoral immune responses, and B cell migration were analyzed during the course of CIA. Results Sdc4 –/– mice were resistant to the induction of CIA, which is T cell and B cell dependent, but AIA and CAIA, which are T cell dependent and T cell independent, respectively, occurred with equal frequency in WT mice and Sdc4 –/– mice. Furthermore, Sdc4 –/– mice had reduced numbers of B cells and deficient GC formation in draining lymph nodes (DLNs) during the course of CIA, resulting in reduced production of collagen‐specific autoantibodies. Compared with B cells from WT mice, B cells from Sdc4 –/– mice showed reduced chemotactic migration toward stromal cell–derived factor 1 (SDF‐1) and reduced SDF‐1–mediated Akt phosphorylation. Consistent with these findings, in vivo transfer experiments showed that fewer Sdc4 –/– B cells than WT B cells were found in and around the follicles in the DLNs. Conclusion Our findings suggest that syndecan 4 contributes to the development of CIA by promoting GC formation and autoantibody production through its regulation of SDF‐1–mediated B cell migration.
A-kinase anchoring proteins as novel regulators of airway smooth muscle function
Authors: W.J. Poppinga, A. Oldenburger, W. Timens, P. Skroblin, E. Klussmann, H. Meurs, M. Schmidt, H. Maarsingh
Journal: European Respiratory Journal (2011)

Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease mainly caused by cigarette smoking (CS). Compartmentalization of cAMP signaling regulates cellular responses to (local) changes in cAMP levels. In this respect, A-kinase anchoring proteins (AKAPs) compartmentalize cAMP signaling by differentially docking proteins involved in cAMP signaling, including β2-adrenoceptors and the cAMP effectors PKA and Epac. Interestingly, AKAP79 (aka AKAP5) is involved in β2-adrenoceptor desensitization, which is opposed by AKAP250 (aka AKAP12). Here we studied the expression pattern and functions of AKAPs in regulating inflammatory cytokine release and the responsiveness to β2-agonists.  AKAP79, AKAP250 and AKAP450 (aka AKAP9) are expressed in human airway smooth muscle (hASM). Treatment with CS downregulated AKAP250 and (to a lesser extent) AKAP79, but not AKAP450. In lung tissue of COPD patients all these AKAPs were downregulated. In hASM cells, CS-induced IL-8 release was dose-dependently decreased by the β2-agonist fenoterol as well as by direct activation of PKA and (only marginally) of Epac. CS-induced IL-8 release was augmented by the PKA-binding blocking peptide st-Ht31, a generic AKAP inhibitor. Importantly, in the presence of st-Ht31 fenoterol was unable to reduce CS-induced IL-8, whereas the PKA activator was still fully effective.  In conclusion, AKAPs are expressed in the airways and coordinate the communication between β2-adrenoceptors and cAMP effectors in order to reduce CS-induced inflammation. Since AKAP expression is altered in COPD, AKAPs could contribute to the pathophysiology of this disease. Supported by Stichting Astma Bestrijding and a Rosalind Franklin Fellowship.
Cysteinyl leukotrienes overproduction and mast cell activation in aspirin-provoked bronchospasm in asthma
Authors: K Sladek, A Szczeklik
Journal: European Respiratory Journal (1993)

In order to examine the hypothesis that in aspirin-induced asthma (AIA) cyclooxygenase inhibition is associated with enhanced release of leukotrienes (LTs), we measured urinary leukotriene E4 (LTE4) and 11-dehydro-thromboxane B2 (TXB2) (as a measure of cyclooxygenase production) following challenge with oral aspirin or inhaled methacholine, in 10 AIA patients. We also determined serum tryptase and eosinophilic catonic protein (ECP) levels, in order to evaluate mast cell and eosinophil activation. Urinary LTE4 excretion was increased sevenfold 4-6 h after aspirin challenge, while 11-dehydro-TXB2 decreased gradually reaching 50% baseline levels 24 h after challenge (p < 0.05). This was accompanied by a significant fall in blood eosinophil count at 6 h, and a tendency to a rise in ECP. The intensity of both LTE4 and 11-dehydro-TXB2 responses depended on the dose of aspirin used (p < 0.001, analysis of variance (ANOVA)). The accompanying maximum fall in forced expiratory volume in one second (FEV1) was not correlated with peak LTE4 levels. In contrast to aspirin, methacholine challenge producing comparable bronchial obstruction, did not alter eicosanoid excretion or serum tryptase or ECP levels. In a separate study, lysine-aspirin inhalation challenge was performed in seven AIA patients, four of whom had responded with a rise in serum tryptase to oral aspirin challenge. Challenge with inhaled aspirin led to similar bronchoconstriction as with oral challenge, but non-respiratory symptoms such as scarlet flush or rhinorrhea were absent, and serum tryptase levels remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
State-Dependent Differences in Emotion Regulation Between Unmedicated Bipolar Disorder and Major Depressive Disorder
Authors: Maria M. Rive, Roel J. T. Mocking, Maarten W. J. Koeter, Guido van Wingen, Stella J. de Wit, Odile A. van den Heuvel, Dick J. Veltman, Henricus G. Ruhé, Aart H. Schene
Journal: JAMA Psychiatry (2015)

Major depressive disorder (MDD) and bipolar disorder (BD) are difficult to distinguish clinically during the depressed or remitted states. Both mood disorders are characterized by emotion regulation disturbances; however, little is known about emotion regulation differences between MDD and BD. Better insight into these differences would be helpful for differentiation based on disorder-specific underlying pathophysiological mechanisms. Previous studies comparing these disorders often allowed medication use, limiting generalizability and validity. Moreover, patients with MDD and BD were mostly compared during the depressed, but not the remitted, state, while state might potentially modulate differences between MDD and BD.To investigate positive and negative emotion regulation in medication-free patients with MDD and BD in 2 mood states: depressed or remitted.A cross-sectional study conducted from May 2009 to August 2013 comparing behavioral and functional magnetic resonance imaging emotion regulation data of 42 patients with MDD, 35 with BD, and 36 healthy control (HC) participants free of psychotropic medication recruited from several psychiatric institutions across the Netherlands.A voluntary emotion regulation functional magnetic resonance imaging task using positive and negative pictures.Behavioral and functional magnetic resonance imaging blood oxygen level-dependent responses during emotion regulation.In the remitted state, only patients with BD showed impaired emotion regulation (t = 3.39; P < .001; Cohen d = 0.70), irrespective of emotion type and associated with increased dorsolateral prefrontal cortex activity compared with those with MDD and healthy control participants (P = .008). In the depressed state, patients with MDD and BD differed with regard to happy vs sad emotion regulation (t = 4.19; P < .001; Cohen d = 1.66) associated with differences in rostral anterior cingulate activity (P < .001). Patients with MDD regulated sad and happy emotions poorly compared with those with BD and healthy control participants, while they demonstrated no rostral anterior cingulate difference between happy and sad emotion regulation. In contrast, patients with BD performed worse than those with MDD on sad emotion regulation but normal on happy emotion regulation, and they demonstrated significantly less rostral anterior cingulate activity while regulating happy compared with sad emotions.Medication-free patients with MDD vs BD appear to differ in brain activations during emotion regulation, both while depressed and in remission. These different neuropathophysiological mechanisms between MDD and BD may be useful for further development of additional diagnostic tools.
Studies on the Mechanism of Isoantigenic Variant Formation in Heterozygous Mouse Tumors. III. Behavior of <italic>H-2</italic> Antigens D and K When Located in the <italic>Trans</italic> Position<xref ref-type="fn" rid="FN2">2</xref>
Authors: Eva Klein, George Klein
Journal: JNCI Journal of the National Cancer Institute (1964)

Previous studies on isoantigenic variation in heterozygous mouse tumors have shown that cells with genetic information controlling H-2 antigens D and K in the cis position, i.e., on the same chromosome, did not give rise to D−K+ variants, while D−K− and D+K− variants were readily obtained. This was tentatively attributed to a chromosomal mechanism involving either deletion or, more probably, somatic crossing over. Another explanation that could not be excluded, however, was that D is a precursor of K. In the present work, neoplasms were studied that contained the genetic determinants for the same two antigens on two different homologous chromosomes, i.e., in the trans position. In this situation, the previously missing D−K+ variants were readily obtained. This makes the precursor hypothesis less probable and strengthens the postulate that the formation of isoantigenic variants has a chromosomal mechanism.
Over-expression of Th17-related cytokines in bronchial and nasal submucosa in severe asthma
Authors: Fabio Luigi Massimo Ricciardolo, Sabrina Benedetto, Antonino Di Stefano, GianMario Massaglia, Bruno Andreetto, Gabriella Favatà, Salvatore Conticello, Giorgio Ciprandi
Journal: European Respiratory Journal (2012)

In severe asthma neutrophil recruitment in bronchial submucosa is associated with steroid resistance, and in addition Th17-derived cytokines are important in induction and activation of neutrophils.  We evaluated the differences in inflammatory cells and Th17-related cytokine in bronchial and nasal submucosa between severe asthmatics (SA) and mild asthmatics (MA).  Bronchial and nasal biopsies obtained from 20 SA and 20 MA were investigated by immunohistochemistry.  Bronchial sub-mucosa (BS) of SA showed a higher number of neutrophils, CD4+ and CD8+ compared to MA. Furthermore, the number of IL17-A+, IL17-F+ e IL-22+ cells in SA was significantly higher. Forced Expiratory Volume (FEV1) negatively correlated with: CD8+, neutrophils and IL 22+ cells in BS; the number of neutrophils correlated with IL 17F+ cells and CD8+; CD4+ and CD8+ with IL22+ cells. Double staining for CD4 or CD8 and IL17F or IL22 showed that all IL 17F+ and IL22+ cells are also CD4+ or CD8+.  In nasal sub-mucosa (NS) of SA we found higher number of lymphocytes CD4+, CD8+, mast cells and macrophages, but also of IL 17A+, IL17F+, IL 21+ and IL22+ cells. FEV1 negatively correlated with: IL-17A+, IL-17F+, IL-21+ and IL-22+cells in NS. Moreover, the number of CD4+, IL-17F+and IL-22+cells in BS correlated positively with the equivalent cells in NS.  We showed that in SA an exaggerated neutrophil/lymphocyte infiltration in conjunction with an amplified expression of Th-17 related cytokines in both bronchial and nasal submucosa suggesting an involvement of IL-17 pathway in the progression to an irreversible steroid-resistant inflammatory process.
Consensus Statements on Radiation Therapy of Prostate Cancer: Guidelines for Prostate Re-Biopsy After Radiation and for Radiation Therapy With Rising Prostate-Specific Antigen Levels After Radical Prostatectomy
Authors: J D Cox, M J Gallagher, E H Hammond, R S Kaplan, P F Schellhammer
Journal: Journal of Clinical Oncology (1999)

PURPOSE: To develop evidence-based guidelines for (1) prostate re-biopsy after radiation and (2) radiation therapy with rising prostate-specific antigen (PSA) levels after radical prostatectomy in the management of patients with localized prostatic cancer. DESIGN: The American Society of Therapeutic Radiology and Oncology (ASTRO) challenged a multidisciplinary consensus panel to address consensus on specific issues in each of the two topics. Four well-analyzed patient data sets were presented for review and questioning by the panel. The panel sought criteria that would be valid for patients in standard clinical practice as well as for patients enrolled in clinical trials. Subsequent to an executive session that followed these presentations, the panel presented its consensus guidelines. RESULTS AND CONCLUSIONS: Based on the data presented, the prostate re-biopsy negative rates ranged from 62% to 80% for patients with stage T1-2 tumors. The panel judged that prostate re-biopsy is not necessary as standard follow-up care and that the absence of a rising PSA level after radiation therapy is the most rigorous end point of total tumor eradication. Further, the panel judged that re-biopsy may be an important research tool. Based on the data presented, the long-term (5 years or more) PSA remission rate after salvage radiation therapy ranges from 27% to 45%. The panel requested results from prospective randomized trials to evaluate optimally this information. The panel judged that the total dose of radiation should be 64 Gy or slightly higher and that, in patients with or without radiation therapy, there is no standard role for androgen suppressant therapy for rising PSA values after prostatectomy.
Treatment of R-3327 Prostate Tumors with a Somatostatin Analogue (Somatuline) as Adjuvant Therapy following Surgical Castration
Authors: Arthur E. Bogden, John E. Taylor, Jacques-Pierre Moreau, David H. Coy
Journal: Cancer Research (1990)

This study addresses, in an animal tumor model, the clinical problem of “escape from castration inhibition.” Somatuline (BIM-23014C), an octapeptide analogue of somatostatin with enhanced potency and longer duration of biological activity was administered as a therapeutic agent, over a period of 90 and 197 days, to male Copenhagen rats bearing syngeneic Dunning R-3327-H prostate tumors. Androgen sensitivity was confirmed by the response of tumors to castration and by the significant inhibition of tumor growth in intact animals by treatment with a luteinizing hormone-releasing hormone antagonist (BIM-21009). Inhibition of tumor growth resulting from castration persisted for 102 days, after which progressive regrowth occurred, indicating an escape from castration inhibition. When Somatuline treatment was initiated as an adjuvant therapy 5 days after castration, the rate of tumor regrowth during escape was significantly retarded. During the period of 197 days postcastration, tumors in the vehicle-treated, intact controls grew to an average diameter of 38.6 ± 7.6 mm and tumors in vehicle-treated castrate controls grew to an average diameter of 23.3 ± 4.1 mm (60% test/control). Treatment with the luteinizing hormone-releasing hormone antagonist induced no significant additional tumor inhibitory effects in castrated animals which developed tumors having an average diameter of 30.2 ± 8.2 mm (78% test/control). Treatment of tumors in castrate animals with Somatuline, on the other hand, induced a significant ( P < 0.01) tumor-inhibitory effect that was greater than that produced by castration alone, developing an average tumor diameter of only 14.3 ± 2.6 mm, (37% test/control). A growth inhibitory effect was also inducible in animals having tumors that had already escaped castration inhibition. The relative nontoxicity of a somatostatin analogue such as Somatuline suggests that chronic or maintenance therapy of slow-growing prostate cancers may be both feasible and acceptable in a clinical setting.
Some gender features of the chronic obstructive pulmonary disease
Authors: Natalia Lareva, Elena Luzina
Journal: European Respiratory Journal (2013)

Aim: to estimate COPD features and treatment in men and women.  Methods: 120 women and 131 men with COPD were included in retrospective study. We assessed medical history, clinical features and treatment programs. Mann-Whitney and Pearson9s Chi-squared tests were used.  Results: Men and women didn9t differ from each other on age (60.2±15.8 and 60.8±14.4 years, p>0.05). I stage of COPD met in 14% of women (vs 5% of men, p=0.049); II and III stages of COPD met equally often among men women (62% and 63%, p>0.05 and 37% and 23%, p>0.05, respectively). Smoking as the most important risk factor was more frequent in men than in women (74% vs 48%, p  Conclusion. There are some features of medical history, risk factors and clinical progress of COPD in men and women, however patients are treated without gender consideration. More investigations are need to individualize medial programs in men and women suffering from COPD.
Cardiovascular complications in renal failure.
Authors: S G Rostand, J D Brunzell, R O Cannon, R G Victor
Journal: Journal of the American Society of Nephrology (1991)

Cardiovascular diseases are a leading cause of death in end-stage renal disease (ESRD) largely as a result of the progressively increasing age of ESRD patients and the broad constellation of uremia-associated factors that can adversely affect cardiac function. Hypertension, one of the leading causes of renal failure, is a major culprit in this process, causing left ventricular hypertrophy, cardiac chamber dilation, increased left ventricular wall stress, redistribution of coronary blood flow, reduced coronary artery vasodilator reserve, ischemia, myocardial fibrosis, heart failure, and arrhythmias. In addition to impairing the coronary microcirculation, hypertension may contribute to the development of atherosclerotic coronary artery disease, particularly in the presence of the many lipid abnormalities observed in ESRD. These patients have reduced high-density lipoprotein cholesterol and increased plasma triglyceride concentrations, and there is a defect in cholesterol transport. Other abnormalities that may contribute to atherosclerotic coronary artery disease in ESRD are reduced high-density lipoprotein cholesterol synthesis and reduced activity of the reverse cholesterol pathway. Treatment with fibric acids, nicotinic acids, and lovastatin may be useful in lowering cholesterol and triglyceride concentrations in some of these patients. The incidence of coronary artery disease in ESRD populations is difficult to determine. About 25 to 30% of ESRD patients with angina have no evidence of significant coronary artery disease, and an undetermined number have silent coronary disease. The presence of resting electrocardiographic abnormalities caused by hypertension or conduction defects makes it difficult to accurately diagnosis coronary artery disease in ESRD populations by noninvasive methods, including exercise testing and thallium scintigraphy with or without the use of dipyridamole. Hypotension is a frequent complication of the dialytic process. Many factors have been implicated, including autonomic neuropathy. There is no consensus on the function of the efferent limb of the sympathetic nervous system. The afferent limb (arterial baroreflex function) is felt to be impaired. Further, there may be defects in the ability of the cardiovascular system to respond to sympathetic nerve activity. Most studies of autonomic function have used indirect measurements. Studies are underway that use techniques to assess sympathetic function directly. Such experiments with microneuropathy suggest greater skeletal sympathetic muscle discharge in uremic patients than in normal patients.
Clinical and histological determinants of nonalcoholic steatohepatitis and advanced fibrosis in elderly patients
Authors: Mazen Noureddin, Katherine P. Yates, Ivana A. Vaughn, Brent A. Neuschwander-Tetri, Arun J. Sanyal, Arthur McCullough, Raphael Merriman, Bilal Hameed, Edward Doo, David E. Kleiner, Cynthia Behling, Rohit Loomba
Journal: Hepatology (2013)

The characteristics of nonalcoholic fatty liver disease (NAFLD) in elderly patients are unknown. Therefore, we aimed to examine the differences between elderly and nonelderly patients with NAFLD and to identify determinants of nonalcoholic steatohepatitis (NASH) and advanced fibrosis (bridging fibrosis or cirrhosis) in elderly patients. This is a cross-sectional analysis of adult participants who were prospectively enrolled in the NASH Clinical Research Network studies. Participants were included based on availability of the centrally reviewed liver histology data within 1 year of enrollment, resulting in 61 elderly (age ≥65 years) and 735 nonelderly (18-64 years) participants. The main outcomes were the presence of NASH and advanced fibrosis. Compared to nonelderly patients with NAFLD, elderly patients had a higher prevalence of NASH (56% versus 72%, P = 0.02), and advanced fibrosis (25% versus 44%, P = 0.002). Compared to nonelderly patients with NASH, elderly patients with NASH had higher rates of advanced fibrosis (35% versus 52%, P = 0.03), as well as other features of severe liver disease including the presence of ballooning degeneration, acidophil bodies, megamitochondria, and Mallory-Denk bodies ( P ≤ 0.05 for each). In multiple logistic regression analyses, independent determinants of NASH in elderly patients included higher aspartate aminotransferase (AST) (odds ratio [OR] = 1.12, P = 0.007) and lower platelets (OR = 0.98, P = 0.02); and independent determinants of advanced fibrosis included higher AST (OR = 1.08, P = 0.007), lower alanine aminotransferase value (OR = 0.91, P = 0.002), and an increased odds of having low high-density lipoprotein (OR = 8.35, P = 0.02). Conclusion: Elderly patients are more likely to have NASH and advanced fibrosis than nonelderly patients with NAFLD. Liver biopsy may be considered in elderly patients and treatment should be initiated in those with NASH and advanced fibrosis. (Hepatology 2013;58:1644–1654)