tbuckley/cabot-search huggingface dataset:
Preladenant as an Adjunctive Therapy With Levodopa in Parkinson Disease
Authors: Robert A. Hauser, Fabrizio Stocchi, Olivier Rascol, Susan B. Huyck, Rachel Capece, Tony W. Ho, Peter Sklar, Christopher Lines, David Michelson, David Hewitt
Journal: JAMA Neurology (2015)

Preladenant is an adenosine 2A receptor antagonist that reduced "off" time in a placebo-controlled phase 2b trial in patients with Parkinson disease (PD). We sought to confirm its efficacy in phase 3 trials.To evaluate preladenant as an adjunct to levodopa in patients with PD and motor fluctuations.Two 12-week, phase 3, randomized, placebo-controlled, double-blind trials performed from July 15, 2010, to April 16, 2013. The setting included neurology clinics, clinical research centers, and hospitals in the Americas, the European Union, Eastern Europe, India, and South Africa. Participants included patients with moderate to severe PD taking levodopa who were experiencing motor fluctuations.In trial 1, a total of 778 eligible patients were randomized to the addition of preladenant (2 mg, 5 mg, or 10 mg twice daily), placebo, or rasagiline mesylate (1 mg/d) in a 1:1:1:1:1 ratio. In trial 2, a total of 476 eligible patients were randomized to the addition of preladenant (2 mg or 5 mg twice daily) or placebo in a 1:1:1 ratio.The primary outcome measure was change in off time from baseline to week 12.In trial 1, neither preladenant nor rasagiline was superior to placebo in reducing off time from baseline to week 12. The differences vs placebo were -0.10 hour (95% CI, -0.69 to 0.46 hour) for preladenant 2 mg twice daily, -0.20 hour (95% CI, -0.75 to 0.41 hour) for preladenant 5 mg twice daily, -0.00 hour (95% CI, -0.62 to 0.53 hour) for preladenant 10 mg twice daily, and -0.30 hour (95% CI, -0.90 to 0.26 hour) for rasagiline mesylate 1 mg/d. In trial 2, preladenant was not superior to placebo in reducing off time from baseline to week 12. The differences vs placebo were -0.20 hour (95% CI, -0.72 to 0.35 hour) for preladenant 2 mg twice daily and -0.30 hour (95% CI, -0.86 to 0.21 hour) for preladenant 5 mg twice daily. Preladenant was well tolerated, with the most common adverse event that showed an increase over placebo in both trials being constipation (6%-8% for preladenant vs 1%-3% for placebo).In these phase 3 trials, preladenant did not significantly reduce off time compared with placebo. That the active control rasagiline also failed to demonstrate a significant reduction in off time suggests that issues of study design or conduct may have affected these trials.clinicaltrials.gov Identifier: NCT01155466 and NCT01227265.
Compulsory Treatment in Chronic Anorexia Nervosa by All Means? Searching for a Middle Ground Between a Curative and a Palliative Approach
Authors: Manuel Trachsel, Verina Wild, Nikola Biller-Andorno, Tanja Krones
Journal: The American Journal of Bioethics (2015)

Geppert (2015) has argued that mental disorders like anorexia nervosa (AN) do not fulfill the classic criteria for futility. We agree with her central thesis that “the contention that an ‘end-stage...
Abnormal epigenetic modifications in peripheral blood mononuclear cells from patients with alopecia areata
Authors: M. Zhao, G. Liang, X. Wu, S. Wang, P. Zhang, Y. Su, H. Yin, Y. Tan, J. Zhang, Q. Lu
Journal: British Journal of Dermatology (2011)

Alopecia areata (AA) is a hair loss disease caused by T-cell-mediated autoimmune reactions against anagen-stage hair follicles. Although the exact aetiology is poorly understood, there is evidence to suggest that both genetic and environmental factors are involved in AA pathogenesis.To analyse DNA methylation and histone modification patterns in peripheral blood mononuclear cells (PBMCs) of patients with AA.PBMC samples were obtained from 25 patients with AA and 20 healthy controls. Global DNA methylcytosine levels, as well as histone acetylation and methylation levels, were measured by enzyme-linked immunosorbent assay. mRNA expression levels were determined using real-time quantitative reverse transcription-polymerase chain reaction.Genomic DNA methylation in PBMCs of patients with AA was increased relative to controls. DNMT1, MBD1 and MBD4 expression levels were significantly higher in AA PBMCs than in controls, and DNMT1 transcription levels positively correlated with global DNA methylation levels in patient samples. Histone H3 acetylation was significantly increased and histone H3 lysine 4 methylation was significantly decreased in patient PBMCs compared with healthy controls. Histone H3 acetylation levels were positively correlated with AA disease severity, and with RANTES (CCL5) mRNA expression in PBMCs of patients with AA. These changes were accompanied by increased p300 (EP300), histone deacetylase 1 (HDAC1), myeloid/lymphoid or mixed lineage leukemia (MLL), SET7/9 (SETD7), G9A (EHMT2), JMJD2C (KDM4C) and JARID1A (KDM5A) expression, as well as reduced HDAC2, HDAC7, LSD1 (KDM1A), JMJD2A (KDM4A) and JMJD2B (KDM4B) expression.DNA methylation and histone modification status are altered in PBMCs of patients with AA, possibly due to the deregulation of epigenetic regulatory genes. These changes may contribute to the activation of pathological immune responses in AA.
Transplantation Immunity to Simian Virus 40-Transformed Cells in Tumor-Bearing Mice. I. Development of Cellular Immunity to Simian Virus 40 Tumor-Specific Transplantation Antigens During Tumorigenesis by Transplanted Cells2
Authors: Joyce M. Zarling, Satvir S. Tevethia
Journal: JNCI Journal of the National Cancer Institute (1973)

The immune response of inbred BALB/c mice to tumor-specific transplantation antigens (TSTA) of transplanted syngeneic cells transformed by simian virus 40 (SV40) was studied throughout the period of tumorigenesis. Immune lymphoid cells, capable of specifically preventing or delaying tumor growth of admixed SV40-transformed mouse or hamster cells when inoculated into adult hosts, were detected in lymph nodes, spleens, and peritoneal exudates of mice with established tumors. Furthermore, tumor-bearing mice resisted high secondary challenges of SV40-transformed cells when inoculated at a site distant from the primary inoculation site, which thus demonstrated the presence of a functional effector mechanism for tumor rejection. By 4 days after the inoculation of 105 SV40-transformed cells, mice could resist challenges of similar doses of the virus-transformed cells. Transformed cells inoculated only a day after a previous inoculation at a distant site were delayed in developing a tumor; however, the rate of development of the tumor at the first site was unaffected. These results indicate that cellular immunity to SV40 TSTA develops early during tumorigenesis by transplanted cells; nevertheless, the tumors develop and grow progressively. It is suggested that either the level of immunity is not sufficient during early tumorigenesis to prevent the tumor from establishing or, alternatively, there is a local efferent block at the site of tumor development.
The difference between surfactant protein D (SPD) and C-reactive protein (CRP) levels in patients (pts) with chronic obstructive pulmonary disease acute exacerbations (AE COPD) and community acquired pneumonia (CAP)
Authors: Tetyana Pertseva, Olga Shtepa, Valeriia Dmytrychenko, Olexandr Fesenko
Journal: European Respiratory Journal (2014)

The aim of study was to find out is there any difference between plasma SPD and CRP levels in pts with AE COPD and CAP.

Study population. 20 patients with AE COPD, 35 patients with CAP and 10 healthy persons (H) made the study sample.

Methods. Plasma SPD and CRP were measured in addition to physical examination, spirometry and chest X-Ray.

Results are shown in table 1.

View this table:



There was no any correlation between SPD and CRP in pts with AE COPD, CAP and in H (R = -0,047, p = 0,845; R = 0,095, p = 0,589; R = 0,055, p = 0,881 respectively).

Conclusions: 1) SPD level significantly increased in pts with AE COPD and CAP and may be a specific marker of the severity of local inflammation of the lung tissue. 2) There wasn't statistically significant difference between SPD level in pts with AE COPD and CAP. 3) Plasma CRP was strongly higher in pts with CAP and can be more significant as a differential criterion of diagnostic AE COPD and CAP.
Comparison of nebulized and intravenous terbutaline during exacerbations of pulmonary infection in patients with cystic fibrosis
Authors: MJ Finnegan, DV Hughes, ME Hodson
Journal: European Respiratory Journal (1992)

Twenty three patients completed a double-blind study, comparing intravenous and nebulized terbutaline, during the first four days of a pulmonary exacerbation of cystic fibrosis (CF), with follow-up to day 10. Routine treatment with chest physiotherapy and appropriate intravenous antibiotics was given to all patients. The best peak flow rate (PF), forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), in the past year and at entry to the study, revealed no significant difference between the groups. However, on day 10, PF, FEV1 and FVC, of the nebulizer group remained significantly reduced compared to best values in the previous year, whereas the PF and FEV1 in the intravenous group were not significantly reduced compared to the best values in the previous year. Comparison of regression lines showing the overall rate of improvement of PF, FEV1 and FVC between the two groups showed that the rate of improvement of each parameter was more rapid in the group receiving intravenous terbutaline. This was statistically significant for PF. It is possible that during acute exacerbations of infection, sputum retention makes it more difficult for the inhaled bronchodilators to reach the airways and intravenous therapy is, therefore, more beneficial.
Implementation of Screening, Brief Intervention, and Referral to Treatment for Adolescents in Pediatric Primary Care
Authors: Stacy Sterling, Andrea H. Kline-Simon, Derek D. Satre, Ashley Jones, Jennifer Mertens, Anna Wong, Constance Weisner
Journal: JAMA Pediatrics (2015)

<h3>Importance</h3> Early intervention for substance use is critical to improving adolescent outcomes. Studies have found promising results for Screening, Brief Intervention, and Referral to Treatment (SBIRT), but little research has examined implementation. <h3>Objective</h3> To compare SBIRT implementation in pediatric primary care among trained pediatricians, pediatricians working in coordination with embedded behavioral health care practitioners (BHCPs), and usual care (UC). <h3>Design, Setting, and Participants</h3> The study is a 2-year (November 1, 2011, through October 31, 2013), nonblinded, cluster randomized, hybrid implementation and effectiveness trial examining SBIRT implementation outcomes across 2 modalities of implementation and UC. Fifty-two pediatricians from a large general pediatrics clinic in an integrated health care system were randomized to 1 of 3 SBIRT implementation arms; patients aged 12 to 18 years were eligible. <h3>Interventions</h3> Two modes of SBIRT implementation, (1) pediatrician only (pediatricians trained to provide SBIRT) and (2) embedded BHCP (BHCP trained to provide SBIRT), and (3) UC. <h3>Main Outcomes and Measures</h3> Implementation of SBIRT (primary outcome), which included assessments, brief interventions, and referrals to specialty substance use and mental health treatment. <h3>Results</h3> The final sample included 1871 eligible patients among 47 pediatricians; health care professional characteristics did not differ across study arms. Patients in the pediatrician-only (adjusted odds ratio [AOR], 10.37; 95% CI, 5.45-19.74;<i>P</i>&lt; .001) and the embedded BHCP (AOR, 18.09; 95% CI, 9.69-33.77;<i>P</i>&lt; .001) arms had higher odds of receiving brief interventions compared with patients in the UC arm. Patients in the embedded BHCP arm were more likely to receive brief interventions compared with those in the pediatrician-only arm (AOR, 1.74; 95% CI, 1.31-2.31;<i>P</i>&lt; .001). The embedded BHCP arm had lower odds of receiving a referral compared with the pediatrician-only (AOR, 0.58; 95% CI, 0.43-0.78;<i>P</i>&lt; .001) and UC (AOR, 0.65; 95% CI, 0.48-0.89;<i>P</i>= .006) arms; odds of referrals did not differ between the pediatrician-only and UC arms. <h3>Conclusions and Relevance</h3> The intervention arms had better screening, assessment, and brief intervention rates than the UC arm. Patients in the pediatrician-only and UC arms had higher odds of being referred to specialty treatment than those in the embedded BHCP arm, suggesting lingering barriers to having pediatricians fully address substance use in primary care. Findings also highlight age and ethnic groups less likely to receive these important services. <h3>Trial Registration</h3> Clinicaltrials.gov Identifier:NCT02408952
Immunotherapy of patients with advanced cancer using tumor-infiltrating lymphocytes and recombinant interleukin-2: a pilot study.
Authors: S L Topalian, D Solomon, F P Avis, A E Chang, D L Freerksen, W M Linehan, M T Lotze, C N Robertson, C A Seipp, P Simon
Journal: Journal of Clinical Oncology (1988)

Clinical investigations using the adoptive transfer of lymphokine-activated killer (LAK) cells and recombinant interleukin-2 (rIL-2) to treat patients with advanced cancer have yielded encouraging results. We have thus sought ways to enhance the effectiveness of adoptive immunotherapy while minimizing its toxic side effects. Murine experiments have identified tumor-infiltrating lymphocytes (TIL) as killer cells more effective than LAK cells and less dependent on adjunctive systemically administered IL-2 to mediate antitumor effects. Accordingly, we performed a pilot protocol to investigate the feasibility and practicality of administering IL-2-expanded TIL to humans with metastatic cancers. Twelve patients, including six with melanoma, four with renal cell carcinoma, one with breast carcinoma, and one with colon carcinoma, were treated with varying doses and combinations of TIL (8.0 X 10(9) to 2.3 X 10(11) cells per patient), IL-2 (10,000 to 100,000 U/kg three times daily to dose-limiting toxicity), and cyclophosphamide (CPM) (up to 50 mg/kg). Two partial responses (PR) to therapy were observed: pulmonary and mediastinal masses regressed in a patient with melanoma, and a lymph node mass regressed in a patient with renal cell carcinoma. One additional patient with breast cancer experienced a partial regression of disease in lymph nodal and cutaneous sites with complete elimination of malignant cells from a pleural effusion, although cutaneous disease recurred at 4 weeks. The toxicities of therapy were similar to those ascribed to IL-2; no toxic effects were directly attributable to TIL infusions. In five of six melanoma patients, TIL demonstrated lytic activity specific for the autologous tumor target in short-term chromium-release assays, distinct from the nonspecific lytic activity characteristic of LAK cells. This study represents an initial attempt to identify and use lymphocyte subsets with enhanced tumoricidal capacity in the adoptive immunotherapy of human malignancies.
Does raising awareness of lung cancer symptoms in primary care alter referral patterns
Authors: Ronan Astin, Elizabeth Paddison, Adam Woolf, Natalie Soobadoo, Duncan Powrie
Journal: European Respiratory Journal (2011)

Background:  Patients with lung cancer often present late with advanced disease. This results from both symptomatic patients not presenting to primary care and delayed referral following presentation.   Aim:  To examine whether sending General Practitioners (GPs) a reminder of the “red light” symptoms of lung cancer would increase urgent referrals and lead to earlier diagnosis.   Method:  All 67 sugeries in South East Essex PCT received a postal reminder of the referral criteria for lung cancer. All suspected cancer referrals to Chest Clinic for 10 weeks before and after this were audited retrospectively and each case followed to completion on the pathway.   Results:  121 patients were referred over 20 weeks. The total number of referrals increased post intervention from 57 to 64 (12%) though this was not statistically significant (p=0.6). There was a statistically significant increase in referrals in the first 3 weeks post intervention (p=0.046) but this effect was lost by week 4 (p>0.2). More patients were discharged from the pathway in the post intervention group (28.1% vs 24.6%, p>0.2) and fewer diagnosed with cancer (26.6% vs 28.1%, p>0.2). Referrals due to haemoptysis increased in the post intervention group (10% vs 5.2%) but this did not reach significance (p=0.06).   Conclusion:  Sending out referral guidelines resulted in an initial increase in referral numbers. This effect was lost after 3 weeks and did not improve cancer detection rates however numbers in this study were small. This suggests that resources need to be focussed on increasing patient as well as GP awareness if outcomes are to improve.
Comparison of redox and D29 phage methods for detection of isoniazid and rifampicin resistance in Mycobacterium tuberculosis
Authors: P.A. da Silva, M.M.S. Boffo, I.G. de Mattos, A.B.S. Silva, J.C. Palomino, A. Martin, H.E. Takiff
Journal: Clinical Microbiology and Infection (2006)
Carboplatin (Paraplatin; JM8) and etoposide (VP-16) as first-line combination therapy for small-cell lung cancer.
Authors: I E Smith, B D Evans, M E Gore, M D Vincent, L Repetto, J R Yarnold, H T Ford
Journal: Journal of Clinical Oncology (1987)

Fifty-two previously untreated patients with small-cell lung carcinoma (SCLC) were treated with a combination of carboplatin 300 mg/m2 intravenously (IV) on day 1 and etoposide 100 mg/m2 IV on days 1 through 3 every 28 days for four courses. Patients with limited disease (LD) subsequently received thoracic radiotherapy; no prophylactic cranial radiotherapy was used. Forty-four patients (85%) achieved an objective response, including 82% (29% complete remissions) of LD patients and 88% (13% complete remissions) of extensive-disease (ED) patients. Median response duration for LD patients was 7 months and 5.5 months for ED patients. Median survival for both LD and ED patients was 9.5 months. Myelosuppression was the main toxicity, with World Health Organization (WHO) grade 3/4 leucopenia occurring in 44% of patients. There was one (2%) treatment-related neutropenic death. Treatment was otherwise well tolerated, and in particular no renal toxicity, neurotoxicity, or ototoxicity was seen. This new combination is highly active in terms of response rate, but response duration and survival is disappointing, and might be improved by prolonged treatment or by the use of additional drugs in combination.
Extracellular matrix influences the inflammatory response of primary bronchial epithelial cells
Authors: Oskar Hallgren, Leif Bjermer, Gunilla Westergren-Thorsson
Journal: European Respiratory Journal (2012)

Rationale:   Airway remodelling is a feature in many chronic airway diseases. This is manifested as alterations in the extracellular matrix composition. Our aim was to investigate how different extracellular matrix molecules influenced the production of inflammatory cytokines in epithelial cells.    Methods:   Primary human bronchial epithelial cells were grown on plates coated with the extracellular matrix proteins collagen-1, collagen-4 and fibronectin. The cells were challenged with a cytomix consisting of TNF-alpha and IL-1-beta (both 10ng / ml) and the cytokine production was examined with proteome profiler antibody arrays (R&D) that detect the production of 40 cytokines simultaneously.    Results:   Basal and induced production of IL-1-aplha was similar in cells grown on collagen-1 and fibronectin but IL-1-alpha could not be detected in cells grown on collagen-4. Low levels of G-SCF were detected in cells on collagen-1 or fibronectin stimulated with cytomix, but when cell were grown on collagen-4 the levels were dramatically higher. There were no difference in basal and induced production of GRO-alpha and Il-8 on cells grown on collagen-1, collagen-4 or fibronectin. The basal level of Il-6 was dramatically reduced on collagen-4 compared to collagen-1 and fibronectin. However, the cytomix triggered similar levels of IL-6 production regardless of matrix substrate.    Conclusions:   In this study we show that the extracellular matrix actively contributes to modify cell phenotypes. Cells grown on collagen-4 that represents a “homeostatic matrix” produced a different repertoire of inflammatory mediators than cells grown on “remodeled matrix proteins” collagen-1 and fibronectin.
Insulin therapy correlates with increased risk of asthma among patients with diabetes in a Taiwanese population cohort
Authors: Chiung-Zuei Chen, Chih-Hui Hsu, Chung-Yi Li, Chun-Hsiang Yu, Tzuen-Ren Hsiue
Journal: European Respiratory Journal (2014)

Rationale: Recent reports have suggested that anti-diabetes agents such as metformin has reduced both airway inflammatory and remodeling properties. In contrast, insulin promotes airway smooth muscle contraction and enhances airway hyper-responsiveness- a cardinal feature of asthma. However, all of these results are from in-vitro studies. The aim of this study was to investigate whether diabetes and different anti-diabetes agents prescription associates with the risk of asthma.  Methods: We conducted a prospective population-based case-control study using the Taiwan National Heath Insurance (NHI) claim database from 2000 to 2010 to compare the incidence of asthma with Cox proportional hazards regression model in patients with diabetes (n = 19,428) and an matched control group (n = 38,856). A nested case-control study including 3,596 patients from NHI database was also conducted to estimate the association between anti-diabetes agents and risk of asthma.  Results: The incidence of asthma was significantly higher in those with a diagnosis of diabetes in regression models adjusted for age, sex, and obesity (hazard ratio [HR] 1.33; 95% CI: 1.26-1.41). There was a significant increased risk of asthma among diabetic patients who were prescribed insulin therapy (OR 1.16; 95%CI: 1.02-1.31), but the risk was not associated with any oral anti-diabetes agents.  Conclusions: Individuals with diabetes are at increased risk of asthma. Diabetic patients who were prescribed insulin further increase risk of asthma by 16%. These results support the current knowledge that insulin has the potential to influences lung structure and function and thus modulating asthma predisposition.