tbuckley/cabot-search huggingface dataset:
Attenuation of myocardial ischemia/reperfusion injury in mice with myocyte-specific overexpression of endothelial nitric oxide synthase
Authors: Friedrich Brunner, Robert Maier, Penelope Andrew, Gerald Wölkart, Rudolf Zechner, Bernd Mayer
Journal: Cardiovascular Research (2002)

The role of nitric oxide (NO) in myocardial ischemia/reperfusion injury remains controversial as both NO donors and NO synthase (NOS) inhibitors have shown to be protective. We generated transgenic (TG) mice that overexpress endothelial NOS (eNOS) exclusively in cardiac myocytes to determine the effects of high cardiac NO levels on ischemia/reperfusion injury and cellular Ca(2+) homeostasis. Wild-type (WT) mice served as controls.Hearts were perfused in vitro and subjected to 20 min of total no-flow ischemia and 30 min of reperfusion (n=5 per group). Left ventricular function, cGMP levels and intracellular Ca(2+) transients (Ca(2+)(i)) were determined.Left ventricular pressure was reduced (maximum, -33%) and basal cardiac cGMP was increased (twofold) in TG hearts, and the changes were reversed by NOS blockade with N(G)-nitro-L-arginine methyl ester (L-NAME). Relative to baseline, recovery of reperfusion contractile function was significantly better in hearts from TG (98%) than WT (51%) mice, and L-NAME abolished this effect. Heart rate and coronary perfusion pressure were not different between groups. Systolic and diastolic Ca(2+)(i) concentrations were similar in WT and TG hearts, but Ca(2+)(i) overload during early reperfusion tended to be less in TG hearts. Kinetic analysis of pressure curves and Ca(2+)(i) transients revealed a faster left ventricular diastolic relaxation and abbreviated aequorin light signals in TG hearts at baseline and during reperfusion.High levels of NO/cGMP strongly protect against ischemia/reperfusion injury, the protection is largely independent of changes in Ca(2+)(i) modulation, but relates to reduced preischemic performance. Myocyte-specific NO augmentation may aid in studies of the (patho)physiological roles of cardiac-derived NO.
Randomized Trial of Peanut Consumption in Infants at Risk for Peanut Allergy
Authors: George Du Toit, Graham Roberts, Peter H. Sayre, Henry T. Bahnson, Suzana Radulovic, Alexandra F. Santos, Helen A. Brough, Deborah Phippard, Monica Basting, Mary Feeney, Victor Turcanu, Michelle L. Sever, Margarita Gomez Lorenzo, Marshall Plaut, Gideon Lack
Journal: New England Journal of Medicine (2015)

The prevalence of peanut allergy among children in Western countries has doubled in the past 10 years, and peanut allergy is becoming apparent in Africa and Asia. We evaluated strategies of peanut consumption and avoidance to determine which strategy is most effective in preventing the development of peanut allergy in infants at high risk for the allergy.
ST-Segment–Elevation Myocardial Infarction Treatment and the Seductive Lure of Observational Analyses
Authors: Daniel Muñoz, Christopher B. Granger
Journal: Circulation (2011)

andomized trials have demonstrated the clinical superi- ority of timely transfer for primary percutaneous coronary intervention (PCI) compared with onsite fibrinolytic therapy for reperfusion in the setting of ST-segment-elevation myocardial infarction (STEMI). 1,2On this point, there is relative clarity.What remains nebulous, however, is the degree to which these findings apply broadly across care systems that often have substantial transfer delays.
Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease
Authors: Christopher L German, Michelle G Baladi, Lisa M McFadden, Glen R Hanson, Annette E Fleckenstein
Journal: Pharmacological Reviews (2015)

Dopamine (DA) plays a well recognized role in a variety of physiologic functions such as movement, cognition, mood, and reward. Consequently, many human disorders are due, in part, to dysfunctional dopaminergic systems, including Parkinson's disease, attention deficit hyperactivity disorder, and substance abuse. Drugs that modify the DA system are clinically effective in treating symptoms of these diseases or are involved in their manifestation, implicating DA in their etiology. DA signaling and distribution are primarily modulated by the DA transporter (DAT) and by vesicular monoamine transporter (VMAT)-2, which transport DA into presynaptic terminals and synaptic vesicles, respectively. These transporters are regulated by complex processes such as phosphorylation, protein-protein interactions, and changes in intracellular localization. This review provides an overview of 1) the current understanding of DAT and VMAT2 neurobiology, including discussion of studies ranging from those conducted in vitro to those involving human subjects; 2) the role of these transporters in disease and how these transporters are affected by disease; and 3) and how selected drugs alter the function and expression of these transporters. Understanding the regulatory processes and the pathologic consequences of DAT and VMAT2 dysfunction underlies the evolution of therapeutic development for the treatment of DA-related disorders.
Changes in Phasic Coronary Blood Flow Velocity Profile in Relation to Changes in Hemodynamic Parameters During Stress in Patients With Aortic Valve Stenosis
Authors: Panaghiotis N. Petropoulakis, Michael K. Kyriakidis, Costas A. Tentolouris, Costas V. Kourouclis, Pavlos K. Toutouzas
Journal: Circulation (1995)

Alterations in phasic coronary flow profile have been demonstrated at rest in patients with aortic valve stenosis (AVS) but have never been studied under conditions of hemodynamic stress.Thirty-four patients with significant pure AVS (21 with exertional symptoms [group 1], 13 asymptomatic [group 2]) and 9 control subjects (group 3), all with normal coronary arteries, were studied successively at rest, during rapid atrial pacing, and after dobutamine infusion (5 to 30 micrograms.kg-1.min-1 i.v.) by proximal left anterior descending (LAD) intracoronary Doppler flow velocimetry concomitant with hemodynamic measurements. Systolic retrograde coronary flow velocity (CFV) was recorded only in patients with AVS, and its resting peak value was positively correlated with peak aortic pressure gradient (APG) (r = .63, P < .001). In group 1, there was lower aortic valve area (0.58 +/- 0.10 versus 0.75 +/- 0.08 cm2, P < .001) and higher resting APG and peak systolic retrograde CFV than in group 2, and also higher resting peak diastolic and mean CFV than in groups 2 and 3. In the two AVS groups, there were no changes from rest in APG and retrograde CFV at peak pacing rate; however, these parameters increased concomitantly and significantly at peak dobutamine stress. The ratio of the resting systolic to diastolic CFV curve area was inversely correlated with mean APG (r = -.54, P < .001); it was significantly lower in group 1 than in groups 2 and 3 (0.19 +/- 0.07 versus 0.29 +/- 0.10 and 0.30 +/- 0.04, respectively, both P < .005) and increased at peak pacing (group 1, to 0.29 +/- 0.14; group 2, to 0.39 +/- 0.12; group 3, to 0.38 +/- 0.07; all P < .001). At peak dobutamine stress, it decreased in patients with AVS (group 1, to 0.05 +/- 0.05; group 2, to 0.08 +/- 0.03; both P < .001) but did not change in group 3 (0.25 +/- 0.05). From rest to peak dobutamine stress, in both AVS groups there was increased retrograde systolic (group 1, 441 +/- 483%; group 2, 681 +/- 356%; both P < .001), decreased total systolic (group 1, -66 +/- 25%, P < .001; group 2, -19 +/- 24%; P = NS), and increased diastolic (group 1, 33.4 +/- 31.7%; group 2, 197.7 +/- 105.1%; both P < .001; group 1 versus group 2, P < .001) CFV curve area. In contrast, group 3 showed comparable increases in both systolic (143.5 +/- 44.4%) and diastolic (197.1 +/- 75.2%) CFV area (both P < .001). The stress-induced increases in the mean CFV and blood flow exceeded or were comparable with the concomitant increases in the estimated myocardial metabolic demand in groups 2 and 3 but were significantly lower in group 1.Stress-induced changes in LAD phasic CFV profile differ significantly between patients with and without AVS. In AVS, these changes are closely related to the concomitant stress-induced changes in hemodynamic parameters.
Nesiritide, Renal Function, and Associated Outcomes During Hospitalization for Acute Decompensated Heart Failure
Authors: Vincent M. van Deursen, Adrian F. Hernandez, Amanda Stebbins, Vic Hasselblad, Justin A. Ezekowitz, Robert M. Califf, Stephen S. Gottlieb, Christopher M. O’Connor, Randall C. Starling, W.H. Wilson Tang, John J. McMurray, Kenneth Dickstein, Adriaan A. Voors
Journal: Circulation (2014)

Contradictory results have been reported on the effects of nesiritide on renal function in patients with acute decompensated heart failure. We studied the effects of nesiritide on renal function during hospitalization for acute decompensated heart failure and associated outcomes.A total of 7141 patients were randomized to receive either nesiritide or placebo and creatinine was recorded in 5702 patients at baseline, after infusion, discharge, peak/nadir levels until day 30. Worsening renal function was defined as an increase of serum creatinine >0.3 mg/dL and a change of ≥25%. Median (25(th)-75(th) percentile) baseline creatinine was 1.2 (1.0-1.6) mg/dL and median baseline blood urea nitrogen was 25 (18-39) mmol/L. Changes in both serum creatinine and blood urea nitrogen were similar in nesiritide-treated and placebo-treated patients (P=0.20 and P=0.41) from baseline to discharge. In a multivariable model, independent predictors of change from randomization to hospital discharge in serum creatinine were a lower baseline blood urea nitrogen, higher systolic blood pressure, lower diastolic blood pressure, previous weight gain, and lower baseline potassium (all P<0.0001). The frequency of worsening renal function during hospitalization was similar in the nesiritide and placebo group (14.1% and 12.8%, respectively; odds ratio with nesiritide 1.12; confidence interval, 0.95-1.32; P=0.19) and was not associated with death alone and death or rehospitalization at 30 days. However, baseline, discharge, and change in creatinine were associated with death alone and death or rehospitalization for heart failure (all tests, P<0.0001).Nesiritide did not affect renal function in patients with acute decompensated heart failure. Baseline, discharge, and change in renal function were associated with 30-day mortality or rehospitalization for heart failure.
Long-term results of a phase II study with neoadjuvant docetaxel chemotherapy and complete androgen blockade in locally advanced and high-risk prostate cancer
Authors: Mark Thalgott, Thomas Horn, Matthias M Heck, Tobias Maurer, Matthias Eiber, Margitta Retz, Michael Autenrieth, Kathleen Herkommer, Bernd J Krause, Jürgen E Gschwend, Uwe Treiber, Hubert R Kübler
Journal: Journal of Hematology & Oncology (2014)

Patients with locally advanced and high-risk prostate cancer (LAPC) are prone to experience biochemical recurrence despite radical prostatectomy (RP). We evaluated feasibility, safety and activity of a neoadjuvant chemohormonal therapy (NCHT) with 3-weekly full dose docetaxel and complete androgen blockade (CAB) in locally advanced and high-risk prostate cancer patients (LAPC) undergoing RP. Patients (n = 30) were selected by Kattans' preoperative score and received trimestral buserelin 9,45 mg, bicalutamide 50 mg/day and 3 cycles docetaxel (75 mg/m2) followed by RP. Primary endpoints were biochemical (PSA) and local downstaging. Secondary endpoints included toxicity and operability assessments, pathological complete response (pCR), time to PSA progression, 5-year biochemical recurrence free survival (bRFS) and overall survival (OS). Median baseline PSA was 25.8 ng/ml (2.1–293), and the predicted probability of 5-year bRFS was 10% (0–55). NCHT induced PSA-reduction was 97.3% (81.3-99.9%; p < 0.001) and post-RP 96.7% of patients were therapy responders, with undetectable PSA-values. Post- vs. pretreatment MRI indicated a median tumor volume reduction of 46.4% (−31.3-82.8; p < 0.001). A pathological downstaging was observed in 48.3%. Severe hematologic toxicities (≥CTC3) were frequent with 53.8% leucopenia, 90% neutropenia and 13.3% febrile neutropenia. RP was performed in all patients. While resectability was hindered in 26.7%, continence was achieved in 96.7%. Pathologic analyses revealed no pCR. Lymph node- and extracapsular involvement was observed in 36.7% and 56.7% with 33.3% positive surgical margins. After a median of 48.6 (19.9-87.8) months, 55.2% of therapy responders experienced PSA-recurrence. The estimated median time to PSA-progression was 38.6 months (95%CI 30.9-46.4) and 85.3 months (95%CI 39.3–131.3) for OS. The 5-year bRFS was improved to 40%, but limiting for interpretation adjuvant treatment was individualized. NCHT is feasible despite high hematotoxicity, with excellent functional results. Significant downstaging was observed without pCR. NCHT seems to improve the cohort adjusted 5-year bRFS, but clinical value needs further investigation in randomized trials.
Pulmonary platelet kinetics in asthma.
Authors: P W Ind, A M Peters, F Malik, J P Lavender, C T Dollery
Journal: Thorax (1985)

Platelets produce a range of bronchoconstrictor mediators. Measurements of plasma factors have implicated platelet activation in allergic asthma, and sensitised guinea pigs challenged with ovalbumin show pulmonary platelet aggregation accompanying bronchoconstriction. To investigate this further we injected autologous platelets labelled with indium 111 and red cells labelled with technetium 99m into three young volunteers with atopic asthma and three non-asthmatic volunteers and, after equilibration of platelets between blood and splenic pool, monitored lung 99mTc and 111In activities continuously. Comparison with the corresponding activities in blood samples allowed calculation of pulmonary platelet to red cell transit time ratio (tp/tr). This ratio was 0.9, 1.02, and 0.98 in the non-asthmatic subjects compared with 1.04, 0.97, and 1.17 in the asthmatic subjects. This argues against the existence of an intrapulmonary platelet pool in normal subjects; transpulmonary transit time was slightly prolonged in one asthmatic subject. Bronchial challenge with Dermatophagoides pteronyssinus was performed in the asthmatic subjects and monitoring continued for a further 30 minutes. Antigen induced falls in FEV1 of 20-50% were accompanied by small decreases in the 111In but not in the 99mTc lung signal. In line with this tp/tr fell to 0.89, 0.89, and 1.05. Antigen induced bronchoconstriction was therefore not accompanied by intrapulmonary platelet accumulation. Platelet survival was normal at 10.2 days in both groups of subjects.
Sample sizes for clinical trials using sputum eosinophils as a primary outcome
Authors: Angira Dasgupta, Shiyuan Zhang, Lehana Thabane, Parameswaran Nair
Journal: European Respiratory Journal (2013)

Clinical trials do not report sputum eosinophil data in a consistent method and this makes it difficult to compare across studies and to evaluate the sample sizes estimated in these studies. The objectives of the paper are: 1) to systematically review reporting of effect size and sample calculations in randomised controlled trials using sputum eosinophil count as a primary outcome and 2) to illustrate sample size estimation under different methods of data representation using data from an effective anti-eosinophil treatment strategy (mepolizumab). Randomised controlled trials in adults (excluding allergen provocation models) of treatment of asthma and chronic obstructive pulmonary disease for the past 10 years were searched in Ovid MEDLINE and 20 studies were identified that met all the inclusion criteria. Only nine studies discussed sample size calculation. Change from baseline was used as an outcome in 11 studies and was expressed as change in absolute percentage count, percentage change from baseline or as fold changes. Assuming a minimal clinically important reduction of 15% in absolute terms, 18 subjects in each arm will be required to achieve 80% power using an ANCOVA analysis, which we recommend, to detect significance with an alpha error of 0.05.
Phylogenetic Analysis of the Vertebrate Galectin Family
Authors: Denis Houzelstein, Isabelle R. Gonçalves, Andrew J. Fadden, Sukhvinder S. Sidhu, Douglas N. W. Cooper, Kurt Drickamer, Hakon Leffler, Françoise Poirier
Journal: Molecular Biology and Evolution (2004)

Galectins form a family of structurally related carbohydrate binding proteins (lectins) that have been identified in a large variety of metazoan phyla. They are involved in many biological processes such as morphogenesis, control of cell death, immunological response, and cancer. To elucidate the evolutionary history of galectins and galectin-like proteins in chordates, we have exploited three independent lines of evidence: (i) location of galectin encoding genes (LGALS) in the human genome; (ii) exon-intron organization of galectin encoding genes; and (iii) sequence comparison of carbohydrate recognition domains (CRDs) of chordate galectins. Our results suggest that a duplication of a mono-CRD galectin gene gave rise to an original bi-CRD galectin gene, before or early in chordate evolution. The N-terminal and C-terminal CRDs of this original galectin subsequently diverged into two different subtypes, defined by exon-intron structure (F4-CRD and F3-CRD). We show that all vertebrate mono-CRD galectins known to date belong to either the F3- or F4- subtype. A sequence of duplication and divergence events of the different galectins in chordates is proposed.
Haploinsufficiency for ribosomal protein genes causes selective activation of p53 in human erythroid progenitor cells
Authors: Shilpee Dutt, Anupama Narla, Katherine Lin, Ann Mullally, Nirmalee Abayasekara, Christine Megerdichian, Frederick H. Wilson, Treeve Currie, Arati Khanna-Gupta, Nancy Berliner, Jeffery L. Kutok, Benjamin L. Ebert
Journal: Blood (2010)
Role of Psychosocial Variables on Chemotherapy-Induced Nausea and Vomiting and Health-Related Quality of Life among Cancer Patients: A European Study
Authors: Luigi Grassi, Maria Alejandra Berardi, Federica Ruffilli, Elena Meggiolaro, Elisabeth Andritsch, Agustina Sirgo, Rosangela Caruso, Eva Juan Linares, Marta Bellé, Sara Massarenti, Maria Giulia Nanni
Journal: Psychotherapy and Psychosomatics (2015)

Background: Chemotherapy-induced nausea and vomiting (CINV) continue to be a distressing problem still reported by cancer patients, with negative consequences on quality of life (QoL). Aims: To prospectively explore the association of psychosocial variables, including emotional distress, maladaptive coping styles and the doctor-patient relationship, with CINV and QoL among cancer outpatients. Methods: A prospective study was conducted on 302 consecutive cancer patients (response rate 80.9%) in Austria, Italy and Spain. The Distress Thermometer (DT), the Mini-Mental Adjustment to Cancer (Mini-MAC), and the Patient Satisfaction with Doctor Questionnaire (PSQ) were used to assess psychosocial variables before chemotherapy. In the 5 days after chemotherapy, CINV was examined by using a daily diary, and the Functional Living Index for Emesis (FLIE) was used to assess QoL. Results: More than half of the patients reported nausea (54%), and a small percentage reported vomiting (14%). CINV had a negative impact on QoL (FLIE caseness, p &lt; 0.01). Maladaptive coping (i.e. hopelessness-helplessness and anxious preoccupation) and emotional distress were associated with CINV (p &lt; 0.05) and poorer QoL (p &lt; 0.05). In logistic regression analysis, nausea was predicted by Mini-MAC/H (OR = 1.1, p = 0.03) and younger age (OR = 0.97, p = 0.04); negative impact on QoL was predicted by grade of chemotherapy emetogenesis (OR = 1.7, p &lt; 0.01) and Mini-MAC/H (OR = 1.2, p = 0.04). Conclusions: Screening and assessment of psychological variables, especially coping, could help in identifying cancer patients at risk for chemotherapy-induced nausea, in spite of the use of antiemetic treatment.
Prognosis of advanced hepatocellular carcinoma: comparison of three staging systems in two French clinical trials
Authors: S. Collette, F. Bonnetain, X. Paoletti, M. Doffoel, O. Bouché, J.L. Raoul, P. Rougier, F. Masskouri, L. Bedenne, J.C. Barbare
Journal: Annals of Oncology (2008)
A new potential biomarker for childhood tuberculosis
Authors: T. Thomas, S. Brighenti, J. Andersson, D. Sack, R. Raqib
Journal: Thorax (2011)

One of the major research areas for tuberculosis (TB) focuses not only on diagnostics but also on biomarkers that can provide prognostic data about the disease course and response to treatment. Although progress has been made, improved tests for paediatric TB are especially needed. Young children are at increased risk of progressing to TB after exposure, and may suffer from disseminated forms of the disease. Due to the paucibacillary nature of paediatric disease, the current armamentarium and future pipeline of TB diagnostics that largely rely on microbial growth and/or molecular detection are unlikely to demonstrate performance equivalent to that in adults. Thus, an accurate surrogate marker of disease may be crucial to improving the diagnosis of paediatric TB. We have tested and evaluated a novel B-cell assay called the antibodies in lymphocyte supernatant, or ALS, which has performed very well in diagnosing TB disease both in Asia1 2 and Africa (manuscript in preparation). Here, we report the performance of ALS as a biomarker in children with culture-confirmed TB.

The ALS assay is based on a principle similar to that of the enzyme-linked immunosorbent spot assay, measuring antibody-secreting cells in cultures of peripheral blood mononuclear cells (PBMCs). The ALS assay detects antibody secretion from in vivo activated plasma B …
Brain Penetration and Efficacy of Different Mebendazole Polymorphs in a Mouse Brain Tumor Model
Authors: Ren-Yuan Bai, Verena Staedtke, Teresia Wanjiku, Michelle A. Rudek, Avadhut Joshi, Gary L. Gallia, Gregory J. Riggins
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Mebendazole (MBZ), first used as an antiparasitic drug, shows preclinical efficacy in models of glioblastoma and medulloblastoma. Three different mebendazole polymorphs (A, B, and C) exist, and a detailed assessment of the brain penetration, pharmacokinetics, and antitumor properties of each individual mebendazole polymorph is necessary to improve mebendazole-based brain cancer therapy. Experimental Design and Results: In this study, various marketed and custom-formulated mebendazole tablets were analyzed for their polymorph content by IR spectroscopy and subsequently tested in an orthotopic GL261 mouse glioma model for efficacy and tolerability. The pharmacokinetics and brain concentration of mebendazole polymorphs and two main metabolites were analyzed by LC/MS. We found that polymorph B and C both increased survival in a GL261 glioma model, as B exhibited greater toxicity. Polymorph A showed no benefit. Polymorph B and C both reached concentrations in the brain that exceeded the IC50 in GL261 cells 29-fold. In addition, polymorph C demonstrated an AUC0–24h brain-to-plasma (B/P) ratio of 0.82, whereas B showed higher plasma AUC and lower B/P ratio. In contrast, polymorph A presented markedly lower levels in the plasma and brain. Furthermore, the combination with elacridar was able to significantly improve the efficacy of polymorph C in GL261 glioma and D425 medulloblastoma models in mice. Conclusions: Among mebendazole polymorphs, C reaches therapeutically effective concentrations in the brain tissue and tumor with fewer side effects, and is the better choice for brain cancer therapy. Its efficacy can be further enhanced by combination with elacridar. Clin Cancer Res; 21(15); 3462–70. ©2015 AACR.