tbuckley/cabot-search huggingface dataset:
Chest Vest therapy increases FENO and may lead to F508del CFTR maturation
Authors: Nadzeya Marozkina, Laura Smith, Calvin Cotton, Benjamin Gaston
Journal: European Respiratory Journal (2014)

RATIONALE. Chest Vest therapy is used for airway clearance in cystic fibrosis (CF). Endothelial nitric oxide synthase (eNOS)-mimetic compounds modestly correct F508del CFTR protein expression in primary human airway pseudostratified epithelial cells cultured at air liquid interface (ALI) (Marozkina et al., PNAS 107:11393, 2010). We have shown that cyclic compressive stress (CCS; passive airflow) on the airway side of ALI cultures activates subciliary eNOS, and clinical evidence suggests that CCS methods, including Vest, in vivo cause clinical improvement in CF. METHODS To assess eNOS activation in vivo, healthy adults had fraction of exhaled NO (F ENO , MINO, Aerocrine) testing while fasting before and after airway clearance Vest treatment (10 Hz; 10 min). Primary airway epithelial cells were attached to a NEMI rodent ventilator and ventilated for 2 hr in a 37o C incubator after a 2 hr pre-incubation with either 100μM NOS inhibitor (L-NAME) or control diluent. Cells were harvested and immunostained with anti-CFTR antibody M3A7 (Millipore). RESULTS. F508del CFTR B band (partially mature protein) expression increased with CCS by 85% relative to no ventilation. C band was essentially undetectable in the control wells, but increased to a CFTR/actin ration of 0.46 +/- 0.12; this effect was partially inhibited by L-NAME (only a 1.8 +/- 0.31-fold increase relative to control, n = 6 wells, p = 0.002 by ANOVA). In vivo, Vest treatment increased F ENO  by 2.4 +/- 0.56 ppb from baseline (n = 9; p = 0.0031 by paired t- test). CONCLUSIONS. In addition to mechanical effects on mucous, airway clearance techniques such as use of the Vest may activate eNOS, leading to increased F508del CFTR expression and maturation.
Elevated creatinine is a sensitive severity marker in community acquired pneumonia
Authors: Joanne Sloan, Janet Wilson, Carly Griffin, Morven Wilkie, James Chalmers, Stuart Schembri
Journal: European Respiratory Journal (2012)

Background  It is recognised that acute kidney injury (AKI), as classified by the International Kidney Disease Group Improving Global outcomes staging classification, is associated with increased 30-day mortality in patients with community acquired pneumonia (CAP). This study aimed to determine if increases in serum creatinine not meeting the criteria for AKI were associated with increased 30-day mortality.  Methods  A retrospective study of patients admitted over a 6 month period, with radiologically confirmed CAP, was performed in a teaching hospital. Baseline creatinine, admission creatinine, AKI severity and 30-day mortality were recorded.  Results  210 patients (52% male, 48% female) were included in the study with a median age of 76 years. 26 (12.4%) patients met the criteria for AKI. 57 (27.1%) patients had rises in creatinine above baseline, but not meeting AKI criteria. As expected AKI scoring was associated with increased 30 day mortality.  Greater than 20% rises in creatinine above baseline were strongly associated with a higher 30 day mortality rate.  Log rank test p=0.002.  Conclusions  Creatinine rises as low as 20% above baseline in patients with CAP are associated with higher 30 day mortality rates than for patients without creatinine rises.
Effectiveness of non-invasive ventilation in stable chronic obstructive pulmonary disease with nocturnal desaturation: Prospective open-label randomized parallel-group study
Authors: Vera Baturova, Elena Zolotova, Alexey Svet, Alexey Nesterov, Kira Dalgatova
Journal: European Respiratory Journal (2013)

In some patients with chronic obstructive pulmonary disease (COPD) hypoventilation occurs nightly, leading to a nocturnal desaturation pulseoximetry pattern. Hypoxemia with SpO2≤88% due to alveolar hypoventilation is associated with the disease progression rapidity and health-related quality of life (HRQOL) deterioration. This suggests better outcomes and HRQOL in COPD patients with nocturnal desaturation receiving non-invasive ventilation (NIV), when compared to standard COPD therapy. The aim of our study was to estimate the effectiveness of nocturnal NIV on the long-term outcomes of COPD with night-time desaturation.  We conducted an overnight pulseoximetry in 45 stable COPD patients and enrolled 25 patients with persistent nocturnal desaturation with basal SpO2≤88%. We then randomized the sample and prescribed NIV in addition to standard therapy to the treatment group (n=11) vs. standard therapy (n=14) for 6 months. Stable COPD patients with nocturnal desaturation receiving NIV in addition to the standard therapy didn9t declare higher HRQOL, when assessed by SF36 scores (PH 43.6±9.2, MH 44.9±6.7 vs. PH 45.9±9.9, MH 39.5±4.7). In stable COPD patients with nocturnal desaturation the addition of NIV was associated with lower exacerbation rate within 6-month period (0.11 vs. 0.39 exacerbations per patient) and longer time to a subsequent exacerbation by Kaplan-Meier test (p  The supplement of overnight NIV to standard therapy in stable COPD with nocturnal hypoxemia isn9t associated with substantial improvement in HRQOL, but reduces exacerbation rate and increases time to a subsequent exacerbation.
Ghrelin ameliorates cachectic status in the mouse model of lung cancer model
Authors: Hironobu Tsubouchi, Shigehisa Yanagi, Nobuhiro Matsumoto, Masamitsu Nakazato
Journal: European Respiratory Journal (2013)

Cachexia is a wasting syndrome associated with cancer, AIDS, and systemic inflammatory diseases. It is characterized by dramatic weight loss, food intake reduction, and skeletal muscle atrophy. Specific strategies to exert ameliorative effects on cachectic status have not been contrived. Ghrelin is an orexigenic peptide produced predominantly in the stomach. Ghrelin acts on the hypothalamus and the pituitary gland, induces growth hormone secretion and stimulates food intake through binding to its receptor, growth hormone secretagogue receptor (GHS-R). We reported that urethane-induced lung carcinogenesis highly occurred in the lung epithelium-specific Pten-deleted (Pten-KO) mice. To investigate the pharmacological potential of ghrelin for the treatment of lung cancer-induced cachexia, we administered urethane intraperitoneally to the 10-week-old Pten-KO mice and their wild mice. Ghrelin 10 nmol/mouse or PBS was given to Pten-KO mice intraperitoneally twice daily for 4 weeks starting from 28 weeks after administration of urethane. Reduction of food intake, body weight loss, and gastrocnemius muscle weight loss of Pten-KO mice were severer than those of wild-type controls at 28 weeks after urethane administration. Ghrelin-treated Pten-KO mice had smaller reductions of food intake, body weight, and muscle weight than PBS-treated Pten-KO mice. The intramuscular expression levels of MuRF-1 and Atragin-1, both of which were the markers of skeletal muscle catabolism of ghrelin-treated Pten-KO mice were significantly lower than those of PBS-treated Pten-KO mice. These results indicate that ghrelin administration exerts a therapeutic potential for cancer-induced cachexia in mice.
ABCA3 mutations disturb lipid homeostasis in alveolar epithelial cells
Authors: Eva Kaltenborn, Sabrina Frixel, Gerhard Liebisch, Gerd Schmitz, Ralf Zarbock, Matthias Griese
Journal: European Respiratory Journal (2013)

Interstitial lung diseases (ILDs) are characterized by various degrees of inflammation and fibrosis; however, the causatives are largely unknown. Among others, gene defects in the gene coding for the surfactant lipid transporter ABCA3, localized exclusively to alveolar type II cells (ATII) in the lung, were found in children presenting with ILD.

Since ABCA3 is a lipid transporter, aim of this study was to determine whether ABCA3 mutations disturb lipid homeostasis of ATII.

Therefore, the effects of the two clinically relevant ABCA3 mutations p.Q215K and p.E292V were investigated in A549 cells, a cell culture model system for ATII, by mass spectrometry, Oil Red O staining, qPCR, and western blotting.

In A549 cells harbouring mutant ABCA3, we found accumulation of cholesterol; especially cholesterol esters (CE) were elevated approx. 2-fold compared to ABCA3-WT cells. Concurrently, the size of neutral lipid droplets, in which excess free cholesterol is stored in the form of CE, was significantly increased about 2-fold by ABCA3 mutations. Carboxylesterase 1, which plays a role in lipid droplet formation, was up-regulated more than 5000-fold in cells harbouring ABCA3 mutations. ABCA3 mutations also induced a significant reduction of several SREBP regulated genes involved in cholesterol and fatty acid metabolism. Additionally, expression of the cholesterol and phospholipid transporter ABCA1 was elevated at least 4-fold by mutant ABCA3.

In conclusion, here we show that ABCA3 mutations induce intracellular cholesterol accumulation and disturb cellular lipid homeostasis. Among other factors, this ABCA3-mediated deregulation might contribute to the development of ILD in children.

Supported by BMBF-GOLDnet and DFG 970/7-3.
The difference in 'wearing time' in three valid accelerometers in patients with COPD
Authors: Annemie Smeets, Jaume Torrent Pallicer, Miek Hornikx, David Donaire-Gonzalez, Heleen Demeyer, Carlos Augusto Marcal Camillo, Elena Gimeno-Santoz, Judith Garcia-Aymerich, Thierry Troosters
Journal: European Respiratory Journal (2014)

Rationale   Lack of physical activity and a sedentary lifestyle are independent predictors of health. Patients with COPD are proven to be less active compared to healthy subjects. Several accelerometers are valid to measure physical activity in COPD. Little is known about the agreement in wearing time between devices.   Methods   Ten patients with COPD (FEV 1 /FVC: 52±13%; FEV 1 : 61±21%predicted) wore 3 valid accelerometers (SenseWear Pro Armband (SW), Dynaport MoveMonitor (DMM) and ActiGraph GT3X (ACT)) simultaneously day and night up to 1 week. Proprietary algorithms for wearing time detection were used for SW and DMM. For ACT, 2 different algorithms on the vertical axis counts for a time window of 60 minutes (ACT1) and the vector magnitude unit from 3 axes for 90 minutes (VMU) (ACT2) were tested.   Results   DMM was accurate in recording wearing time (Δ(SW-DMM)=-8±8 minutes (p=0.35)). In both algorithms, ACT underestimated wearing time. The underestimation was higher using ACT1 (ACT1: Δ(SW-ACT)=522±36 minutes (p   Conclusion   When investigating inactive time, it is important to discern it from non-wearing time. ACT significantly underestimates wearing time. This may lead to an underestimated sedentary time, which may have consequences for the interpretation of physical activity/sedentarism in patients with COPD. DMM more accurately reflects wearing time.
Abstract 588: Extracorporeal Cardiopulmonary Resuscitation for Induction of Hypothermia in Patients with Out-of-Hospital Cardiac Arrest
Authors: Ken Nagao, Kimio Kikushima, Kazuhiro Watanabe, Eizo Tachibana, Takaeo Mukouyama, Yoshiteru Tominaga, Katsushige Tada, Nobutaka Chiba, Asuka Kasai, Taketomo Soga, Masakazu Matsuzaki, Kei Nishikawa, Yutaka Tateda, Harumi Ikeda, Tsukasa Yagi
Journal: Circulation (2008)

Therapeutic hypothermia is beneficial to neurological outcome for comatose survivors after out-of-hospital cardiac arrest. However, there are few data of extracorporeal cardiopulmonary resuscitation (ECPR) for induction of hypothermia for patients with out-of-hospital cardiac arrest. We did a prospective study of ECPR with hypothermia for patients with out-of-hospital cardiac arrest. The criteria for inclusion were an age of 18 to 74 years, a witnessed cardiac arrest, collapse-to-patient’s-side interval &lt;15 minutes, cardiac arrest due to presumed cardiac etiology, and persistent cardiac arrest on ER arrival in spite of the prehospital defibrillations. After arrival at the emergency room, cardiopulmonary bypass plus intra-aortic balloon pumping was immediately performed, and then coronary reperfusion therapy during cardiac arrest was added if needed. Mild hypothermia (34°C for 3 days) was immediately induced during cardiac arrest or after return of spontaneous circulation. We selected suitable patients who received conventional CPR with normothermia among a prospective multi-center observational study of patients who had out-of-hospital cardiac arrest in Kanto region of Japan “the SOS-KANTO study” for the control group. The primary endpoint was favorable neurological outcome at the time of hospital discharge. A total of 558 patients were enrolled; 127 received ECPR with hypothermia and 431 received conventional CPR with normothermia. The ECPR with hypothermia group had significantly higher frequency of the favorable neurological outcome than the conventional CPR with normothermia group (12% vs. 2%, unadjusted odds ratio, 8.1; 95% CI; 3.2 to 20.0). The adjusted odds ratio for the favorable neurological outcome after ECPR with hypothermia was 7.4 (95% CI; 2.8 to 19.3, p&lt;0.0001). Among the ECPR with hypothermia group, early attainment of a target core temperature of 34°C increased its efficacy (adjusted odds ratio, 0.99; 95% CI; 0.98 to 1.00, p=0.04). ECPR with hypothermia improved the chance of neurologically intact survival for adult patients with out-of-hospital cardiac arrest, and the early attainment of a target temperature enhanced its efficacy.
A randomized phase II/III trial of a tumor vascular disrupting agent fosbretabulin tromethamine (CA4P) with carboplatin (C) and paclitaxel (P) in anaplastic thyroid cancer (ATC): Final survival analysis for the FACT trial.
Authors: J. A. Sosa, R. Elisei, B. Jarzab, C. S. Bal, H. Koussis, A. W. Gramza, R. Ben-Yosef, B. J. Gitlitz, B. Haugen, S. M. Karandikar, F. R. Khuri, L. F. Licitra, S. C. Remick, S. Marur, C. Lu, F. G. Ondrey, S. Lu, J. Balkissoon
Journal: Journal of Clinical Oncology (2011)

5502 Background: CA4P, a vascular disrupting agent (VDA), has shown clinical activity as monotherapy in patients with ATC. Results include a durable CR in a phase I trial and a median survival of 4.7 months with 34% of patients alive at 6 months and 23% of patients alive at 1-year in a Phase 2 trial. Interim results previously presented from this phase II/III study evaluating CA4P in combination with carboplatin (C) + paclitaxel (P) in patients with ATC suggested a survival benefit with the combination therapy. Final survival and safety data are now available. Methods: This is a multicenter, open-label, 2:1 randomized trial for patients with histologically confirmed ATC. 80 out of 180 planned patients were randomized to receive up to 6 cycles of C + P with CA4P (CA4P Arm) or without CA4P (Control Arm). The targeted sample size of 180 patients was not reached due to slow enrollment. After 6 cycles of therapy, patients on the CA4P Arm without progression could continue to receive CA4P until disease progression. The primary objective of this study is overall survival (OS). Secondary objectives include safety, 1-year survival, and progression-free survival. Results: 75 of the 80 randomized patients received treatment with a median (min, max) follow up of 4.7 (0.1, 32.6) months. All deaths have been due to disease progression except 2 patients whose deaths were attributed to disease related complications. The median survival time for the CA4P Arm was 5.2 months vs. 4.0 months for the Control Arm (hazard ratio and 95% CI of 0.65 [0.38, 1.10]) from the intent-to-treat analysis. This would suggest a 35% reduction in the risk of death. One year survival was 27% on the CA4P Arm vs. 9% on the Control Arm (p =0.065, Fisher's Exact Test). Grade 1-2 hypertension and Grade 3-4 neutropenia were more common on the CA4P Arm. Conclusions: This trial, the largest prospective randomized trial ever conducted in ATC, suggests that CA4P improves OS with a tripling of 1-year survival. The regimen continues to be well-tolerated, with AEs and deaths primarily related to ATC and disease progression.
A commensal symbiotic factor derived from<i>Bacteroides fragilis</i>promotes human CD39<sup>+</sup>Foxp3<sup>+</sup>T cells and T<sub>reg</sub>function
Authors: Kiel M Telesford, Wang Yan, Javier Ochoa-Reparaz, Anudeep Pant, Christopher Kircher, Marc A Christy, Sakhina Begum-Haque, Dennis L Kasper, Lloyd H Kasper
Journal: Gut Microbes (2015)

Polysaccharide A (PSA) derived from the human commensal Bacteroides fragilis is a symbiosis factor that stimulates immunologic development within mammalian hosts. PSA rebalances skewed systemic T helper responses and promotes T regulatory cells (Tregs). However, PSA-mediated induction of Foxp3 in humans has not been reported. In mice, PSA-generated Foxp3+ Tregs dampen Th17 activity thereby facilitating bacterial intestinal colonization while the increased presence and function of these regulatory cells may guard against pathological organ-specific inflammation in hosts. We herein demonstrate that PSA induces expression of Foxp3 along with CD39 among naïve CD4 T cells in vitro while promoting IL-10 secretion. PSA-activated dendritic cells are essential for the mediation of this regulatory response. When cultured with isolated Foxp3+ Tregs, PSA enriched Foxp3 expression, enhanced the frequency of CD39+HLA-DR+ cells, and increased suppressive function as measured by decreased TNFα expression by LPS-stimulated monocytes. Our findings are the first to demonstrate in vitro induction of human CD4+Foxp3+ T cells and enhanced suppressive function of circulating Foxp3+ Tregs by a human commensal bacterial symbiotic factor. Use of PSA for the treatment of human autoimmune diseases, in particular multiple sclerosis and inflammatory bowel disease, may represent a new paradigm in the approach to treating autoimmune disease.
Anti-leukemic activity of axitinib against cells harboring the BCR-ABL T315I point mutation
Authors: Seiichi Okabe, Tetsuzo Tauchi, Yuko Tanaka, Juri Sakuta, Kazuma Ohyashiki
Journal: Journal of Hematology & Oncology (2015)

The BCR-ABL; breakpoint cluster region-Abelson point mutation T315I is resistant to ABL tyrosine kinase inhibitors. However, axitinib, a vascular endothelial growth factor receptor inhibitor, is effective against this mutation. In this study, we investigated axitinib activity against ponatinib-resistant cells and found that axitinib inhibited cellular growth and apoptosis in Ba/F3 T315I-mutant cells and T315I-mutant primary samples, but not in ponatinib-resistant Ba/F3 cells and primary samples. Thus, an alternative strategy may be required to improve the prognosis of Philadelphia-chromosome-positive leukemia patients harboring BCR-ABL point mutations.
Intranasal insulin delivery and therapy1Abbreviations: α-CD, α-cyclodextrin; β-CD, β-cyclodextrin; γ-CD, γ-cyclodextrin; AUC, area under the plasma/serum concentration versus time curve; Cmax, maximum or peak plasma/serum concentration; Cmin, minimum plasma/serum concentration; DDPC, didecanoyl-L-α-phosphatidylcholine; DM-β-CD, dimethyl-β-cyclodextrin; EDTA, ethylenediaminetetraacetic acid; FITC, fluorescein isothiocyanate; HLB, hydrophile–lipophile balance; hGH, human growth hormone; HP-β-CD, …
Authors: Michael Hinchcliffe, Lisbeth Illum
Journal: Advanced Drug Delivery Reviews (1999)
Double induction strategy including high dose cytarabine in combination with all-trans retinoic acid: effects in patients with newly diagnosed acute promyelocytic leukemia
Authors: E Lengfelder, A Reichert, C Schoch, D Haase, T Haferlach, H Löffler, P Staib, A Heyll, W Seifarth, S Saussele, C Fonatsch, W Gassmann, W-D Ludwig, A Hochhaus, D Beelen, C Aul, M-C Sauerland, A Heinecke, R Hehlmann, B Wörmann, W Hiddemann, T Büchner
Journal: Leukemia (2000)
Early Cannabis Use, Polygenic Risk Score for Schizophrenia and Brain Maturation in Adolescence
Authors: Leon French, Courtney Gray, Gabriel Leonard, Michel Perron, G. Bruce Pike, Louis Richer, Jean R. Séguin, Suzanne Veillette, C. John Evans, Eric Artiges, Tobias Banaschewski, Arun W. L. Bokde, Uli Bromberg, Ruediger Bruehl, Christian Buchel, Anna Cattrell, Patricia J. Conrod, Herta Flor, Vincent Frouin, Jurgen Gallinat, Hugh Garavan, Penny Gowland, Andreas Heinz, Herve Lemaitre, Jean-Luc Martinot, Frauke Nees, Dimitri Papadopoulos Orfanos, Melissa Marie Pangelinan, Luise Poustka, Marcella Rietschel, Michael N. Smolka, Henrik Walter, Robert Whelan, Nic J. Timpson, Gunter Schumann, George Davey Smith, Zdenka Pausova, Tomáš Paus
Journal: JAMA Psychiatry (2015)

Cannabis use during adolescence is known to increase the risk for schizophrenia in men. Sex differences in the dynamics of brain maturation during adolescence may be of particular importance with regard to vulnerability of the male brain to cannabis exposure.
Mania in late life: focus on age at onset
Authors: R C Young, G L Klerman
Journal: American Journal of Psychiatry (1992)

The authors review current understanding of manic syndromes and bipolar disorders in the elderly, emphasizing the limited number of systematic studies available. Discussion is focused on the validity of late age at onset as a nosologic distinction in geriatric patients. This issue is contrasted with possible age-associated effects on early-onset illness. Data regarding incidence and prevalence in the elderly are assessed, and the high average age at onset of mania is noted. The review cites evidence that relatively low rates of familial affective disorder and increased frequency of certain diseases and drug use are associated with late age at onset. Aspects of psychopathology in the elderly, course of illness, and outcomes including chronicity, mortality, and cognitive impairment/dementia are considered. Management of these elderly patients is briefly discussed, highlighting questions concerning response to lithium salts.
Declining Rates of Extracapsular Extension After Radical Prostatectomy: Evidence for Continued Stage Migration
Authors: Faiyaaz M. Jhaveri, Eric A. Klein, Patrick A. Kupelian, Craig Zippe, Howard S. Levin
Journal: Journal of Clinical Oncology (1999)

Prostate-specific antigen (PSA)-based screening is responsible for a profound clinical stage migration in newly detected prostate cancers. Extracapsular extension (ECE) is an important predictor of outcome after radical prostatectomy (RP). We examined trends in the rate of ECE for cancers detected by PSA screening in 731 RP specimens between 1987 and 1997, when screening became routine urologic practice in the United States.The rates of ECE were examined in 311 prostates with nonpalpable (stage T1c) disease and 420 with palpable but clinically localized (stage T2) disease. Specimens were step-sectioned and examined by a senior pathologist. Rates of ECE were compared with respect to time, and logistic regression was used to identify predictors of ECE.The rate of ECE decreased from 81% to 36% during the 10-year observation period. Multivariateanalysis involving clinical tumor stage, preoperative serum PSA level, and Gleason score demonstrated that year of treatment was an independent predictor of ECE, with a two-fold reduction of risk occurring during the study period (P <. 001; odds ratio, 1.96; 95% confidence interval, 1.37 to 2.78).PSA screening has resulted in a downward trend in pathologic stage in clinically localized prostate cancer, independent of preoperative PSA level, tumor stage, and Gleason score. This time-dependent downward stage migration suggests the need for continuous updating of predictive nomograms and caution in interpreting differences in contemporarily treated patients compared with historical controls. Further study is needed to determine whether this trend will translate into improved disease-free survival.