tbuckley/cabot-search huggingface dataset:
Tiotropium reduces asthma exacerbations in asthmatic patients with persistent airflow obstruction uncontrolled despite treatment in accordance with guidelines
Authors: Huib Kerstjens, Ronald Dahl, Ekkehard Beck, Mark Vandewalker, Michael Engel, Ralf Sigmund, Wolfgang Seibold, Petra Moroni-Zentgraf, Eric Bateman
Journal: European Respiratory Journal (2012)

Introduction : Some asthmatics remain symptomatic despite high-dose (HD) inhaled corticosteroids (ICS), long-acting β2-agonists (LABA) and additional treatments in accordance with guidelines and may have frequent asthma exacerbations.

Methods : We performed a prespecified combined analysis of 2 replicate double-blind, parallel group trials comparing the effect of adding tiotropium Respimat® 5 mcg or placebo on exacerbation frequency in 912 asthmatics receiving at least HD ICS+LABA. At study entry, patients had a postbronchodilator (BD) FEV1 <80% predicted, asthma control questionnaire score (ACQ) ≥1.5, and at least one severe exacerbation in the preceding year. Severe exacerbations were defined as necessitating systemic corticosteroids for ≥3 days.

Results : Baseline characteristics were similar between treatment groups. The addition of tiotropium was associated with a 21% risk reduction (HR 0.79, P =0.03) in time to first severe exacerbation. Tiotropium also reduced the risk of any asthma exacerbation by 31% ( P <0.0001), defined by significant increase in symptoms or PEF drop ≥30% over ≥2 days. There were significant improvements in ACQ and Asthma Quality of Life Questionnaire in one trial and a trend towards improvement in the ACQ in the other one. No deaths occurred; adverse events were balanced across treatments in both trials.

Conclusion: In asthmatics that remain uncontrolled despite HD ICS+LABA, the addition of tiotropium significantly reduces the risk of asthma exacerbations requiring treatment with systemic corticosteroids.

Study supported by Boehringer Ingelheim and Pfizer.
Prostate cancer radiation therapy with reduced planning target volume (PTV) margins.
Authors: Kelly Sun, Timothy Brand, Brent Tinnel, Madeera Kathpal, Stephanie Ninneman, Grant Hughs, John B. Halligan, Michael Brown, Joseph P. Brooks, Dusten Macdonald
Journal: Journal of Clinical Oncology (2015)

124 Background: Electromagnetic tracking of the prostate during radiation therapy for prostate cancer allows decreased PTV margins which may reduce dose to nearby tissues. Sandler, et al. reported a reduction in patient-reported acute morbidity with this strategy (Sandler HM, et al. Urology, 2010 May;75 (5):1004-8). We conducted a similar prospective study and compare our results with Sandler’s Assessing Impact of Margin Reduction (AIM) study and with a group treated with radiation therapy without reduced PTV margins from the Sanda, et al. PROST-QA cohort (Sanda MG, et al. NEJM, 2008 Mar 20;358 (12):1250-61). Methods: 25 patients with low-to-intermediate risk prostate cancer were treated on a prospective study with definitive intensity-modulated radiation therapy with 3 mm circumferential PTV margins and daily electromagnetic localization. An EPIC quality of life questionnaire was completed prior to treatment and at the last treatment. Using data from the referenced publications, we performed a two-tailed t-test to compare EPIC scores from our cohort with the AIM and PROST-QA cohorts treated with external beam radiation therapy alone. Results: Table lists mean pre- and post-treatment EPIC scores and the differences between them. Conclusions: Our patients fared similarly to the PROST-QA cohort, but had a significantly greater mean decrement in the urinary irritation and sexual domains in comparison to the AIM cohort. Clinical trial information: NCT01589939. [Table: see text]
Extended possibilities of thoracoscopy at patients with mediastinal pathology
Authors: Armen Benyan, Evgeny Korymasov, Sergey Pushkin, Ildar Kameev, Mikhail Medvedchikov-Ardiya
Journal: European Respiratory Journal (2013)

Objective. Accumulation of experience of performing thoracoscopy at patients with mediastinal pathology determines the extension of indications. This is displayed in enlargement of sizes of extracting pathological objects and increasing difficulty of intervention.  Methods. Since 1999 till 2012 we have performed 110 thoracoscopic operations at patients with mediastinal pathology. We have separated 3 types of thoracoscopy: diagnostic operations – at 57 patients, removing of tumors and cysts – at 45 patients, sanation of mediastinitis – at 8 patients.  Results. Mediastinal lymphadenopathy was the most frequent indication for diagnostic thoracoscopy. Thoracoscopic lymph node biopsy revealed sarcoidosis at 50 patients, Hodgkin9s disease – at 6 patients, malignant histiocytosis – at 3 patients. Also, at 7 patients biopsy of tumor diagnosed lymphoma at 5 patients and malignant thymoma – at 2 patients.  Thoracoscopic removal of benign tumors and cysts is possible regardless of sizes of pathology. We have operated 5 patients neurinoma, 10 patients with thymoma, 10 patients with mediastinal cyst, 5 patients with pericardial cyst, 8 patients with lipoma, 1 patient with leiomyoma of esophagus. The largest size of extracted tumors was until 14 cm. Pericardial window and pericardectomy had been done at 6 patients.  We used thoracoscopy at 8 patients with different types of mediastinitis and found its priority at limited abscesses.  Conclusion. The possibilities of thoracoscopy at patients with mediastinal pathology are defined by present experience and had the permanent tendency to expansion.
Two years treatment with almitrine bismesylate in patients with hypoxic chronic obstructive airways disease
Authors: P A Bardsley, P Howard, W DeBacker, P Vermeire, M Mairesse, C Ledent, M Radermecker, T Bury, J Ansquer
Journal: European Respiratory Journal (1991)

Eighty nine patients with hypoxic chronic obstructive airways disease (COAD) were enrolled into the 1 year Vectarion International Multicentre Study-VIMS in 4 centres, Sheffield (UK), and Antwerp, Liege and Namur (Belgium). At the end of the year the remainder were invited to continue taking placebo or almitrine bismesylate (100-200 mg daily) in the same double blind manner for a further 12 months. In the almitrine treated patients mean arterial oxygen tension (Pao2) at the end of the treatment period improved from 7.5 (0.5) kPa to 8.2 (1.3) kPa (p less than 0.01) and arterial carbon dioxide tension (Paco2) fell from 6.1 (0.8) kPa to 5.8 (0.9) kPa (p less than 0.01). Forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and measurements of breathlessness were unchanged. In the placebo treated group changes in the above variables were not significant. Twenty nine patients withdrew from the almitrine group with seven deaths and six cases of peripheral neuropathy, and 22 patients withdrew from the placebo group with six deaths and two cases of peripheral neuropathy. Death rates between the groups were not significantly different. In conclusion, 2 yrs of almitrine treatment (100-200 mg daily) leads to a persistent slight improvement in PaO2 and PaCO2 but no benefit in survival was demonstrated. Patients in this study had a high incidence of drug related side-effects. Lower dose schedules should be investigated.
Abstract 17681: Hydrogen Sulfide Attenuates Inflammasome Formation Following Myocardial Ischemia/Reperfusion Injury
Authors: Stefano Toldo, Anindita Das, Eleonora Mezzaroma, Benjamin W Van Tassell, Rakesh C Kukreja, Antonio Abbate, Fadi N Salloum
Journal: Circulation (2012)

Background: The infarct-sparing and anti-inflammatory effects of hydrogen sulfide (H2S) following ischemic injury have been demonstrated in the heart and other organs. Whether H2S attenuates inflam...
Responsiveness of the clinical COPD questionaire to pulmonary rehabilitation
Authors: Deniz Dilaver, Samantha S.C. Kon, Amy L. Clark, Claire M. Nolan, Jane L. Canavan, Sarah E. Jones, Michael I. Polkey, William D.-C. Man
Journal: European Respiratory Journal (2013)

Background   The Clinical COPD Questionnaire(CCQ) is a simple to use health status instrument, takes two minutes to complete and has good psychometric properties (van der Molen T 2003). The minimum clinically important difference is 0.4 points (Kocks 2006), however limited data exists on the responsiveness of the CCQ to pulmonary rehabilitation (PR).   Aims   To demonstrate the response of the CCQ to PR in comparison with other well established health status instruments.   Methods   275 COPD patients referred to an 8-week outpatient PR programme were recruited. CCQ, St George’s Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT) and the Chronic Respiratory Disease Questionnaire (CRQ) were measured pre and post PR. Paired t tests were used to assess change. Correlations betweeen change in CCQ with change in other health status questionnaires were assessed using Spearman9s rank. Effect sizes were calculated using the means and standard deviations of the two groups (pre and post PR).   Results   219 COPD patients completed PR. Baseline characteristics are presented as mean (SD) or median (25th,75th centiles); Age 71 years (64,76), FEV 1  pred 50% (34,65), MRC 3 (2,4), Male : Female 124:95. There was a significant change in all domains of the CCQ and a mean change in total CCQ score of -0.4 (-0.5,-0.2) (p   Conclusion   The CCQ is similarly responsive to PR as other commonly used health status instruments. It may be a simple practical alternative to longer questionnaires as an outcome measure.
Affective State and Thyrotropin and Prolactin Responses After Repeated Injections of Thyrotropin-Releasing Hormone in Depressed Patients
Authors: RUDOLPH H. EHRENSING, ABBA J. KASTIN, DON S. SCHALCH, HENRY G. FRIESEN, J. RODOLFO VARGAS, ANDREW V. SCHALLY
Journal: American Journal of Psychiatry (1974)

Eight patients with serious depression were given 1000 µg. of thyrotropin-releasing hormone (TRH) or saline intravenously for three days in a double-blindstudy. All patients then received 1000 µg. of TRH daily for the next seven days. The group receiving saline showed the greatest improvement; only one patient improved substantially while receiving TRH. Plasma thyrotropin and prolactin responses to TRH were distinctly diminished in three of the most severely depressed patients. The authors suggest that in depression the primary value of TRH may be as a diagnostic tool in differentiating among various types of depression.
Abstract 3512: Disruption of Whole Nitric Oxide Synthase System Causes Impaired Glucose Tolerance and Insulin Resistance in Mice in Vivo
Authors: Sei Nakata, Masato Tsutsui, Hiroaki Shimokawa, Ken Sabanai, Yasuko Yatera, Kiyoko Shibata, Tsuyoshi Morishita, Osamu Suda, Hiromi Tasaki, Yasuhide Nakashima, Nobuyuki Yanagihara, Yutaka Otsuji
Journal: Circulation (2007)

Background : Nitric oxide (NO) synthase (NOS) system consists of 3 different isoforms, including neuronal (nNOS), inducible (iNOS), and endothelial NOSs (eNOS). We have recently succeeded in developing mice lacking all NOS genes (triply n/i/eNOS-KO mice) ( PNAS 2005). Our preliminary study has revealed that the triply-KO mice develop acute myocardial infarction (AMI). The present study was designed to investigate abnormalities of glucose metabolism, an important risk factor of MI, in those mice. Methods and Results : Experiments were performed in 3-month-old male wild-type (WT) and triply-KO mice (n=5–7). At 15 minutes after intravenous glucose administration (1 g/kg), plasma glucose levels (mg/dl) were significantly higher in the triply-KO (475 ± 44) than in the WT mice (241 ± 20) ( P&lt; 0.05), and plasma insulin levels (ng/dl) were significantly lower in the triply-KO (0.50 ± 0.03) than in the WT mice (0.78 ± 0.03) ( P&lt; 0.05). In the triply-KO mice, the size of pancreatic islets (islet/pancreatic area, 0.64 ± 0.16 vs. 2.81 ± 0.64%) was significantly smaller ( P&lt; 0.05), and significant apoptosis of pancreatic islets (apoptotic/total islets, 19 ± 2 vs. 3 ± 1%) (TUNEL staining) was noted as compared with the WT mice ( P&lt; 0.05). Furthermore, insulin sensitivity (as assessed by insulin-induced [ 3 H]-glucose uptake in isolated soleus muscle) (fold increase) was markedly reduced in the triply-KO mice (1.1 ± 0.03) as compared with the WT mice (2.1 ± 0.3) ( P&lt; 0.05), associated with an impairment of insulin-induced translocation of glucose transporter-4 (GLUT-4) to the cellular membrane (immunofluorescent staining) ( P&lt; 0.05). Importantly, supplementation of NO by long-term treatment with isosorbide dinitrate (0.4 mg/day, 6 weeks, dermal application) significantly reversed all these abnormalities of glucose metabolism in the triply-KO mice; plasma glucose (280 ± 28) and insulin levels (0.89 ± 0.10) after glucose tolerance test, insulin sensitivity (1.5 ± 0.08), and GLUT-4 translocation were all improved (all P&lt; 0.05). Conclusions : These results indicate that disruption of whole NOSs system causes impaired glucose tolerance and insulin resistance in mice in vivo, suggesting a critical role of endogenous NO/NOSs system in maintaining glucose metabolism.
GOG0182-ICON5: 5-arm phase III randomized trial of paclitaxel (P) and carboplatin (C) vs combinations with gemcitabine (G), PEG-lipososomal doxorubicin (D), or topotecan (T) in patients (pts) with advanced-stage epithelial ovarian (EOC) or primary peritoneal (PPC) carcinoma
Authors: M. A. Bookman
Journal: Journal of Clinical Oncology (2006)

5002 Background: P-C is a global standard for treatment of EOC and PPC (GCIG Consensus Conference 2005). Although effective, most patients recur with resistant disease. Agents were selected for new combinations based on clinical activity, interaction with cisplatin in tumor models, and feasibility. Methods: Eligible pts had appropriate initial surgery without other therapy, GOG/WHO PS 0–2, and adequate vital organ function. Pts were stratified by group, diagnosis (EOC vs PPC), stage (III vs IV), macroscopic residual tumor (yes vs no), and intent for interval cytoreduction (yes vs no). An event-triggered interim analysis (IA) of progression-free survival (PFS) was to identify arms for full accrual. The primary endpoint was overall survival (OS), determined by an event-triggered pair-wise comparison to the standard regimen (intent-to-treat), with a 90% chance of detecting a true hazard ratio (HR) of 1.33, limiting type I error to 1.25% (two-tailed) for each comparison. Sample size to be adjusted based on accrual rate and IA. Results: Accrual exceeded 1200/yr. IA for PFS (May 2004) with 1,345 events. Median PFS ranged from 15.4–17.5 m. PFS HRs ranged from 0.94–1.07 with the standard error of each log HR approximately 0.086. Extension was not recommended, and accrual closed at 4312 pts (177 ineligible). Median age 58 yrs; 13% PPC, 14% stage IV, 22% microscopic. 81% completed therapy, 4% progressed, 9% discontinued for toxicity. At least 42 deaths possibly treatment-related (&lt;1%). Expected hematologic toxicity related to regimen intensity. Conclusions: For the regimens evaluated, there is no evidence that adding a third active cytotoxic agent prolongs PFS in EOC. Analysis of OS and impact of stratification factors are in progress. [Table: see text] [Table: see text]
Güneş ışığı, solaryum kabini ve D vitamini
Authors: Konferans organizatörü:Henry W. Lim, Katılımcılar:Barbara A. Gilchrest, Kevin D. Cooper, Heike A. Bischoff-Ferrari, Darrell S. Rigel, W. Howard Cyr, Sharon Miller, Vincent A. DeLeo, Tim K. Lee, Catherine A. Demko, Martin A. Weinstock, Antony Young, Laura Saul Edwards, Timothy M. Johnson veStephen P. StoneDetroit, Michigan, Boston, Cleveland, Ohio, Rockville, Maryland, Vancouver, British Columbia, Canada, Providence, Rhode Island, London, United Kingdom, Washington, Ann Arbor, ve Springfield, Detroit, St. Luke's, British Columbia Cancer Agency, DCl, Springfield.
Journal: Journal of the American Academy of Dermatology (2005)
Fitness effects of a deletion mutation increasing transcription of the 6-phosphogluconate dehydrogenase gene in Escherichia coli.
Authors: R D Miller, D E Dykhuizen, D L Hartl
Journal: Molecular Biology and Evolution (1988)

Directed evolution in microbial organisms provides an experimental approach to molecular evolution in which selective forces can be controlled and favorable mutations analyzed at the molecular level. Here we present an analysis of a mutation selected in Escherichia coli in response to growth in a chemostat in which the limiting nutrient was gluconate. The selectively favored mutation, designated gnd+ (862), occurred in the gene gnd coding for 6-phosphogluconate dehydrogenase, used in gluconate metabolism. Although the allele is strongly favored in chemostats in which the limiting nutrient is gluconate, the selective effects of gnd+ (862) are highly dependent on growth conditions. In chemostats in which growth is limited by a mixture of gluconate and either ribose, glucose, or succinate, the gnd+ (862) allele is favored, disfavored, or neutral according to the relative concentrations of the substrates. The gnd+ (862) allele results from a deletion of 385 nucleotide pairs in the region 5' to the promoter of gnd, and one endpoint of the deletion is contiguous with the terminus of an IS5 insertion sequence located near gnd in E. coli K12. The gnd+ (862) allele shows a marked increase in transcription that accounts for most or all of the increased enzyme activity.
Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer.
Authors: W Hryniuk, M N Levine
Journal: Journal of Clinical Oncology (1986)

We have analyzed the relationship between dose intensity of cyclophosphamide, methotrexate, and fluorouracil (CMF)-containing adjuvant chemotherapy of stage II breast cancer and 3-year relapse-free survival. Studies using only one or two drugs of CMF or melphalan instead of cyclophosphamide were included in the analysis by using simple techniques developed for this purpose. There was a clear-cut relationship between relapse-free survival and dose intensity in trials containing all four prognostic groups: less than 50 years, one to three and more than three positive nodes; and greater than or equal to 50 years, one to three and more than three positive nodes (P less than 10(-5)). Relapse-free survival also correlated with dose intensity for each of the four prognostic groups analyzed separately (P less than .005). Dose intensity was an independently significant correlate of relapse-free survival in multivariate analysis (P less than 10(-5)). This is a retrospective study, and the hypothesis that dose intensity contributes to outcome independently of other variables should be tested prospectively. Methods of increasing dose intensity also require testing in randomized trials before they can be applied to routine clinical practice.
Mass balance study with ixabepilone using Accelerator Mass Spectrometry
Authors: J. H. Beumer, G. Lappin, M. Cohen, S. Galbraith, R. C. Garner, J. H. Beijnen, T. Griffin, J. H. Schellens
Journal: Journal of Clinical Oncology (2004)

2036 Background: Ixabepilone (BMS-247550) is a semi-synthetic, microtubule stabilizing epothilone B analog which is more potent than taxanes and active in taxane-resistant cancer models. We studied the pharmacokinetics and excretion of 14C-labeled ixabepilone. Due to autoradiolysis however, it was only possible to administer 80 nCi of 14C-ixabepilone, compared to ca 100 μCi dosed in a typical human radio-tracer study. Accelerator Mass Spectrometry (AMS) was therefore used as 14C-detection method. This technology was originally developed for carbon dating but has recently found a novel use in drug development. Methods: Eight patients with advanced cancer (3M/5F; median age 54.5 y; PS 0–2) received an intravenous dose of 70 mg, 80 nCi 14C-ixabepilone over 3h. Plasma, urine and feces, collected up to 7 days after administration, were analysed by AMS and parent compound was quantified using LC/MS/MS. Results: Using AMS, we could accurately measure <4 dpm/mL plasma, 0.01 dpm/mL urine and 0.1 dpm/g faeces. Plasma parameters and recovery of 14C are shown below. Ixabepilone clearance was 25.2±5.2 L/h and Vss was 1143±317 L. Tmax was 2.8±0.6 and 2.3±0.8 h for 14C and ixabepilone respectively. The principal route of elimination was in feces. Ixabepilone was well metabolised, accounting for only a minor part of total radioactivity in both plasma and urine. Conclusions: A mass balance study with ixabepilone was conducted using very low levels of radioactivity. Ixabepilone was well metabolised and radioactivity was principally excreted in the feces. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb
Neoadjuvant Chemotherapy in Pancreatic Cancer
Authors: Thomas Hank, Markus W. Büchler, John P. Neoptolemos
Journal: JAMA Surgery (2021)

To the Editor The Invited Commentary on the study by Perri et al1 says that “larger and prospective trials…are required to inform management strategies and to improve patient outcomes”2 for pancreatic ductal adenocarcinoma yet fails to mention the large existing evidence base.
Periodic limb movements during sleep reflect hypercoagulability in obstructive sleep apnea patients
Authors: Kimihiko Murase, Takefumi Hitomi, Satoshi Hamada, Masanori Azuma, Yoshiro Toyama, Yuka Harada, Kiminobu Tanizawa, Tomohiro Handa, Chikara Yoshimura, Toru Oga, Michiaki Mishima, Kazuo Chin
Journal: European Respiratory Journal (2013)

Background : Both periodic limb movements during sleep (PLMS) and obstructive sleep apnea (OSA) are major causes of sleep disorders and are reported to be associated with cardiovascular diseases (CVD). However, whether the combination of PLMS and OSA promotes a greater risk of CVD than each condition alone is uncertain.   Objectives : To investigate whether patients with both PLMS and OSA have a more elevated hypercoagulability than those with OSA only by examining plasma fibrinogen levels.   Methods : Plasma fibrinogen levels were measured in 254 patients who had moderate to severe OSA revealed by diagnostic polysomnography.   Results : In 46 (18%) of 254 patients, PLMS were found. Fibrinogen levels were significantly higher in patients with both PLMS and OSA than in those with OSA only (298.2±76.1 vs. 270.0±52.6 mg/dL, p    Conclusion : PLMS were positively associated with plasma fibrinogen levels in OSA patients. Since the plasma fibrinogen level is an established predictive factor of future CVD events, PLMS can be a useful clinical sign to identify OSA patients with high risk of CVD.