tbuckley/cabot-search huggingface dataset:
Contractile Leg Fatigue after Cycle Exercise
Authors: Didier Saey, Richard Debigaré, Pierre LeBlanc, M. Jeffery Mador, Claude H. Côté, Jean Jobin, François Maltais
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

We evaluated whether contractile fatigue of the quadriceps occurs after cycling exercise in patients with chronic obstructive pulmonary disease (COPD) and whether it could contribute to exercise limitation. Eighteen COPD patients performed two constant work-rate cycling exercises up to exhaustion. These tests were preceded by nebulization of placebo or 500 μg of ipratropium bromide. Muscle fatigue was defined as a postexercise reduction in quadriceps twitch force of more than 15% of the resting value. There was an increase in endurance time postipratropium compared with placebo nebulization (440 ± 244 seconds vs. 322 ± 188 seconds, p = 0.06). Nine patients developed contractile fatigue after placebo exercise. In these patients, ipratropium did not increase the endurance time (394 ± 220 seconds with placebo vs. 400 ± 119 seconds with ipratropium) despite an 11% improvement in FEV1. In the nine patients who did not fatigue after placebo exercise, endurance time increased from 249 ± 124 seconds with placebo to 479 ± 298 seconds with ipratropium (p < 0.05). There was a significant correlation between the improvement in endurance time with ipratropium and quadriceps twitch force at 10 minutes after placebo exercise (r = 0.59, p = 0.01). The occurrence of contractile fatigue during exercise may explain why bronchodilation fails to improve exercise tolerance in some COPD patients.
The Intestinotrophic Peptide, GLP-2, Counteracts Intestinal Atrophy in Mice Induced by the Epidermal Growth Factor Receptor Inhibitor, Gefitinib
Authors: Kristine Juul Hare, Bolette Hartmann, Hannelouise Kissow, Jens Juul Holst, Steen Seier Poulsen
Journal: Clinical Cancer Research (2007)

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been introduced as antitumor agents in the treatment of cancers overexpressing the receptor. The treatment has gastrointestinal side effects which may decrease patient compliance and limit the efficacy. Glucagon-like peptide-2 (GLP-2) is an intestinal hormone with potent intestinotrophic properties and therapeutic potential in disorders with compromised intestinal capacity. The growth stimulation is highly specific to the gastrointestinal tract, and no effects are observed elsewhere. The aim of this study was to examine whether the inhibition of the EGFR induces intestinal atrophy and if this can be counteracted by treatment with GLP-2.Mice were treated for 10 days with either gefitinib orally, GLP-2 as injections, or a combination of both. After sacrifice, the weight and length of the segments of the gastrointestinal tract were determined, and histologic sections were analyzed by morphometric methods.A significant atrophy of the small-intestinal wall was observed after treatment with gefitinib because both intestinal weight and morphometrically estimated villus height and cross-sectional area were decreased. The same parameters were increased by GLP-2 treatment alone, and when GLP-2 was combined with the gefitinib treatment, the parameters remained unchanged.Treatment with an EGFR tyrosine kinase inhibitor in mice results in small-intestinal growth inhibition that can be completely prevented by simultaneous treatment with GLP-2. This suggests that the gastrointestinal side effects elicited by treatment with EGFR tyrosine kinase inhibitors can be circumvented by GLP-2 treatment.
A Phase 2, Randomized, Dose-Finding Study of the Novel Once-Weekly Human GLP-1 Analog, Semaglutide, Compared With Placebo and Open-Label Liraglutide in Patients With Type 2 Diabetes
Authors: Michael A. Nauck, John R. Petrie, Giorgio Sesti, Edoardo Mannucci, Jean-Pierre Courrèges, Marie L. Lindegaard, Christine B. Jensen, Stephen L. Atkin
Journal: Diabetes Care (2015)

To investigate the dose-response relationship of semaglutide versus placebo and open-label liraglutide in terms of glycemic control in patients with type 2 diabetes.This was a 12-week, randomized, double-blind phase 2 trial. Patients (n = 415) were randomized to receive a subcutaneous injection of semaglutide once weekly without dose escalation (0.1-0.8 mg) or with dose escalation (E) (0.4 mg steps to 0.8 or 1.6 mg E over 1-2 weeks), open-label liraglutide once daily (1.2 or 1.8 mg), or placebo. The primary end point was change in HbA1c level from baseline. Secondary end points included change in body weight, safety, and tolerability.Semaglutide dose-dependently reduced the level of HbA1c from baseline (8.1 ± 0.8%) to week 12 by up to -1.7%, and body weight by up to -4.8 kg (1.6 mg E, P < 0.001 vs. placebo). Up to 81% of patients achieved an HbA1c level of <7%. HbA1c level and weight reductions with semaglutide 1.6 mg E were greater than those with liraglutide 1.2 and 1.8 mg (based on unadjusted CIs), but adverse events (AEs) and withdrawals occurred more frequently. The incidence of nausea, vomiting, and withdrawal due to gastrointestinal AEs increased with the semaglutide dose; most events were mild to moderate, transient, and ameliorated by dose escalation. There were no major episodes of hypoglycemia and few cases of injection site reactions.After 12 weeks, semaglutide dose-dependently reduced HbA1c level and weight in patients with type 2 diabetes. No unexpected safety or tolerability concerns were identified; gastrointestinal AEs typical of glucagon-like peptide 1 receptor agonists were mitigated by dose escalation. On this basis, weekly semaglutide doses of 0.5 and 1.0 mg with a 4-week dose escalation were selected for phase 3.
Response to Letters Regarding Article, “Mechanisms of Myocardial Infarction in Women Without Angiographically Obstructive Coronary Artery Disease”
Authors: Harmony R. Reynolds, Sohah N. Iqbal, James N. Slater, Frederick Feit, Ivan Pena-Sing, Michael J. Attubato, Leonid Yatskar, Rebecca T. Kalhorn, Judith S. Hochman, Monvadi B. Srichai, Leon Axel, G.B. John Mancini, David A. Wood, Iryna V. Lobach
Journal: Circulation (2012)
Increasing Use of Contralateral Prophylactic Mastectomy for Breast Cancer Patients: A Trend Toward More Aggressive Surgical Treatment
Authors: Todd M. Tuttle, Elizabeth B. Habermann, Erin H. Grund, Todd J. Morris, Beth A. Virnig
Journal: Journal of Clinical Oncology (2007)

Many patients with unilateral breast cancer choose contralateral prophylactic mastectomy to prevent cancer in the opposite breast. The purpose of our study was to determine the use and trends of contralateral prophylactic mastectomy in the United States.We used the Surveillance, Epidemiology and End Results database to review the treatment of patients with unilateral breast cancer diagnosed from 1998 through 2003. We determined the rate of contralateral prophylactic mastectomy as a proportion of all surgically treated patients and as a proportion of all mastectomies.We identified 152,755 patients with stage I, II, or III breast cancer; 4,969 patients chose contralateral prophylactic mastectomy. The rate was 3.3% for all surgically treated patients; 7.7%, for patients undergoing mastectomy. The overall rate significantly increased from 1.8% in 1998 to 4.5% in 2003. Likewise, the contralateral prophylactic mastectomy rate for patients undergoing mastectomy significantly increased from 4.2% in 1998 to 11.0% in 2003. These increased rates applied to all cancer stages and continued to the end of our study period. Young patient age, non-Hispanic white race, lobular histology, and previous cancer diagnosis were associated with significantly higher rates. Large tumor size was associated with a higher overall rate, but with a lower rate for patients undergoing mastectomy.The use of contralateral prophylactic mastectomy in the United States more than doubled within the recent 6-year period of our study. Prospective studies are needed to understand the decision-making processes that have led to more aggressive breast cancer surgery.
Dopamine as a Prolactin (PRL) Inhibitor
Authors: Nira Ben-Jonathan, Robert Hnasko
Journal: Endocrine Reviews (2001)

Dopamine is a small and relatively simple molecule that fulfills diverse functions. Within the brain, it acts as a classical neurotransmitter whose attenuation or overactivity can result in disorders such as Parkinson's disease and schizophrenia. Major advances in the cloning and characterization of biosynthetic enzymes, transporters, and receptors have increased our knowledge regarding the metabolism, release, reuptake, and mechanism of action of dopamine. Dopamine reaches the pituitary via hypophysial portal blood from several hypothalamic nerve tracts that are regulated by PRL itself, estrogens, and several neuropeptides and neurotransmitters. Dopamine binds to type-2 dopamine receptors that are functionally linked to membrane channels and G proteins and suppresses the high intrinsic secretory activity of the pituitary lactotrophs. In addition to inhibiting PRL release by controlling calcium fluxes, dopamine activates several interacting intracellular signaling pathways and suppresses PRL gene expression and lactotroph proliferation. Thus, PRL homeostasis should be viewed in the context of a fine balance between the action of dopamine as an inhibitor and the many hypothalamic, systemic, and local factors acting as stimulators, none of which has yet emerged as a primary PRL releasing factor. The generation of transgenic animals with overexpressed or mutated genes expanded our understanding of dopamine-PRL interactions and the physiological consequences of their perturbations. PRL release in humans, which differs in many respects from that in laboratory animals, is affected by several drugs used in clinical practice. Hyperprolactinemia is a major neuroendocrine-related cause of reproductive disturbances in both men and women. The treatment of hyperprolactinemia has greatly benefited from the generation of progressively more effective and selective dopaminergic drugs.
Outcome of sustained virological responders with histologically advanced chronic hepatitis C
Authors: Timothy R. Morgan, Marc G. Ghany, Hae-Young Kim, Kristin K. Snow, Mitchell L. Shiffman, Jennifer L. De Santo, William M. Lee, Adrian M. Di Bisceglie, Herbert L. Bonkovsky, Jules L. Dienstag, Chihiro Morishima, Karen L. Lindsay, Anna S. F. Lok
Journal: Hepatology (2010)

Abstract Retrospective studies suggest that subjects with chronic hepatitis C and advanced fibrosis who achieve a sustained virological response (SVR) have a lower risk of hepatic decompensation and hepatocellular carcinoma (HCC). In this prospective analysis, we compared the rate of death from any cause or liver transplantation, and of liver-related morbidity and mortality, after antiviral therapy among patients who achieved SVR, virologic nonresponders (NR), and those with initial viral clearance but subsequent breakthrough or relapse (BT/R) in the HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) Trial. Laboratory and/or clinical outcome data were available for 140 of the 180 patients who achieved SVR. Patients with nonresponse (NR; n = 309) or who experienced breakthrough or relapse (BT/R; n = 77) were evaluated every 3 months for 3.5 years and then every 6 months thereafter. Outcomes included death, liver-related death, liver transplantation, decompensated liver disease, and HCC. Median follow-up for the SVR, BT/R, and NR groups of patients was 86, 85, and 79 months, respectively. At 7.5 years, the adjusted cumulative rate of death/liver transplantation and of liver-related morbidity/mortality in the SVR group (2.2% and 2.7%, respectively) was significantly lower than that of the NR group (21.3% and 27.2%, P &lt; 0.001 for both) but not the BT/R group (4.4% and 8.7%). The adjusted hazard ratio (HR) for time to death/liver transplantation (HR = 0.17, 95% confidence interval [CI] = 0.06-0.46) or development of liver-related morbidity/mortality (HR = 0.15, 95% CI = 0.06-0.38) or HCC (HR = 0.19, 95% CI = 0.04-0.80) was significant for SVR compared to NR. Laboratory tests related to liver disease severity improved following SVR. Conclusion: Patients with advanced chronic hepatitis C who achieved SVR had a marked reduction in death/liver transplantation, and in liver-related morbidity/mortality, although they remain at risk for HCC.
Parabronchial smooth muscle constitutes an airway epithelial stem cell niche in the mouse lung after injury
Authors: Thomas Volckaert, Erik Dill, Alice Campbell, Caterina Tiozzo, Susan Majka, Saverio Bellusci, Stijn P. De Langhe
Journal: Journal of Clinical Investigation (2011)

During lung development, parabronchial SMC (PSMC) progenitors in the distal mesenchyme secrete fibroblast growth factor 10 (Fgf10), which acts on distal epithelial progenitors to promote their proliferation. β-catenin signaling within PSMC progenitors is essential for their maintenance, proliferation, and expression of Fgf10. Here, we report that this Wnt/Fgf10 embryonic signaling cascade is reactivated in mature PSMCs after naphthalene-induced injury to airway epithelium. Furthermore, we found that this paracrine Fgf10 action was essential for activating surviving variant Clara cells (the cells in the airway epithelium from which replacement epithelial cells originate) located at the bronchoalveolar duct junctions and adjacent to neuroendocrine bodies. After naphthalene injury, PSMCs secreted Fgf10 to activate Notch signaling and induce Snai1 expression in surviving variant Clara cells, which subsequently underwent a transient epithelial to mesenchymal transition to initiate the repair process. Epithelial Snai1 expression was important for regeneration after injury. We have therefore identified PSMCs as a stem cell niche for the variant Clara cells in the lung and established that paracrine Fgf10 signaling from the niche is critical for epithelial repair after naphthalene injury. These findings also have implications for understanding the misregulation of lung repair in asthma and cancer.
Stem Cell Marker CD133 Affects Clinical Outcome in Glioma Patients
Authors: Felix Zeppernick, Rezvan Ahmadi, Benito Campos, Christine Dictus, Burkhard M. Helmke, Natalia Becker, Peter Lichter, Andreas Unterberg, Bernhard Radlwimmer, Christel C. Herold-Mende
Journal: Clinical Cancer Research (2008)

The CD133 antigen has been identified as a putative stem cell marker in normal and malignant brain tissues. In gliomas, it is used to enrich a subpopulation of highly tumorigenic cancer cells. According to the cancer stem cell hypothesis, CD133-positive cells determine long-term tumor growth and, therefore, are suspected to influence clinical outcome. To date, a correlation between CD133 expression in primary tumor tissues and patients' prognosis has not been reported.To address this question, we analyzed the expression of the CD133 stem cell antigen in a series of 95 gliomas of various grade and histology by immunohistochemistry on cryostat sections. Staining data were correlated with patient outcome.By multivariate survival analysis, we found that both the proportion of CD133-positive cells and their topological organization in clusters were significant (P < 0.001) prognostic factors for adverse progression-free survival and overall survival independent of tumor grade, extent of resection, or patient age. Furthermore, proportion of CD133-positive cells was an independent risk factor for tumor regrowth and time to malignant progression in WHO grade 2 and 3 tumors.These findings constitute the first conclusive evidence that CD133 stem cell antigen expression correlates with patient survival in gliomas, lending support to the current cancer stem cell hypothesis.
Intravital imaging of intestinal lacteals unveils lipid drainage through contractility
Authors: Kibaek Choe, Jeon Yeob Jang, Intae Park, Yeseul Kim, Soyeon Ahn, Dae-Young Park, Young-Kwon Hong, Kari Alitalo, Gou Young Koh, Pilhan Kim
Journal: Journal of Clinical Investigation (2015)

Lacteals are lymphatic vessels located at the center of each intestinal villus and provide essential transport routes for lipids and other lipophilic molecules. However, it is unclear how absorbed molecules are transported through the lacteal. Here, we used reporter mice that express GFP under the control of the lymphatic-specific promoter Prox1 and a custom-built confocal microscope and performed intravital real-time visualization of the absorption and transport dynamics of fluorescence-tagged fatty acids (FAs) and various exogenous molecules in the intestinal villi in vivo. These analyses clearly revealed transepithelial absorption of these molecules via enterocytes, diffusive distribution over the lamina propria, and subsequent transport through lacteals. Moreover, we observed active contraction of lacteals, which seemed to be directly involved in dietary lipid drainage. Our analysis revealed that the smooth muscles that surround each lacteal are responsible for contractile dynamics and that lacteal contraction is ultimately controlled by the autonomic nervous system. These results indicate that the lacteal is a unique organ-specific lymphatic system and does not merely serve as a passive conduit but as an active pump that transports lipids. Collectively, using this efficient imaging method, we uncovered drainage of absorbed molecules in small intestinal villus lacteals and the involvement of lacteal contractibility.
Long-Term Prognosis in Patients With Type 1 and 2 Diabetes Mellitus After Coronary Artery Bypass Grafting
Authors: Martin J. Holzmann, Björn Rathsman, Björn Eliasson, Jeanette Kuhl, Ann-Marie Svensson, Thomas Nyström, Ulrik Sartipy
Journal: Journal of the American College of Cardiology (2015)
Long-term Improvements in Lifespan and Pathology in CNS and PNS After BMT Plus One Intravenous Injection of AAVrh10-GALC in Twitcher Mice
Authors: Mohammad A Rafi, Han Zhi Rao, Paola Luzi, David A Wenger
Journal: Molecular Therapy (2015)

Krabbe disease is an autosomal recessive disorder resulting from defects in the lysosomal enzyme galactocerebrosidase (GALC). GALC deficiency leads to severe neurological features. The only treatment for presymptomatic infantile patients and later-onset patients is hematopoietic stem cell transplantation (HSCT). This treatment is less than ideal with most patients eventually developing problems with gait and expressive language. Several naturally occurring animal models are available, including twitcher (twi) mice, which have been used for many treatment trials. Previous studies demonstrated that multiple injections of AAVrh10-GALC into the central nervous system (CNS) of neonatal twi mice resulted in significant improvements. Recently we showed that one i.v. injection of AAVrh10-GALC on PND10 resulted in normal GALC activity in the CNS and high activity in the peripheral nervous system (PNS). In the present study, a single i.v. injection of AAVrh10-GALC was given 1 day after bone marrow transplantation (BMT) on PND10. The mice show greatly extended lifespan and normal behavior with improved CNS and PNS findings. Since HSCT is the standard of care in human patients, adding this single i.v. injection of viral vector may greatly improve the treatment outcome. Krabbe disease is an autosomal recessive disorder resulting from defects in the lysosomal enzyme galactocerebrosidase (GALC). GALC deficiency leads to severe neurological features. The only treatment for presymptomatic infantile patients and later-onset patients is hematopoietic stem cell transplantation (HSCT). This treatment is less than ideal with most patients eventually developing problems with gait and expressive language. Several naturally occurring animal models are available, including twitcher (twi) mice, which have been used for many treatment trials. Previous studies demonstrated that multiple injections of AAVrh10-GALC into the central nervous system (CNS) of neonatal twi mice resulted in significant improvements. Recently we showed that one i.v. injection of AAVrh10-GALC on PND10 resulted in normal GALC activity in the CNS and high activity in the peripheral nervous system (PNS). In the present study, a single i.v. injection of AAVrh10-GALC was given 1 day after bone marrow transplantation (BMT) on PND10. The mice show greatly extended lifespan and normal behavior with improved CNS and PNS findings. Since HSCT is the standard of care in human patients, adding this single i.v. injection of viral vector may greatly improve the treatment outcome.
Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre, double-blind, randomised, phase 2b dose-selection study
Authors: Alejandro Llanos-Cuentas, Marcus V Lacerda, Ronnatrai Rueangweerayut, Srivicha Krudsood, Sandeep K Gupta, Sanjay K Kochar, Preetam Arthur, Nuttagarn Chuenchom, Jörg J Möhrle, Stephan Duparc, Cletus Ugwuegbulam, Jörg-Peter Kleim, Nick Carter, Justin A Green, Lynda Kellam
Journal: The Lancet (2013)
Measurement of anal pressure and motility.
Authors: B D Hancock
Journal: Gut (1976)

A fine open perfused system and a closed balloon system for the measurement of anal pressure and motility have been compared.Measurements were made in 40 normal subjects and 84 patients with haemorrhoids.The rate of perfusion had a marked effect on the recorded pressure and motility details.The motility pattern was seen most clearly with the balloon probe and the pressure recorded was reproducible and easy to measure, making this a convenient method for recording activity of the internal anal sphincter.Anal motility in normal subjects was characterised by slow pressure waves (10-20/min).The frequencywasfastestinthedistal analcanalandthisfrequencygradient may represent a normal mechanism to keep the anal canal empty.Ultra slow pressure waves (0-6-1 9/ min) were seen in 42 % of patients with haemorrhoids and 5 % of normal subjects and arose from a synchronous contraction of the whole internal sphincter.Many methods have been used to measure anal pres- sure and motility and conflicting results reported.Differences in methods may account for many of these.The two main methods available for measurement of anal pressure use fine water-filled polyethylene tubes or small balloons connected to a strain gauge pressure transducer.Fine tubes have the advantage that they cause only slight physical disturbance of the sphincter.It seems essential to perfuse the system to prevent blockage, but it is not clear whether all workers have done this, nor is it known whether the rate of perfusion affects the recording (Hill et al., 1960; Harris and Pope, 1964; Duthie and Watts 1965; Phillips and Edwards, 1965).Small water-filled balloons incorporated into a probe of uniform diameter are convenient to use because they can be secured easily in position, though they do disturb the resting state of the sphincter to some extent.Fluctuations in pressure are seen more clearly with the balloon system, possibly because they are in contact with a larger area of sphincter.(Lawson and Nixon, 1967; Kerremans, 1969).Small strain gauges in the anal canal have also been used effectively to study force and motility, but the probes are difficult to construct and prone to mechanical failure (Wankling et al.