tbuckley/cabot-search huggingface dataset:
Ochratoxin A Secretion in Primary Cultures of Rabbit Renal Proximal Tubule Cells
Authors: CARLOTTA E. GROVES, GRAZYNA NOWAK, MARK MORALES
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Primary cultures of rabbit renal proximal tubule cells grown under improved culture conditions were used to study the transepithelial transport of the nephrotoxic mycotoxin ochratoxin A. The basal-to-apical transepithelial flux, i.e. , secretion, of this fluorescence organic acid was measured in primary cultures of rabbit renal proximal tubule cells. The basal-to-apical flux of ochratoxin A increased with time and reached a steady state after 12 h. On the other hand, the apical-to-basal flux, i.e. , reabsorption, of ochratoxin A was minimal over time. The secretory flux of ochratoxin A was as much as eightfold greater than the reabsorptive flux, indicating that net secretion is the primary mechanism for ochratoxin A clearance by the proximal tubule. The kinetic analysis of ochratoxin A flux revealed secretion to be a saturable and very high-affinity process with an apparent K 50 of 0.33 ± 0.21 mM. A saturating concentration of the prototypical organic anion substrate para -aminohippurate (PAH) reduced ochratoxin A secretion by approximately 75%. The kinetic analysis of PAH inhibition of ochratoxin A secretion revealed an IC 50 of 195 mM, which is similar to the IC 50 for PAH inhibition of peritubular ochratoxin A uptake in tubule suspensions and the K m values for peritubular PAH uptake. The organic anions probenecid, octanoate, and α-ketoglutarate reduced ochratoxin A excretion to the same degree as PAH, whereas the amino acid phenylalanine had a minimal effect on ochratoxin A secretion. Thus, collectively, these observations indicate that the secretion of ochratoxin A in primary cultures of rabbit renal proximal tubules is limited to the organic anion secretory pathway. The high affinity measured for the basal-to-apical flux of ochratoxin A suggests that at concentrations typical of naturally occurring exposures, transepithelial secretion by the organic anion transport pathway represents a significant avenue for excretion of this mycotoxin by the renal proximal tubule.
Activated Notch1 Induces Lung Adenomas in Mice and Cooperates with Myc in the Generation of Lung Adenocarcinoma
Authors: Thaddeus D. Allen, Elena M. Rodriguez, Kirk D. Jones, J. Michael Bishop
Journal: Cancer Research (2011)

Notch1 encodes the canonical member of the mammalian Notch receptor family. Activating lesions frequently affect Notch1 in T-cell acute lymphoblastic leukemia (T-ALL) and, recently, have been found in non-small-cell lung cancer (NSCLC) as well. We explored the oncogenic potential of activated Notch1 in the lung by developing a transgenic mouse model in which activated Notch1 was overexpressed in the alveolar epithelium. The initial response to activated Notch1 was proliferation and the accumulation of alveolar hyperplasia, which was then promptly cleared by apoptosis. After an extended latency period, however, pulmonary adenomas appeared in the transgenic mice but failed to progress to become carcinomas. Interestingly, Myc and MycL1 were expressed in the adenomas, suggesting that selection for enhanced Myc activity may facilitate tumorigenesis. Using mice engineered to coexpress activated Notch1 and Myc, we found that supplementing Myc expression resulted in increased frequency of Notch1 intracellular domain (N1ICD)-induced adenoma formation and enabled progression to adenocarcinoma and metastases. Cooperation stemmed from synergistic activation of tumor cell cycling, a process that apparently countered any impedance to tumorigenesis posed by Myc and/or activated Notch1-induced apoptosis. Significantly, cooperation was independent of RAS activation. Taken together, the data suggest that activated Notch1 substitutes for RAS activation synergistically with Myc in the development of NSCLC. These tumor models should be valuable for exploring the role of activated Notch1 in the genesis of NSCLC and for testing therapies targeting either activated Notch1 or its downstream effectors.
Novel Jet-Injection Technology for Nonviral Intratumoral Gene Transfer in Patients with Melanoma and Breast Cancer
Authors: Wolfgang Walther, Robert Siegel, Dennis Kobelt, Thomas Knösel, Manfred Dietel, Andreas Bembenek, Jutta Aumann, Martin Schleef, Ruth Baier, Ulrike Stein, Peter M. Schlag
Journal: Clinical Cancer Research (2008)

This phase I clinical trial evaluated safety, feasibility, and efficiency of nonviral intratumoral jet-injection gene transfer in patients with skin metastases from melanoma and breast cancer.Seventeen patients were enrolled. The patients received five jet injections with a total dose of 0.05 mg beta-galactosidase (LacZ)-expressing plasmid DNA (pCMVbeta) into a single cutaneous lesion. Clinical and laboratory safety monitoring were done. Systemic plasmid clearance was monitored by quantitative real-time PCR of blood samples throughout the study. All lesions were resected after 2 to 6 days. Intratumoral plasmid DNA load, DNA distribution, and LacZ expression was analyzed by quantitative real-time PCR, quantitative reverse transcription-PCR, Western blot, immunohistochemistry, and 5-bromo-4-chloro-3-indolyl-beta-D-galactoside staining.Jet injection of plasmid DNA was safely done in all patients. No serious side effects were observed. Thirty minutes after jet injection, peak plasmid DNA levels were detected in the blood followed by rapid decline and clearance. Plasmid DNA and LacZ mRNA and protein expression were detected in all treated lesions. Quantitative analysis revealed a correlation of plasmid DNA load and LacZ-mRNA expression confirmed by Western blot. Immunohistochemistry and 5-bromo-4-chloro-3-indolyl-beta-D-galactoside staining showed LacZ-protein throughout the tumor. Transfected tumor areas were found close and distant to the jet-injection site with varying levels of DNA load and transgene expression.Intratumoral jet injection of plasmid DNA led to efficient LacZ reporter gene expression in all patients. No side effects were experienced, supporting safety and applicability of this novel nonviral approach. A next step with a therapeutic gene product should determine antitumor efficacy of jet-injection gene transfer.
Longitudinal MRI Study of Hippocampal Volume in Trauma Survivors With PTSD
Authors: Omer Bonne, Dalia Brandes, Asaf Gilboa, J. Moshe Gomori, Martha E. Shenton, Roger K. Pitman, Arieh Y. Shalev
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: The authors prospectively explored whether a reduction in the volume of the hippocampus occurs in recent trauma survivors who develop posttraumatic stress disorder (PTSD). METHOD: Thirty-seven survivors of traumatic events were assessed within a week of the traumatic event and 6 months later. The assessment included magnetic resonance imaging of the brain (including 124 coronal slices of 1.5-mm thickness), psychometric testing, and structured clinical interviews. The Clinician-Administered PTSD Scale conferred PTSD diagnoses at 6 months. RESULTS: Ten subjects (27%) had PTSD at 6 months. The subjects with PTSD did not differ from those without PTSD in hippocampal volume (right or left) at 1 week or 6 months. There was no reduction in hippocampal volume in the PTSD subjects between 1 week and 6 months. CONCLUSIONS: Smaller hippocampal volume is not a necessary risk factor for developing PTSD and does not occur within 6 months of expressing the disorder. This brain abnormality might occur in individuals with chronic or complicated PTSD.
Phase I Study of Recombinant Interleukin-21 in Patients With Metastatic Melanoma and Renal Cell Carcinoma
Authors: John A. Thompson, Brendan D. Curti, Bruce G. Redman, Shailender Bhatia, Jeffrey S. Weber, Sanjiv S. Agarwala, Eric L. Sievers, Steven D. Hughes, Todd A. DeVries, Diana F. Hausman
Journal: Journal of Clinical Oncology (2008)

Purpose A phase I study of patients with metastatic malignant melanoma (MM) and renal cell carcinoma (RCC) evaluated the safety and maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of recombinant human interleukin-21 (rIL-21). Patients and Methods Patients who had one or fewer prior systemic treatments for metastatic MM or RCC were treated with rIL-21 administered for two 5-day cycles on days 1 through 5 and 15 through 19 of a treatment course; rIL-21 was administered by rapid intravenous infusion in an outpatient setting. Cohorts of patients received doses ranging from 3 to 100 μg/kg/dose, and an expanded cohort was treated at the MTD. Patients with stable disease (SD) or better could receive additional treatment cycles. Results Forty-three patients were treated (24 MM; 19 RCC), including 28 in the expanded cohort. Dose-limiting toxicities consisted primarily of transient grade 3 laboratory abnormalities. The MTD was estimated to be 30 μg/kg. The most common adverse events included flu-like symptoms, pruritus, and rash. Twelve patients received up to five additional two-cycle courses of treatment without cumulative toxicity, except for one patient with reversible grade 4 hepatotoxicity. Serum concentrations of rIL-21 increased in a dose-proportional manner. Dose-dependent increases in soluble CD25 reflected lymphocyte activation. Antitumor activity was observed in both MM (one complete response and 11 SD) and RCC (four partial responses, 13 SD). Conclusion Outpatient therapy with rIL-21 at 30 μg/kg was well tolerated, had dose-dependent pharmacokinetics and pharmacodynamics, and was associated with antitumor activity in patients with MM and RCC.
Impact of social standing on sports injury prevention in a WHO safe community: intervention outcome by household employment contract and type of sport
Authors: T Timpka, K Lindqvist, J Ekstrand, N Karlsson
Journal: British Journal of Sports Medicine (2005)

As physical activity is promoted as part of a healthy lifestyle, sports injuries are becoming an important public health concern in many countries. The objective of this study is to investigate rates of sports injuries before and after implementation of a WHO Safe Community program.Sports injury data were collected pre- and post-implementation from all individuals below 65 years of age during 1 year in the targeted municipality (population 41,000) and in a control municipality (population 26,000). A quasi-experimental design was used and individuals were divided into three categories based on household relationship to the labour market.There were no differences between socio-economic categories regarding pre-intervention injury rates. No statistically significant post-intervention changes in injury rate were observed in the control area or among any females in either area. In the intervention area, a statistically significant (p = 0.011) decrease in injury rate was observed among male members of households in which the vocationally important member was employed. A statistically significant decrease was observed in injuries sustained in team sports among male members of households in which the vocationally important member was employed (p = 0.001) and among members of households in which the vocationally important member was self employed (p<0.05).The study indicates areas for improvement in the civic network based WHO Safe Community model. The results show that females, participants in individual sports, and members of non-vocationally active households were less affected by the interventions. These facts have to be addressed in planning future community based sports injury prevention programmes and their evaluations.
ASPIRIN TREATMENT AND OUTCOMES AFTER PCI: RESULTS OF THE INTRACORONARY STENTING AND ANTITHROMBOTIC REGIMEN – ASPIRIN AND PLATELET INHIBITION (ISAR-ASPI) REGISTRY
Authors: Katharina Mayer, Isabell Bernlochner, Siegmund Braun, Stefanie Schulz, Martin Orban, Tanja Morath, Lisena Cala, Petra Hoppmann, Heribert Schunkert, Laugwitz Karl-Ludwig, Adnan Kastrati, Dirk Sibbing, Deutsches Herzzentrum München, I. Medizinische Klinik
Journal: Journal of the American College of Cardiology (2014)
Role of monocyte chemotactic protein-3 and -4 in children with virus exacerbation of asthma
Authors: J. Santiago, J. L. Hernández-Cruz, M. E. Manjarrez-Zavala, R. Montes-Vizuet, D. P. Rosete-Olvera, A. M. Tapia-Díaz, H. Zepeda-Peney, L. M. Terán
Journal: European Respiratory Journal (2008)

Macrophages play a crucial role in respiratory viral infections. However, the mechanisms by which these cells are recruited locally are not fully understood. The current authors studied the role of the chemokines monocyte chemotactic protein (MCP)-1, -2, -3 and -4 on monocyte/macrophage recruitment during respiratory viral infections. Levels of these chemokines were investigated in nasal aspirates from 6–12-yr-old children suffering from respiratory viral infections, caused by rhinoviruses, influenza viruses, parainfluenza viruses, adenoviruses and respiratory syncytial virus. MCP-3 and -4 were significantly higher in samples derived from virus-infected children compared with samples from the same children when they had been asymptomatic. Concentrations of both chemokines were found to significantly correlate with the number of recruited nasal macrophages. Chemotaxis assays showed that purified MCP-3 and -4 from nasal aspirates showed biological activity in vitro . There were no significant differences in MCP-1 and -2 levels between both groups. The present data indicates that monocyte chemotactic protein-3 and -4 may have an important role in macrophage recruitment in children with proven upper respiratory viral infections. These chemokines could be potential targets for therapeutic intervention in respiratory viral infections.
The European Register of Hereditary Angioedema: Experience and Preliminary Results
Authors: L.C. Zingale, K. Bork, H. Farkas, A. Bygum, L. Bouillet, T. Caballero, H. Longhurst, E. Waage Nielsen, B. Bilo, C. Bucher, R. Perricone, M. Cicardi
Journal: Journal of Allergy and Clinical Immunology (2007)
Pulmonary complications after long term amiodarone treatment.
Authors: J Roca, M Heras, R Rodriguez-Roisin, J Magrina, A Xaubet, G Sanz
Journal: Thorax (1992)

BACKGROUND: Amiodarone hydrochloride is an antiarrhythmic agent useful in arrhythmias refractory to standard therapy. Although interstitial pneumonitis is known to be its most serious side effect, several aspects of amiodarone lung toxicity are still controversial. METHODS: Pulmonary side effects were examined in a sample of 61 symptomless patients (mean (SD) age 55 (7) years) who had had long term treatment with amiodarone (daily maintenance dose 400 mg), selected from 482 men attending the University of Barcelona myocardial infarction project. To allow for the confounding effects of coronary artery disease and tobacco history on lung function, 46 patients who had taken amiodarone for more than one year were matched with a control group from the same population. Subjects underwent measurement of lung volumes, arterial blood gas analysis and an incremental bicycle exercise test. RESULTS: Most lung function values were close to predicted values, though there was a small increase in resting alveolar-arterial oxygen tension difference (A-aDO2) at rest (4.8 (1.4) kPa in both groups). There were no differences in the results of forced spirometry or static lung volumes between the two groups, or in the fall in A-aDO2 from rest to exercise. There was a small difference between the amiodarone and the control group in transfer factor for carbon monoxide corrected for lung volume (KCO 1.67 (0.3) and 1.83 (0.3) mmol min-1 kPa-1 l-1 respectively) and in exercise capacity (140 (25) and 120 (30)w). Only three patients showed lung function impairment consistent with pneumonitis. No relation between lung function measures and cumulative doses of amiodarone or desethylamiodarone was found. CONCLUSIONS: The prevalence of clinically evident pulmonary side effects was 4.9%, which is lower than that reported in studies in which higher daily maintenance doses of amiodarone were given. The slightly lower KCO values and lower work load achieved by the patients taking amiodarone suggest a small effect of amiodarone in doses of 400 mg on lung function. A role for individual susceptibility to pulmonary complications of amiodarone treatment is suggested.
Molecular basis for the modulation of native T-type Ca2+ channels in vivo by Ca2+/calmodulin-dependent protein kinase II
Authors: J. Yao
Journal: Journal of Clinical Investigation (2006)

Ang II receptor activation increases cytosolic Ca2+ levels to enhance the synthesis and secretion of aldosterone, a recently identified early pathogenic stimulus that adversely influences cardiovascular homeostasis. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a downstream effector of the Ang II–elicited signaling cascade that serves as a key intracellular Ca2+ sensor to feedback-regulate Ca2+ entry through voltage-gated Ca2+ channels. However, the molecular mechanism(s) by which CaMKII regulates these important physiological targets to increase Ca2+ entry remain unresolved. We show here that CaMKII forms a signaling complex with α1H T-type Ca2+ channels, directly interacting with the intracellular loop connecting domains II and III of the channel pore (II-III loop). Activation of the kinase mediated the phosphorylation of Ser1198 in the II-III loop and the positive feedback regulation of channel gating both in intact cells in situ and in cells of the native adrenal zona glomerulosa stimulated by Ang II in vivo. These data define the molecular basis for the in vivo modulation of native T-type Ca2+ channels by CaMKII and suggest that the disruption of this signaling complex in the zona glomerulosa may provide a new therapeutic approach to limit aldosterone production and cardiovascular disease progression.
Melanocytes in squamous cell carcinoma of the skin
Authors: S.J. Diaz-Cano
Journal: British Journal of Dermatology (2000)

Journal Article Melanocytes in squamous cell carcinoma of the skin Get access S.J. Diaz‐Cano S.J. Diaz‐Cano Department of Histopathology and Morbid Anatomy, St Bartholomew’s and the Royal London School of Medicine and Dentistry, The Royal London Hospital, Whitechapel, London E1 1BB, U.K. E‐mail: s.j.diaz‐cano@mds.qmw.ac.uk Search for other works by this author on: Oxford Academic Google Scholar British Journal of Dermatology, Volume 142, Issue 1, 1 January 2000, Page 184, https://doi.org/10.1046/j.1365-2133.2000.03270.x Published: 01 January 2000
Inhaled steroids and mortality in COPD: bias from unaccounted immortal time
Authors: S. Suissa
Journal: European Respiratory Journal (2004)

A recent observational study, which suggested that inhaled corticosteroids (ICS) with or without long-acting bronchodilators are effective at reducing all-cause mortality in chronic obstructive pulmonary disease (COPD) patients, may be subject to immortal time bias. This bias was assessed using a population-based cohort of 3,524 newly treated COPD patients from Saskatchewan, Canada, observed from 1990–1999. Regular users of bronchodilators or ICS were followed for 3 yrs, during which time 860 deaths occurred. Cox's proportional hazards model was used to compare the hierarchical intention-to-treat approach employed in the recent study, a technique subject to bias from two sources of immortal time, with the conventional intention-to-treat approach and the according-to-treatment approach. The adjusted rate ratio of death using the hierarchical intention-to-treat approach was 0.66 (95% confidence interval (CI) 0.57–0.76) for ICS use relative to bronchodilator use, compared with 0.75 (95% CI 0.62–0.90) with the conventional intention-to-treat approach. Conversely, the rate ratio was 0.94 (95% CI 0.81–1.09) with the according-to-treatment approach, which accounts for both sources of immortal time. In this study, regular inhaled corticosteroid use in chronic obstructive pulmonary disease was not found to reduce all-cause mortality. Suggestion of this benefit from a previous observational study is the result of bias from unaccounted immortal time in its cohort design and analysis.
Pharmacoepidemiology of Anemia in Kidney Transplant Recipients
Authors: Wolfgang C. Winkelmayer, Reshma Kewalramani, Mark Rutstein, Steven Gabardi, Tania Vonvisger, Anil Chandraker
Journal: Journal of the American Society of Nephrology (2004)

ABSTRACT. Anemia has long been known to be a complication of end-stage renal disease (ESRD), and it has been linked to cardiovascular morbidity and mortality. Although kidney transplant recipients (KTR) are prone to experiencing cardiovascular outcomes, little is known about the epidemiology of anemia in this population. With few exceptions, studies to date have not fully evaluated the associations between posttransplant anemia (PTA) and medications commonly used in KTR, particularly immunosuppressant drugs, angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB). The authors aimed to specifically investigate possible associations between these drugs and PTA. Detailed medical information was retrospectively collected on 374 consecutive KTR from our transplant clinic. Univariate/multivariate linear regression models were used to test for associations between hematocrit (HCT) and other covariates, and logistic regression models were used to detect independent predictors of PTA, defined as HCT <33%. The mean time since transplantation was 7.7 yr, and mean creatinine was 2.2 mg/dl. The prevalence of PTA was 28.6%. Ten percent of all patients were on erythropoietin therapy, but only 41.6% of patients whose HCT was <30 received this treatment. From multivariate analyses, the authors found that female gender and lower renal function were associated with lower HCT (both P < 0.001). Patients on ACEI had significantly lower HCT (P = 0.005) compared with patients without such treatment. In addition, a significant curvilinear dose-response relationship was found between ACEI dose and HCT. Among the immunosuppressant drugs, mycophenolate mofetil (P = 0.05) and tacrolimus (P = 0.02) were associated with a lower HCT. The authors conclude that PTA is prevalent and undertreated in KTR. Several medications that are possibly modifiable correlates of PTR deserve further study.
Female and male lifestyle habits and IVF: what is known and unknown
Authors: H. Klonoff-Cohen
Journal: Human Reproduction Update (2005)

There is no greater tribute to the importance and efficacy of IVF than the fact that >1×106 babies have been born to infertile couples since its clinical introduction in 1978. Despite enormous advances regarding the technical aspects of the IVF procedure, the parents' contribution has virtually been ignored when considering aspects that influence success rates. This systematic review focuses on the effects of female and male lifestyle habits (specifically: smoking, alcohol and caffeine use, and psychological stress) on the reproductive endpoints of IVF (i.e. oocyte aspiration, fertilization, embryo transfer, achievement of a pregnancy, live birth delivery, and perinatal outcomes, e.g. low birthweight, multiple gestations). What is currently known in the field of lifestyle habits and IVF? There is compelling evidence that smoking has a negative influence on IVF outcomes, whereas for stress, the evidence is suggestive but insufficient due to the heterogeneity of studies. The evidence for the effects of alcohol and caffeine on IVF is inadequate, and therefore unknown, due to the scarcity of studies.