tbuckley/cabot-search huggingface dataset:
Inotropic responses to isoproterenol and phosphodiesterase inhibitors in intact guinea pig hearts: comparison of cyclic AMP levels and phosphorylation of sarcoplasmic reticulum and myofibrillar proteins.
Authors: S T Rapundalo, R J Solaro, E G Kranias
Journal: Circulation Research (1989)

The influence of selective (milrinone: 10, 50, 100 microM) and nonselective phosphodiesterase (isobutylmethylxanthine: 0.1, 10, 100 microM) inhibitors and beta-adrenergic stimulation (isoproterenol: 0.01, 0.1 microM) on phospholamban and myofibrillar protein phosphorylation was studied in guinea pig hearts perfused with [32P]orthophosphate. Changes in protein phosphorylation were compared to alterations in tissue cyclic AMP (cAMP) levels and positive inotropic effects induced by these agents. Isoproterenol (0.01 microM), milrinone (50 microM), and isobutylmethylxanthine (100 microM) all produced similar, twofold increases in dP/dt and -dP/dt but only stimulation with isobutylmethylxanthine and isoproterenol was associated with significant increases in phospholamban phosphorylation. At these equipotent doses, the effects of isobutylmethylxanthine were associated with higher increases (3.1-fold) in cAMP than those observed with isoproterenol (twofold). Milrinone (50 microM) produced a 2.5-fold increase in cAMP levels but failed to change phospholamban phosphorylation. Higher doses of milrinone (100 microM) resulted in relatively high (4.1-fold) cAMP levels, and this was associated with increased (1.5-fold) phosphorylation of phospholamban. Phosphorylation of troponin I was significantly increased at 0.01 microM and 0.1 microM isoproterenol, while phosphorylation of C protein was observed only at 0.1 microM isoproterenol. Isobutylmethylxanthine and milrinone did not significantly increase phosphorylation of either troponin I or C protein at any of the doses studied. These findings indicate that cardiotonic agents acting via the cAMP pathway may produce similar inotropic responses at different levels of cAMP and phosphorylation of sarcoplasmic reticulum and myofibrillar proteins.
Effects of a Short Course of Eszopiclone on Continuous Positive Airway Pressure Adherence
Authors: Christopher J. Lettieri
Journal: Annals of Internal Medicine (2009)

Background: Adherence to short-term continuous positive airway pressure (CPAP) may predict long-term use. Unfortunately, initial CPAP intolerance may lead to poor adherence or abandonment of therapy. Objective: To determine whether a short course of eszopiclone at the onset of therapy improves long-term CPAP adherence more than placebo in adults with obstructive sleep apnea. Design: Parallel randomized, placebo-controlled trial from March 2007 to December 2008. Randomization, maintained and concealed centrally by pharmacy personnel, was computer-generated using fixed blocks of 10. Referring physicians, investigators, and patients were blinded to the treatment assignment until after the final data were collected. (ClinicalTrials.gov registration number: NCT00612157) Setting: Academic sleep disorder center. Patients: 160 adults (mean age, 45.7 years [SD, 7.3]; mean apnea–hypopnea index, 36.9 events/h [SD, 23]) with newly diagnosed obstructive sleep apnea initiating CPAP. Intervention: Eszopiclone, 3 mg (n = 76), or matching placebo (n = 78) for the first 14 nights of CPAP. Measurements: Use of CPAP was measured weekly for 24 weeks. Adherence to CPAP (primary outcome) and the rate of CPAP discontinuation and improvements in symptoms (secondary outcomes) were compared. Follow-up at 1, 3, and 6 months was completed by 150, 136, and 120 patients, respectively. Results: Patients in the eszopiclone group used CPAP for 20.8% more nights (95% CI, 7.2% to 34.4%; P = 0.003), 1.3 more hours per night for all nights (CI, 0.4 to 2.2 hours; P = 0.005), and 1.1 more hours per night of CPAP use (CI, 0.2 to 2.1 hours; P = 0.019). The hazard ratio for discontinuation of CPAP was 1.90 (CI, 1.1 to 3.4; P = 0.033) times higher in the placebo group. Side effects were reported in 7.1% of patients and did not differ between groups. Limitations: Patients had severe obstructive sleep apnea treated at a specialized sleep center with frequent follow-up; results may not be generalizable to different settings. Patients' tolerance to CPAP and their reasons for discontinuation were not assessed. Conclusion: Compared with placebo, a short course of eszopiclone during the first 2 weeks of CPAP improved adherence and led to fewer patients discontinuing therapy. Primary Funding Source: Sepracor.
The Antihypertensive Effect of Positive Airway Pressure on Resistant Hypertension of Patients with Obstructive Sleep Apnea: A Randomized, Double-Blind, Clinical Trial
Authors: Ana Claudia de Oliveira, Denis Martinez, Daniela Massierer, Miguel Gus, Sandro Cadaval Gonçalves, Flávia Ghizzoni, Ana Maria Steinhorst, Leila Beltrami Moreira, Sandra Costa Fuchs, Flávio Danni Fuchs
Journal: American Journal of Respiratory and Critical Care Medicine (2014)
Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor
Authors: Arthur Kavanaugh, Philip J Mease, Juan J Gomez-Reino, Adewale O Adebajo, Jürgen Wollenhaupt, Dafna D Gladman, Eric Lespessailles, Stephen Hall, Marla Hochfeld, ChiaChi Hu, Douglas Hough, Randall M Stevens, Georg Schett
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Objectives</h3> Apremilast, an oral phosphodiesterase 4 inhibitor, regulates inflammatory mediators. Psoriatic Arthritis Long-term Assessment of Clinical Efficacy 1 (PALACE 1) compared apremilast with placebo in patients with active psoriatic arthritis despite prior traditional disease-modifying antirheumatic drug (DMARD) and/or biologic therapy. <h3>Methods</h3> In the 24-week, placebo-controlled phase of PALACE 1, patients (N=504) were randomised (1:1:1) to placebo, apremilast 20 mg twice a day (BID) or apremilast 30 mg BID. At week 16, patients without ≥20% reduction in swollen and tender joint counts were required to be re-randomised equally to either apremilast dose if initially randomised to placebo or remained on their initial apremilast dose. Patients on background concurrent DMARDs continued stable doses (methotrexate, leflunomide and/or sulfasalazine). Primary outcome was the proportion of patients achieving 20% improvement in modified American College of Rheumatology response criteria (ACR20) at week 16. <h3>Results</h3> At week 16, significantly more apremilast 20 mg BID (31%) and 30 mg BID (40%) patients achieved ACR20 versus placebo (19%) (p&lt;0.001). Significant improvements in key secondary measures (physical function, psoriasis) were evident with both apremilast doses versus placebo. Across outcome measures, the 30-mg group generally had higher and more consistent response rates, although statistical comparison was not conducted. The most common adverse events were gastrointestinal and generally occurred early, were self-limiting and infrequently led to discontinuation. No imbalance in major adverse cardiac events, serious or opportunistic infections, malignancies or laboratory abnormalities was observed. <h3>Conclusions</h3> Apremilast was effective in the treatment of psoriatic arthritis, improving signs and symptoms and physical function. Apremilast demonstrated an acceptable safety profile and was generally well tolerated. <h3>Clinical trial registration number</h3> NCT01172938.
Role of Lung Transplantation in the Treatment of Bronchogenic Carcinomas for Patients With End-Stage Pulmonary Disease
Authors: Marc de Perrot, Susan Chernenko, Thomas K. Waddell, Yaron Shargall, Andrew F. Pierre, Michael Hutcheon, Shaf Keshavjee
Journal: Journal of Clinical Oncology (2004)

To determine the role of lung transplantation in the treatment of patients presenting with bronchogenic carcinoma and end-stage lung disease.An international survey was conducted to determine the outcome of patients with bronchogenic carcinoma in the explanted lung at the time of transplantation. A group of 69 patients was collected from 33 centers.Twenty-six patients underwent 29 lung transplantations for advanced multifocal bronchioloalveolar carcinoma (BAC) as the primary indication for transplantation, and 13 developed a recurrence, with an overall 5-year actuarial survival of 39%. Incidental bronchogenic carcinomas classified as stage I (n = 22), II (n = 12), and III (n = 2), or as incidental multifocal BAC (n = 7), were found in the explanted lung of the remaining 43 patients. The 5-year actuarial survival was 51% in patients with stage I carcinomas, and was significantly better than for patients with stage II and III carcinomas (survival of 14%) or with incidental multifocal BAC (survival of 23%). Time from transplantation to recurrence and from recurrence to death was significantly longer in patients with multifocal BAC than in patients with other types of bronchogenic carcinoma. In addition, the site of recurrence was limited to the transplanted lung in 88% of the patients with multifocal BAC, whereas it was always widespread in patients with other types of bronchogenic carcinoma.This study demonstrates that long-term survival can be achieved after lung transplantation in patients with stage I bronchogenic carcinoma or with advanced multifocal BAC.
Effects of acetorphan, an enkephalinase inhibitor, on experimental and acute diarrhoea.
Authors: P Baumer, E Danquechin Dorval, J Bertrand, J M Vetel, J C Schwartz, J M Lecomte
Journal: Gut (1992)

Acetorphan is an orally active inhibitor of enkephalinase (EC 3.4.24.11) with antidiarrhoeal activity in rodents apparently through protection of endogenous enkephalins and a purely antisecretory mechanism. Its antidiarrhoeal activity in man was assessed in an experimental model of cathartic induced secretory diarrhoea as well as in acute diarrhoea of presumed infectious origin. In six healthy volunteers receiving castor oil and pretreated with acetorphan or placebo in a crossover controlled trial, the drug significantly decreased the number and weight of stools passed during 24 hours. About 200 outpatients with severe acute diarrhoea (more than five stools per day) were included in a randomised double blind study of acetorphan against placebo. The significant antidiarrhoeal activity of acetorphan was established using a variety of criteria: (i) the duration of both diarrhoea and treatment were diminished; (ii) no acetorphan treated patient withdrew from the study whereas five dropped out because of worsening in the placebo group; (iii) the frequency of symptoms associated with diarrhoea--for example, abdominal pain or distension, nausea and anorexia--remaining after two weeks was nearly halved; (iv) using visual analogue scales acetorphan treatment was found more effective than placebo by both investigators and patients. There was statistically no significant difference between acetorphan and placebo in respect of side effects, particularly constipation, which often accompanies the antidiarrhoeal activity of mu opioid receptor agonists this difference is attributable to the lack of antipropulsive activity of acetorphan in man. The efficacy and tolerance of acetorphan suggest that enkephalinase inhibition may represent a novel therapeutic approach for the symptomatic management of acute secretory diarrhoea without impairing intestinal transit.
Toll-like receptor 4 imparts ligand-specific recognition of bacterial lipopolysaccharide
Authors: Egil Lien, Terry K. Means, Holger Heine, Atsutoshi Yoshimura, Shoichi Kusumoto, Koichi Fukase, Matthew J. Fenton, Masato Oikawa, Nilofer Qureshi, Brian Monks, Robert W. Finberg, Robin R. Ingalls, Douglas T. Golenbock
Journal: Journal of Clinical Investigation (2000)

Lipopolysaccharide (LPS) is the main inducer of shock and death in Gram-negative sepsis. Recent evidence suggests that LPS-induced signal transduction begins with CD14-mediated activation of 1 or more Toll-like receptors (TLRs). The lipid A analogues lipid IVa and Rhodobacter sphaeroides lipid A (RSLA) exhibit an uncommon species-specific pharmacology. Both compounds inhibit the effects of LPS in human cells but display LPS-mimetic activity in hamster cells. We transfected human TLR4 or human TLR2 into hamster fibroblasts to determine if either of these LPS signal transducers is responsible for the species-specific pharmacology. RSLA and lipid IVa strongly induced NF-κB activity and IL-6 release in Chinese hamster ovary fibroblasts expressing CD14 (CHO/CD14), but these compounds antagonized LPS antagonists in CHO/CD14 fibroblasts that overexpressed human TLR4. No such antagonism occurred in cells overexpressing human TLR2. We cloned TLR4 from hamster macrophages and found that human THP-1 cells expressing the hamster TLR4 responded to lipid IVa as an LPS mimetic, as if they were hamster in origin. Hence, cells heterologously overexpressing TLR4 from different species acquired a pharmacological phenotype with respect to recognition of lipid A substructures that corresponded to the species from which the TLR4 transgene originated. These data suggest that TLR4 is the central lipid A–recognition protein in the LPS receptor complex.
Biochemical correlates of neuropsychiatric illness in maple syrup urine disease
Authors: Emilie R. Muelly, Gregory J. Moore, Scott C. Bunce, Julie Mack, Don C. Bigler, D. Holmes Morton, Kevin A. Strauss
Journal: Journal of Clinical Investigation (2013)

Maple syrup urine disease (MSUD) is an inherited disorder of branched chain amino acid metabolism presenting with neonatal encephalopathy, episodic metabolic decompensation, and chronic amino acid imbalances. Dietary management enables survival and reduces risk of acute crises. Liver transplantation has emerged as an effective way to eliminate acute decompensation risk. Psychiatric illness is a reported MSUD complication, but has not been well characterized and remains poorly understood. We report the prevalence and characteristics of neuropsychiatric problems among 37 classical MSUD patients (ages 5–35 years, 26 on dietary therapy, 11 after liver transplantation) and explore their underlying mechanisms. Compared with 26 age-matched controls, MSUD patients were at higher risk for disorders of cognition, attention, and mood. Using quantitative proton magnetic resonance spectroscopy, we found lower brain glutamate, N-acetylaspartate (NAA), and creatine concentrations in MSUD patients, which correlated with specific neuropsychiatric outcomes. Asymptomatic neonatal course and stringent longitudinal biochemical control proved fundamental to optimizing long-term mental health. Neuropsychiatric morbidity and neurochemistry were similar among transplanted and nontransplanted MSUD patients. In conclusion, amino acid dysregulation results in aberrant neural networks with neurochemical deficiencies that persist after transplant and correlate with neuropsychiatric morbidities. These findings may provide insight into general mechanisms of psychiatric illness.
Monitoring the glioma tropism of bone marrow-derived progenitor cells by 2-photon laser scanning microscopy and positron emission tomography
Authors: K. Hasenbach, S. Wiehr, C. Herrmann, J. Mannheim, F. Cay, G. von Kurthy, T. Bolmont, S. A. Grathwohl, M. Weller, C. Lengerke, B. J. Pichler, G. Tabatabai
Journal: Neuro-Oncology (2012)

Intracerebral experimental gliomas attract intravenously injected murine or human bone marrow–derived hematopoietic progenitor and stem cells (HPC) in vitro, ex vivo, and in vivo, indicating that these progenitor cells might be suitable vehicles for a cell-based delivery of therapeutic molecules to malignant gliomas. With regard to therapeutic application, it is important to investigate cell fates in vivo (i.e., the time-dependent intratumoral and systemic distribution after intravenously injection). Conventional histological analysis has limitations in this regard because longitudinal monitoring is precluded. Here, we used 2-photon laser scanning microscopy (2PLSM), positron emission tomography (PET), and MRI to study the fate of intravenously injected HPC carrying fluorescence, bioluminescence, and PET reporter genes in glioma-bearing mice. Our 2PLSM-based monitoring studies revealed that HPC homing to intracerebral experimental gliomas occurred already within the first 6 h and was most efficient within the first 24 h after intravenous injection. The highest PET signals were detected in intracerebral gliomas, whereas the tracer uptake in other organs, notably spleen, lung, liver, and muscle, remained at background levels. The results have important implications for designing schedules for therapeutic cell-based anti-glioma approaches. Moreover, the PET reporter-based imaging technique will allow noninvasive monitoring of cell fate in future cell-based therapeutic antiglioma approaches.
B and T cells collaborate in antiviral responses via IL-6, IL-21, and transcriptional activator and coactivator, Oct2 and OBF-1
Authors: Alex Karnowski, Stephane Chevrier, Gabrielle T. Belz, Adele Mount, Dianne Emslie, Kathy D’Costa, David M. Tarlinton, Axel Kallies, Lynn M. Corcoran
Journal: The Journal of Experimental Medicine (2012)

A strong humoral response to infection requires the collaboration of several hematopoietic cell types that communicate via antigen presentation, surface coreceptors and their ligands, and secreted factors. The proinflammatory cytokine IL-6 has been shown to promote the differentiation of activated CD4+ T cells into T follicular helper cells (TFH cells) during an immune response. TFH cells collaborate with B cells in the formation of germinal centers (GCs) during T cell–dependent antibody responses, in part through secretion of critical cytokines such as IL-21. In this study, we demonstrate that loss of either IL-6 or IL-21 has marginal effects on the generation of TFH cells and on the formation of GCs during the response to acute viral infection. However, mice lacking both IL-6 and IL-21 were unable to generate a robust TFH cell–dependent immune response. We found that IL-6 production in follicular B cells in the draining lymph node was an important early event during the antiviral response and that B cell–derived IL-6 was necessary and sufficient to induce IL-21 from CD4+ T cells in vitro and to support TFH cell development in vivo. Finally, the transcriptional activator Oct2 and its cofactor OBF-1 were identified as regulators of Il6 expression in B cells.
George E. Brown memorial lecture. Role of atrial peptides in body fluid homeostasis.
Authors: B J Ballermann, B M Brenner
Journal: Circulation Research (1986)

Extracts of mammalian atria, but not ventricles, induce marked diuresis, natriuresis, and reduction in blood pressure when infused systemically in rats and dogs. These extracts also inhibit aldosterone biosynthesis and renal renin release. Natriuretic peptides, 21 amino acids and longer, have been isolated from atria of rodents and man, and share a nearly homologous amino acid sequence at the carboxyterminus. Natriuretic activity resides in a 17-amino acid ring formed by a disulfide bridge, and the C-terminal Phe-Arg appears necessary for full biological potency. The deoxyribonucleic acid-encoding atrial natriuretic peptides have been cloned and the gene structure elucidated. Reduction of the diuretic and natriuretic responses to an acute volume load by right atrial appendectomy first suggested a role for atrial peptides in the physiological response to plasma volume expansion. Subsequently, release of peptides with natriuretic and spasmolytic properties from isolated heart preparations in response to right atrial distension was demonstrated by bioassay and radioimmunoassay. The presence of these peptides in normal rat and human plasma in concentrations of 20-100 pM, and the findings of increased levels in response to acute and chronic plasma volume expansion, rapid atrial tachyarrhythmias, systemic hypertension, congestive heart failure, and renal insufficiency imply that they play an important role in body fluid homeostasis. The mechanisms by which atrial peptides increase renal salt and water excretion are as yet unclear. Renal vascular effects have been consistently demonstrated, and limited evidence for direct actions on tubule ion transport has also been reported recently. In vitro, these peptides cause precontracted vascular and nonvascular smooth muscle to relax, mediated by a direct action on smooth muscle cells. Specific receptors for these peptides have been characterized in crude membranes prepared from whole kidney homogenates and adrenal glomerulosa cells, in intact glomeruli and cultured glomerular mesangial cells, and in intact bovine aortic smooth muscle and endothelial cells. Natriuretic peptides stimulate cyclic guanosine monophosphate accumulation in target tissues, and augment particulate guanylate cyclase activity in membrane fractions, suggesting that cyclic guanosine monophosphate is the second messenger mediating their cellular action.
The Long-Term Health Consequences of Child Physical Abuse, Emotional Abuse, and Neglect: A Systematic Review and Meta-Analysis
Authors: Rosana E. Norman, Munkhtsetseg Byambaa, Rumna De, Alexander Butchart, James Scott, Theo Vos
Journal: PLoS Medicine (2012)

Rosana Norman and colleagues conduct a systematic review and meta-analysis to assess the relationship between child physical abuse, emotional abuse, and neglect, and subsequent mental and physical health outcomes.
A Potential Role for Mechanical Forces in the Detachment of Podocytes and the Progression of CKD
Authors: Wilhelm Kriz, Kevin V. Lemley
Journal: Journal of the American Society of Nephrology (2014)

Loss of podocytes underlies progression of CKD. Detachment of podocytes from the glomerular basement membrane (GBM) rather than apoptosis or necrosis seems to be the major mechanism of podocyte loss. Such detachment of viable podocytes may be caused by increased mechanical distending and shear forces and/or impaired adhesion to the GBM. This review considers the mechanical challenges that may lead to podocyte loss by detachment from the GBM under physiologic and pathophysiologic conditions, including glomerular hypertension, hyperfiltration, hypertrophy, and outflow of filtrate from subpodocyte spaces. Furthermore, we detail the cellular mechanisms by which podocytes respond to these challenges, discuss the protective effects of angiotensin blockade, and note the questions that must be addressed to better understand the relationship between podocyte detachment and progression of CKD.
An Immunodeficiency Disease with<i>RAG</i>Mutations and Granulomas
Authors: Catharina Schuetz, Kirsten Huck, Sonja Gudowius, Mosaad Megahed, Oliver Feyen, Bernd Hubner, Dominik T. Schneider, Burkhard Manfras, Ulrich Pannicke, Rein Willemze, Ruth Knüchel, Ulrich Göbel, Ansgar Schulz, Arndt Borkhardt, Wilhelm Friedrich, Klaus Schwarz, Tim Niehues
Journal: New England Journal of Medicine (2008)

We describe three unrelated girls who had an immunodeficiency disease with granulomas in the skin, mucous membranes, and internal organs. All three girls had severe complications after viral infections, including B-cell lymphoma associated with Epstein-Barr virus (EBV). Other findings were hypogammaglobulinemia, a diminished number of T and B cells, and sparse thymic tissue on ultrasonography. Molecular analysis revealed that the patients were compound heterozygotes for mutations in recombination activating gene 1 or 2 (RAG1 or RAG2). In each case, both parents were heterozygous carriers of a RAG mutation. The mutations were associated with reduced function of RAG in vitro (3 to 30% of normal activity). The parents and one sibling in the three families were healthy.
Oncogenic Function of ATDC in Pancreatic Cancer through Wnt Pathway Activation and β-Catenin Stabilization
Authors: Lidong Wang, David G. Heidt, Cheong J. Lee, Huibin Yang, Craig D. Logsdon, Lizhi Zhang, Eric R. Fearon, Mats Ljungman, Diane M. Simeone
Journal: Cancer Cell (2009)