tbuckley/cabot-search huggingface dataset:
Nodular regenerative hyperplasia in patients with inflammatory bowel disease treated with azathioprine
Authors: G Vernier-Massouille, J Cosnes, M Lemann, P Marteau, W Reinisch, D Laharie, G Cadiot, Y Bouhnik, M De Vos, A Boureille, B Duclos, P Seksik, J-Y Mary, J-F Colombel
Journal: Gut (2007)

To assess the characteristics and clinical course of nodular regenerative hyperplasia (NRH) in patients with inflammatory bowel disease treated with azathioprine, so as to estimate the frequency of this complication and search for risk factors.Cases were identified through a systematic survey of patients followed at 11 centres. At one centre, the cumulative risk of NRH was estimated and a case-control study was undertaken to identify risk factors.37 cases of NRH (30 male, 7 female) were identified between 1994 and 2005. The median dose of azathioprine was 2 mg/kg/d (range 1.5 to 3.0). The median time between the start of azathioprine and the diagnosis of NRH was 48 months (range 6 to 187). After a median follow up period of 16 months (range 1 to 138), 14 patients developed complications of portal hypertension. Using multivariate analysis, male sex and stricturing behaviour were the two risk factors associated with NRH in patients treated with azathioprine. The cumulative risk calculated from the database (one centre) was 0.5% at 5 years (95% confidence interval, 0.11 to 0.89) and 1.25% at 10 years (0.29 to 2.21).NRH is a rare but potentially severe complication of azathioprine in patients with inflammatory bowel disease. Clinicians should be aware of this complication, and should monitor liver function tests and platelet counts closely in their patients.
Imipramine and Buspirone in Treatment of Patients With Generalized Anxiety Disorder Who Are Discontinuing Long-Term Benzodiazepine Therapy
Authors: Karl Rickels, Nicholas DeMartinis, Felipe García-España, David J. Greenblatt, Laura A. Mandos, Moira Rynn
Journal: American Journal of Psychiatry (2000)

OBJECTIVE: Patients with generalized anxiety disorder (N=107) who had been long-term benzodiazepine users (average duration of use=8.5 years) were enrolled in a benzodiazepine discontinuation program that assessed the effectiveness of concomitant imipramine (180 mg/day) and buspirone (38 mg/day) compared to placebo in facilitating benzodiazepine discontinuation. METHOD: After a benzodiazepine stabilization period taking either diazepam, lorazepam, or alprazolam, patients were treated for 4 weeks with imipramine, buspirone, or placebo under double-blind conditions while benzodiazepine intake was kept stable (treatment phase). Patients then entered a 4–6 week benzodiazepine taper and a 5-week posttaper phase with imipramine, buspirone, and placebo treatment being continued until 3 weeks into the posttaper phase, at which time all patients were switched to placebo for 2 weeks. Benzodiazepine plasma levels were assayed weekly. Benzodiazepine-free status was assessed 3 and 12 months posttaper. RESULTS: Study subjects were long-term benzodiazepine users with an average of three unsuccessful prior taper attempts. The success rate of the taper in this study was significantly higher for patients who received imipramine (82.6%), and nonsignificantly higher for patients who received buspirone (67.9%), than for patients who received placebo (37.5%). The imipramine effect remained highly significant even after the analysis adjusted for three other independent predictors of taper success: benzodiazepine dose, level of anxious symptoms at baseline, and duration of benzodiazepine therapy. CONCLUSIONS: Management of benzodiazepine discontinuation can be facilitated significantly by co-prescribing imipramine before and during the benzodiazepine taper. Daily benzodiazepine dose, severity of baseline symptoms of anxiety and depression, and duration of benzodiazepine use were additional significant predictors of successful taper outcome.
Association of the Serotonin Transporter Gene With Smoking Behavior
Authors: Ilana Kremer, Rachel Bachner-Melman, Alon Reshef, Leonid Broude, Lubov Nemanov, Inga Gritsenko, Uriel Heresco-Levy, Yoel Elizur, Richard P. Ebstein
Journal: American Journal of Psychiatry (2005)

In an ongoing molecular genetic study of temperament, participants were genotyped to examine the association of smoking with two polymorphisms of the serotonin transporter gene (SERT): the promoter region, 5-HTTLPR, and an intronic variable-number-of-tandem-repeats region (VNTR).Full information was available for 330 families, and 244 "ever smokers" were identified (54 past smokers, 190 current smokers). The average number of cigarettes smoked per day was 13.12, and the mean Fagerstrom Tolerance Questionnaire score was 4.79. Associations of genotype, Tridimensional Personality Questionnaire scores, and smoking phenotype were tested by using a robust family design with a variance-components framework and by case-control analysis.There was a significant excess of the 5-HTTLPR long allele with the 12-repeat VNTR in current smokers, past smokers, and ever smokers, compared to participants who had never smoked. The results from the population design were confirmed in the family-based analysis. No association was observed between two quantitative measures of smoking and the polymorphisms. A weak association was observed between novelty seeking and the VNTR polymorphism and between reward and 5-HTTLPR. Smokers, regardless of gender, scored significantly higher on novelty seeking and did not differ on harm avoidance or reward.There was a highly significant association between SERT and the categorical definition of smoking, irrespective of dependence level, suggesting that this gene influences the initiation of smoking. Mediation analysis failed to substantiate the hypothesis that novelty seeking partially mediates the effect of SERT on smoking. SERT appears to independently contribute to novelty seeking and smoking.
The dynamics of gene expression of interleukin-19 and interleukin-20 and their receptors in psoriasis
Authors: K. Otkjaer, K. Kragballe, A.T. Funding, J.T. Clausen, P.L. Noerby, T. Steiniche, L. Iversen
Journal: British Journal of Dermatology (2005)

Interleukin (IL)-20 and IL-19 are recently discovered members of the IL-10 family of cytokines. The skin of transgenic mice overexpressing IL-20 shows histological changes resembling some of those seen in psoriasis, i.e. thickened epidermis, hyperkeratosis and a compact stratum corneum. IL-19 and IL-20, as well as their receptor complexes, IL-20Ralpha/IL-20Rbeta and IL-22Ralpha/IL-20Rbeta, are expressed in human skin.To study the dynamics of IL-19 and IL-20 gene expression as well as the expression of their receptor subunits in psoriatic skin lesions.Punch biopsies from patients with plaque-type psoriasis were collected before, during and after 28 days of treatment with either calcipotriol or ciclosporin (CsA). IL-20, IL-19, IL-20Ralpha, IL-20Rbeta and IL-22Ralpha mRNA expression were determined by quantitative reverse transcriptase-polymerase chain reaction.We found IL-19 and IL-20 mRNA expression in lesional psoriatic skin to be strongly upregulated compared with nonlesional psoriatic skin by a factor of 65 and 22, respectively. In contrast to previous reports, IL-20Ralpha and IL-20Rbeta mRNA levels showed a modest but statistically significant decrease in lesional psoriatic skin compared with nonlesional psoriatic skin. During treatment with calcipotriol or CsA, IL-19 and IL-20 mRNA levels decrease in accordance with the clinical improvement of psoriasis. Neither IL-19, IL-20, nor receptor subunit mRNA expression in lesional psoriatic skin reaches the levels of nonlesional skin during this short-term treatment. These findings are in line with the residual disease activity observed at the end of treatment.The increased IL-19 and IL-20 mRNA expression levels in lesional psoriatic skin suggest that these two cytokines play a role in the pathogenesis of psoriasis. An imbalance in the receptor complexes for IL-19 and IL-20 might contribute to their suspected pathogenic effects.
Serotonin Transporter Occupancy of Five Selective Serotonin Reuptake Inhibitors at Different Doses: An [<sup>11</sup>C]DASB Positron Emission Tomography Study
Authors: Jeffrey H. Meyer, Alan A. Wilson, Sandra Sagrati, Doug Hussey, Anna Carella, William Z. Potter, Nathalie Ginovart, Edgar P. Spencer, Andy Cheok, Sylvain Houle
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: Minimum therapeutic doses of paroxetine and citalopram produce 80% occupancy for the serotonin (5-HT) transporter (5-HTT). The authors used [11C]DASB positron emission tomography to measure occupancies of three other selective serotonin reuptake inhibitors (SSRIs) at minimum therapeutic doses. The relationship between dose and occupancy was also investigated. METHOD: Striatal 5-HTT binding potential was measured in 77 subjects before and after 4 weeks of medication administration. Binding potential is proportional to the density of receptors not blocked by medication. Subjects received citalopram, fluoxetine, sertraline, paroxetine, or extended-release venlafaxine. Healthy subjects received subtherapeutic doses; subjects with mood and anxiety disorders received therapeutic doses. Percent reduction in 5-HTT binding potential for each medication and dose was calculated. To obtain test-retest data, binding potential was measured before and after 4 weeks in six additional healthy subjects. RESULTS: Substantial occupancy occurred at subtherapeutic doses for all SSRIs. Compared to test-retest data, each drug at the minimum therapeutic dose had a significant effect on striatal 5-HTT binding potential. Mean occupancy at this dose was 76%–85%. At higher plasma SSRI concentrations, 5-HTT occupancy tended to increase above 80%. For each drug, as the dose (or plasma level) increased, occupancy increased nonlinearly, with a plateau for higher doses. CONCLUSIONS: At tolerable doses, SSRIs have increasing occupancy with increasing plasma concentration or dose. Occupancy of 80% across five SSRIs occurs at minimum therapeutic doses. This suggests that 80% 5-HTT blockade is important for therapeutic effect. Occupancy should be measured during development of antidepressant compounds targeting the 5-HTT.
Positive "alveolar" responses to antigen inhalation provocation tests: their validity and recognition.
Authors: D J Hendrick, R Marshall, J A Faux, J M Krall
Journal: Thorax (1980)

The validity of inhalation tests in the investigation of extrinsic allergic alveolitis was assessed from the results of 144 antigen and control tests in 31 subjects. A definitive pattern of positive late responses was observed. Reactions to nebulised bird serum and droppings in subjects with bird fancier9s lung were identical to reactions after "natural" exposures in aviaries or lofts, and to reactions after "occupational" challenges in subjects with farmer9s lung and mushroom worker9s lung. In general, positive tests were easily recognised subjectively from symptoms and signs appropriate to an influenza-like illness and undue respiratory effort on exercise. They were associated with significant changes in six readily available objective monitoring measurements--exercise minute ventilation (greater than or equal to +15%), body temperature (&gt; 37.2 degrees C), circulating neutrophils (greater than or equal to +2500/mm3), exercise respiratory frequency (greater than or equal to +25%), circulating lymphocytes (greater than ore equal to -500/mm3 with lymphopenia), and forced vital capacity (greater than or equal to -15%). These confirmatory monitoring tests had specificities of approximately 95% and sensitivities of 85-48%. Measurement of diffusing capacity, lung volume subdivisions, or resting minute ventilation/respiratory frequency proved to be too insensitive to be useful, as did auscultation and chest radiography. We conclude that responses that do provoke significant changes in these less sensitive tests are unnecessarily distressing and, presumable, unnecessarily hazardous.
HDAC6 as a target for neurodegenerative diseases: what makes it different from the other HDACs?
Authors: Claudia Simões-Pires, Vincent Zwick, Alessandra Nurisso, Esther Schenker, Pierre-Alain Carrupt, Muriel Cuendet
Journal: Molecular Neurodegeneration (2013)

Abstract Histone deacetylase (HDAC) inhibitors have been demonstrated to be beneficial in animal models of neurodegenerative diseases. Such results were mainly associated with the epigenetic modulation caused by HDACs, especially those from class I, via chromatin deacetylation. However, other mechanisms may contribute to the neuroprotective effect of HDAC inhibitors, since each HDAC may present distinct specific functions within the neurodegenerative cascades. Such an example is HDAC6 for which the role in neurodegeneration has been partially elucidated so far. The strategy to be adopted in promising therapeutics targeting HDAC6 is still controversial. Specific inhibitors exert neuroprotection by increasing the acetylation levels of α-tubulin with subsequent improvement of the axonal transport, which is usually impaired in neurodegenerative disorders. On the other hand, an induction of HDAC6 would theoretically contribute to the degradation of protein aggregates which characterize various neurodegenerative disorders, including Alzheimer’s, Parkinson’s and Hutington’s diseases. This review describes the specific role of HDAC6 compared to the other HDACs in the context of neurodegeneration, by collecting in silico , in vitro and in vivo results regarding the inhibition and/or knockdown of HDAC6 and other HDACs. Moreover, structure, function, subcellular localization, as well as the level of HDAC6 expression within brain regions are reviewed and compared to the other HDAC isoforms. In various neurodegenerative diseases, the mechanisms underlying HDAC6 interaction with other proteins seem to be a promising approach in understanding the modulation of HDAC6 activity.
Preventative strategies for periampullary tumours in FAP
Authors: M.H. Wallace, R.K.S. Phillips
Journal: Annals of Oncology (1999)

Almost all patients with familial adenomatous polyposis develop duodenal polyps most of which occur in a cluster around the ampulla of Vater. Between 5 and 10% of FAP patients will die from upper gastrointestinal cancer, usually periampullary in origin. In an attempt to prevent cancer a screening programme has been developed using a well defined staging system to detect those patients most at risk of developing the disease. Treatment options are limited, with endoscopic clearance being contraindicated in most cases. The only certain method of preventing duodenal cancer is prophylactic radical surgery which has its own associated morbidity and mortality. Future developments may include new drug treatments or even gene therapy. Until then patients with FAP should all be considered for clinical trials as research continues.
Inhibition of Cysteine Cathepsin Protease Activity Enhances Chemotherapy Regimens by Decreasing Tumor Growth and Invasiveness in a Mouse Model of Multistage Cancer
Authors: Katherine M. Bell-McGuinn, Alfred L. Garfall, Matthew Bogyo, Douglas Hanahan, Johanna A. Joyce
Journal: Cancer Research (2007)

Abstract Increases in protease expression and activity are associated with malignant progression and poor patient prognosis in a number of human cancers. Members of the papain family of cysteine cathepsins are among the protease classes that have been functionally implicated in cancer. Inhibition of the cysteine cathepsin family using a pan-cathepsin inhibitor, JPM-OEt, led to tumor regression in the RIP1-Tag2 (RT2) mouse model of pancreatic islet cell tumorigenesis. The present study was designed to determine whether this cathepsin inhibitor, when used in combination with chemotherapy, would increase antitumor efficacy. RT2 mice were treated in a late-stage regression trial with three different chemotherapy regimens, alone or in combination with the cathepsin inhibitor, JPM-OEt. Cyclophosphamide was administered in either a maximum tolerated dose (MTD) regimen, a “metronomic” continuous low-dose regimen, or a “chemo-switch” regimen consisting of MTD followed by metronomic dosing. Mice were sacrificed at a defined end point and tumor burden was assessed followed by a detailed analysis of cell proliferation, apoptosis, vascularization, and invasiveness in the treated and control lesions. An additional cohort of mice was followed for survival analysis. The cathepsin inhibitor plus the chemo-switch regimen of cyclophosphamide led to the most pronounced reduction in tumor burden and greatest increase in overall survival. Cysteine cathepsin inhibition resulted in a significant decrease in tumor invasiveness, which was further augmented in combination with each of the chemotherapy dosing regimens. These results encourage the development and continuing evaluation of cysteine cathepsin inhibitors as cancer therapeutics. [Cancer Res 2007;67(15):7378–85]
Left Ventricular Oxygen Utilization in Intact Dogs: Effect of Systemic Hemodynamic Factors
Authors: WILLIAM A. NEILL, HERBERT J. LEVINE, RICHARD J. WAGMAN, RICHARD GORLIN
Journal: Circulation Research (1963)

The influence of acute changes in systemic hemodynamics on the rate of oxygen utilization by the left ventricle has been studied in intact anesthetized dogs. Certain types of hemodynamic changes caused reproducible alterations in the relationship between oxygen consumption of the left ventricle and its external mechanical work. The relationship of left ventricular minute oxygen consumption to the product of mean systolic aortic pressure and systolic ejection period per minute was constant over an extreme range of varied types of hemodynamic alterations. Changes in oxygen consumption were proportionately less than concomitant changes in heart rate. These findings are in accord with previous studies of isolated heart preparations.
Heterogeneity within tissue-specific macrophage and dendritic cell populations during cutaneous inflammation in atopic dermatitis
Authors: R.C.M. Kiekens, T. Thepen, A.J. Oosting, I.C. Bihari, J.G.J. Van De Winkel, C.A.F.M. Bruijnzeel-Koomen, E.F. Knol
Journal: British Journal of Dermatology (2001)

Macrophages and dendritic cells may play a role in chronicity of atopic dermatitis (AD); however, so far only limited data are documented on the distribution of these cells in the skin during cutaneous inflammation.To gain better insight into the presence and distribution of macrophage and dendritic cell (sub)populations in acutely and chronically inflamed skin of AD patients.Chronic inflammatory reactions were studied in lesional AD skin biopsies; the atopy patch test was used as a model for the initiation of AD lesions, representing acute inflammation. To determine the number and phenotype of different dermal macrophage and dendritic cell populations immunohistochemistry and digital imaging were used.There was an increase in macrophage numbers in acutely and chronically inflamed AD skin, whereas absolute dendritic cell numbers were unchanged, compared with non-lesional AD skin. Furthermore, phenotypically heterogeneous and overlapping macrophage and dendritic cell populations were present in inflamed AD skin. The classic macrophage marker CD68 and prototypic dendritic cell marker CD1a could bind to the same cell subpopulation in the dermis of inflamed AD skin. Mannose receptors were expressed mainly by macrophages in inflamed AD skin.In this study we observed changes in macrophage number and phenotype during cutaneous inflammation in AD. Dendritic cell numbers did not change; however, phenotypically dendritic cell and macrophage subpopulations showed increasing overlap during inflammation in AD skin. We show for the first time that within tissue-specific macrophage populations further subpopulations are present, and that monocyte-derived cells may express markers for both dendritic cells and macrophages. Our results point to the existence of a heterogeneous pool of macrophage/dendritic cell-like cells, from which subpopulations of dermal macrophages and dendritic cells arise.
Phase II Study of Vandetanib or Placebo in Small-Cell Lung Cancer Patients After Complete or Partial Response to Induction Chemotherapy With or Without Radiation Therapy: National Cancer Institute of Canada Clinical Trials Group Study BR.20
Authors: Andrew M. Arnold, Lesley Seymour, Michael Smylie, Keyue Ding, Yee Ung, Brian Findlay, Christopher W. Lee, Marina Djurfeldt, Marlo Whitehead, Peter Ellis, Glenwood Goss, Adrien Chan, Jacinta Meharchand, Yasmin Alam, Richard Gregg, Charles Butts, Peter Langmuir, Frances Shepherd
Journal: Journal of Clinical Oncology (2007)

This double-blind randomized phase II trial examined whether vandetanib, an inhibitor of vascular endothelial and epidermal growth factor receptors, could prolong progression-free survival in responding patients with small-cell lung cancer.Eligible patients with complete response (CR) or partial response (PR) to combination chemotherapy (+/- thoracic or prophylactic cranial radiation) received oral vandetanib 300 mg/d or matched placebo. With 100 patients and 77 events, the study had 80% power to detect an improvement in median progression-free survival from 4 to 6.5 months (one-sided, 10%-level test).Between May 2003 and March 2006, 107 patients were accrued; 46 had limited disease and 61 extensive disease. There were fewer patients with a performance status of 0 (n = 11 v 20), and fewer had CR to initial therapy (n = 4 v 8) in the vandetanib arm. Vandetanib patients had more toxicity and required more dose modifications for gastrointestinal toxicity and rash. Asymptomatic Corrected QT interval (QTC) prolongation was observed in eight vandetanib patients. Median progression-free survival for vandetanib and placebo was 2.7 and 2.8 months, respectively (hazard ratio [HR], 1.01; 80% CI, 0.75 to 1.36; one-sided P = .51). Overall survival for vandetanib was 10.6 versus 11.9 months for placebo (HR, 1.43; 80% CI, 1.00 to 2.05; one-sided P = 0.9). In planned subgroup analyses, a significant interaction was noted (P = .01): limited-stage vandetanib patients had longer overall survival (HR, 0.45; one-sided P = .07) and extensive-stage vandetanib patients shorter survival compared with placebo (HR, 2.27; one-sided P = .996).Vandetanib failed to demonstrate efficacy as maintenance therapy for small-cell lung cancer.