tbuckley/cabot-search huggingface dataset:
Circulating polymers in 1-antitrypsin deficiency
Authors: Lu Tan, Jennifer A. Dickens, Dawn L. DeMeo, Elena Miranda, Juan Perez, S. Tamir Rashid, James Day, Adriana Ordoñez, Stefan J. Marciniak, Imran Haq, Alan F. Barker, Edward J. Campbell, Edward Eden, Noel G. McElvaney, Stephen I. Rennard, Robert A. Sandhaus, James M. Stocks, James K. Stoller, Charlie Strange, Gerard Turino, Farshid N. Rouhani, Mark Brantly, David A. Lomas
Journal: European Respiratory Journal (2014)

To the Editor: 

Most individuals carry two wild-type M alleles of the SERPINA1 gene which encodes α1-antitrypsin. 95% of severe deficiency of α1-antitrypsin is associated with the Z allele (Glu342Lys; denoted PiZZ in the homozygote), and with the retention and polymerisation of α1-antitrypsin within hepatocytes [1]. These polymers are contained within periodic acid–Schiff-positive, diastase-resistant inclusions that are associated with neonatal hepatitis, cirrhosis and hepatocellular carcinoma. The concomitant lack of circulating α1-antitrypsin predisposes the Z α1-antitrypsin homozygote to early-onset emphysema. Polymers of α1-antitrypsin form within the lung as a result of local inflammation and exposure to cigarette smoke [2]. They have also been identified in the skin of an individual with α1-antitrypsin deficiency and panniculitis [3] and in a renal biopsy from an individual with α1-antitrypsin deficiency and vasculitis [4]. It is unknown whether these polymers form locally or are deposited in these tissues from a circulating source, and whether extrahepatic polymers are associated with any disease phenotypes. We have assessed whether polymers of α1-antitrypsin are present within serum, from where they originate, and whether they are associated with clinical features in individuals with PiZZ α1-antitrypsin deficiency. In this investigation we used ELISA with the anti-α1-antitrypsin polymer monoclonal antibody (2C1) [5] to assess the presence of polymers in the plasma of 1) 518 individuals with PiZZ α1-antitrypsin deficiency; 2) an individual with α1-antitrypsin deficiency who underwent liver transplantation; and 3) 293 individuals with a mixture of α1-antitrypsin phenotypes. The specificity of the 2C1 antibody was confirmed by using it to immunoprecipitate polymers from the plasma of individuals with and without a positive signal …
Long-term effectiveness of a staged assessment for paediatric problematic severe asthma
Authors: James Sharples, Atul Gupta, Louise Fleming, Cara J. Bossley, Marcella Bracken-King, Pippa Hall, Abigail Hayward, Michelle Puckey, Ian M. Balfour-Lynn, M. Rosenthal, Andrew Bush, Sejal Saglani
Journal: European Respiratory Journal (2012)

Long-term effectiveness of a staged assessment for paediatric problematic severe asthma
The influence of food on 8-methoxypsoralen serum concentration and minimal phototoxic dose
Authors: N. BECH-THOMSEN, H.R. ANGELO, E.A. KNUDSEN
Journal: British Journal of Dermatology (1992)

Ten adult volunteers were given three oral doses of 0·46-0·56 mg/kg body weight of 8-methoxypsoralen (8-MOP) in a liquid formulation under fasting conditions, and after ingestion of a low-fat or fat-rich breakfast. 8-MOP serum levels and photosensitivity were measured 0·5–4 h after drug ingestion. The 1-h 8-MOP serum levels and photosensitivity were significantly higher in fasting conditions than after ingestion of a low-fat or fat-rich meal (intra-individual median difference in photosensitivity 7·5 J/cm2). On 12 of 20 occasions when the drug was taken after food ingestion, the 1-h 8-MOP serum concentration was below 30 ng/ml. A survey of 43 out-patients undergoing regular PUVA treatment showed that the frequency of erythemal reactions was significantly higher when 8-MOP was ingested with a > 50% smaller quantity of food than usual (P < 0·005). This study demonstrated food-induced variations in 8-MOP photosensitivity both in an experimental situation and in an out-patient survey. In order to optimize the therapeutic effect of PUVA, the quantity of food taken before 8-MOP should remain constant, and the timing of UVA irradiation should be adjusted according to the preceding food intake.
Nadir Testosterone Within First Year of Androgen-Deprivation Therapy (ADT) Predicts for Time to Castration-Resistant Progression: A Secondary Analysis of the PR-7 Trial of Intermittent Versus Continuous ADT
Authors: Laurence Klotz, Chris O'Callaghan, Keyue Ding, Paul Toren, David Dearnaley, Celestia S. Higano, Eric Horwitz, Shawn Malone, Larry Goldenberg, Mary Gospodarowicz, Juanita M. Crook
Journal: Journal of Clinical Oncology (2015)

Three small retrospective studies have suggested that patients undergoing continuous androgen deprivation (CAD) have superior survival and time to progression if lower castrate levels of testosterone (< 0.7 nmol/L) are achieved. Evidence from prospective large studies has been lacking.The PR-7 study randomly assigned patients experiencing biochemical failure after radiation therapy or surgery plus radiation therapy to CAD or intermittent androgen deprivation. The relationship between testosterone levels in the first year and cause-specific survival (CSS) and time to androgen-independent progression in men in the CAD arm was evaluated using Cox regression.There was a significant difference in CSS (P = .015) and time to hormone resistance (P = .02) among those who had first-year minimum nadir testosterone ≤ 0.7, > 0.7 to ≤ 1.7, and ≥ 1.7 nmol/L. Patients with first-year nadir testosterone consistently > 0.7 nmol/L had significantly higher risks of dying as a result of disease (0.7 to 1.7 nmol/L: hazard ratio [HR], 2.08; 95% CI, 1.28 to 3.38; > 1.7 nmol/L: HR, 2.93; 95% CI, 0.70 to 12.30) and developing hormone resistance (0.7 to 1.7 nmol/L: HR, 1.62; 95% CI, 1.20 to 2.18; ≥ 1.7 nmol/L: HR, 1.90; 95% CI, 0.77 to 4.70). Maximum testosterone ≥ 1.7 nmol/L predicted for a higher risk of dying as a result of disease (P = .02).Low nadir serum testosterone (ie, < 0.7 mmol/L) within the first year of androgen-deprivation therapy correlates with improved CSS and duration of response to androgen deprivation in men being treated for biochemical failure undergoing CAD.
Hepatitis C virus induces the expression of CCL17 and CCL22 chemokines that attract regulatory T cells to the site of infection
Authors: José-Ignacio Riezu-Boj, Esther Larrea, Rafael Aldabe, Laura Guembe, Noelia Casares, Eva Galeano, Iciar Echeverria, Pablo Sarobe, Ignacio Herrero, Bruno Sangro, Jesús Prieto, Juan-José Lasarte
Journal: Journal of Hepatology (2010)
Ouabain Effects on Cardiac Contraction, Action Potential, and Cellular Potassium
Authors: PAUL MüLLER
Journal: Circulation Research (1965)

Transmembrane potential, isometric tension, and K 42 content of sheep or calf myocardial bundles were recorded simultaneously during periods up to 30 hours. Ouabain at low concentrations (1.5 x 10 -8 M/L) decreased intracellular K to a new steady level which was reached after several hours. Its value depended on drug concentration. The effect was reversible. There was a striking temporal parallelism between the potassium loss and the inotropic effect which was suggestive of a close relationship between the two phenomena. Action potentials during these experiments did not change in a consistent way.
GAMMA GLOBULIN AND ANTIBODY FORMATION IN VITRO
Authors: G. J. Thorbecke, R. M. Asofsky, G. M. Hochwald, G. W. Siskind
Journal: The Journal of Experimental Medicine (1962)

Antibody formation in vitro by red and white pulp of the spleen and by bone marrow tissue was studied at various days after an intravenous booster injection of soluble antigens such as ovalbumin and bovine gamma globulin (BGG). When the booster injection of antigen was given early (10 days) after an intravenous primary injection, high antibody formation could be demonstrated in the spleen primarily 2 to 3 days after the injection, but much less afterwards. When the booster injection was given later (1 month) after the primary, the antibody production by the spleen lasted longer and higher serum titers were obtained. The bone marrow formed antibody in both cases but, particularly with the short interval between injections, its response was delayed as compared to the spleen. It was also shown that during antibody formation the production of gamma globulin in vitro was enhanced. Histologically the antibody production was always correlated to immature plasma cell proliferation, located at the border of red and white pulp and in the red pulp of the spleen. When endotoxin had been injected at the time of a primary BGG injection, and a second antigen injection was given 5 to 10 days later, a booster response could be elicited which was sometimes limited to the white pulp on day 1, and on day 2 was divided between "red" and "white" pulp. The response induced at day 10, at the peak of secondary nodule proliferation, lasted very long and was accompanied by an enormous plasma cellular proliferation in and around the periarteriolar lymphoid areas of the spleen. The possible importance of the secondary nodules of the white pulp in the preparation for a secondary response is discussed.
Public views of UK Population Biomedical Collection are being taken into account
Authors: T M. Dexter
Journal: BMJ (2002)

EDITOR—We think it important to respond to Kaye's letter concerning the proposed UK Population Biomedical Collection, a project sponsored by the Wellcome Trust, the Medical Research Council, and the Department of Health.1 Kaye suggests that the collection will be a test run for the establishment of a national population collection, but this may mislead readers.

The proposed collection will include DNA samples from roughly half a million adult …
Contribution of persistent C-Jun N-terminal kinase activity to the survival of human vestibular schwannoma cells by suppression of accumulation of mitochondrial superoxides
Authors: Wei Ying Yue, J. Jason Clark, Augusta Fernando, Frederick Domann, Marlan R. Hansen
Journal: Neuro-Oncology (2011)

Vestibular schwannomas (VSs) result from inactivating mutations in the merlin tumor suppressor gene. The merlin protein suppresses a variety of progrowth kinase–signaling cascades, including extracellular regulated kinase/mitogen-activated protein kinase (ERK/MAPK), c-Jun N-terminal kinase (JNK), and phosphatidyl-inositol 3-kinase (PI3-K)/Akt. Recent studies indicate that ERKs and Akt are active in human VSs, and here we show that JNKs are also persistently active in human VS cells. With use of cultures of human VSs, we investigated the contribution of each of these signals to the proliferative and survival response of VS cells. Inhibition of ERK or Akt signaling reduced VS cell proliferation but did not increase apoptosis, whereas inhibition of JNK with SP600125, I-JIP, or siRNA knock-down reduced VS cell proliferation and survival by inducing apoptosis. By contrast, JNK activity promotes apoptosis in normal Schwann cells. Inhibition of JNK increased the fluorescence intensity of VS cells loaded with 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (H2DCFDA), a fluorescent probe for reactive oxygen species (ROS). Furthermore, ebselen, a ROS scavenger, rescued VS cells with suppressed JNK from apoptosis, suggesting that JNK activity protects VS cells from apoptosis by limiting accumulation of ROS. VS cultures treated with JNK inhibitors demonstrated significantly higher levels of MitoSOX Red fluorescence, implying that persistent JNK activity specifically suppresses superoxide production in the mitochondria. Overexpression of superoxide dismutase 2 (MnSOD; mitochondrial SOD) prevented apoptosis in VS cells with suppressed JNK signaling. Taken together, these results indicate that persistent JNK activity enhances VS cell survival, at least in part, by suppressing accumulation of mitochondrial superoxides.
Hepatitis C virus core protein exerts an inhibitory effect on suppressor of cytokine signaling (SOCS)-1 gene expression
Authors: Hideyuki Miyoshi, Hajime Fujie, Yoshizumi Shintani, Takeya Tsutsumi, Seiko Shinzawa, Masatoshi Makuuchi, Norihiro Kokudo, Yoshiharu Matsuura, Tetsuro Suzuki, Tatsuo Miyamura, Kyoji Moriya, Kazuhiko Koike
Journal: Journal of Hepatology (2005)
Evaluation of the Digital Rectal Examination as a Screening Test for Prostate Cancer
Authors: F. H. Schroder, A. B. Kruger, J. Rietbergen, R. Kranse, P. v. d. Maas, P. Beemsterboer, R. Hoedemaeker
Journal: JNCI Journal of the National Cancer Institute (1998)

Background: The utility of digital rectal examination (DRE) as a screening test for early detection of prostate cancer has not been established. Therefore, we evaluated the usefulness of DRE as a stand-alone screening test and in conjunction with measured serum prostate- specific antigen (PSA) levels of 0-3.9 ng/mL and transrectal ultrasonography (TRUS). Methods: Our study population consisted of 10 523 men aged 54-76 years who were randomly assigned to the screening arm of the Rotterdam, The Netherlands, section of the European Randomized Study of Screening for Prostate Cancer. The underlying prevalence of detectable prostate cancer was estimated by logistic regression analysis and used for calculating the sensitivity of DRE as a test. Pathologic characteristics of 105 radical prostatectomy specimens were used to determine the aggressiveness of the tumors diagnosed (and missed) by DRE. Results: The overall detection rate for prostate cancer in this population when serum PSA measurement, DRE, and TRUS were used was 4.5%, and the detection rate with DRE alone was 2.5%. The positive predictive value of DRE ranged from 4% to 11% in men with PSA levels of 0-2.9 ng/mL and from 33% to 83% in men with PSA levels of 3.0-9.9 ng/mL or more. Most tumors detected by DRE in men with PSA levels of less than 4.0 ng/mL were small (mean volumes = 0.24-0.83 mL), and most were well differentiated (Gleason scores of 6 or less). Minimal, moderate, and advanced cancers were seen in 42%, 42%, and 16% of men, respectively, with a PSA level of 4.0 ng/ mL or less. DRE alone allowed detection of 264 (55.8%) of 473 cancers; 82 (17.3%) of the 473 cancers would have remained undetected by PSA-based screening alone (i.e., no follow-up procedures for PSA values of 0-3.9 ng/ mL). Conclusions: For PSA values of 0-3.9 ng/mL, the positive predictive value and sensitivity of DRE, tumor volume, and tumor grade were strongly dependent on PSA level. DRE has a poor performance in low PSA ranges.
Epidemiology of Bronchioloalveolar Carcinoma: Improvement in Survival After Release of the 1999 WHO Classification of Lung Tumors
Authors: Jason A. Zell, S.-H. Ignatius Ou, Argyrios Ziogas, Hoda Anton-Culver
Journal: Journal of Clinical Oncology (2005)

Purpose Classification changes for bronchioloalveolar carcinoma (BAC) by the WHO in May 1999 narrowed its definition. This study was undertaken in an attempt to characterize the impact of these changes on the epidemiology of BAC. Patients and Methods This retrospective study involves data analysis from the population-based Cancer Surveillance Programs of three Southern California counties from 1995 to 2003. BAC cases diagnosed after May 1999 are compared with BAC cases before that time by clinicopathologic variables including survival. Results Incident cases (11,969) of non–small-cell lung cancer (NSCLC) were analyzed, including 626 cases of BAC (5.2%). Median overall survival (OS) for BAC patients diagnosed after May 1999 (&gt; 53 months) was significantly improved over median OS for BAC patients before May 1999 (32 months; P = .012). This survival benefit remained after adjustment for sex, smoking status, and stage at presentation (hazard ratio for time of diagnosis before May 1999 compared with a diagnosis after May 1999 = 1.43; P = .015). Median OS for non-BAC NSCLC patients diagnosed before May 1999 (9 months) did not differ from the median OS of such patients afterwards (10 months; P = .09). Conclusion This epidemiologic study is the first to demonstrate a survival advantage for BAC patients diagnosed after May 1999 compared with BAC patients diagnosed before this time—a finding that persists after adjustment for sex, smoking status, and stage at presentation. We believe that this observed survival benefit likely reflects changes in the revised 1999 WHO classification.
Tracking of Left Ventricular Mass in Children: Race and Sex Comparisons
Authors: Richard M. Schieken, Pamela F. Schwartz, Monica M. Goble
Journal: Circulation (1998)

Background —Increased left ventricular (LV) mass is a predictor of cardiovascular disease in adults. The mechanism(s) for these observations are not fully understood. Methods and Results —We repeatedly studied a biracial sample of children from ages 11 through 17 years. At visits 1 through 5, height, weight, and pubertal stage were determined. Blood pressure and heart rate were measured. M-mode and two-dimensional echocardiograms were performed with a 3.5-MHz transducer with the subject in the supine position. LV mass was calculated. Repeated-measures analysis using a mixed modeling approach was performed for LV mass. At all ages, boys had greater LV mass than girls. For the population as a whole, we found significant tracking correlations for LV mass between each interval of measurement and throughout the entire period of examination. The tracking correlation for the entire sample from visit 1 through visit 5 was r =.41. The LV mass in white children tracked from the youngest to the oldest. Black children tracked similarly from ages 1 to 15 years, but tracking was not significant across the widest interval, visit 1 through visit 5. Racial differences were found in the interactions of systolic blood pressure and heart rate, which magnified the differences in LV mass. During adolescence, LV mass tracks significantly in both black and white children. Conclusions —Interactive effects such as weight, blood pressure, and heart rate magnify sex and race differences in LV mass.
Two waves of recombinase gene expression in developing thymocytes.
Authors: A Wilson, W Held, H R MacDonald
Journal: The Journal of Experimental Medicine (1994)

During T cell development in the thymus, T cell receptor (TCR) alpha, beta, gamma, and delta genes are rearranged and expressed. TCR rearrangement strictly depends upon the coordinate activity of two recombinase activating genes, Rag-1 and Rag-2. In this study we have followed the expression of these genes at different stages of intrathymic development. The results indicate that there are two periods of high Rag-1 and Rag-2 mRNA expression. The first wave peaks early at the CD25+CD4-CD8-CD3- stage of development and coincides with the initial appearance of transcripts derived from fully rearranged TCR beta, gamma, and delta genes, whereas the second wave occurs later at the CD4+CD8+ stage coincident with full-length TCR alpha mRNA expression. Active downregulation of Rag-1 and Rag-2 mRNA expression appears to occur in vivo between the two peaks of recombinase activity. This phenomenon can be mimicked in vitro in response to artificial stimuli such as phorbol myristate acetate and calcium ionophore. Collectively our data suggest that recombinase expression is actively regulated during early thymus development independently of cell surface expression of a mature heterodimeric TCR protein complex.
Shared Decision Making for Antidepressants in Primary Care
Authors: Annie LeBlanc, Jeph Herrin, Mark D. Williams, Jonathan W. Inselman, Megan E. Branda, Nilay D. Shah, Emma M. Heim, Sara R. Dick, Mark Linzer, Deborah H. Boehm, Kristen M. Dall-Winther, Marc R. Matthews, Kathleen J. Yost, Kathryn K. Shepel, Victor M. Montori
Journal: JAMA Internal Medicine (2015)

For antidepressants, the translation of evidence of comparative effectiveness into practice is suboptimal. This deficit directly affects outcomes and quality of care for patients with depression. To overcome this problem, we developed the Depression Medication Choice (DMC) encounter decision aid, designed to help patients and clinicians consider the available antidepressants and the extent to which they improved depression and other issues important to patients.
Childhood and the evolution of higher-effort teaching
Authors: Mark Nielsen, Ceri Shipton
Journal: Behavioral and Brain Sciences (2015)

Abstract Kline presents an excellent synthesis of teaching theory and research, with cogent arguments regarding its prevalence. In this, she claims that “active teaching” is human specific, and presents tangible reasons why. But in doing so, she overlooks a critical aspect of the human condition that may have arisen only recently in our evolutionary history: Childhood as a life stage.
Acquired streptococcal necrotizing fasciitis following excision of malignant melanoma
Authors: None Gibbon, None Bewley
Journal: British Journal of Dermatology (1999)

Necrotizing fasciitis is an uncommon condition which may complicate any surgical procedure, including 'minor' dermatological procedures. However, it may arise de novo in the absence of any discernible trauma. We report a patient who acquired a fulminant form of this condition following excision of a malignant melanoma. The development of necrotizing fasciitis in association with melanoma has not previously been reported.
Fused FDG–PET/contrast-enhanced CT detects occult subdiaphragmatic involvement of Hodgkin's lymphoma thereby identifying patients requiring six cycles of anthracycline-containing chemotherapy and consolidation radiation of spleen
Authors: M. Picardi, A. Soricelli, F. Grimaldi, E. Nicolai, A. Gallamini, F. Pane
Journal: Annals of Oncology (2010)
PEG-PLA nanoparticles modified with APTEDB peptide for enhanced anti-angiogenic and anti-glioma therapy
Authors: Guangzhi Gu, Quanyin Hu, Xingye Feng, Xiaoling Gao, Jiang Menglin, Ting Kang, Di Jiang, Qingxiang Song, Hongzhuan Chen, Jun Chen
Journal: Biomaterials (2014)
Normal mouse intestinal mucus release requires cystic fibrosis transmembrane regulator–dependent bicarbonate secretion
Authors: Mary Abigail S. Garcia, Ning Yang, Paul M. Quinton
Journal: Journal of Clinical Investigation (2009)

The mechanisms underlying mucus-associated pathologies in cystic fibrosis (CF) remain obscure. However, recent studies indicate that CF transmembrane conductance regulator (CFTR) is required for bicarbonate (HCO3-) transport and that HCO3- is critical for normal mucus formation. We therefore investigated the role of HCO3- in mucus secretion using mouse small intestine segments ex vivo. Basal rates of mucus release in the presence or absence of HCO3- were similar. However, in the absence of HCO3-, mucus release stimulated by either PGE2 or 5-hydroxytryptamine (5-HT) was approximately half that stimulated by these molecules in the presence of HCO3-. Inhibition of HCO3- and fluid transport markedly reduced stimulated mucus release. However, neither absence of HCO3- nor inhibition of HCO3- transport affected fluid secretion rates, indicating that the effect of HCO3- removal on mucus release was not due to decreased fluid secretion. In a mouse model of CF (mice homozygous for the most common human CFTR mutation), intestinal mucus release was minimal when stimulated with either PGE2 or 5-HT in the presence or absence of HCO3-. These data suggest that normal mucus release requires concurrent HCO3- secretion and that the characteristically aggregated mucus observed in mucin-secreting organs in individuals with CF may be a consequence of defective HCO3- transport.