tbuckley/cabot-search huggingface dataset:
Effect of Lung Volume Reduction Surgery on Diaphragm Length in Severe Chronic Obstructive Pulmonary Disease
Authors: YAROSLAV LANDO, PHILLIP M. BOISELLE, DANIEL SHADE, SATOSHI FURUKAWA, ANNE MARIE KUZMA, JOHN M. TRAVALINE, GERARD J. CRINER
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Lung volume reduction surgery (LVRS) has been suggested as improving respiratory mechanics in patients with severe chronic obstructive pulmonary disease (COPD). We hypothesized that LVRS might lengthen the diaphragm, increase its area of apposition with the chest wall, and thereby improve its mechanical function. To determine the effect of bilateral LVRS on diaphragm length, we measured diaphragm length at TLC, using plain chest roentgenograms (CXRs), in 25 patients (11 males and 14 females) before LVRS and 3 to 6 mo after LVRS. A subgroup of seven patients (reference data) also had diaphragm length measurements made with CXRs, using films made within a year before their presurgical evaluation. Right hemidiaphragm silhouette length (PADL) and the length of the most vertically oriented portion of the right hemidiaphragm muscle (VDML) were measured. Diaphragm dome height was determined from the: (1) distance between the dome and transverse diameter at the manubrium; and (2) highest point of the dome referenced horizontally to the vertebral column. Patients also underwent spirometry, measurements of lung volumes and diffusion capacity, an incremental symptom-limited maximum exercise test, and measurements of 6 min walk distance (6MWD) and transdiaphragmatic pressures during maximum static inspiratory efforts (Pdimax sniff) and bilateral supramaximal electrophrenic twitch stimulation (Pditwitch) both before and 3 mo after LVRS. Patients were 58 +/- 8 yr of age, with severe COPD and hyperinflation (FEV1 = 0.68 +/- 0.23 L, FVC = 2.56 +/- 7.3 L, and TLC = 143 +/- 22% predicted). Following LVRS, PADL increased by 4% (from 13.9 +/- 1.9 cm to 14.5 +/- 1.7 cm; p = 0.02), VDML increased by 44% (from 2.08 +/- 1.5 cm to 3.00 +/- 1.6 cm, p = 0.01), and diaphragm dome height increased by more than 10%. In contrast, diaphragm lengths were similar in subjects with CXRs made before LVRS and within 1 yr before evaluation. The increase in diaphragm length correlated directly with postoperative reductions in TLC and RV, and also with increases in transdiaphragmatic pressure with maximal sniff (Pdimax sniff), maximal oxygen consumption (V O2max), maximal minute ventilation (V Emax), and maximum voluntary ventilation following LVRS. We conclude that LVRS leads to a significant increase in diaphragm length, especially in the area of apposition of the diaphragm with the rib cage. Diaphragm lengthening after LVRS is most likely the result of a reduction in lung volume. Increases in diaphragm length after LVRS correlate with postoperative improvements in diaphragm strength, exercise capacity, and maximum voluntary ventilation.
Bronchoscopic and bronchographic findings in 12 patients with sarcoidosis and severe or progressive airways obstruction.
Authors: Z F Udwadia, J R Pilling, P F Jenkins, B D Harrison
Journal: Thorax (1990)

Twelve patients (8 men), aged 33-67 (mean 49) years, with histologically proved sarcoidosis underwent bronchoscopy. All had symptoms, signs (wheeze in 11, high pitched inspiratory "squeaks" in six, stridor in three), and physiological abnormalities characteristic of severe or worsening airways obstruction. Eleven patients also underwent bronchography. At the time of bronchoscopy four patients had stage II, one stage III, and seven stage IV sarcoidosis. All patients had a peak expiratory flow (PEF) of 70% predicted or less and a maximum expiratory flow at 50% (MEF50) and 25% (MEF25) of vital capacity below 35% predicted. The ratio of their forced expiratory volume in one second to forced vital capacity (FEV1/FVC) ranged from 37% to 65%. Fibreoptic bronchoscopy showed single or multiple areas of segmental bronchial stenoses in 10 patients, two of whom had stenotic webs. Bronchography showed that the sites and severity of stenoses were more widespread than suspected from the bronchoscopic findings. Five of the 11 patients undergoing bronchography had bronchiectasis, which was restricted to the upper lobes in three and a lower lobe in one and affected both upper and lower lobes in one patient. The bronchiectasis had not been suspected or diagnosed from the chest radiography or the bronchoscopy.
Transesophageal Endoscopic Ultrasound with Fine Needle Aspiration in the Preoperative Staging of Malignant Pleural Mesothelioma
Authors: Kurt G. Tournoy, Sjaak A. Burgers, Jouke T. Annema, Frank Vermassen, Marleen Praet, Marianne Smits, Houke M. Klomp, Jan P. van Meerbeeck, Paul Baas
Journal: Clinical Cancer Research (2008)

Surgical resection as part of a multimodality approach in malignant pleural mesothelioma (MPM) has a high morbidity and mortality. Because mediastinal lymph node (MLN) metastases are a negative prognostic factor, preoperative staging is of paramount importance. Transesophageal endoscopic ultrasound with real-time guided fine needle aspiration (EUS-FNA) enables accurate MLN staging in lung cancer.The feasibility and yield of EUS-FNA in MLN staging were prospectively analyzed in patients with presumed early-stage MPM considered for multimodality therapy. MLN reference pathology was defined by either pathologic staging or the formal demonstration of malignant cells by either EUS-FNA or mediastinoscopy.Thirty-two consecutive patients (81% males; median age, 61 years) with proven MPM underwent EUS-FNA. In 11 (34%) patients, a negative EUS-FNA or mediastinoscopy was not confirmed by surgical MLN dissection because of clinical deterioration or disease progression. In 21 (66%) patients, a formal pathology of the MLN was obtained and staging with EUS-FNA was positive in 4 (19%). Mediastinoscopy did not result in a greater yield of MLN metastasis as compared with EUS-FNA. Thoracotomy with complete lymph node dissection was done in 17 (81%). The overall prevalence of MLN metastasis was 24%, and the sensitivity of EUS-FNA was 80% (95% confidence interval, 28-99%) with a specificity of 100% (95% confidence interval, 79-100%). One patient had esophageal perforation related to EUS-FNA.EUS-FNA is feasible and sensitive for MLN staging in patients with MPM who are candidate for multimodality treatment. These data warrant further evaluation.
High Prognostic Value of p16<sup><i>INK4</i></sup> Alterations in Gastrointestinal Stromal Tumors
Authors: Regine Schneider-Stock, Carsten Boltze, Jerzy Lasota, Markku Miettinen, Brigitte Peters, Matthias Pross, Albert Roessner, Thomas Günther
Journal: Journal of Clinical Oncology (2003)

Gastrointestinal stromal tumors (GISTs) represent a distinctive (but histologically heterogeneous) group of neoplasms, the malignant potential of which is often uncertain. To determine the prognostic relevance of p16INK4 alterations in GISTs, we investigated a larger group of GISTs and correlated the genetic findings with clinicopathological factors and patient survival.We evaluated the methylation status of the promotor by methylation-specific polymerase chain reaction (PCR), the presence of mutations by PCR-SSCP-sequencing, the loss of heterozygosity at the p16INK4 locus (using the c5.1 marker), and the immunohistochemical expression of p16INK4 protein in 43 GISTs in 39 patients.p16INK4 alterations were found in 25 of 43 GISTs (58.1%), with benign, borderline, or malignant GISTs showing no differences in the type and frequency of alteration. p16INK4 alterations were correlated with a loss of p16INK4 protein expression (P <.01). Patients who had tumors with p16INK4 alterations had a poorer prognosis than patients with tumors without such alterations (P =.02). There was a high predictive value for p16INK4 alterations only in the group of benign and borderline GISTs (P <.01) with regard to clinical outcome. Univariate Cox's proportional hazard regression analysis revealed a strong correlation between p16INK4 alterations, tumor size, mitotic index, and overall survival (P <.02), whereas multivariate Cox's analysis confirmed only p16INK4 alterations as an independent prognostic factor.We believe that the evaluation of p16INK4 alteration status is a helpful prognosticator, particularly in the benign and borderline groups of GISTs.
The G protein βγ subunit mediates reannealing of adherens junctions to reverse endothelial permeability increase by thrombin
Authors: Nebojsa Knezevic, Mohammad Tauseef, Tracy Thennes, Dolly Mehta
Journal: The Journal of Experimental Medicine (2009)

The inflammatory mediator thrombin proteolytically activates protease-activated receptor (PAR1) eliciting a transient, but reversible increase in vascular permeability. PAR1-induced dissociation of Gα subunit from heterotrimeric Gq and G12/G13 proteins is known to signal the increase in endothelial permeability. However, the role of released Gβγ is unknown. We now show that impairment of Gβγ function does not affect the permeability increase induced by PAR1, but prevents reannealing of adherens junctions (AJ), thereby persistently elevating endothelial permeability. We observed that in the naive endothelium Gβ1, the predominant Gβ isoform is sequestered by receptor for activated C kinase 1 (RACK1). Thrombin induced dissociation of Gβ1 from RACK1, resulting in Gβ1 interaction with Fyn and focal adhesion kinase (FAK) required for FAK activation. RACK1 depletion triggered Gβ1 activation of FAK and endothelial barrier recovery, whereas Fyn knockdown interrupted with Gβ1-induced barrier recovery indicating RACK1 negatively regulates Gβ1-Fyn signaling. Activated FAK associated with AJ and stimulated AJ reassembly in a Fyn-dependent manner. Fyn deletion prevented FAK activation and augmented lung vascular permeability increase induced by PAR1 agonist. Rescuing FAK activation in fyn−/− mice attenuated the rise in lung vascular permeability. Our results demonstrate that Gβ1-mediated Fyn activation integrates FAK with AJ, preventing persistent endothelial barrier leakiness.
Whole-exome resequencing distinguishes cystic kidney diseases from phenocopies in renal ciliopathies
Authors: Heon Yung Gee, Edgar A. Otto, Toby W. Hurd, Shazia Ashraf, Moumita Chaki, Andrew Cluckey, Virginia Vega-Warner, Pawaree Saisawat, Katrina A. Diaz, Humphrey Fang, Stefan Kohl, Susan J. Allen, Rannar Airik, Weibin Zhou, Gokul Ramaswami, Sabine Janssen, Clementine Fu, Jamie L. Innis, Stefanie Weber, Udo Vester, Erica E. Davis, Nicholas Katsanis, Hanan M. Fathy, Nikola Jeck, Gunther Klaus, Ahmet Nayir, Khawla A. Rahim, Ibrahim Al Attrach, Ibrahim Al Hassoun, Savas Ozturk, Dorota Drozdz, Udo Helmchen, John F. O'Toole, Massimo Attanasio, Richard A. Lewis, Gudrun Nürnberg, Peter Nürnberg, Joseph Washburn, James MacDonald, Jeffrey W. Innis, Shawn Levy, Friedhelm Hildebrandt
Journal: Kidney International (2013)
RESPONSE: Re: Folylpolyglutamyl Synthetase Gene Transfer and Glioma Antifolate Sensitivity in Culture and In Vivo
Authors: M Aghi, C M Kramm, X O Breakefield
Journal: JNCI Journal of the National Cancer Institute (1999)

Although antifolates are popular agents for use in chemotherapy, they display minimal toxicity against slow-growing tumors and are toxic to actively replicating cells in normal tissues. These drugs are converted intracellularly into polyglutamate derivatives by the enzyme folylpolyglutamyl synthetase (FPGS). Because tumors with high expression of FPGS often respond to nontoxic antifolate doses, we investigated whether augmenting tumoral FPGS activity by gene delivery would enhance tumoral antifolate sensitivity.9L rat gliosarcoma cells were stably transfected with a human FPGS complementary DNA (cDNA), producing 9L/FPGS cells. The sensitivity of these cells to the antifolates methotrexate and edatrexate was measured in culture and in subcutaneous tumors, as was their ability to increase the chemosensitivity of nearby nontransfected cells, i.e., a bystander effect. The antifolate sensitivity of nonselected cells transduced with a hybrid amplicon vector that expressed FPGS was also ascertained.In comparison with 9L cells, 9L/FPGS cells displayed enhanced sensitivity to 4-hour pulses of antifolate. Subcutaneous 9L/FPGS tumors responded as well to methotrexate given every third day as 9L tumors did to daily treatment. A modest bystander effect was observed with edatrexate treatment in culture and in vivo. The observed bystander effect appeared to result from the release of antifolates by transfected cells after the removal of extracellular drug. In culture, enhanced antifolate sensitivity was also seen in other stably transfected rodent and human glioma cell lines, including one with high pre-existing FPGS activity, and in canine and human glioblastoma cell lines transduced with a vector bearing FPGS cDNA.FPGS gene delivery enhances the antifolate sensitivity of several glioma cell lines and merits further evaluation as a therapeutic strategy.
British maternal mortality in the 19th and early 20th centuries
Authors: G. Chamberlain
Journal: Journal of the Royal Society of Medicine (2006)

In the 19th and first half of the 20th century, everybody knew about death in childbirth, particularly those women who were about to go through the process. Although death rates from many other conditions were high, they at least were among people who had been ill beforehand. Death in relation to childbirth was mostly in fit young women who had been quite well before becoming pregnant. They died, often leaving the baby, and other children in the family from previous births, with a widowed husband. It is only recently that the Church of England prayer book removed the service for the ‘churching of women who had recently given birth’ which starts by giving thanks to God for:
Aerosol kinetics and bronchodilator efficacy during continuous positive airway pressure delivered by face mask
Authors: S. N. Parkes, A. D. Bersten
Journal: Thorax (1997)

BACKGROUND: Rates of fresh gas flow (FGF) commonly used when continuous positive airway pressure (CPAP) is delivered by face mask theoretically reduce the delivery and availability of therapeutic aerosols. As it may be hazardous for patients with acute respiratory failure to interrupt mask CPAP, the effects of CPAP on aerosol kinetics and bronchodilator efficacy were investigated. METHOD: The effect of CPAP at 10 cm H2O at a FGF rate of 50 l/min on the delivery of technetium labelled aerosol generated from a readily available jet nebuliser was measured using a bench model of spontaneous respiration. In a separate clinical study the bronchodilator responses to incremental doses of nebulised salbutamol were measured in nine stable asthmatic subjects in a random sequence of conventional nebulisation (control) or nebulisation whilst receiving CPAP via a tight fitting face mask. Each patient acted as his or her own control. RESULTS: CPAP significantly reduced total aerosol delivery to the face mask from 6.85 (1.52)% to 1.3 (0.37)% of the initial nebuliser charge. In the clinical study a significant bronchodilator response to nebulised salbutamol was seen during both conventional nebulisation and nebulisation whilst receiving CPAP by face mask. The shape of the dose-response curves and the magnitude of the total increase in the forced expiratory volume in one second (FEV1) was identical for CPAP and control conditions. CONCLUSIONS: Despite a reduction in aerosol presented to the proximal airway, the bronchodilator response to inhaled beta 2 agonists in stable asthmatic subjects was not affected when CPAP was delivered by face mask. Despite a high rate of FGF, nebulised beta 2 agonists are effective when administered in conjunction with CPAP delivered by face mask.
Risk of Pneumonitis in Breast Cancer Patients Treated With Radiation Therapy and Combination Chemotherapy With Paclitaxel
Authors: A. G. Taghian, S. I. Assaad, A. Niemierko, I. Kuter, J. Younger, R. Schoenthaler, M. Roche, S. N. Powell
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: Some chemotherapy (CT) drugs, including taxanes, may enhance the effectiveness of radiation therapy (RT). However, combining these therapies may increase the incidence of radiation pneumonitis, a lung inflammation. In a retrospective cohort study, we evaluated the incidence of radiation pneumonitis in breast cancer patients treated with RT and standard adjuvant CT by use of doxorubicin (Adriamycin) and cyclophosphamide, with and without paclitaxel. Methods: Forty-one patients with breast cancer were treated with RT and adjuvant CT, including paclitaxel. Paclitaxel and RT (to breast– chest wall in all and lymph nodes in some) were delivered sequentially in 20 patients and concurrently in 21 patients. Paclitaxel was given weekly in some patients and every 3 weeks in other patients. The incidence of radiation pneumonitis was compared with that among patients in our database whose treatments did not include paclitaxel (n = 1286). The percentage of the lung volume irradiated was estimated. The Cox proportional hazards model was used to find covariates that may be associated with the observed outcomes. All P values were two-sided. Results: Radiation pneumonitis developed in six of the 41 patients. Three patients received paclitaxel concurrently with RT, and three received it sequentially (P = .95). The mean percentage of lung volume irradiated was 20% in patients who developed radiation pneumonitis and 22% in those who did not (P = .6). For patients treated with CT including paclitaxel, the crude rate of developing radiation pneumonitis was 14.6% (95% confidence interval [CI] = 5.6% to 29.2%). For patients treated with CT without paclitaxel, the crude rate of pneumonitis was 1.1% (95% CI = 0.2% to 2.3%). The difference between the crude rates with or without paclitaxel is highly statistically significant (P<.0001). The mean time to develop radiation pneumonitis in patients treated concurrently with RT and paclitaxel was statistically significantly shorter in patients receiving paclitaxel weekly than in those receiving it every 3 weeks (P = .002). Conclusions: The use of paclitaxel and RT in the primary treatment of breast cancer should be undertaken with caution. Clinical trials with the use of combination CT, including paclitaxel plus RT, whether concurrent or sequential, must evaluate carefully the incidence of radiation pneumonitis.
PERIPHERAL SHOCK AND ITS CENTRAL EFFECTS
Authors: J. L. Thomas
Journal: BMJ (1916)

PERIPHERA-L SHOCK,#[A. ,I1 anly otlher procedure nothing else could hlave been done, and yet I could niot butt sympathize witlh hiis conviction that such a step ouglit to lhave been avoided.Certificates are also objected to on account of tlle attendlant disturbance of btusiness affairs.A profes- sional mian lioldiing several appointimients suddenly lost hiis uleniory of recenit evenlts, altlhouIgh retaininig hiis general iintelligence.His affairs were nmanaged by hi,s son, wlo wvas hiis partner, to the satisfaction of every one.Unforttuniately, as so frequently lhappens, the old gentle- man became restless at niglht, and care in an institution was advised.He -was quite willing to go away volun- tarily, but owina to hiis defective mnemnory lhe could lhardly remiiain as a voluntary patienlt, not being able to remember his position.W'llen certificates were proposed it transpired tlhat they would mean a loss of £400 a year, as his appointments would lhave to be given up; and, inoreover, the
Severe lactic acidosis during treatment of chronic hepatitis B with entecavir in patients with impaired liver function
Authors: Christian M. Lange, Jörg Bojunga, Wolf Peter Hofmann, Katrin Wunder, Ulrike Mihm, Stefan Zeuzem, Christoph Sarrazin
Journal: Hepatology (2009)

Entecavir is a potent nucleoside inhibitor of the hepatitis B virus (HBV) polymerase with a high antiviral efficacy and a high genetic barrier to viral resistance. After approval in 2006, knowledge on the side effect profile in patients with advanced liver disease and impaired liver function is still limited. Here, we report on 16 patients with liver cirrhosis and chronic hepatitis B who were treated with entecavir. Five of these patients developed lactic acidosis during entecavir treatment. All patients who developed lactic acidosis had highly impaired liver function (Model for End-Stage Liver Disease [MELD] score >or= 20). Lactic acidosis (lactate 26-200 mg/dL, pH 7.02-7.40, base excess -5 mmol/L to -18 mmol/L) occurred between 4 and 240 days after treatment initiation with entecavir. Lactic acidosis was lethal in one patient but resolved in the other cases after termination/interruption of entecavir treatment. No increased lactate serum concentrations were observed during treatment with entecavir in the other 11 patients with chronic hepatitis B and liver cirrhosis who all had MELD scores below 18. The MELD score correlated with the development of lactic acidosis (P < 0.005) as well as its single parameters bilirubin, international normalized ratio, and creatinine. In contrast, Child-Pugh Score did not correlate with the development of lactic acidosis. Our data indicate that entecavir should be applied cautiously in patients with impaired liver function.
Technologies for global health
Authors: Peter Howitt, Ara Darzi, Guang-Zhong Yang, Hutan Ashrafian, Rifat Atun, James Barlow, Alex Blakemore, Anthony MJ Bull, Josip Car, Lesong Conteh, Graham S Cooke, Nathan Ford, Simon AJ Gregson, Karen Kerr, Dominic King, Myutan Kulendran, Robert A Malkin, Azeem Majeed, Stephen Matlin, Robert Merrifield, Hugh A Penfold, Steven D Reid, Peter C Smith, Molly M Stevens, Michael R Templeton, Charles Vincent, Elizabeth Wilson
Journal: The Lancet (2012)
The Design of Phase II Clinical Trials Testing Cancer Therapeutics: Consensus Recommendations from the Clinical Trial Design Task Force of the National Cancer Institute Investigational Drug Steering Committee
Authors: Lesley Seymour, S. Percy Ivy, Daniel Sargent, David Spriggs, Laurence Baker, Larry Rubinstein, Mark J. Ratain, Michael Le Blanc, David Stewart, John Crowley, Susan Groshen, Jeffrey S. Humphrey, Pamela West, Donald Berry
Journal: Clinical Cancer Research (2010)

The optimal design of phase II studies continues to be the subject of vigorous debate, especially studies of newer molecularly targeted agents. The observations that many new therapeutics "fail" in definitive phase III studies, coupled with the numbers of new agents to be tested as well as the increasing costs and complexity of clinical trials, further emphasize the critical importance of robust and efficient phase II design. The Clinical Trial Design Task Force (CTD-TF) of the National Cancer Institute (NCI) Investigational Drug Steering Committee (IDSC) has published a series of discussion papers on phase II trial design in Clinical Cancer Research. The IDSC has developed formal recommendations about aspects of phase II trial design that are the subject of frequent debate, such as endpoints (response versus progression-free survival), randomization (single-arm designs versus randomization), inclusion of biomarkers, biomarker-based patient enrichment strategies, and statistical design (e.g., two-stage designs versus multiple-group adaptive designs). Although these recommendations in general encourage the use of progression-free survival as the primary endpoint, randomization, inclusion of biomarkers, and incorporation of newer designs, we acknowledge that objective response as an endpoint and single-arm designs remain relevant in certain situations. The design of any clinical trial should always be carefully evaluated and justified based on characteristic specific to the situation.