tbuckley/cabot-search huggingface dataset:
Role of inducible nitric oxide synthase in induction of RhoA expression in hearts from diabetic rats
Authors: Hesham Soliman, Graham P. Craig, Prabhakar Nagareddy, Violet G. Yuen, Guorong Lin, Ujendra Kumar, John H. McNeill, Kathleen M. MacLeod
Journal: Cardiovascular Research (2008)

Recent studies from our laboratory demonstrated that increased expression of the small GTP-binding protein RhoA and activation of the RhoA/rho kinase (ROCK) pathway play an important role in the contractile dysfunction associated with diabetic cardiomyopathy in hearts from streptozotocin (STZ)-induced diabetic rats. Nitric oxide (NO) has been reported to be a positive regulator of RhoA expression in vascular smooth muscle, and we have previously found that the expression of inducible NO synthase (iNOS) is increased in hearts from STZ-diabetic rats. Therefore, in this study, we investigated the hypothesis that induction of iNOS positively regulates RhoA expression in diabetic rat hearts. To determine whether NO and iNOS could increase RhoA expression in the heart, cardiomyocytes from non-diabetic rats were cultured in the presence of the NO donor sodium nitroprusside (SNP) or lipopolysaccharide (LPS) in the absence and presence of the selective iNOS inhibitor, N6-(1-iminoethyl)-l-lysine dihydrochloride (L-NIL). In a second study, 1 week after induction of diabetes with STZ, rats were treated with L-NIL (3 mg/kg/day) for 8 more weeks to determine the effect of iNOS inhibition in vivo on RhoA expression and cardiac contractile function. Expression of iNOS was elevated in cardiomyocytes isolated from diabetic rat hearts. Both SNP and LPS increased RhoA expression in non-diabetic cardiomyocytes. The LPS-induced elevation in RhoA expression was accompanied by an increase in iNOS expression and prevented by L-NIL. Treatment of diabetic rats with L-NIL led to a significant improvement in left ventricular developed pressure and rates of contraction and relaxation concomitant with normalization of total cardiac nitrite levels, RhoA expression, and phosphorylation of the ROCK targets LIM (Lin-11, Isl-1, Mec-3) kinase and ezrin/radixin/moesin. These data suggest that iNOS is involved in the increased expression of RhoA in diabetic hearts and that one of the mechanisms by which iNOS inhibition improves cardiac function is by preventing the upregulation of RhoA and its availability for activation.
Impairment of neutrophil reactivity to elastin peptides in COPD
Authors: Aurélie Dupont, Sandra Dury, Valérie Gafa, François Lebargy, Gaëtan Deslée, Moncef Guenounou, Frank Antonicelli, Richard Le Naour
Journal: Thorax (2013)

Neutrophils play an important role in the inflammatory process associated with chronic obstructive pulmonary disease (COPD). Lung-infiltrating neutrophils secrete elastinolytic proteases that participate in elastin breakdown and the formation of elastin peptides (EPs).We hypothesized that circulating neutrophil-associated immune response may be modulated by EPs during COPD.Neutrophils obtained from patients with either stable or exacerbated COPD and controls were cultured with or without EPs. Cell chemotaxis was analysed by the Boyden method and cytokine expression was analysed by ELISA and real-time reverse transcriptase PCR. Bacterial phagocytosis and killing of ingested bacteria were evaluated after incubation with Pseudomonas aeruginosa. Reactive oxygen species (ROS) measurement and elastin receptor expression were determined by flow cytometry.Chemotactic activity of neutrophils from patients with COPD towards the VGVAPG EP was reduced compared with controls. VGVAPG increased proinflammatory cytokine synthesis and bacterial load, but reduced ROS production in neutrophils from controls and from patients with stable COPD. Patients with exacerbated COPD were unresponsive to VGVAPG treatment. These findings were associated with a decreased or almost complete loss of S-Gal elastin receptor expression in neutrophils from patients with stable or exacerbated COPD, respectively.The study demonstrates that the response of neutrophils from patients with COPD to VGVAPG varied according to COPD phase and critical level of S-Gal expression. S-Gal downregulation could result from a feedback mechanism induced by high levels of EPs.
Effects of etanercept versus sulfasalazine in early axial spondyloarthritis on active inflammatory lesions as detected by whole-body MRI (ESTHER): a 48-week randomised controlled trial
Authors: I-H Song, KG Hermann, H Haibel, CE Althoff, J Listing, GR Burmester, A Krause, M Bohl-Bühler, B Freundlich, M Rudwaleit, J Sieper
Journal: Annals of the Rheumatic Diseases (2011)

Purpose To evaluate the potential of etanercept versus sulfasalazine to reduce active inflammatory lesions on whole-body MRI in active axial spondyloarthritis with a symptom duration of less than 5 years. Methods Patients were randomly assigned to etanercept (n=40) or sulfasalazine (n=36) treatment over 48 weeks. All patients showed active inflammatory lesions (bone marrow oedema) on MRI in either the sacroiliac joints or the spine. MRI was performed at weeks 0, 24 and 48 and was scored for active inflammatory lesions in sacroiliac joints and the spine including posterior segments and peripheral enthesitis by two radiologists, blinded for treatment arm and MRI time point. Results In the etanercept group, the reduction of the sacroiliac joint score from 7.7 at baseline to 2.0 at week 48 was significantly (p=0.02) larger compared with the sulfasalazine group from 5.4 at baseline to 3.5 at week 48. A similar difference in the reduction of inflammation was found in the spine from 2.2 to 1.0 in the etanercept group versus from 1.4 to 1.3 in the sulfasalazine group between baseline and week 48, respectively (p=0.01). The number of enthesitic sites also improved significantly from 26 to 11 in the etanercept group versus 24 to 26 in the sulfasalazine group (p=0.04 for difference). 50% of patients reached clinical remission in the etanercept group versus 19% in the sulfasalazine group at week 48. Conclusion In patients with early axial spondyloarthritis active inflammatory lesions detected by whole-body MRI improved significantly more in etanercept versus sulfasalazine-treated patients. This effect correlated with a good clinical response in the etanercept group.
Lipid Changes and Statins in Chronic Renal Insufficiency
Authors: Eberhard Ritz, Christoph Wanner
Journal: Journal of the American Society of Nephrology (2006)

It has been known for a long time that chronic kidney disease (CKD) is associated with dyslipidemia, but the full extent of abnormalities has been appreciated only recently, because routine laboratory tests fail to disclose the entire spectrum of lipid abnormalities. Lipids, particularly HDL cholesterol, are predictive of cardiovascular events, but a paradoxic inverse relation between cholesterol concentration and cardiovascular death has been noted in uremic patients. This currently is thought to be explained by the confounding effect of microinflammation and possibly calcification, but this is not definitely proved. Several retrospective analyses that included patients with mild or moderate CKD documented benefit from lowering of cholesterol by statins. In contrast, the Die Deutsche Diabetes Dialyse (4D) study and a small Scandinavian study failed to show a benefit from lowering of cholesterol by statins in ESRD. Pathomechanistically, it is possible that nonclassical pathomechanisms override statin-sensitive mechanisms as also suggested by the observation that statins fail to reduce carotid intima-media thickening. Although, experimentally, exposure to lipids (particularly oxidized lipids) aggravates progression, data on the effect of statins on progression in patients with CKD are not definite. The most likely explanation is that the impact of numerous confounders obscures their effect on progression. The increase in urinary protein excretion of patients who are treated with statins had been a cause of concern, but the underlying mechanism (i.e. interference with proximal tubular reabsorption of protein) meanwhile has been well documented.
Peginterferon alfa-2A (40 KD) (PEGASYS) in combination with ribavirin (RBV): efficacy and safety results from a phase III, randomized, double-blind, multicentre study examining effect of duration of treatment and RBV dose
Authors: S.J. Hadziyannis, H. Cheinquer, T. Morgan, M. Diago, D.M. Jensen, H. Sette, G. Ramadori, H.C. Bodenheimer, P. Marcellin, S.-D. Lee, P.J. Roberts, A.M. Ackrill
Journal: Journal of Hepatology (2002)
Evaluation of colonic myoelectrical activity in health and functional disorders.
Authors: L Bueno, J Fioramonti, Y Ruckebusch, J Frexinos, P Coulom
Journal: Gut (1980)

Electrical activity of the colon was investigated in six healthy volunteers and 22 patients presenting functional colonic disorders associated with pain, constipation, or diarrhoea. Myoelectrical activity during 10 hours, including two daily meals, was recorded from eight groups of nickel-chrome electrodes using a 1.5 m length probe introduced by the rectal route. Electromyograms of volunteers consisted of slow waves at two distinct rhythms, approximately 3 and 10 cycles per minute, during 16 to 28% of the recording time respectively for each site. Action potentials were also recorded as 11 to 80 short spike bursts (SSB) per hour lasting 1.5 to 3.5 s at any site and 20-26 long spike bursts (LSB) per hour, lasting 17 to 21 s, occurring in series of four to eight propagated bursts. Additional high-velocity propagated bursts were recorded during the three hour postprandial period. Three typical changes in spike activity patterns were detected: an increase by 170-420% of the number of SSB associated to a high spiking activity was recorded in 13 patients (group I), the absence of SSB, a low spiking activity level and only 3 to 8 LSB per hour (group II), in six patients; and the postprandial response was absent (group III) in three other investigated patients. Evidence for three groups of motor disturbances and their possible relation to clinical manifestations of functional disorders is presented.
Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial
Authors: Michael Roden, Jianping Weng, Jens Eilbracht, Bruno Delafont, Gabriel Kim, Hans J Woerle, Uli C Broedl
Journal: The Lancet Diabetes & Endocrinology (2013)
The Problem of Oat-Cell Carcinoma
Authors: J. Gordon Scannell
Journal: New England Journal of Medicine (1970)

OAT-cell carcinoma has always had a deadly fascination for those who deal with cancer of the lung. A recent report in the Lancet* by a distinguished working party of the Medical Research Council clearly emphasizes the special nature of this highly malignant form of bronchogenic carcinoma and reinforces the widely held opinion that a bronchoscopic diagnosis of oat-cell carcinoma may be a categorical contraindication to operation.It is too much to expect universal agreement on the cell characteristics of any malignant tumor of the lung. Oat-cell, or small-cell undifferentiated, carcinoma, however, is generally accepted as histologically distinct from squamous-cell and . . .
Insulin's effect on the liver: "Direct or indirect?" continues to be the question
Authors: J. Girard
Journal: Journal of Clinical Investigation (2006)

Previous studies suggest that insulin can inhibit hepatic glucose production (HGP) by both direct and indirect actions. The indirect effects include inhibition of glucagon secretion, reduction in plasma nonesterified fatty acid levels, reduction of the amount of gluconeogenic precursor supplied to the liver, and change in neural input to the liver. A study in this issue of the JCI demonstrates that, in overnight-fasted dogs, an acute, selective increase of portal insulin induces a rapid inhibition of HGP, and a 4-fold rise in head insulin level does not enhance the inhibition of HGP in response to portal insulin infusion. This study demonstrates that insulin's direct effects on the liver dominate the control of HGP. These data balance previous studies in mice that suggested that indirect effects of insulin via the hypothalamus are the primary determinant of HGP.
Randomised controlled trials in psychiatry: important but poorly accepted
Authors: G. Andrews
Journal: BMJ (1999)

<h3>Introduction</h3> Treatment of bipolar disorder is the focus of several clinical trials, however the understanding of the outcomes for establishing treatment effectiveness within these trials is limited. Further, there is limited literature which reports on the outcomes considered to be important to patients, indicating that patient perspectives are often not considered when selecting outcomes of effectiveness within trials. This protocol describes a systematic review which aims to describe the outcomes being used within trials to measure treatment effectiveness, commenting on the inclusion of patient-important outcomes within previous trials. <h3>Methods and analysis</h3> This protocol is reported using the Preferred Reporting Items for Systematic Reviews and Meta-analyses Protocols statement. OVID MEDLINE, OVID Embase, OVID APA PsycINFO, Web of Science, the Wiley Cochrane Library, ClinicalTrials.gov and the International Clinical Trials Registry Platform databases will be searched for eligible studies. Screening, full-text and data extraction stages will be completed in duplicate using the Covidence platform for systematic reviews. Eligible studies will include clinical trials of interventions in bipolar disorder, in order to identify outcomes used to assess treatment effectiveness, and qualitative studies, to determine which outcomes have been reported as important by patients. Risk of bias for included studies will be assessed using the Cochrane Risk of Bias Tool for randomised controlled trials, and the Newcastle-Ottawa Scale for observational research. <h3>Ethics and dissemination</h3> This review will involve dissemination to key stakeholders, including primary end users such as patients, clinicians and trialists. Knowledge translation tools will be generated to share the relevant conclusions of this review. Results will be communicated to the scientific community through peer-reviewed publications, conferences and workshops. No ethics approval will be sought as this study is based on literature. <h3>PROSPERO registration number</h3> CRD42021214435.
Strategies for Reducing the Door-to-Balloon Time in Acute Myocardial Infarction
Authors: Elizabeth H. Bradley, Jeph Herrin, Yongfei Wang, Barbara A. Barton, Tashonna R. Webster, Jennifer A. Mattera, Sarah A. Roumanis, Jeptha P. Curtis, Brahmajee K. Nallamothu, David J. Magid, Robert L. McNamara, Janet Parkosewich, Jerod M. Loeb, Harlan M. Krumholz
Journal: New England Journal of Medicine (2006)

Prompt reperfusion treatment is essential for patients who have myocardial infarction with ST-segment elevation. Guidelines recommend that the interval between arrival at the hospital and intracoronary balloon inflation (door-to-balloon time) during primary percutaneous coronary intervention should be 90 minutes or less. However, few hospitals meet this objective. We sought to identify hospital strategies that were significantly associated with a faster door-to-balloon time.We surveyed 365 hospitals to determine whether each of 28 specific strategies was in use. We used hierarchical generalized linear models and data on patients from the Centers for Medicare and Medicaid Services to determine the association between hospital strategies and the door-to-balloon time.In multivariate analysis, six strategies were significantly associated with a faster door-to-balloon time. These strategies included having emergency medicine physicians activate the catheterization laboratory (mean reduction in door-to-balloon time, 8.2 minutes), having a single call to a central page operator activate the laboratory (13.8 minutes), having the emergency department activate the catheterization laboratory while the patient is en route to the hospital (15.4 minutes), expecting staff to arrive in the catheterization laboratory within 20 minutes after being paged (vs. >30 minutes) (19.3 minutes), having an attending cardiologist always on site (14.6 minutes), and having staff in the emergency department and the catheterization laboratory use real-time data feedback (8.6 minutes). Despite the effectiveness of these strategies, only a minority of hospitals surveyed were using them.Several specific hospital strategies are associated with a significant reduction in the door-to-balloon time in the management of myocardial infarction with ST-segment elevation.
Intratumoral T Cells, Recurrence, and Survival in Epithelial Ovarian Cancer
Authors: Lin Zhang, Jose R. Conejo-Garcia, Dionyssios Katsaros, Phyllis A. Gimotty, Marco Massobrio, Giorgia Regnani, Antonis Makrigiannakis, Heidi Gray, Katia Schlienger, Michael N. Liebman, Stephen C. Rubin, George Coukos
Journal: New England Journal of Medicine (2003)

Although tumor-infiltrating T cells have been documented in ovarian carcinoma, a clear association with clinical outcome has not been established.We performed immunohistochemical analysis of 186 frozen specimens from advanced-stage ovarian carcinomas to assess the distribution of tumor-infiltrating T cells and conducted outcome analyses. Molecular analyses were performed in some tumors by real-time polymerase chain reaction.CD3+ tumor-infiltrating T cells were detected within tumor-cell islets (intratumoral T cells) in 102 of the 186 tumors (54.8 percent); they were undetectable in 72 tumors (38.7 percent); the remaining 12 tumors (6.5 percent) could not be evaluated. There were significant differences in the distributions of progression-free survival and overall survival according to the presence or absence of intratumoral T cells (P<0.001 for both comparisons). The five-year overall survival rate was 38.0 percent among patients whose tumors contained T cells and 4.5 percent among patients whose tumors contained no T cells in islets. Significant differences in the distributions of progression-free survival and overall survival according to the presence or absence of intratumoral T cells (P<0.001 for both comparisons) were also seen among 74 patients with a complete clinical response after debulking and platinum-based chemotherapy: the five-year overall survival rate was 73.9 percent among patients whose tumors contained T cells and 11.9 percent among patients whose tumors contained no T cells in islets. The presence of intratumoral T cells independently correlated with delayed recurrence or delayed death in multivariate analysis and was associated with increased expression of interferon-gamma, interleukin-2, and lymphocyte-attracting chemokines within the tumor. The absence of intratumoral T cells was associated with increased levels of vascular endothelial growth factor.The presence of intratumoral T cells correlates with improved clinical outcome in advanced ovarian carcinoma.
Different roles for PI3Kγ and δ in asthma
Authors: Benedikt Mothes, Kirsten Bucher, Bernd Nürnberg, Sandra Beer-Hammer
Journal: European Respiratory Journal (2014)

Background: The predominantly haematopoeticaly expressed class I PI3-kinases γ and δ have been shown to be important in the development of asthma bronchiale. So far, it is not clear which specific roles these two PI3Ks play in asthma.  Aim: To determine the biological function of PI3Kγ and PI3Kδ in asthma.  Methods: We examined C57BL/6N mice deficient for the catalytic subunit of PI3Kγ and δ, i.e. p110γ and p110δ, together with their WT littermates in an experimental ovalbumin-induced asthma model. Severity of asthma was analysed by measuring lung functions using the isolated perfused mouse lung. Cellular changes were analysed by collecting BAL fluid (BALf) and lung tissue by flow cytometry.  Results: Ovalbumin-induced asthma resulted in a significant increase in AHR upon methacholine challenge in WT mice and a significant inflammation in WT lungs. Interestingly, measurement of AHR in both KO mouse models revealed no reduction. However, analysis of BALf showed a significant reduction of eosinophils, neutrophils and T cells in p110γ and p110δ KO mice. Analysis of lung tissue of asthmatic mice revealed elevated cell counts in p110γ KO lungs only. In p110γ KO mice levels of neutrophils were significantly increased in comparison to WT, whereas in p110δ KO neutrophils and eosinophils were significantly reduced. IgE levels were elevated in asthmatic p110γ KO mice.  Conclusion: Despite our observation, that deficiency for p110γ or p110δ in asthmatic mice produces different inflammatory patterns the AHR is not reduced in both models. Reduced cell counts in BALf of p110γ KO mice seemed to be caused by an interference with diapedesis, whereas reduced cell counts in p110δ KO mice may be caused by a reduced differentiation of inflammatory cells in our model.
Smac Mimetic LBW242 Sensitizes XIAP-Overexpressing Neuroblastoma Cells for TNF-α–Independent Apoptosis
Authors: Georg Eschenburg, Angelika Eggert, Alexander Schramm, Holger N. Lode, Patrick Hundsdoerfer
Journal: Cancer Research (2012)

Despite intensive treatment regimens, high-risk and late-stage neuroblastoma tends to have a poor survival outcome. Overexpression of the apoptotic regulator, X-linked inhibitor of apoptosis protein (XIAP), has been associated with chemotherapy resistance in several cancers including neuroblastoma. Here, we report preclinical evidence that XIAP offers an effective therapeutic target in neuroblastoma. Human and murine neuroblastoma cells were treated with the Smac mimetic LBW242 alone or in combination with cytotoxic drugs used clinically to treat neuroblastoma. Expression of XIAP protein, but not mRNA, was highly increased in neuroblastoma cells compared to healthy adrenal gland tissue, consistent with a posttranscriptional regulation of XIAP expression. Treatment with LBW242 sensitized human and murine neuroblastoma cells to chemotherapy-induced apoptosis, which was mediated by activation of both the intrinsic and extrinsic apoptosis pathways. Although Smac mimetics have been reported to stimulate TNF-α-induced apoptosis by degradation of cellular IAP (cIAP)-1/2, we found that LBW242-mediated sensitization in neuroblastoma cells occurred in a TNF-α-independent manner, despite induction of cIAP-1/2 degradation and TNF-α expression. Together, our findings show that XIAP targeting sensitizes neuroblastoma to chemotherapy-induced apoptosis, suggesting a novel therapeutic approach to treat this childhood malignancy.
Bactericidal Antibiotics Induce Mitochondrial Dysfunction and Oxidative Damage in Mammalian Cells
Authors: Sameer Kalghatgi, Catherine S. Spina, James C. Costello, Marc Liesa, J. Ruben Morones-Ramirez, Shimyn Slomovic, Anthony Molina, Orian S. Shirihai, James J. Collins
Journal: Science Translational Medicine (2013)

Mitochondrial dysfunction and oxidative damage induced by bactericidal antibiotics in mammalian cells may be alleviated by an antioxidant or prevented by preferential use of bacteriostatic antibiotics.
A Retrospective Analysis of Adjuvant Chemotherapy in Elderly Patients. Experience of Our Institution
Authors: Aranzazu González-Vicente, Beatriz González-Astorga, Javier García-García, Verónica Conde-Herrero, Julia Ruiz-Vozmediano, Encarnación González-Flores, Lucia Castillo-Portellano, Joaquina Martinez-Galán, Cynthia González-Rivas, Jesús Soberino-García, José Antonio Ortega-Dominguez, Juan Ramón lgado De Pérez
Journal: Annals of Oncology (2013)