tbuckley/cabot-search huggingface dataset:
The use of high frequency chest wall oscillation during an acute infective pulmonary exacerbation of cystic fibrosis
Authors: Ann Banks, Georgina Davies, Penny Agent, Leyla Osman, Diana Bilton, Margaret Hodson
Journal: European Respiratory Journal (2012)

BACKGROUND Cystic fibrosis (CF) patients hospitalised for an acute infective pulmonary exacerbation require increased airway clearance. Specialist physiotherapists may be a limited resource. We investigated the use of high frequency chest wall oscillation (HFCWO), in addition to 'usual' airway clearance techniques (ACTs).

OBJECTIVE The aim was to assess the utility of HFCWO (The Vest® Airway Clearance System, Hill-Rom) as a self administered therapy compared to European ACTs in facilitating recovery from an acute infective pulmonary exacerbation in people with CF when used in addition to supervised physiotherapy.

METHOD A non-blinded randomised, controlled design was used. Patients who met inclusion criteria were randomised to control or HFCWO groups. All patients received four daily sessions, two supervised by a specialist CF physiotherapist and two carried out independently. The control group carried out their usual ACTs, the study group used HFCWO with pauses to huff and cough. The primary outcome measurement was change in FEV1.

RESULTS n = 36 (64% male). Data was analysed using the Wilcoxon Rank Sum test.

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CONCLUSION Change in FEV1 was not significantly different between groups, however a significant improvement in FVC was demonstrated. HFCWO should be further explored as an adjunct in treatment of infective pulmonary exacerbations of CF.
Association Between Visceral and Subcutaneous Adipose Depots and Incident Cardiovascular Disease Risk Factors
Authors: Tobin M. Abraham, Alison Pedley, Joseph M. Massaro, Udo Hoffmann, Caroline S. Fox
Journal: Circulation (2015)

Background— Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) vary in volume and quality. We evaluated whether fat volume or attenuation (indirect measure of quality) predicts metabolic risk factor changes. Methods and Results— Framingham Heart Study Multi-detector Computed Tomography Substudy participants (n=1730, 45% women) were followed up over a mean of 6.2 years. Baseline VAT and SAT volume (in cm 3 ) and attenuation (in Hounsfield units) were assessed. Outcomes included blood pressure, lipids, and glucose. We constructed multivariable regression models predicting change from baseline to follow-up. Baseline VAT was associated with metabolic risk factors at follow-up. Per 500-cm 3 increase in baseline VAT, glucose was 2.34 mg/dL higher (95% confidence interval, 1.71–2.97) and high-density lipoprotein was 1.62 mg/dL lower (95% confidence interval, 0.97–2.28) in women ( P &lt;0.0001 for both). These findings remained significant after adjustment for body mass index. Results for SAT were similar although less striking. Lower (more negative) fat attenuation was associated with more adverse metabolic profiles at follow-up. For example, per 5-unit decrease in baseline VAT Hounsfield units, log triglycerides increased by 0.08 mg/dL (95% confidence interval, 0.05–0.12; P =0.005), which remained significant after adjustment for baseline VAT. Among men, VAT and SAT Hounsfield units were associated with changes in cardiovascular disease risk factors but were mostly attenuated after baseline volume adjustment. Conclusions— VAT volume and SAT volume are associated with incident metabolic risk factors beyond overall adiposity. Decreases in fat attenuation are also associated with incident risk factors. These findings suggest that both volume and quality of VAT and SAT contribute to metabolic risk.
The role of physiological deadspace and shunt in the gas exchange of patients with pulmonary hypertension: a study of exercise and prostacyclin infusion
Authors: B Otulana, T Higenbottam
Journal: European Respiratory Journal (1988)

Haemodynamic and gas exchange measurements were made at rest, on supine exercise and on acute vasodilatation with intravenous prostacyclin in eight patients with pulmonary hypertension. This enabled an assessment of the contribution of V/Q imbalance to the abnormal gas exchange on the condition. At rest arterial oxygen tension, PaO2 (mean 8.1 +/- 1.7 kPa) and mixed venous oxygen tension, PVO2 (3.6 +/- 0.4) were reduced. The physiological shunt, Qs/Qt (15 +/- 17%) and the dead space, Vd/Vt (0.47 +/- 0.11) were elevated above normal. Exercise produced an increase in cardiac index, a fall in PVO2, no significant change in PaO2 and also no appreciable changes in the Vd/Vt and Qs/Qt. Intravenous prostacyclin increased the cardiac index and raised the PVO2 and the PaO2 but again with no significant changes in Vd/Vt and Qs/Qt. We conclude that ventilation-perfusion imbalance as shown by increased Vd/Vt and Qs/Qt, contributes significantly to the abnormal gas exchange in pulmonary hypertension. But neither index was altered by exercise or vasodilation; the latter improves the hypoxemia by increasing the PVO2 from an increase in the cardiac output.
Studies on the Relation of Membrane Immunofluorescence to Epstein-Barr Virus Infection&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Virginia C. Dunkel, Robert F. Zeigel
Journal: JNCI Journal of the National Cancer Institute (1970)

A comparison was made between the presence of cell-surface antigen, as determined by indirect membrane immunofluorescence, and the presence of Epstein-Barr (EB) virus antigen, as determined by direct immunofluorescence on acetone-fixed cells, in HR1-K, Raji, 64-10, and 64-10 INF cells. All sera tested with the EB virus-containing cell lines HR1-K and 64-10 INF were positive for membrane immunofluorescence, and a direct relationship existed between virus infection and membrane reactivity. Electron microscopic studies further revealed that only surface membranes of virus-producing cells in the HR1-K and 64-10 INF cultures were covered with a layer of antibody. The 64-10 cell line was negative in both tests. The Raji cell line was negative when tested for virus; however, 5 of 18 sera from patients with Burkitt's lymphoma did contain antibodies reacting with surface antigens in a small percentage of cells. It was observed also that fluorescence at the membrane can result from adsorption of EB virus particles onto the surface of uninfected cells.
Significance of age, tumor location and histological subtype in lung cancer with brain metastasis
Authors: Katalin Fábián, Márton Gyulai, József Furák, Márta Jäckel, Péter Várallyay, Judit Pápay, György Losonczy, Judit Moldvay
Journal: European Respiratory Journal (2013)

Development of brain metastasis is common in lung cancer and influences both the quality of life and the overall survival of the patients.  We studied the clinico-pathological data of 1025 patients, who had cytologically or histologically confirmed lung cancer. Of them 575 patients had brain metastasis that was diagnosed by CT scan or MRI. 450 patients, who did not develop cerebral metastasis during long-term follow up served as a control.  Brain metastasis was found to develop more frequently in younger patients (59.5 years versus 62.2 years, p  Our results suggest that brain metastasis is more common in lung ADC and SCLC. Furthermore, patients with younger age, female gender and tumors in the central airways have a higher risk to develop brain metastasis.
VX‐509 (Decernotinib), an Oral Selective JAK‐3 Inhibitor, in Combination With Methotrexate in Patients With Rheumatoid Arthritis
Authors: Mark C. Genovese, Ronald F. van Vollenhoven, César Pacheco‐Tena, Yanqiong Zhang, Nils Kinnman
Journal: Arthritis & Rheumatology (2015)

Objective To assess the efficacy and safety of decernotinib (VX‐509), an oral selective inhibitor of JAK‐3, in patients with rheumatoid arthritis (RA) in whom the response to methotrexate treatment was inadequate. Methods In this 24‐week, double‐blind, randomized phase IIb study, 358 patients with active RA received either placebo (n = 71) or VX‐509 at dosages of 100 mg/day (n = 71), 150 mg/day (n = 72), 200 mg/day (n = 72), or 100 mg twice daily (n = 72). Primary measures of efficacy at week 12 were the response rate according to the American College of Rheumatology 20% improvement criteria (ACR20) and change from baseline in the Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP). Results At week 12, the ACR20 response rates were 46.5%, 66.7%, 56.9%, and 68.1% in the groups receiving VX‐509 at dosages of 100 mg/day, 150 mg/day, 200 mg/day, and 100 mg twice daily, respectively, and 18.3% in the placebo group ( P &lt; 0.001 for all comparisons). At week 12, the mean change from baseline in the DAS28‐CRP was significantly greater in each VX‐509 group compared with the placebo group ( P &lt; 0.001). Improvements were maintained at week 24, as shown by the ACR20, ACR50, and ACR70 response rates and mean change from baseline in the DAS28‐CRP. The most common adverse event in the VX‐509 group was headache (8.7%), and elevated levels of transaminases, lipoproteins, and creatinine were observed. Conclusion VX‐509 significantly improved the signs and symptoms of RA at weeks 12 and 24 compared with the placebo group when it was administered in combination with methotrexate. Safety signals included infection and increases in liver transaminase and lipid levels.
A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis
Authors: A Pardanani, A Tefferi, C Jamieson, N Y Gabrail, C Lebedinsky, G Gao, F Liu, C Xu, H Cao, M Talpaz
Journal: Blood Cancer Journal (2015)

Abstract In this phase 2 open-label randomized study, 31 patients with intermediate-2 or high-risk myelofibrosis received fedratinib 300, 400 or 500 mg once daily in consecutive 4-week cycles. Mean spleen volume reductions at 12 weeks (primary end point) were 30.3% (300 mg), 33.1% (400 mg) and 43.3% (500 mg). Spleen response rates (patients achieving ⩾35% spleen reduction) at 12/24 weeks were 30%/30% (300 mg), 50%/60% (400 mg) and 64%/55% (500 mg), respectively. By 4 weeks, improvements in myelofibrosis (MF)-associated symptoms were observed. At 48 weeks, 68% of patients remained on fedratinib and 16% had discontinued because of adverse events (AEs). Common grade 3/4 AEs were anemia (58%), fatigue (13%), diarrhea (13%), vomiting (10%) and nausea (6%). Serious AEs included one case of reversible hepatic failure and one case of Wernicke’s encephalopathy (after analysis cutoff). Fedratinib treatment led to reduced STAT3 phosphorylation but no meaningful change in JAK2 V617F allele burden. Significant modulation ( P&lt; 0.05, adjusted for multiple comparisons) of 28 cytokines was observed, many of which correlated with spleen reduction. These data confirm the clinical activity of fedratinib in MF. After the analysis cutoff date, additional reports of Wernicke's encephalopathy in other fedratinib trials led to discontinuation of the sponsored clinical development program.
Total-Body Examination vs Lesion-Directed Skin Cancer Screening
Authors: Isabelle Hoorens, Katrien Vossaert, Lore Pil, Barbara Boone, Sofie De Schepper, Katia Ongenae, Lieven Annemans, Ines Chevolet, Lieve Brochez
Journal: JAMA Dermatology (2015)

Skin cancer is the most frequent cancer type. It remains unknown if and how screening programs can be organized in a cost-effective manner.To compare the 2 screening strategies of systematic total-body examination (TBE) and lesion-directed screening (LDS), with a focus on the participation rate, detection rate, anxiety, and cost.Population-based cross-sectional screenings by a team of 6 dermatologists were organized in 2 sociodemographically similar regions. The TBE was organized in a community of 9325 inhabitants 18 years and older (Wichelen, East Flanders, Belgium) during a 5-day screening (March 14-18, 2014). The LDS was organized in a sociodemographically comparable community (Nevele, East Flanders, Belgium) of 9484 adult inhabitants during a 4-day screening (April 22 and 25-27, 2014). The first population received a personal invitation for a standard TBE. In the second population, individuals were invited for an LDS if they had a lesion meeting 1 or more of the following criteria: ABCD rule (A, asymmetry; B, borders; C, colors; and D, differential structures), ugly duckling sign, new lesion lasting longer than 4 weeks, or red nonhealing lesions.In total, 1982 individuals were screened, and 47 skin cancers (2.4%) were histologically confirmed, including 9 melanomas (0.5%), 37 basal cell carcinomas (1.9%), and 1 squamous cell carcinoma or Bowen disease (0.1%).The positive predictive value for all suspicious lesions was 56.6% (47 of 83). The participation rate was 17.9% (1668 of 9325) in the TBE group vs 3.3% (314 of 9484) in the LDS group (P < .01). The skin cancer detection rate per 100 participants did not differ significantly between the 2 groups, with rates of 2.3% (39 of 1668) in the TBE group vs 3.2% (8 of 248) in the LDS group (P = .40). The operational effectiveness per 100 invitees was 0.4% (39 of 9325) in the TBE group vs 0.1% (8 of 9484) in the LDS group (P < .01). In addition, LDS was 5.6 times less time consuming than TBE. Participants in the LDS group had significantly higher baseline anxiety levels compared with participants in the TBE group (3.7 vs 3.3 points on a visual analog scale, P < .01). In screenees without a suspicious lesion, anxiety levels significantly dropped after screening.Total-body examination yielded a higher absolute number of skin cancers. Lesion-directed screening had a similar detection rate of 3.2% (8 of 248) but was 5.6 times less time consuming. When performed by dermatologists, LDS is an acceptable alternative screening method in health care systems with limited budgets or long waiting lists.
Abstract 274: Physical Coupling Supports Local Ca2+ Coupling Between SR Subdomains and the Mitochondria in Heart Muscle
Authors: Cecilia Garcia-Perez, Gyorgy Hajnoczky, Gyorgy Csordas
Journal: Circulation (2007)

Propagation of ryanodine receptor (RyR) dependent SR Ca2+ release to the mitochondria is locally supported by high [Ca2+] microdomains at close contacts between the organelles. The objective of this study was to clarify if the close associations of SR and mitochondria underlying the local Ca2+ communication were secured via a physical coupling. Crude and Percoll-purified mitochondrial fractions of rat heart homogenates were tested for the presence of mitochondria-associated SR fragments capable of RyR-dependent Ca2+ mobilization and Ca2+ delivery to the mitochondria. SR and mitochondrial marker proteins were analyzed by Western blot or visualized in situ by immunofluorescent labeling and imaged using confocal microscopy. Mitochondrial matrix [Ca2+] ([Ca2+]m) was monitored using fluorescence imaging of rhod-2-loaded adherent individual vesicles. Ample presence of SR markers (calsequestrin, SERCA2a, phospholamban) was detected in the crude mitochondria, whereas after percoll purification they were barely detectable in the ‘heavy’ fraction but remained present in the ‘light’ fraction. ‘Immunomitochemistry’ revealed various sizes of SR particles in the crude fraction, a large portion of which was colocalized with mitochondria, while showed less SR markers in the percoll-purified heavy fraction. Fluorescence Ca2+ imaging in the adherent particles revealed well-detectable [Ca2+]m responses to caffeine stimulation that was prevented by Ca2+ predepletion of the SR using the SERCA inhibitor thapsigargin (Tg), or by inhibitors of mitochondrial Ca2+ uptake. Because the Ca2+ released from SR was diluted in the large volume of the incubation medium without causing a change in the bulk [Ca2+], only local Ca2+ regulation could mediate the Ca2+ transfer to the mitochondria. Despite the hardly detectable presence of SR, the percoll-purified ‘heavy’ mitochondrial fraction still displayed a caffeine-induced [Ca2+]m rise that was abolished by Tg-pretreatment. Our data suggest that the SR-mitochondrial associations where the local Ca2+ coupling is established, are supported by physical links between the two organelles and the mitochondria bound SR surface represents a relatively small fraction of the total SR.
Distinguishing pulmonary hypertension in interstitial lung disease by ventilation and perfusion defects as measured by cardiopulmonary exercise testing
Authors: Matthew Bartels, Wilawan Thirapatarapon, Hilary Armstrong
Journal: European Respiratory Journal (2012)

Introduction: Pulmonary hypertension (PH) is common in interstitial lung disease (ILD) and is associated with worse prognosis. Comparing ventilation (VD) and perfusion defects (PD) on cardiopulmonary exercise testing (CPET) can detect PH, but has not been assessed in ILD.

Aims and Objectives: We proposed using CPET to detect PH in patients with ILD by assessment of VD and PD by mixed expired CO2 (PeCO2) and end-tidal CO2 (PetCO2).

Methods: 75 patients with ILD referred for CPET were included who had pulmonary function tests, right heart catheterization, CPET all done within 4 months of each other. Data were assessed at rest, end of unloaded warm up (WU), ventilatory threshold (VT), and peak exercise (PE) for PeCO2, PetCO2, PeCO2/PetCO2 and the activity pattern of PeCO2 versus PetCO2.

Results: ILD patients with PH demonstrated significantly lower PetCO2 and PeCO2 at all levels of exercise and low PeCO2/PetCO2 only at WU.

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VD and PD in CPET in ILD patients





Activity pattern has marked changes with exercise in ILD patients with PH.

![Figure][1] 



Conclusions: Evaluation of ventilation and perfusion defects by CPET can detect pulmonary hypertension in patients with ILD.

 [1]: pending:yes
PRE-FRONTAL LOBOTOMY
Authors: JOSEF A. KINDWALL, DAVID CLEVELAND
Journal: American Journal of Psychiatry (1945)

The 15 cases reported range in age from 16 to 62, and presented a wide variety of symptoms, from apparent psychotic deterioration to a chronic but non-psychotic tension state. These patients were all considered to have a hopeless prognosis and most of them had been in hospital for many years, one continuously for 18 years. All but 4 had received one or more forms of shock treatment. The first lobotomy operation of the series was performed April 1, 1942, the last on January 28, 1944; hence the report cannot deal with end-results. However, the first patient is gainfully employed for the first time in his life, but has had a convulsive seizure; 5 of the others are with their families, comfortable and socially acceptable; one of them doing regular housework. One patient is attending a special school. The rest are still in hospital but one of them has freedom of the grounds, not possible before, and makes day-visits away from the hospital. None of the 15, so far, was made worse, and all showed some degree of improvement. Two aged patients, not included in this series, died of post-operative hypostatic pneumonia. Each patient's history is presented as a graph representing onset of illness, the time of hospital residence, and the patient's status in the categories of mental comfort, social acceptability, and capacity for work, before and after lobotomy. (Only 5 representative graphs are reproduced here.) The technique of the operation, its dangers, and the anatomical considerations involved are briefly discussed. It is suggested that anxiety may be an important common factor in a wide variety of syndromes, allayed by lobotomy; and that the operation may intervene to modify the physical basis for a pathogenic degree of "cerebrotonia." In some cases, edema and/or tenderness and blister formation appeared during the month following lobotomy, and is thought to be a trophic disturbance of central origin. There has also been transient diuresis with low specific gravity, in connection with prolonged or periodic enuresis.
Airflow Limitation and Histology Shift in the National Lung Screening Trial. The NLST-ACRIN Cohort Substudy
Authors: Robert P. Young, Fenghai Duan, Caroline Chiles, Raewyn J. Hopkins, Greg D. Gamble, Erin M. Greco, Constantine Gatsonis, Denise Aberle
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Annual computed tomography (CT) is now widely recommended for lung cancer screening in the United States, although concerns remain regarding the potential harms, including those from overdiagnosis.To examine the effect of airflow limitation on overdiagnosis by comparing lung cancer incidence, histology, and stage shift in a subgroup of the National Lung Screening Trial (NLST).In an NLST subgroup (n = 18,714), screening participants were randomized to annual computed tomography (CT, n = 9,357) or chest radiograph (n = 9,357) screening and monitored for a mean of 6.1 years. After baseline prebronchodilator spirometry, to identify the presence of airflow limitation, 18,475 subjects (99%) were assigned as having chronic obstructive pulmonary disease (COPD) or no COPD. Lung cancer prevalence, incidence, histology, and stage shift were compared after stratification by COPD.For screening participants with spirometric COPD (n = 6,436), there was a twofold increase in lung cancer incidence (incident rate ratio, 2.15; P < 0.001) and, when compared according to screening arm, no excess lung cancers and comparable histology. Compared with chest radiography, there was also a trend favoring reduced late-stage and increased early-stage cancers in the CT arm (P = 0.054). For those with normal baseline spirometry (n = 12,039), we found an excess of lung cancers during screening in the CT arm, almost exclusively early-stage adenocarcinoma-related cancers (histology shift and overdiagnosis). After correction for these excess cancers, stage shift was marginal (P = 0.077).In the CT arm of the NLST-ACRIN (American College of Radiology Imaging Network) cohort, COPD status was associated with a doubling of lung cancer incidence, no apparent overdiagnosis, and a more favorable stage shift.
Preclinical evaluation of GSK2245035, a potent and selective toll-like receptor 7 (TLR7) agonist
Authors: Diana Quint, Jo Hessey, Diane Coe, Fiona Priest, Aimee Hillegas, Deidre Dalmas Wilk, Mark Price, Chris Edwards, Keith Biggadike
Journal: European Respiratory Journal (2014)

Introduction GSK2245035 is a novel small molecule TLR7 agonist in development as an immunomodulatory, intranasal treatment for allergic airways disease aiming to reduce Th2 and enhance Th1/Treg responses to aeroallergens via the local induction of type1 interferons (IFN).

Methods Human blood and PBMC assays were conducted to determine the potency of GSK2240035 for IFNα vs TNFα induction. The immunomodulatory effect of GSK2245035 on T cell cytokine responses was assessed in allergen activated human PBMC cultures . In vitro profiling of GSK2245035 was conducted in Cynomolgus monkey blood; target engagement in the airways was evaluated by intranasal (IN) dosing to Cynomolgus monkeys and measuring nasal scrape IFN stimulated gene expression (ISG) and systemic biomarkers.

Results GSK2245035 is a highly potent TLR7 agonist inducing IFNα production in human in vitro assays (pEC50 PBMC 9.7: blood 9.2) whilst showing selectivity over TNFα induction (pEC50 PBMC 6.4: blood 4.9). Other cytokines (IL12, IFNγ and IL10) that regulate Th2 cell responses were also induced. GSK2245035 reduced levels of Th2 cytokines released in allergen driven atopic PBMC cultures and enhanced IL10 and IFNγ production. GSK2245035 showed comparable IFNα potency and IFNα/TNFα selectivity in Cynomolgus monkey and human blood cultures. IN delivery in Cynomolgus monkeys enabled identification of a panel of ISGs upregulated in nasal tissue and systemic biomarkers of target engagement (IP-10).

Conclusions GSK2245035 is a potent inducer of IFNα and modulates the Th2 response to allergens in vitro . PD biomarkers of target engagement in Cynomolgus monkey were identified aiding selection of starting dose in clinical studies.