tbuckley/cabot-search huggingface dataset:
Restored glial glutamate transporter EAAT2 function as a potential therapeutic approach for Alzheimer’s disease
Authors: Kou Takahashi, Qiongman Kong, Yuchen Lin, Nathan Stouffer, Delanie A. Schulte, Liching Lai, Qibing Liu, Ling-Chu Chang, Sky Dominguez, Xuechao Xing, Gregory D. Cuny, Kevin J. Hodgetts, Marcie A. Glicksman, Chien-Liang Glenn Lin
Journal: The Journal of Experimental Medicine (2015)

Glutamatergic systems play a critical role in cognitive functions and are known to be defective in Alzheimer’s disease (AD) patients. Previous literature has indicated that glial glutamate transporter EAAT2 plays an essential role in cognitive functions and that loss of EAAT2 protein is a common phenomenon observed in AD patients and animal models. In the current study, we investigated whether restored EAAT2 protein and function could benefit cognitive functions and pathology in APPSw,Ind mice, an animal model of AD. A transgenic mouse approach via crossing EAAT2 transgenic mice with APPSw,Ind. mice and a pharmacological approach using a novel EAAT2 translational activator, LDN/OSU-0212320, were conducted. Findings from both approaches demonstrated that restored EAAT2 protein function significantly improved cognitive functions, restored synaptic integrity, and reduced amyloid plaques. Importantly, the observed benefits were sustained one month after compound treatment cessation, suggesting that EAAT2 is a potential disease modifier with therapeutic potential for AD.
EFFECTS OF HUMAN PANCREATIC TUMOUR GROWTH HORMONE RELEASING FACTOR ON GROWTH HORMONE AND SOMATOMEDIN C LEVELS IN PATIENTS WITH IDIOPATHIC GROWTH HORMONE DEFICIENCY
Authors: JoãoL.C. Borges, MarieC. Gelato, AlanD. Rogol, Mary Lee Vance, RobertM. Macleod, D. Lynn Loriaux, Jean Rivier, RobertM. Blizzard, Richard Furlanetto, WilliamS. Evans, DonaldL. Kaiser, GeorgeR. Merriam, Joachim Spiess, Wylie Vale, MichaelO. Thorner
Journal: The Lancet (1983)
Inhibition of β-adrenoceptors alleviated mucus secretion and emphysema in cigarette smoke exposed rat model
Authors: Fei Wang, Ji-Hong Li, Bei He
Journal: European Respiratory Journal (2011)

Background: The sympathetic nervous (SN) is probably over activated in COPD. Some retrospective studies found that treatment with β-blockers may reduce the risk of exacerbations and improve survival in COPD patients. However, our preliminary data showed that no significant change of lung function in COPD patients after treatment with β-blocker. The aim of the study is to elucidate whether inhibition of the SN over activation may improve lung pathological change in smoke exposed rat model.

Methods: The rats were randomly divided into 3 groups: control group (C, n=9), smoke-exposed group (S, n=8) and smoke-exposed plus proptanolol group (S/P, n=8). S and S/P rats were exposed to cigarette smoke for 3 months, and S/P rats were further treated with proptanolol for 1 month. Lung tissue pathologic score and mean linear intercept (MLI) were determined.

Results: The scores of mucus secretion, goblet-cell metaplasia, smooth muscle cells (SMC) proliferation, and MLI were significant different in the 3 groups (see table 1), however, no significant difference was found in other aspects of pathological changes.

View this table:

Table 1. Lung tissue pathologic scores in the 3 groups (mean ± SD)





Conclusion: In cigarette smoke exposed rat model, inhibition of β-adrenoceptors alleviated mucus secretion and emphysema.
A survey of badminton injuries.
Authors: L. D. Hensley, D. C. Paup
Journal: British Journal of Sports Medicine (1979)

A Badminton Injury Questionnaire (BIQ) was developed to survey the type and frequency of injuries that are likely to occur from playing competitive badminton. Two hundred and thirty-one players, ranging from club players to international champions, completed the survey which indicated an injury incidence rate of .09 and .14 injuries per person per year for male and female badminton players respectively. Badminton participation resulted in relatively few injuries, most of which were cramps, blisters, strains and sprains of the lower extremities and a surprisingly low incidence of tennis elbow.
Safety and feasibility of exhaled breath condensate collection in ventilated infants and children
Authors: W. G. Muller, F. Morini, S. Eaton, M. Peters, A. Jaffe
Journal: European Respiratory Journal (2006)

The aim of this study was to develop a technique for the collection of exhaled breath condensate (EBC) from ventilated children and assess its safety and feasibility. Collection of EBC is used to investigate markers of oxidative stress in the lower airway. No studies have assessed its safety in ventilated children. An in vitro model was developed by connecting a ventilator to an artificial lung; 14 clinical and ventilatory parameters were measured during EBC collection from ventilated children. Levels of 8-isoprostane were measured following collection with and without humidification of the inhaled gas. Amount of water vapour collected was linearly related to time and to minute ventilation in the in vitro model. EBC collections (n = 68) were made from ventilated children. In the nonhumidified group, the mean (range) positive end-expiratory pressure increased by 4.1% (2.8–5.5%) and the peak inspiratory flow decreased by 6.1% (11.0–1.3%) during collection. Detectable levels of 8-isoprostane were only found in 10 out of 18 nonhumidified EBC samples (median (range) 4.7 pg·mL -1 (0–5.8)). Collection of exhaled breath condensate from ventilated infants and children is feasible and safe. Discontinuation of humidification is likely to be important in standardising the measurement of inflammatory parameters in exhaled breath condensate collected from ventilated children.
Peginterferon Alfa-2a Alone, Lamivudine Alone, and the Two in Combination in Patients with HBeAg-Negative Chronic Hepatitis B
Authors: Patrick Marcellin, George K.K. Lau, Ferruccio Bonino, Patrizia Farci, Stephanos Hadziyannis, Rui Jin, Zhi-Meng Lu, Teerha Piratvisuth, Georgios Germanidis, Cihan Yurdaydin, Moises Diago, Selim Gurel, Ming-Yang Lai, Peter Button, Nigel Pluck
Journal: New England Journal of Medicine (2004)

Available treatments for hepatitis B e antigen (HBeAg)-negative chronic hepatitis B are associated with poor sustained responses. As a result, nucleoside and nucleotide analogues are typically continued indefinitely, a strategy associated with the risk of resistance and unknown long-term safety implications.We compared the efficacy and safety of peginterferon alfa-2a (180 microg once weekly) plus placebo, peginterferon alfa-2a plus lamivudine (100 mg daily), and lamivudine alone in 177, 179, and 181 patients with HBeAg-negative chronic hepatitis B, respectively. Patients were treated for 48 weeks and followed for an additional 24 weeks.After 24 weeks of follow-up, the percentage of patients with normalization of alanine aminotransferase levels or hepatitis B virus (HBV) DNA levels below 20,000 copies per milliliter was significantly higher with peginterferon alfa-2a monotherapy (59 percent and 43 percent, respectively) and peginterferon alfa-2a plus lamivudine (60 percent and 44 percent) than with lamivudine monotherapy (44 percent, P=0.004 and P=0.003, respectively; and 29 percent, P=0.007 and P=0.003, respectively). Rates of sustained suppression of HBV DNA to below 400 copies per milliliter were 19 percent with peginterferon alfa-2a monotherapy, 20 percent with combination therapy, and 7 percent with lamivudine alone (P<0.001 for both comparisons with lamivudine alone). Loss of hepatitis B surface antigen occurred in 12 patients in the peginterferon groups, as compared with 0 patients in the group given lamivudine alone. Adverse events, including pyrexia, fatigue, myalgia, and headache, were less frequent with lamivudine monotherapy than with peginterferon alfa-2a monotherapy or combination therapy.Patients with HBeAg-negative chronic hepatitis B had significantly higher rates of response, sustained for 24 weeks after the cessation of therapy, with peginterferon alfa-2a than with lamivudine. The addition of lamivudine to peginterferon alfa-2a did not improve post-therapy response rates.
Hemodynamic and clinical effects of tezosentan, an intravenous dual endothelin receptor antagonist, in patients hospitalized for acute decompensated heart failure
Authors: Guillermo Torre-Amione, James B Young, Wilson S Colucci, Basil S Lewis, Craig Pratt, Gad Cotter, Karl Stangl, Uri Elkayam, John R Teerlink, Aline Frey, Maurizio Rainisio, Isaac Kobrin
Journal: Journal of the American College of Cardiology (2003)
Suppression of Phosphoinositide 3-Kinase Signaling and Alteration of Multiple Ion Currents in Drug-Induced Long QT Syndrome
Authors: Zhongju Lu, Chia-Yen C. Wu, Ya-Ping Jiang, Lisa M. Ballou, Chris Clausen, Ira S. Cohen, Richard Z. Lin
Journal: Science Translational Medicine (2012)

Many drugs, including some commonly used medications, can cause abnormal heart rhythms and sudden death, as manifest by a prolonged QT interval in the electrocardiogram. Cardiac arrhythmias caused by drug-induced long QT syndrome are thought to result mainly from reductions in the delayed rectifier potassium ion (K(+)) current I(Kr). Here, we report a mechanism for drug-induced QT prolongation that involves changes in multiple ion currents caused by a decrease in phosphoinositide 3-kinase (PI3K) signaling. Treatment of canine cardiac myocytes with inhibitors of tyrosine kinases or PI3Ks caused an increase in action potential duration that was reversed by intracellular infusion of phosphatidylinositol 3,4,5-trisphosphate. The inhibitors decreased the delayed rectifier K(+) currents I(Kr) and I(Ks), the L-type calcium ion (Ca(2+)) current I(Ca,L), and the peak sodium ion (Na(+)) current I(Na) and increased the persistent Na(+) current I(NaP). Computer modeling of the canine ventricular action potential showed that the drug-induced change in any one current accounted for less than 50% of the increase in action potential duration. Mouse hearts lacking the PI3K p110α catalytic subunit exhibited a prolonged action potential and QT interval that were at least partly a result of an increase in I(NaP). These results indicate that down-regulation of PI3K signaling directly or indirectly via tyrosine kinase inhibition prolongs the QT interval by affecting multiple ion channels. This mechanism may explain why some tyrosine kinase inhibitors in clinical use are associated with increased risk of life-threatening arrhythmias.
Biomarkers Signal Contaminant Effects on the Organs of English Sole ( <i>Parophrys vetulus</i> ) from Puget Sound
Authors: Donald C. Malins, Katie M. Anderson, John J. Stegeman, Pawel Jaruga, Virginia M. Green, Naomi K. Gilman, Miral Dizdaroglu
Journal: Environmental Health Perspectives (2006)

Fish living in contaminated environments accumulate toxic chemicals in their tissues. Biomarkers are needed to identify the resulting health effects, particularly focusing on early changes at a subcellular level. We used a suite of complementary biomarkers to signal contaminant-induced changes in the DNA structure and cellular physiology of the livers and gills of English sole (Parophrys vetulus). These sediment-dwelling fish were obtained from the industrialized lower Duwamish River (DR) in Seattle, Washington, and from Quartermaster Harbor (QMH), a relatively clean reference site in south Puget Sound. Fourier transform–infrared (FT-IR) spectroscopy, liquid chromatography/mass spectrometry (LC/MS), and gas chromatography/mass spectrometry (GC/MS) identified potentially deleterious alterations in the DNA structure of the DR fish livers and gills, compared with the QMH fish. Expression of CYP1A (a member of the cytochrome P450 multigene family of enzymes) signaled changes in the liver associated with the oxidation of organic xenobiotics, as previously found with the gill. The FT-IR models demonstrated that the liver DNA of the DR fish had a unique structure likely arising from exposure to environmental chemicals. Analysis by LC/MS and GC/MS showed higher concentrations of DNA base lesions in the liver DNA of the DR fish, suggesting that these base modifications contributed to this discrete DNA structure. A comparable analysis by LC/MS and GC/MS of base modifications provided similar results with the gill. The biomarkers described are highly promising for identifying contaminant-induced stresses in fish populations from polluted and reference sites and, in addition, for monitoring the progress of remedial actions.
Circulating Tumor Cells Predict Survival in Early Average-to-High Risk Breast Cancer Patients
Authors: Brigitte Rack, Christian Schindlbeck, Julia Jückstock, Ulrich Andergassen, Philip Hepp, Thomas Zwingers, Thomas W. P. Friedl, Ralf Lorenz, Hans Tesch, Peter A. Fasching, Tanja Fehm, Andreas Schneeweiss, Werner Lichtenegger, Matthias W. Beckmann, Klaus Friese, Klaus Pantel, Wolfgang Janni
Journal: JNCI Journal of the National Cancer Institute (2014)

Circulating tumor cells (CTCs) have been shown to predict reduced survival outcomes in metastatic breast cancer.CTCs were analyzed in 2026 patients with early breast cancer before adjuvant chemotherapy and in 1492 patients after chemotherapy using the CellSearch System. After immuno-magnetic enrichment for cells expressing the epithelial-cell adhesion molecule, CTCs were defined as nucleated cells expressing cytokeratin and lacking CD45. The patients were followed for a median of 35 months (range = 0-54). Kaplan-Meier analyses and the log-rank test were used for survival analyses. All statistical tests were two-sided.Before chemotherapy, CTCs were detected in 21.5% of patients (n = 435 of 2026), with 19.6% (n = 136 of 692) of node-negative and 22.4% (n = 299 of 1334) of node-positive patients showing CTCs (P < .001). No association was found with tumor size, grading, or hormone receptor status. After chemotherapy, 22.1% of patients (n = 330 of 1493) were CTC positive. The presence of CTCs was associated with poor disease-free survival (DFS; P < .0001), distant DFS (P < .001), breast cancer-specific survival (P = .008), and overall survival (OS; P = .0002). CTCs were confirmed as independent prognostic markers in multivariable analysis for DFS (hazard ratio [HR] = 2.11; 95% confidence interval [CI] = 1.49 to 2.99; P < .0001) and OS (HR = 2.18; 95% CI = 1.32 to 3.59; P = .002). The prognosis was worst in patients with at least five CTCs per 30 mL blood (DFS: HR = 4.51, 95% CI = 2.59 to 7.86; OS: HR = 3.60, 95% CI = 1.56 to 8.45). The presence of persisting CTCs after chemotherapy showed a negative influence on DFS (HR = 1.12; 95% CI = 1.02 to 1.25; P = .02) and on OS (HR = 1.16; 95% CI = 0.99 to 1.37; P = .06) CONCLUSIONS: These results suggest the independent prognostic relevance of CTCs both before and after adjuvant chemotherapy in a large prospective trial of patients with primary breast cancer.
The Extra-domain A of Fibronectin Is a Vascular Marker of Solid Tumors and Metastases
Authors: Jascha-N. Rybak, Christoph Roesli, Manuela Kaspar, Alessandra Villa, Dario Neri
Journal: Cancer Research (2007)

Abstract One of the most promising new avenues for the development of more selective and efficacious cancer therapies relies on the antibody-mediated targeted delivery of bioactive agents (e.g., cytokines) to the tumor environment. The identification of quantitative differences in the expression of accessible vascular proteins in metastatic lesions and host organs facilitate the development of antibody-based strategies, which should be highly efficient and selective, considering the fact that an over-exuberant neovasculature is a characteristic feature of aggressive cancers, and that tumor blood vessels are readily accessible for i.v. administered therapeutic agents. Metastasis is the main cause of death in cancer. The availability of metastasis-specific antigens accessible from the bloodstream will allow a selective delivery of therapeutic agents to metastatic lesions using antibodies as vehicles. Using a combination of vascular biotinylation of 129Sv mice bearing F9 liver metastases and mass spectrometry, we have identified 435 accessible proteins in metastasis and host organ specimens, of which 117 were exclusively detected in metastases. In particular, we found that the alternatively spliced extra-domain A (EDA) of fibronectin is strongly expressed in the neovasculature of liver metastases, while being undetectable in most normal organs. A human antibody to EDA was used to show EDA expression in the neovasculature of metastases and primary tumors of human cancer patients and to target mouse liver metastases and subcutaneous tumors in vivo. Human antibody fragments specific to the EDA domain of fibronectin promise to serve as general vehicles for the efficient and selective delivery of imaging agents or therapeutic molecules to metastatic sites. [Cancer Res 2007;67(22):10948–57]
Effect of muscle glycogen depletion on in vivo insulin action in man.
Authors: C Bogardus, P Thuillez, E Ravussin, B Vasquez, M Narimiga, S Azhar
Journal: Journal of Clinical Investigation (1983)

In rats, muscle glycogen depletion has been associated with increased insulin action. Whether this also occurs in man has not been reported. After 4 d rest, 13 males (E Group) had a percutaneous muscle biopsy of the vastus lateralis muscle followed by a euglycemic clamp at plasma insulin congruent to 100 microU/ml and congruent to 1,900 microU/ml, with simultaneous indirect calorimetry. This was repeated 1 wk later, but after glycogen-depleting exercise the night before the euglycemic clamp. Seven subjects underwent the same protocol but were also re-fed 100 g carbohydrate (CHO) after the exercise (EF group). In both groups, the mean muscle glycogen content was approximately 40% lower (P less than 0.01) after exercise compared with the muscle glycogen content measured after rest. In the E group, the mean muscle glycogen synthase activity (percent independent of glucose-6-phosphate) increased threefold (P less than 0.001) after exercise, but increased only twofold in the EF group (P less than 0.02 between groups). In both groups, the mean basal and insulin-stimulated CHO oxidation rates were lower in the post-exercise, glycogen-depleted condition compared with the rested, glycogen-replete condition. The mean insulin-stimulated CHO storage rate increased significantly in the E group after exercise but not in the EF group. In the E group, the total insulin-stimulated CHO disposal rate (M) was 17 (P less than 0.04) and 10% (P less than 0.03) higher after exercise during the low and high dose insulin infusion, respectively. No significant changes in M were observed in the EF group. For all subjects, after rest and exercise, the M correlated with the CHO storage rates during the low (r = 0.80, P less than 0.001) and high dose (r = 0.77, P less than 0.001) insulin infusions. After exercise, the muscle glycogen synthase activity correlated with the CHO storage rate (r = 0.73, P less than 0.002; r = 0.75, P less than 0.002) during the low and high dose insulin infusions, respectively, and also with M (r = 0.64, P less than 0.008; r = 0.57; P less than 0.02).
Management of infections pre- and post-liver transplantation: Report of an AISF consensus conference
Authors: Stefano Fagiuoli, Agostino Colli, Raffaele Bruno, Antonio Craxì, Giovanni Battista Gaeta, Paolo Grossi, Mario U. Mondelli, Massimo Puoti, Evangelista Sagnelli, Stefania Stefani, Pierluigi Toniutto, Patrizia Burra
Journal: Journal of Hepatology (2014)

The burden of infectious diseases both before and after liver transplantation is clearly attributable to the dysfunction of defensive mechanisms of the host, both as a result of cirrhosis, as well as the use of immunosuppressive agents. The present document represents the recommendations of an expert panel commended by the Italian Association for the Study of the Liver (AISF), on the prevention and management of infectious complications excluding hepatitis B, D, C, and HIV in the setting of liver transplantation. Due to a decreased response to vaccinations in cirrhosis as well as within the first six months after transplantation, the best timing for immunization is likely before transplant and early in the course of disease. Before transplantation, a vaccination panel including inactivated as well as live attenuated vaccines is recommended, while oral polio vaccine, Calmette-Guerin's bacillus, and Smallpox are contraindicated, whereas after transplantation, live attenuated vaccines are contraindicated. Before transplant, screening protocols should be divided into different levels according to the likelihood of infection, in order to reduce costs for the National Health Service. Recommended preoperative and postoperative prophylaxis varies according to the pathologic agent to which it is directed (bacterial vs. viral vs. fungal). Timing after transplantation greatly determines the most likely agent involved in post-transplant infections, and specific high-risk categories of patients have been identified that warrant closer surveillance. Clearly, specifically targeted treatment protocols are needed upon diagnosis of infections in both the pre- as well as the post-transplant scenarios, not without considering local microbiology and resistance patterns.
Identification of novel stem cell markers using gap analysis of gene expression data
Authors: Paul M Krzyzanowski, Miguel A Andrade-Navarro
Journal: Genome biology (2007)

Abstract We describe a method for detecting marker genes in large heterogeneous collections of gene expression data. Markers are identified and characterized by the existence of demarcations in their expression values across the whole dataset, which suggest the presence of groupings of samples. We apply this method to DNA microarray data generated from 83 mouse stem cell related samples and describe 426 selected markers associated with differentiation to establish principles of stem cell evolution.
Ligand-Independent Activation of Vascular Endothelial Growth Factor Receptor 2 by Fluid Shear Stress Regulates Activation of Endothelial Nitric Oxide Synthase
Authors: Zheng-Gen Jin, Hiroto Ueba, Tatsuo Tanimoto, Andreea O. Lungu, Mary D. Frame, Bradford C. Berk
Journal: Circulation Research (2003)

Fluid shear stress generated by blood flowing over the endothelium is a major determinant of arterial tone, vascular remodeling, and atherogenesis. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) plays an essential role in regulation of vascular function and structure by blood flow, but the molecular mechanisms that transduce mechanical force to eNOS activation are not well understood. In this study, we found that laminar flow (shear stress=12 dyne/cm 2 ) rapidly activates vascular endothelial growth factor receptor 2 (VEGFR2) in a ligand-independent manner and leads to eNOS activation in cultured endothelial cells. Flow-stimulated VEGFR2 recruits phosphoinositide 3-kinase and mediates activation of Akt and eNOS. Inhibiting VEGFR2 kinase with selective inhibitors blocks flow-induced activation of Akt and eNOS and production of NO. Decreasing VEGFR2 expression with antisense VEGFR2 oligonucleotides significantly attenuates activation of Akt and eNOS. Furthermore, Src kinases are involved in flow-stimulated VEGFR2 because inhibiting Src kinases by PP2, a selective inhibitor for Src kinases, abolishes flow-induced VEGFR2 tyrosine phosphorylation and downstream signaling. Finally, we show that inhibiting VEGFR2 kinase significantly reduces flow-mediated NO-dependent arteriolar dilation in vivo. These data identify VEGFR2 as a key mechanotransducer that activates eNOS in response to blood flow.
PAROXYSMAL AURICULAR FIBRILLATION COMPLICATING METRAZOL SHOCK THERAPY
Authors: MARTIN H. HOFFMANN, NATHANIEL SANDLER, HANS HECHT
Journal: American Journal of Psychiatry (1940)

A case of paroxsmal auricular fibrillation is presented. The arrhythmia persisted for five hours following the initial injection of metrazol which resulted in a strong epileptiform seizure. The various possible mechanisms are discussed and particular emphasis is laid upon the possibility of its "central" reflex origin.