tbuckley/cabot-search huggingface dataset:
Chronic pancreatitis and cystic fibrosis
Authors: H Witt
Journal: Gut (2003)

Recent discoveries of trypsinogen and trypsin inhibitor mutations in patients with chronic pancreatitis (CP) support the hypothesis that an inappropriate activation of pancreatic zymogens to active enzymes within the pancreatic parenchyma starts the inflammatory process. Current data suggest that CP may be inherited dominant, recessive, or complex as a result of mutations in the above mentioned or yet unidentified genes. Evaluation of patients with CP should include genetic testing. Cystic fibrosis (CF) is an autosomal recessive inherited disorder caused by mutations in the CF transmembrane conductance regulator (<i>CFTR</i>) gene and is characterised by pancreatic insufficiency and chronic bronchopulmonary infection. The progression and severity of pulmonary disease differs considerably between people with identical <i>CFTR</i> mutations and does not seem to correlate with the type or class of the <i>CFTR</i> mutation. The identification of further disease modifying genetic factors will increase the pathophysiological understanding and may help to identify new therapeutic targets.
Tracheo-oesophageal fistula and oesophageal atresia: results of 30 years' experience
Authors: M. P. Holden, G. H. Wooler
Journal: Thorax (1970)

One hundred and sixteen cases of oesophageal atresia and tracheo-oesophageal fistula operated upon during the period 1939-67 are reviewed. Current views on, initially, surgical care and ultimate management are discussed.
Elevated blood pressure and enhanced myocardial contractility in mice with severe IGF-1 deficiency.
Authors: G Lembo, H A Rockman, J J Hunter, H Steinmetz, W J Koch, L Ma, M P Prinz, J Ross, K R Chien, L Powell-Braxton
Journal: Journal of Clinical Investigation (1996)

To circumvent the embryonic lethality of a complete deficiency in insulin-like growth factor 1 (IGF-1), we generated mice homozygous for a site-specific insertional event that created a mutant IGF-1 allele (igf1m). These mice have IGF-1 levels 30% of wild type yet survive to adulthood, thereby allowing physiological analysis of the phenotype. Miniaturized catheterization technology revealed elevated conscious blood pressure in IGF-1(m/m) mice, and measurements of left ventricular contractility were increased. Adenylyl cyclase activity was enhanced in IGF-1(m/m) hearts, without an increase in beta-adrenergic receptor density, suggesting that crosstalk between IGF-1 and beta-adrenergic signaling pathways may mediate the increased contractility. The hypertrophic response of the left ventricular myocardium in response to aortic constriction, however, was preserved in IGF-1(m/m) mice. We conclude that chronic alterations in IGF-1 levels can selectively modulate blood pressure and left ventricular function, while not affecting adaptive myocardial hypertrophy in vivo.
An evaluation of systemic inflammatory response syndrome signs in the Sepsis Occurrence in Acutely ill Patients (SOAP) study
Authors: Charles L. Sprung, Yasser Sakr, Jean-Louis Vincent, Jean-Roger Le Gall, Konrad Reinhart, V. Marco Ranieri, Herwig Gerlach, Jonathan Fielden, C. B. Groba, Didier Payen
Journal: Intensive Care Medicine (2006)
Dutch doctors speak out about past errors to change culture on patient safety
Authors: T. Sheldon
Journal: BMJ (2009)

Twelve leading Dutch doctors have written frankly about serious mistakes they made in the past in an attempt to change a culture of secrecy seen as preventing improvements to patient safety.

The document, Dit nooit meer ( Never Again ), an initiative of the Dutch Institute for Healthcare Improvement, is being sent to all 46 000 members of the Dutch Medical Association as part of a national campaign on patient safety (www.cbo.nl/algemeen/Publicaties/).

It argues that equating medical professionalism with infallibility is a “dangerous illusion” that hinders doctors learning from the mistakes of others.

Arie Nieuwenhuijzen Kruseman, chairman of the association, wrote, “Every victim averted …
Sarcoplasmic reticulum-mitochondrial interaction in the mechanism of acute reperfusion injury
Authors: H. M. Piper, Y. Abdallah, S. Kasseckert, K.-D. Schluter
Journal: Cardiovascular Research (2007)

Currently, restoring blood flow in an acutely occluded vessel represents the most effective, long-term clinical therapy for acute myocardial infarction. Experimental research over the past years has demonstrated that the first minutes of reperfusion represent a window of opportunity for additional therapy that is yet unused in the clinical setting. Experimentally, it has been shown that a considerable part of myocardial injury developing after an episode of prolonged ischaemia and subsequent reperfusion is due to causes emerging during the period of reperfusion.1–6 This type of injury has been termed ‘reperfusion injury’. For a long time it had been difficult to prove the existence of this type of injury; this could only be done by identifying interventions applied just at the time of reperfusion that would reduce the otherwise resulting myocardial injury. Early studies in this area had shown that interventions during reperfusion aimed at controlling cytosolic [Ca2+] or the activation of the contractile machinery in cardiomyocytes could reduce cardiac cell necrosis.7–10 More recently, a protective protocol called ‘postconditioning’11 has been discovered that can be used in the clinical setting. In this protocol, very brief, repetitive bouts of ischaemia are deliberately applied during the first minutes of reperfusion. In ground-breaking work, Ovize and co-workers12,13 showed that postconditiong can reduce the signs of tissue injury, such as the release of myocardial enzymes, in patients receiving acute coronary revascularisation.

In a rapidly growing number of manuscripts, details of the protective signalling of postconditioning and pharmacological interventions designed to exploit its protective potential have been identified. It has become apparent that activation of specific protein kinases can provide and mediate cardiac protection during the reperfusion period. These have been termed ‘reperfusion injury salvage kinases’ (RISK).14–16 …
Early hematopoietic reconstitution after clinical stem cell transplantation: evidence for stochastic stem cell behavior and limited acceleration in telomere loss
Authors: Ian Thornley, Robert Sutherland, Robert Wynn, Rakash Nayar, Lillian Sung, George Corpus, Thomas Kiss, Jeff Lipton, John Doyle, Fred Saunders, Suzanne Kamel-Reid, Melvin Freedman, Hans Messner
Journal: Blood (2002)
C/EBP-β Mediates iNOS Induction by Hypoxia in Rat Pulmonary Microvascular Smooth Muscle Cells
Authors: Xingwu Teng, Dechun Li, John D. Catravas, Roger A. Johns
Journal: Circulation Research (2002)

Exposure of rats to 10% O(2) for 4 days caused pulmonary hypertension and induced expression of both inducible nitric oxide synthase (iNOS) and CCAAT box enhancer binding protein-beta (C/EBP-beta) in rat lung. Electrophoretic mobility shift assays (EMSAs) showed that exposure to 1% O(2) increased the C/EBP-beta binding in rat pulmonary microvascular smooth muscle cells (rPSMs). To test the hypothesis that C/EBP-beta participates in hypoxia-induced iNOS expression in rPSMs, a C/EBP motif at -910 bp of rat iNOS promoter was mutated. rPSMs transfected with the rat iNOS promoter and exposed to 1% O(2) for 24 hours had significantly increased wild-type iNOS promoter activity. The hypoxia-induced promoter activity was abolished by the C/EBP motif mutation. Thus, C/EBP-beta mediates, at least in part, hypoxia-induced iNOS expression in rPSMs.
Lifestyle Interaction With Fat Mass and Obesity-Associated (<i>FTO</i>) Genotype and Risk of Obesity in Apparently Healthy U.S. Women
Authors: Tariq Ahmad, I-Min Lee, Guillaume Paré, Daniel I. Chasman, Lynda Rose, Paul M. Ridker, Samia Mora
Journal: Diabetes Care (2011)

OBJECTIVE Variation in the fat mass and obesity-associated (FTO) gene is associated with obesity. The extent to which separate and combined effects of physical activity and caloric intake modify this association remains unclear. RESEARCH DESIGN AND METHODS FTO polymorphism rs8050136 was measured, and physical activity, caloric intake, and anthropometrics were self-reported in 21,675 apparently healthy Caucasian women. RESULTS The effect of the risk allele (A) on BMI was larger among inactive or higher intake women, with additive effects of inactivity and high intake on the associated genetic risk. Specifically, each A allele was associated with mean BMI difference of +0.73 (SE 0.08) kg/m2 among inactive women (≤median, 8.8 MET-hours/week), compared with +0.31 (0.06) kg/m2, P &amp;lt; 0.0001, among active women (&amp;gt;8.8 MET-hours/week). Similarly, each A allele was associated with mean BMI difference of +0.65 (0.07) among high intake women (&amp;gt;median, 1,679 kcals/day), compared with +0.38 (0.07) kg/m2, P = 0.005, among low intake women (≤1,679 kcals/day). Among inactive/high intake women, each A allele was associated with mean BMI difference of +0.97 (0.11) kg/m2 vs. +0.22 (0.08) kg/m2 among inactive/low intake women, P &amp;lt; 0.0001. Among inactive/high intake women, each A allele carried increased risk of obesity (odds ratio 1.39, 95% CI 1.27–1.52) and diabetes (odds ratio 1.36, 95% CI 1.07–1.73). CONCLUSIONS In this study, lifestyle factors modified the genetic risk of FTO on obesity phenotypes, particularly among women who were both inactive and had high intake. Healthier lifestyle patterns blunted but did not completely eliminate the associated genetic risk.
The results of inferon administration in the treatment of chronic obstructive pulmonary disease
Authors: Shamil Farkhutdinov, Usman Farkhutdinov
Journal: European Respiratory Journal (2012)

Immunity disorders play an important role in the latent inflammatory formation in patients with chronic obstructive pulmonary disease (COPD). A low γ-IFN level may be one of them.  The aim was to study γ-IFN level in patients with COPD and the efficacy of immunomodulator inferon (IFN) in its treatment.  Methods: The study included 45 patients with moderate to severe COPD. The level of γ-interferon, CD3+, CD4+, CD8+, lymphocytes, phagocytic activity of neutrophils by nitro-blue tetrazolium (NBT) test was determined in the patients blood. 23 patients with COPD received standard therapy. IFN was used in the complex therapy of 22 patients.  Results: In patients with COPD the level of γ–interferon has been found to be reduced by 2.0 times, the level of CD3+, CD4+, CD8+ lympocytes by 1.6-1.8 times, the values of NBT –test by 2.5 times. Administration of IFN increased the level of γ–interferon by 1.5 times, improved T-cells and neutrophils activity, produced positive effect on the course of the inflammation. In patients who received standard therapy γ–interferon content remained at a lowered level, impairment of the immune status and symptoms of inflammation have been found.  Conclusion: In patients with COPD γ–interferon content was found to be decreased. IFN administration increased γ–interferon production, eliminated immunity disorders, improved the results of the treatment.
The treatment of stage IIIA Hodgkin's disease.
Authors: T A Lister, M S Dorreen, M Faux, A E Jones, P F Wrigley
Journal: Journal of Clinical Oncology (1983)

Sixty consecutive previously untreated adults with surgically confirmed stage IIIA Hodgkin's disease (39 stage IIIA1, 21 stage IIIA2) began therapy at St. Bartholomew's Hospital between 1969 and 1981. Prior to 1973, treatment consisted of total nodal irradiation (TNI). From 1973 until 1978 patients were randomly allocated to receive either TNI or cyclic combination chemotherapy of mustine, vinblastine, prednisolone, and procarbazine (MVPP) as part of a Medical Research Council Trial. Since 1978 treatment has been allocated according to substage, those with stage IIIA1 receiving TNI and those with stage IIIA2 receiving MVPP. Seven patients received "non protocol" therapy (extended mantle radiotherapy in three patients, mantle and MVPP in four patients), and have been excluded from the study. Complete remission was achieved in 48 of 53 patients regardless of substage or therapy. Seven have relapsed, one after MVPP and six after TNI. The predicted freedom-from-relapse after MVPP was 96% compared with 60% after TNI, both at 10 years (p less than 0.01). The relapse pattern was the same for both substages in the group receiving TNI. Although overall survival of patients receiving TNI was identical to that of those receiving MVPP, TNI must be considered inappropriate therapy for stage IIIA Hodgkin's disease if permanent freedom-from-recurrence is the goal.
Proteinase-Activated Receptors: Transducers of Proteinase-Mediated Signaling in Inflammation and Immune Response
Authors: Martin Steinhoff, Jörg Buddenkotte, Victoria Shpacovitch, Anke Rattenholl, Corinna Moormann, Nathalie Vergnolle, Thomas A. Luger, Morley D. Hollenberg
Journal: Endocrine Reviews (2004)

Serine proteinases such as thrombin, mast cell tryptase, trypsin, or cathepsin G, for example, are highly active mediators with diverse biological activities. So far, proteinases have been considered to act primarily as degradative enzymes in the extracellular space. However, their biological actions in tissues and cells suggest important roles as a part of the body’s hormonal communication system during inflammation and immune response. These effects can be attributed to the activation of a new subfamily of G protein-coupled receptors, termed proteinase-activated receptors (PARs). Four members of the PAR family have been cloned so far. Thus, certain proteinases act as signaling molecules that specifically regulate cells by activating PARs. After stimulation, PARs couple to various G proteins and activate signal transduction pathways resulting in the rapid transcription of genes that are involved in inflammation. For example, PARs are widely expressed by cells involved in immune responses and inflammation, regulate endothelial-leukocyte interactions, and modulate the secretion of inflammatory mediators or neuropeptides. Together, the PAR family necessitates a paradigm shift in thinking about hormone action, to include proteinases as key modulators of biological function. Novel compounds that can modulate PAR function may be potent candidates for the treatment of inflammatory or immune diseases.
Longitudinal change in peak oxygen uptake in COPD patients
Authors: Bente Frisk, Birgitte Espehaug, Liv Inger Strand, Jon Andrew Hardie, Rolf Moe-Nilssen, Tomas Eagan, Per Bakke, Einar Thorsen
Journal: European Respiratory Journal (2014)

INTRODUCTION: Exercise capacity in patients with chronic obstructive pulmonary disease (COPD) is impaired. Peak oxygen uptake (VO2peak) is an important outcome measure with respect to effects of rehabilitation and treatment, but few data are available on the natural longitudinal change.

AIMS: To examine the longitudinal change in VO2peak in COPD patients and examine potential predictors of change.

METHODS: This prospective observational study included 63 patients (35 men) aged 44-77 yrs, with COPD in GOLD stages II-IV with a mean forced expiratory volume in one sec (FEV1) of 51 % of predicted (SD=14). Two incremental exercise tests on treadmill were performed 4.5 yrs (SD=0.9) apart. Spirometry was performed before the exercise tests. The relationship between the change in VO2peak and VO2peak per kg body mass (VO2peak/kg), and the explanatory variables age, sex, body mass, baseline VO2peak and VO2peak/kg, exacerbations during the follow-up period, and changes in FEV1 and body mass between tests were analysed by multivariate regression analysis. 

RESULTS: The mean decline in VO2peak, was 50 (SD=68) mL/min/yr (p<0.001) and 0.6 (SD=1.0) mL/min/kg/yr (p<0.001). The decline in FEV1 was 34 (SD=66) mL/yr (p<0.001). The reduction in VO2peak was larger with a higher baseline VO2peak(p<0.001) and with a larger reduction in FEV1 (p<0.001). The same was found for the change in VO2peak/kg, but the reduction in VO2peak/kg was less with a larger reduction in body mass (p=0.007).

CONCLUSION: Pulmonary function and exercise capacity in COPD patients declined during a follow-up period of 4.5 yrs. The decline in VO2peak and VO2peak/kg was related to the decline in FEV1. The decline in VO2peak/kg was also related to the change in body mass.
Expressed Alu repeats as a novel, reliable tool for normalization of real-time quantitative RT-PCR data
Authors: Manuela Marullo, Chiara Zuccato, Caterina Mariotti, Nayana Lahiri, Sarah J Tabrizi, Stefano Di Donato, Elena Cattaneo
Journal: Genome biology (2010)

We describe a novel strategy for mRNA normalization in quantitative real-time PCR that is based on expressed Alu repeat amplification as a measure for the mRNA fraction. We show that expressed Alu repeat amplification is a fast, accurate normalization tool that can be successfully used for quantification of selected mRNA in the human transcriptome. This result is particularly important for clinical diagnosis and biomarker validation studies based on mRNA detection in human blood.
Significance of Circulating Tumor Cells in Metastatic Triple-Negative Breast Cancer Patients within a Randomized, Phase II Trial: TBCRC 019
Authors: Costanza Paoletti, Yufeng Li, Maria C. Muñiz, Kelley M. Kidwell, Kimberly Aung, Dafydd G. Thomas, Martha E. Brown, Vandana G. Abramson, William J. Irvin, Nancy U. Lin, Minetta C. Liu, Rita Nanda, Julie R. Nangia, Anna M. Storniolo, Tiffany A. Traina, Christos Vaklavas, Catherine H. Van Poznak, Antonio C. Wolff, Andres Forero-Torres, Daniel F. Hayes
Journal: Clinical Cancer Research (2015)

Circulating tumor cells (CTC) are prognostic in metastatic breast cancer (MBC). We tested whether EpCAM-based capture system (CellSearch) is effective in patients with triple-negative (TN) MBC, and whether CTC apoptosis and clustering enhances the prognostic role of CTC.CTC enumeration and apoptosis were determined using the CXC CellSearch kit at baseline and days 15 and 29 in blood drawn from TN MBC patients who participated in a prospective randomized phase II trial of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) with or without tigatuzumab. Association between levels of CTC and patient outcomes was assessed using logistic regression, Kaplan-Meier curves, and Cox proportional hazards modeling.Nineteen of 52 (36.5%), 14 of 52 (26.9%), and 13 of 49 (26.5%) patients who were evaluable had elevated CTC (≥5 CTC/7.5 mL whole blood) at baseline and at days 15 and 29, respectively. Patients with elevated versus not elevated CTC at each time point had worse progression-free survival (PFS; P = 0.005, 0.0003, 0.0002, respectively). The odds of clinical benefit response for those who had elevated versus low CTC at baseline and days 15 and 29 were 0.25 (95% CI: 0.08-0.84; P = 0.024), 0.19 (95% CI: 0.05-0.17; P = 0.014), and 0.06 (95% CI: 0.01-0.33; P = 0.001), respectively. There was no apparent prognostic effect comparing CTC apoptosis versus non-apoptosis. Presence of CTC cluster at day 15 and day 29 was associated with shorter PFS.CTC were detected using CellSearch assay in approximately one-third of TN MBC patients. Elevated CTC at baseline and days 15 and 29 were prognostic, and reductions in CTC levels reflected response.
Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke
Authors: Werner Hacke, Markku Kaste, Erich Bluhmki, Miroslav Brozman, Antoni Dávalos, Donata Guidetti, Vincent Larrue, Kennedy R. Lees, Zakaria Medeghri, Thomas Machnig, Dietmar Schneider, Rüdiger von Kummer, Nils Wahlgren, Danilo Toni
Journal: New England Journal of Medicine (2008)

Intravenous thrombolysis with alteplase is the only approved treatment for acute ischemic stroke, but its efficacy and safety when administered more than 3 hours after the onset of symptoms have not been established. We tested the efficacy and safety of alteplase administered between 3 and 4.5 hours after the onset of a stroke.
Successful Correction of Immune Defects in a Patient with NEMO Mutation by Allogeneic Transplantation Uncovers Intrinsic Epithelial Basis for Colitis
Authors: S PAI, O LEVY, H JABARA, J GLICKMAN, J SACHS, S NURKO, J ORANGE, R GEHA
Journal: Journal of Allergy and Clinical Immunology (2008)
Sensitivity to Epidermal Growth Factor Receptor Inhibitor Requires E-Cadherin Expression in Urothelial Carcinoma Cells
Authors: Peter C. Black, Gordon A. Brown, Teruo Inamoto, Marissa Shrader, Ameeta Arora, Arlene O. Siefker-Radtke, Liana Adam, Dan Theodorescu, Xifeng Wu, Mark F. Munsell, Menashe Bar-Eli, David J. McConkey, Colin P.N. Dinney
Journal: Clinical Cancer Research (2008)

Epidermal growth factor receptor (EGFR) is an attractive target for the treatment of urothelial carcinoma, but a clinical response can be expected in only a small proportion of patients. The aim of this study was to define molecular markers of response to cetuximab therapy in a panel of urothelial carcinoma cell lines.Eleven cell lines were investigated for antiproliferative response to cetuximab based on [(3)H]thymidine incorporation. A variety of markers, including EGFR expression, phosphorylation, and gene amplification, as well as the expression of other growth factor receptors, their ligands, and markers of epithelial-to-mesenchymal transition were investigated. Cohen's kappa statistic was used to estimate the agreement between response and expression of these markers. E-cadherin was silenced by small interfering RNA in two sensitive cell lines, and the effect on the response to cetuximab was measured.We were able to identify a panel of relevant markers pertaining especially to alternate growth factor receptor expression and epithelial-to-mesenchymal transition that predicted response to cetuximab. The data suggested that expression of intact HER-4 (kappa, 1.00; P = 0.008), E-cadherin (kappa, 0.81; P = 0.015), and beta-catenin (kappa, 0.81; P = 0.015) and loss of expression of platelet-derived growth factor receptor beta (kappa, 0.57; P = 0.167) were associated with response to cetuximab therapy. Silencing E-cadherin in two sensitive cell lines reduced responsiveness to cetuximab in both (P < 0.001).A panel of predictive markers for cetuximab response has been established in vitro and is currently being evaluated in a prospective clinical trial of neoadjuvant EGFR-targeted therapy. Most importantly, E-cadherin seems to play a central role in modulation of EGFR response in urothelial carcinoma.
Diffuse Cystic Lung Disease. Part I
Authors: Nishant Gupta, Robert Vassallo, Kathryn A. Wikenheiser-Brokamp, Francis X. McCormack
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

The diffuse cystic lung diseases (DCLDs) are a group of pathophysiologically heterogenous processes that are characterized by the presence of multiple spherical or irregularly shaped, thin-walled, air-filled spaces within the pulmonary parenchyma. Although the mechanisms of cyst formation remain incompletely defined for all DCLDs, in most cases lung remodeling associated with inflammatory or infiltrative processes results in displacement, destruction, or replacement of alveolar septa, distal airways, and small vessels within the secondary lobules of the lung. The DCLDs can be broadly classified according to underlying etiology as those caused by low-grade or high-grade metastasizing neoplasms, polyclonal or monoclonal lymphoproliferative disorders, infections, interstitial lung diseases, smoking, and congenital or developmental defects. In the first of a two-part series, we present an overview of the cystic lung diseases caused by neoplasms, infections, smoking-related diseases, and interstitial lung diseases, with a focus on lymphangioleiomyomatosis and pulmonary Langerhans cell histiocytosis.