tbuckley/cabot-search huggingface dataset:
Respiratory Muscle Endurance Training in Chronic Obstructive Pulmonary Disease
Authors: THOMAS A. SCHERER, CHRISTINA M. SPENGLER, DOMINIK OWASSAPIAN, EDELBERT IMHOF, URS BOUTELLIER
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

Inspiratory muscle training may have beneficial effects in certain patients with chronic obstructive pulmonary disease (COPD). Because of the lack of a home training device, normocapnic hyperpnea has rarely been used as a training mode for patients with COPD, and is generally considered unsuitable to large-scale application. To study the effects of hyperpnea training, we randomized 30 patients with COPD and ventilatory limitation to respiratory muscle training (RMT; n = 15) with a new portable device or to breathing exercises with an incentive spirometer (controls; n = 15). Both groups trained twice daily for 15 min for 5 d per week for 8 wk. Training-induced changes were significantly greater in the RMT than in the control group for the following variables: respiratory muscle endurance measured through sustained ventilation ( + 825 ± 170 s [mean ± SEM] versus − 27 ± 61 s, p < 0.001), inspiratory muscle endurance measured through incremental inspiratory threshold loading ( + 58 ± 10 g versus + 21.7 ± 9.5 g, p = 0.016), maximal expiratory pressure ( + 20 ± 7 cm H2O versus − 6 ± 6 cm H2O, p = 0.009), 6-min walking distance ( + 58 ± 11 m versus + 11 ± 11 m, p = 0.002), V˙ o 2peak ( + 2.5 ± 0.6 ml/kg/min versus − 0.3 ± 0.9 ml/kg/min, p = 0.015), and the SF-12 physical component score ( + 9.9 ± 2.7 versus + 1.8 ± 2.4, p = 0.03). Changes in dyspnea, maximal inspiratory pressure, treadmill endurance, and the SF-12 mental component score did not differ significantly between the RMT and control groups. In conclusion, home-based respiratory muscle endurance training with the new device used in this study is feasible and has beneficial effects in subjects with COPD and ventilatory limitation.
Activity of Sorafenib against Desmoid Tumor/Deep Fibromatosis
Authors: Mrinal M. Gounder, Robert A. Lefkowitz, Mary Louise Keohan, David R. D'Adamo, Meera Hameed, Cristina R. Antonescu, Samuel Singer, Katherine Stout, Linda Ahn, Robert G. Maki
Journal: Clinical Cancer Research (2011)

Desmoid tumors (deep fibromatoses) are clonal connective tissue malignancies that do not metastasize, but have a significant risk of local recurrence, and are associated with morbidity and occasionally mortality. Responses of desmoid patients to sorafenib on an expanded access program led us to review our experience.After Institutional Review Board (IRB) approval, we reviewed data for 26 patients with desmoid tumors treated with sorafenib. Sorafenib was administered at 400 mg oral daily and adjusted for toxicity.Sorafenib was the first-line therapy in 11/26 patients and the remaining 15/26 had received a median of 2 prior lines of therapy. Twenty-three of 26 patients had shown evidence of progressive disease by imaging, whereas 3 patients had achieved maximum benefit or toxicity with chemotherapy. Sixteen of 22 (∼70%) patients reported significant improvement of symptoms. At a median of 6 months (2-29) of treatment, the best response evaluation criteria in solid tumors (RECIST) 1.1 response included 6/24 (25%) patients with partial response (PR), 17/24 (70%) with stable disease, and 1 with progression and death. Twelve of 13 (92%) patients evaluated by MRI had > 30% decrease in T2 signal intensity, an indirect metric for increased fibrosis and loss of cellularity. Eighty percent of patients with radiological benefit had extra-abdominal desmoids.Sorafenib is active against desmoid tumors. A prospective, randomized clinical trial of sorafenib against other active agents is warranted. Loss of MRI T2 signal may be a useful surrogate for defining responses, but requires validation by examination of tumor pathology.
Nucleoside salvage pathway kinases regulate hematopoiesis by linking nucleotide metabolism with replication stress
Authors: Wayne R. Austin, Amanda L. Armijo, Dean O. Campbell, Arun S. Singh, Terry Hsieh, David Nathanson, Harvey R. Herschman, Michael E. Phelps, Owen N. Witte, Johannes Czernin, Caius G. Radu
Journal: The Journal of Experimental Medicine (2012)

Nucleotide deficiency causes replication stress (RS) and DNA damage in dividing cells. How nucleotide metabolism is regulated in vivo to prevent these deleterious effects remains unknown. In this study, we investigate a functional link between nucleotide deficiency, RS, and the nucleoside salvage pathway (NSP) enzymes deoxycytidine kinase (dCK) and thymidine kinase (TK1). We show that inactivation of dCK in mice depletes deoxycytidine triphosphate (dCTP) pools and induces RS, early S-phase arrest, and DNA damage in erythroid, B lymphoid, and T lymphoid lineages. TK1(-/-) erythroid and B lymphoid lineages also experience nucleotide deficiency but, unlike their dCK(-/-) counterparts, they still sustain DNA replication. Intriguingly, dCTP pool depletion, RS, and hematopoietic defects induced by dCK inactivation are almost completely reversed in a newly generated dCK/TK1 double-knockout (DKO) mouse model. Using NSP-deficient DKO hematopoietic cells, we identify a previously unrecognized biological activity of endogenous thymidine as a strong inducer of RS in vivo through TK1-mediated dCTP pool depletion. We propose a model that explains how TK1 and dCK "tune" dCTP pools to both trigger and resolve RS in vivo. This new model may be exploited therapeutically to induce synthetic sickness/lethality in hematological malignancies, and possibly in other cancers.
Disentangling the Effects of Demography and Selection in Human History
Authors: J. E. Stajich
Journal: Molecular Biology and Evolution (2004)

Demographic events affect all genes in a genome, whereas natural selection has only local effects. Using publicly available data from 151 loci sequenced in both European-American and African-American populations, we attempt to distinguish the effects of demography and selection. To analyze large sets of population genetic data such as this one, we introduce "Perlymorphism," a Unix-based suite of analysis tools. Our analyses show that the demographic histories of human populations can account for a large proportion of effects on the level and frequency of variation across the genome. The African-American population shows both a higher level of nucleotide diversity and more negative values of Tajima's D statistic than does a European-American population. Using coalescent simulations, we show that the significantly negative values of the D statistic in African-Americans and the positive values in European-Americans are well explained by relatively simple models of population admixture and bottleneck, respectively. Working within these nonequilibrium frameworks, we are still able to show deviations from neutral expectations at a number of loci, including ABO and TRPV6. In addition, we show that the frequency spectrum of mutations--corrected for levels of polymorphism--is correlated with recombination rate only in European-Americans. These results are consistent with repeated selective sweeps in non-African populations, in agreement with recent reports using microsatellite data.
Postmarketing surveillance of the safety profile of infliximab in 5000 Japanese patients with rheumatoid arthritis
Authors: T Takeuchi, Y Tatsuki, Y Nogami, N Ishiguro, Y Tanaka, H Yamanaka, N Kamatani, M Harigai, J Ryu, K Inoue, H Kondo, S Inokuma, T Ochi, T Koike
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objectives:</h3> A large-scale postmarketing surveillance (PMS) study was carried out to determine the safety profile of infliximab in Japanese patients with rheumatoid arthritis (RA). <h3>Methods:</h3> The PMS study was performed for all patients with RA who were treated with infliximab. They were consecutively registered in the PMS study at the initiation of infliximab treatment and were prospectively monitored with all adverse events noted for a period of 6 months. All case reports, which include safety-related events, were collected monthly. <h3>Results:</h3> Adverse drug reactions (ADRs) were assessed for 6 months in 5000 patients who were consecutively enrolled in the PMS study. The incidence rates of total and serious ADRs were 28.0% and 6.2%, respectively. "Infections" or "respiratory disorders" were most commonly observed among serious ADRs. Bacterial pneumonia developed in 2.2%, tuberculosis in 0.3%, suspected <i>Pneumocystis jiroveci</i> pneumonia (PCP) in 0.4% and interstitial pneumonitis in 0.5%. Bacterial pneumonia (for which individuals of male gender, of older age and those with advanced rheumatoid arthritis and comorbid respiratory disease were most at risk) began to develop immediately after the start of treatment, while tuberculosis, PCP and interstitial pneumonitis developed about 1 month later. Serious infusion reactions were observed in 0.5% and were more likely to occur in patients who had participated in previous clinical trials of infliximab. <h3>Conclusion:</h3> This postmarketing surveillance study of patients treated with infliximab showed that infliximab in combination with low-dose MTX was well tolerated in Japanese patients with active RA.
Angiotensin-Converting Enzyme and Vascular Remodeling
Authors: Sylvia Heeneman, Judith C. Sluimer, Mat J.A.P. Daemen
Journal: Circulation Research (2007)

Vascular remodeling is the result of a close interplay of changes in vascular tone and structure. In this review, the role of angiotension-converting enzyme (ACE) and the impact of ACE inhibition on vascular remodeling processes during vascular injury and restenosis, hypertension, atherosclerosis, and aneurysm formation are discussed. The role of ACE and angiotensin II (Ang II) in neointimal thickening has been firmly established by animal studies and is mediated by Ang II type 1 (AT 1 ) receptor signaling events via monocyte chemoattractant protein-1 and NAD(P)H oxidase. ACE and Ang II are involved in the remodeling of large and resistance arteries during hypertension; here, cell proliferation and matrix remodeling are also regulated by signaling events downstream of the AT 1 receptor. In atherosclerosis, Ang II is involved in the inflammatory and tissue response, mediated by various signaling pathways downstream of the AT 1 receptor. Although ACE inhibition has been shown to inhibit atherosclerotic processes in experimental animal models, results of large clinical trials with ACE inhibitors were not conclusive. Remodeling of vessel dimensions and structure during aneurysm formation is counteracted by ACE inhibition. Here, a direct effect of ACE inhibitors on matrix metalloproteinase activity has to be considered as part of the working mechanism. The role of ACE2 in vascular remodeling has yet to be established; however, ACE2 has been shown to be associated with vascular changes in hypertension and atherosclerosis.
Cellular electrophysiology of atrial fibrillation
Authors: R Bosch
Journal: Cardiovascular Research (2002)

Time for primary review 23 days. 

Atrial fibrillation (AF) is presently the most common cardiac arrhythmia in clinical practice. Its treatment is inadequate. Maintenance of normal sinus rhythm (SR) is obviously the optimal approach, but is difficult to achieve without drugs that have the potential to cause ventricular proarrhythmia and increase mortality. Non-pharmacological therapy is attractive, but to date has not reached the same level of efficacy as in the treatment of arrhythmias other than AF. In order to improve therapeutic approaches, it is important to understand the detailed pathophysiology of the arrhythmia. A key component to the pathophysiology of any cardiac arrhythmia is the cellular milieu in which it occurs. Changes in ion transport processes, including pumps, channels and exchangers, are central to alterations in action potential properties that govern the occurrence of arrhythmias like AF. Action potential duration (APD) determines the refractory period and is therefore a key determinant of the likelihood of reentry. Maximum Na+-current ( I Na) governs phase 0 upstroke velocity, determining conduction velocity (CV) and contributing to the likelihood of reentry. Delayed and early afterdepolarizations produce abnormal activity that can in themselves produce tachyarrhythmias and can trigger reentrant arrhythmia.

This paper reviews these aspects of the cellular electrophysiology of AF, attempting to summarize what is known, what remains to be explored and what this information can teach us about why AF occurs and how to treat it.

The identification of the molecular structure of many ion channels involved in cardiac excitability and their functional correlation with native ionic currents have made it possible to study the effects of pathophysiological conditions, like AF, at different levels from genes to ionic currents. The different steps underlying the expression of an ion channel are depicted in Fig. 1 and have recently been reviewed by Roden and … 

* Corresponding author. Tel.: +49-7071-298-3196; fax: +49-7071-294-121 ralph.bosch{at}uni-tuebingen.de
Expression and function of cystic fibrosis transmembrane conductance regulator in rat intrapulmonary arteries
Authors: R. Robert, J-P. Savineau, C. Norez, F. Becq, C. Guibert
Journal: European Respiratory Journal (2007)

The cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes a cyclic adenosine monophosphate (cAMP)-dependent chloride channel located mainly at the apical membrane of epithelial cells. In myocytes of pulmonary arteries, numerous chloride channels have been identified and described, but not the CFTR. Thus the presence and function of the CFTR was investigated in rat intrapulmonary arteries. CFTR expression, localisation and function were analysed in cultured smooth muscle cells using Reverse transcriptase (RT)-PCR and immunoprecipitation followed by protein kinase A phosphorylation, immunolocalisation and an iodide efflux assay, respectively. The role of the CFTR in pulmonary vasoreactivity was determined in arterial rings using an organ bath system. RT-PCR and immunoprecipitation analyses, as well as the immunolocalisation study, revealed the expression of CFTR gene transcripts and protein. The iodide efflux assay showed the existence of functional cAMP-, calcium- and volume-dependent chloride channels. Furthermore, the following effects were found: 1) inhibition of forskolin/genistein-activated iodide efflux by glibenclamide, diphenylamine-2-carboxylic acid and CFTR-specific inhibitor (CFTR inh )-172; 2) activation of iodide efflux by the benzoquinolizinium derivative CFTR activators MPB-07 and MPB-91; and 3) inhibition of MPB-dependent efflux by CFTR inh -172. Finally, CFTR activators induced concentration-dependent vasorelaxation in rings preconstricted with phenylephrine, in the presence or absence of endothelium. The present results are the first to reveal functional cyclic adenosine monophosphate-regulated cystic fibrosis transmembrane conductance regulator contributing to endothelium-independent vasorelaxation in rat intrapulmonary arterial myocytes.
Membrane cofactor protein (CD46) protects cells from complement-mediated attack by an intrinsic mechanism.
Authors: T J Oglesby, C J Allen, M K Liszewski, D J White, J P Atkinson
Journal: The Journal of Experimental Medicine (1992)

The cleavage of C3 is a critical step for complement (C) activation in the classical and alternative pathways. This reaction is controlled by the regulators of C activation protein family. Membrane cofactor protein (MCP) is a cofactor for the factor I-mediated inactivation of C3b and C4b. As a widely distributed membrane protein, MCP may protect host cells from inadvertent C activation. Human MCP has recently been shown to protect transfected rodent cells from human C-mediated lysis. In this report the relationship of MCP expression to C3b deposition and cytoprotection was examined using NIH/3T3 cells transfected with human MCP and exposed to human serum as a source of C and naturally occurring anti-mouse antibody. MCP inhibited C3b deposition in a dose-dependent fashion and inhibited lysis of the mouse cells expressing it. MCP did not inhibit lysis on bystander cells. These results demonstrate the protective role of MCP, at the cellular level, by an intrinsic mechanism.
Annexin A5 polymorphism (-1C-&gt;T) and the presence of anti-annexin A5 antibodies in the antiphospholipid syndrome
Authors: B de Laat, R H W M Derksen, I J Mackie, M Roest, S Schoormans, B J Woodhams, P G de Groot, W L van Heerde
Journal: Annals of the Rheumatic Diseases (2006)

Annexin A5 is thought to have a role in the pathophysiology of the antiphospholipid syndrome (APS)-a syndrome characterised by recurrent thrombosis and pregnancy morbidity.To investigate whether anti-annexin A5 immunoglobulin (Ig)M or IgG antibodies, or the -1C-->T polymorphism of annexin A5, is a risk factor for thrombosis or miscarriage, and whether the -1C-->T polymorphism is correlated with APS.A cohort study was carried out with a population of 198 patients with primary APS, systemic lupus erythematosus or lupus-like disease. For the detection of anti-annexin A5 antibodies and the measurement of annexin A5 plasma levels, ELISA-type methods were used. The annexin A5 -1C-->T mutation was detected by restriction fragment length polymorphism.71 patients were positive for annexin A5 IgM or IgG antibodies, of whom 53 patients were positive for anti-annexin A5 IgG antibodies and 27 of 198 patients were positive for anti-annexin A5 IgM antibodies. The prevalence of IgM or IgG anti-annexin A5 antibodies was not significantly associated with thrombosis or miscarriage on multivariate analysis. The prevalence of the -1C-->T mutation in the annexin A5 gene (46/198 patients) was significantly associated with miscarriage (odds ratio 2.7, 95% confidence interval 1.1 to 6.7, independent risk factor).The detection of anti-annexin A5 antibodies does not seem relevant for estimating the risk for thrombosis or miscarriage in APS. The -1C-->T mutation was an independent risk factor for miscarriage, which is independent of APS.
Clinical Indicators Suggestive of Vocal Cord Dysfunction
Authors: G. Schwarz, M.T. Santiago, J. Fagin
Journal: Journal of Allergy and Clinical Immunology (2010)

RATIONALE: Vocal cord dysfunction (VCD) is characterized by exaggerated reverse phasic movement of the vocal folds during respiration. It often results in wheezing misinterpreted as lower airway obstruction. We sought to identify common findings in our patients with VCD suggestive of this condition. METHODS: Medical records of eight patients diagnosed with VCD, confirmed by video stroboscopy, were retrospectively reviewed. RESULTS: Of the 8 patients with VCD, 6(75%) were previously diagnosed with asthma, 4(50%) with anxiety and 2(25%) with GERD. Expiratory flow-volume loops were performed on all 8 patients. Inspiratory flow-volume loops were performed on 6(75%) of the 8 patients. In 4(67%) of the 6 the inspiratory component was not assessed. Two (50%) of the 4 uninterpreted inspiratory loops were flat, suggestive of extrathoracic obstruction. Of the 6 asthmatics, 5(83%) had a history of exercise-related respiratory complaints, 4(67%) reported a poor response to bronchodilator therapy and 3(50%) reported symptoms of anxiety. Five (83%) were treated with maintenance therapies, all of whom required multiple medications. All 6 asthmatics were treated with multiple courses of oral corticosteroids. CONCLUSIONS: VCD is a commonly unrecognized entity that is either misdiagnosed as asthma or presents as an undiagnosed asthma comorbidity. Interpretation of inspiratory flow-volume loops is critical for identifying extrathoracic airway obstruction characteristic of VCD. All asthmatics should be routinely evaluated with inspiratory flow-volume loops, particularly those with exercise-related respiratory complaints, a poor response to bronchodilators or symptoms of anxiety. Failure to recognize VCD may result in underutilization of appropriate management (i.e. speech therapy) and overutilization of asthma medications.
Roles of thromboxane A2 and prostacyclin in the development of atherosclerosis in apoE-deficient mice
Authors: Takuya Kobayashi, Yoshio Tahara, Mayumi Matsumoto, Masako Iguchi, Hideto Sano, Toshinori Murayama, Hidenori Arai, Hiroji Oida, Takami Yurugi-Kobayashi, Jun K. Yamashita, Hiroyuki Katagiri, Masataka Majima, Masayuki Yokode, Toru Kita, Shuh Narumiya
Journal: Journal of Clinical Investigation (2004)

Production of thromboxane (TX) A2 and PG I2/prostacyclin (PGI2) is increased in patients with atherosclerosis. However, their roles in atherogenesis have not been critically defined. To examine this issue, we cross-bred atherosclerosis-prone apoE-deficient mice with mice deficient in either the TXA receptor (TP) or the PGI receptor (IP). Although they showed levels of serum cholesterol and triglyceride similar to those of apoE-deficient mice, apoE–/–TP–/– mice exhibited a significant delay in atherogenesis, and apoE–/–IP–/– mice exhibited a significant acceleration in atherogenesis compared with mice deficient in apoE alone. The plaques in apoE–/–IP–/– mice showed partial endothelial disruption and exhibited enhanced expression of ICAM-1 and decreased expression of platelet endothelial cell adhesion molecule 1 (PECAM-1) in the overlying endothelial cells compared with those of apoE–/–TP–/– mice. Platelet activation with thrombin ex vivo revealed higher and lower sensitivity for surface P-selectin expression in platelets of apoE–/–IP–/– and apoE–/–TP–/– mice, respectively, than in those of apoE–/– mice. Intravital microscopy of the common carotid artery revealed a significantly greater number of leukocytes rolling on the vessel walls in apoE–/–IP–/– mice than in either apoE–/–TP–/– or apoE–/– mice. We conclude that TXA2 promotes and PGI2 prevents the initiation and progression of atherogenesis through control of platelet activation and leukocyte-endothelial cell interaction.
Current therapeutic relevance of liver gene transfer
Authors: Jean Michel Heard
Journal: Hepatology (1994)

ABSTRACT The liver represents a model organ for gene therapy. A method has been developed for hepatic gene transfer in vivo by the direct infusion of recombinant retroviral vectors into the portal vasculature, which results in the persistent expression of exogenous genes. To determine if these technologies are applicable for the treatment of hemophilia B patients, preclinical efficacy studies were done in a hemophilia B dog model. When the canine factor IX complementary DNA was transduced directly into the hepatocytes of affected dogs in vivo, the animals constitutively expressed low levels of canine factor IX for more than 5 months. Persistent expression of the clotting factor resulted in reductions of whole blood clotting and partial thromboplastin times of the treated animals. Thus, long–term treatment of hemophilia B patients may be feasible by direct hepatic gene therapy in vivo.