tbuckley/cabot-search huggingface dataset:
Novel aspects of PPARα-mediated regulation of lipid and xenobiotic metabolism revealed through a nutrigenomic study
Authors: Pascal G. P. Martin, Hervé Guillou, Frédéric Lasserre, Sébastien Déjean, Annaig Lan, Jean-Marc Pascussi, Magali SanCristobal, Philippe Legrand, Philippe Besse, Thierry Pineau
Journal: Hepatology (2007)

Abstract Peroxisome proliferator-activated receptor-α (PPARα) is a major transcriptional regulator of lipid metabolism. It is activated by diverse chemicals such as fatty acids (FAs) and regulates the expression of numerous genes in organs displaying high FA catabolic rates, including the liver. The role of this nuclear receptor as a sensor of whole dietary fat intake has been inferred, mostly from high-fat diet studies. To delineate its function under low fat intake conditions (4.8% w/w), we studied the effects of five regimens with contrasted FA compositions on liver lipids and hepatic gene expression in wild-type and PPARα-deficient mice. Diets containing polyunsaturated FAs reduced hepatic fat stores in wild-type mice. Only sunflower, linseed, and fish oil diets lowered hepatic lipid stores in PPARα−/− mice, a model of progressive hepatic triglyceride accumulation. These beneficial effects were associated, in particular, with dietary regulation of Δ9-desaturase in both genotypes, and with a newly identified PPARα-dependent regulation of lipin. Furthermore, hepatic levels of 18-carbon essential FAs (C18:2ω6 and C18:3ω3) were elevated in PPARα−/− mice, possibly due to the observed reduction in expression of the Δ6-desaturase and of enoyl-coenzyme A isomerases. Effects of diet and genotype were also observed on the xenobiotic metabolism-related genes Cyp3a11 and CAR. Conclusion: Together, our results suggest that dietary FAs represent—even under low fat intake conditions—a beneficial strategy to reduce hepatic steatosis. Under such conditions, we established the role of PPARα as a dietary FA sensor and highlighted its importance in regulating hepatic FA content and composition. (Hepatology 2007;45:767–7777.)
Comparison of angioplasty and surgery for unoperated coarctation of the aorta.
Authors: R E Shaddy, M M Boucek, J E Sturtevant, H D Ruttenberg, R B Jaffe, L Y Tani, V E Judd, L G Veasy, E C McGough, G S Orsmond
Journal: Circulation (1993)

The use of balloon coarctation angioplasty instead of surgery as treatment for unoperated coarctation of the aorta is controversial. The efficacy and complications of the two procedures have not been studied before in a prospective fashion.Thirty-six patients were prospectively randomized to either angioplasty (20 patients) or surgery (16 patients). Immediate results and patient follow-up, including physical examination, angiograms, and magnetic resonance imaging, were compared between groups. Reduction in peak systolic pressure gradient across the coarctation was similar (86%) immediately after both balloon coarctation angioplasty and surgery. On follow-up, aneurysms were seen only in the angioplasty group (20%) and not in the surgery group (0%). No aneurysms have shown progression or required surgery. The incidence of other complications was similar in both groups, although two patients experienced neurological complications after surgery. Although not statistically different, the incidence of restenosis (peak systolic pressure gradient > or = 20 mm Hg) tended to be greater in the angioplasty group (25%) than in the surgery group (6%). Restenosis after angioplasty occurred more frequently in patients with an aortic isthmus/descending aorta diameter ratio < 0.65 and was associated with an immediate catheterization residual peak systolic pressure gradient across the coarctation > or = 12 mm Hg.Immediate gradient reduction is similar after balloon coarctation angioplasty and surgical treatment of unoperated coarctation of the aorta. The risks of aneurysm formation and possibly restenosis after angioplasty are higher than after surgery, although the risks of other complications are similar. Balloon coarctation angioplasty may provide an effective initial alternative to surgical repair of unoperated coarctation of the aorta in children beyond infancy, particularly in patients with a well-developed isthmus. Further follow-up is necessary to determine the long-term risks of postangioplasty aneurysms.
Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): a multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study
Authors: John R Teerlink, Marco Metra, G Michael Felker, Piotr Ponikowski, Adriaan A Voors, Beth Davison Weatherley, Alon Marmor, Amos Katz, Jacek Grzybowski, Elaine Unemori, Sam L Teichman, Gad Cotter
Journal: The Lancet (2009)
EFFECTS OF HYPOTENSION DUE TO HEMORRHAGE AND OF BLOOD TRANSFUSION ON RENAL FUNCTION IN DOGS
Authors: A. C. Corcoran
Journal: The Journal of Experimental Medicine (1943)

1. Renal blood flow is decreased by hypotension due to bleeding, and glomerular filtration rate is disproportionately decreased. After a first 40 minute stage of hypotension at about 60 mm. Hg infusion of blood with consequent restoration of the general blood volume and arterial pressure usually results in a return to normal of renal blood flow and function although renal blood flow subsequently tends to decrease. The restoration of renal blood flow and function is associated with an increase of urine flow above the control level. 2. Diodrast clearance loses its value as a measure of renal plasma flow (a) during severe or prolonged hypotension, and (b) immediately after restoration of arterial pressure by infusion after a first stage of hypotension. In the former case (a) it is decreased in consequence of decreased renal extraction of diodrast from blood which itself is presumably the result of distribution of renal blood flow through nephrons whose vascular resistance is low. (b) The disparity after transfusion is due to excretion of diodrast accumulated in the kidney tubules and, presumably, in the interstitial fluid during hypotension. The presence of diodrast and inulin in the renal interstitial fluid explains the addition of these substances to renal venous blood observed in some of these experiments. The shifting equilibrium of diodrast between renal plasma and interstitial fluid may explain some of the instances of low diodrast extraction observed in these experiments during transfusion after hypotension, and may explain also the incomplete renal extraction of diodrast under normal conditions. 3. Dogs with denervated kidneys respond to blood transfusion and restoration of arterial pressure by a disproportionately slow and incomplete return towards normal of renal clearance and, presumably, of renal blood flow. On the basis of these facts it is suggested that high spinal anesthesia may interfere with recovery of renal circulation in cases of shock treated by transfusion. 4. Profound or prolonged and repeated hypotension due to bleeding decreases the ability of normal and denervated kidneys of intact and anesthetized dogs to respond to transfusion and the restoration of arterial pressure by proportionately increased clearance and plasma flow, apparently because of renal vasoconstriction due to the release of humorally circulating vasoconstrictor substances.
Glucose metabolism during ischemia due to excessive oxygen demand or altered coronary flow in the isolated arterially perfused rabbit septum.
Authors: R C Marshall, W W Nash, K I Shine, M E Phelps, N Ricchiuti
Journal: Circulation Research (1981)

The isolated arterially perfused interventricular rabbit septum was adapted for the study of glucose metabolism during ischemia produced by either increased oxygen demand or altered coronary flow.The septum perfused at 1.5 ml/min and stimulated at a rate of 72/min at 37 °C was shown to be a low work preparation in which glucose utilization, lactate production, oxygen consumption, and developed tension were stable for at least 90 minutes.The metabolic and functional responses of the septum were evaluated during nonnoxic increased work produced by introducing a paired stimulus at 90/min and increasing flow to 3.5 ml/min, during demand-induced ischemia produced by introducing a paired stimulus at 90/min and maintaining flow at 1.5 ml/min, and during low flow ischemia produced by decreasing flow and maintaining stimulus rate constant at 72/min.During nonnoxic increased work, glucose utilization increased by 115 ± 26% (±«KM) over control, while oxygen consumption increased by 100 ± 11%, lactate production by 13 ± 9%, and developed tension by 45 ± 8%.Tigsue glycogen, lactate, and lactate:pyruvate ratios were unchanged compared to control.During demand-induced ischemia, glucose utilization increased by 116 ± 24%, while oxygen consumption increased only by 29 ± 7%, lactate production rose by 106 ± 16%, and developed tension declined by 20 ± 4%.Tissue glycogen content was significantly decreased and tissue lactate and lactaterpyruvate ratios were significantly increased during demand-induced ischemia compared to both control and nonnoxic increased work.These results are consistent with accelerated glucose oxidation during nonnoxic increased work and accelerated anaerobic glycolysis during demand-induced ischemia.During severe low flow ischemia, glucose utilization declined by 44 ± 8% while developed tension and oxygen consumption decreased by 80 ± 8% and 74 ± 2%, respectively.The results of this study suggest that the dependence of glucose metabolism in ischemia on residual perfusion for washout of metabolic end products is also observed when ischemia is produced by excessive oxygen demand.Ore Res 49: 640-648, 1981 DURING myocardial ischemia there is a mismatch between oxygen supply and demand.Glucose metabolism during ischemia is dependent on residual perfusion for washout of the metabolic end products, lactate and hydrogen ion (Rovetto etal., 1975).This finding expains the observation that glucose uptake and metabolism accelerate if the myocardium is made hypoxic by perfusion with oxygenfree perfusate at maintained flow rates, but does not accelerate or even declines if the myocardium is made hypoxic by decreasing flow rates (Rovetto et al.,
Effect of continuing or finishing high-level sports on airway inflammation, bronchial hyperresponsiveness, and asthma: A 5-year prospective follow-up study of 42 highly trained swimmers
Authors: Ilkka Helenius, Paula Rytil[auml ], Seppo Sarna, Aki Lumme, Miia Helenius, Ville Remes, Tari Haahtela
Journal: Journal of Allergy and Clinical Immunology (2002)
Radiotherapy and temozolomide in anaplastic astrocytoma: a retrospective multicenter study by the Central Nervous System Study Group of AIRO (Italian Association of Radiation Oncology)
Authors: S. Scoccianti, S. M. Magrini, U. Ricardi, B. Detti, M. Krengli, S. Parisi, F. Bertoni, G. Sotti, S. Cipressi, V. Tombolini, S. Dall'Oglio, M. Lioce, C. Saieva, M. Buglione, C. Mantovani, G. Rubino, P. Muto, V. Fusco, L. Fariselli, C. de Renzis, L. Masini, R. Santoni, L. Pirtoli, G. Biti
Journal: Neuro-Oncology (2012)

Although the evidence for the benefit of adding temozolomide (TMZ) to radiotherapy (RT) is limited to glioblastoma patients, there is currently a trend toward treating anaplastic astrocytomas (AAs) with combined RT + TMZ. The aim of the present study was to describe the patterns of care of patients affected by AA and, particularly, to compare the outcome of patients treated exclusively with RT with those treated with RT + TMZ. Data of 295 newly diagnosed AAs treated with postoperative RT ± TMZ in the period from 2002 to 2007 were reviewed. More than 75% of patients underwent a surgical removal. All the patients had postoperative RT; 86.1% of them were treated with 3D-conformal RT (3D-CRT). Sixty-seven percent of the entire group received postoperative chemotherapy with TMZ (n = 198). One-hundred sixty-six patients received both concomitant and sequential TMZ. Prescription of postoperative TMZ increased in the most recent period (2005-2007). One- and 4-year survival rates were 70.2% and 28.6%, respectively. No statistically significant improvement in survival was observed with the addition of TMZ to RT (P = .59). Multivariate analysis showed the statistical significance of age, presence of seizures, Recursive Partitioning Analysis classes I-III, extent of surgical removal, and 3D-CRT. Changes in the care of AA over the past years are documented. Currently there is not evidence to justify the addition of TMZ to postoperative RT for patients with newly diagnosed AA outside a clinical trial. Results of prospective and randomized trials are needed.
12-Lipoxygenase in Opioid-Induced Delayed Cardioprotection
Authors: Hemal H. Patel, Ryan M. Fryer, Eric R. Gross, Richard A. Bundey, Anna K. Hsu, Marilyn Isbell, Leonard O.V. Eusebi, Roderick V. Jensen, Steven R. Gullans, Paul A. Insel, Kasem Nithipatikom, Garrett J. Gross
Journal: Circulation Research (2003)

12-lipoxygenase (12-LO) has been shown to be a factor in acute ischemic preconditioning (IPC) in the isolated rat heart; however, no studies have been reported in delayed PC. We characterized the role of 12-LO in an intact rat model of delayed PC induced by a delta-opioid agonist SNC-121 (SNC). Rats were pretreated with SNC and allowed to recover for 24 hours. They were then treated with either baicalein or phenidone, 2 selective 12-LO inhibitors. In addition, SNC-pretreated rats had plasma samples isolated at different times after ischemia-reperfusion for liquid chromatographic-mass spectrometric analysis of the major metabolic product of 12-LO, 12-HETE. Similar studies were conducted with inhibitors. Gene array data showed a significant induction of 12-LO message (P<0.05) after opioid pretreatment. This induction in 12-LO mRNA was confirmed by real-time polymerase chain reaction, and 12-LO protein expression was enhanced by SNC pretreatment at 24 hours relative to vehicle treatment. Both baicalein and phenidone attenuated the protective effects of SNC pretreatment on infarct size (50+/-4% and 42+/-3% versus 29+/-2%, P<0.05, respectively). No significant differences were observed in 12-HETE concentrations between baseline control and SNC-treated rats. However, 12-HETE concentrations were increased significantly at both 15 minutes during ischemia and at 1 hour of reperfusion in the SNC-treated rats compared with controls. Baicalein and phenidone attenuated the increase in 12-HETE at 1 hour of reperfusion. These data suggest that SNC-121 appears to enhance message and subsequently the activity and expression of 12-LO protein during times of stress, resulting in delayed cardioprotection.
Eosinophilic inflammation in cough variant asthma
Authors: A Niimi, R Amitani, K Suzuki, E Tanaka, T Murayama, F Kuze
Journal: European Respiratory Journal (1998)

Eosinophils are considered to play a central pathogenetic role in asthma. We previously reported that sputum eosinophilia was observed in patients with cough variant asthma (CVA), as well as in "classic" asthma with wheezing. This study was undertaken to further investigate the involvement of eosinophils in CVA. The serum eosinophil cationic protein (ECP) level, the percentage of eosinophils in bronchoalveolar lavage (BAL) fluid, and the number of eosinophils in bronchial biopsy specimen were examined in 14 patients with CVA, 21 with classic asthma, and in seven healthy controls. For the two asthmatic groups, the clinical severity was classified with scores of 1-3. Pulmonary function and bronchial responsiveness were not significantly different between the patients with classic asthma and those with CVA. BAL, tissue eosinophil and serum ECP were all significantly increased in both classic asthma and CVA when compared with the controls but were not different between classic asthma and CVA. In both groups of asthmatics, the clinical severity significantly correlated with serum ECP and tissue eosinophils. In conclusion, eosinophilic inflammation is involved in cough variant asthma as well as in classic asthma. Anti-inflammatory treatment may be essential in patients with CVA, as in those with classic asthma.
Studies on the mechanism of sinus node dysfunction in the sick sinus syndrome.
Authors: J L Jordan, I Yamaguchi, W J Mandel
Journal: Circulation (1978)

The intrinsic heart rate (IHR) was determined in 17 patients with symptomatic sinus bradycardia by administering atropine 0.04 mg/kg and propranolol 0.2 mg/kg, i.v. In this way, sick sinus (SSS) patients with intrinsic sinus node (SN) dysfunction could be distinguished from those patients with disturbed autonomic regulation of SN function. Sick sinus syndrome patients with normal corrected sinus node recovery time (SNRTC), adjusted for the magnitude and direction of autonomic chronotrophy, consistently had normal IHRs and therefore abnormalities of autonomic regulation. Sick sinus syndrome patients with abnormal adjusted SNRTC consistently had abnormal IHRs and therefore abnormalities of intrinsic SN function. We conclude that more than one pathophysiologic mechanism can produce the clinical manifestations of sick sinus syndrome and that abnormal prolongation of SNRTC is dependent upon the underlying mechanism of sinus node dysfunction.
ADAM10 mediates the house dust mite‐induced release of chemokine ligand CCL20 by airway epithelium
Authors: S. Post, D. Rozeveld, M. R Jonker, R. Bischoff, A. J. van Oosterhout, I. H. Heijink
Journal: Allergy (2015)

House dust mite (HDM) acts on the airway epithelium to induce airway inflammation in asthma. We previously showed that the ability of HDM to induce allergic sensitization in mice is related to airway epithelial CCL20 secretion.As a disintegrin and metalloprotease (ADAM)s have been implicated in chemokine shedding, we sought to determine their involvement in HDM-induced release of chemokines, including CCL20, by airway epithelial cells.We studied the effects of pharmacological ADAM inhibitors as well as ADAM10 and ADAM17 siRNA downregulation on chemokine release using (multiplex) ELISA in supernatants from HDM-exposed human bronchial epithelial 16HBE cells and primary normal human bronchial epithelial cells (NHBE) at 4-24 h.House dust) mite markedly increased CCL20 levels in both 16HBE and NHBE cells (16-24 h). In 16HBE cells, the HDM-induced increase was observed as early as 4 h upon exposure and the use of specific inhibitors indicated the involvement of ADAM10/17-mediated shedding. siRNA knockdown of ADAM10, but not of ADAM17, significantly reduced the HDM-induced release of CCL20 in both 16HBE and NHBE cells. A similar effect was observed for HDM-induced CCL2, CCL5, and CXCL8 release in NHBE cells. The HDM-induced increase in CCL20 levels was not affected by protein synthesis inhibitor cycloheximide nor protein transport inhibitor monensin, indicating that HDM induces surface shedding of chemokines.Our data show for the first time that ADAM10 activity contributes to HDM-induced shedding of chemokines, including CCL20. The ADAM10/CCL20 axis may be a target for novel therapeutic strategies in asthma.
Don't throw out the Bayes with the bathwater
Authors: Philip M. Fernbach, Steven A. Sloman
Journal: Behavioral and Brain Sciences (2011)

Abstract We highlight one way in which Jones &amp; Love (J&amp;L) misconstrue the Bayesian program: Bayesian models do not represent a rejection of mechanism. This mischaracterization obscures the valid criticisms in their article. We conclude that computational-level Bayesian modeling should not be rejected or discouraged a priori, but should be held to the same empirical standards as other models.
Cardiac Myocyte Apoptosis Is Associated With Increased DNA Damage and Decreased Survival in Murine Models of Obesity
Authors: Lili A. Barouch, Daqing Gao, Lei Chen, Karen L. Miller, Wenhong Xu, Alexander C. Phan, Michelle M. Kittleson, Khalid M. Minhas, Dan E. Berkowitz, Chiming Wei, Joshua M. Hare
Journal: Circulation Research (2005)

Disruption of leptin signaling is associated with obesity, heart failure, and cardiac hypertrophy, but the role of leptin in cardiac myocyte apoptosis is unknown. We tested the hypothesis that apoptosis increases in leptin-deficient ob/ob and leptin-resistant db/db mice and is associated with aging and left ventricular hypertrophy, increased DNA damage, and decreased survival. We studied young (2- to 3-month-old) and old (12- to 14-month-old) ob/ob and db/db mice and wild-type (WT) controls (n=2 to 4 per group). As expected, ventricular wall thickness and heart weights were similar among young ob/ob , db/db , and WT mice, but higher in old ob/ob and db/db versus old WT. Young ob/ob and db/db showed markedly elevated apoptosis by TUNEL staining and caspase 3 levels compared with WT. Differences in apoptosis were further accentuated with age. Leptin treatment significantly reduced apoptosis in ob/ob mice both in intact hearts and isolated myocytes. Tissue triglycerides were increased in ob/ob hearts, returning to WT levels after leptin repletion. Furthermore, the DNA damage marker, 8oxoG (8-oxo-7,8-dihydroguanidine), was increased, whereas the DNA repair marker, MYH glycosylase, was decreased in old ob/ob and db/db compared with old WT mice. Both ob/ob and db/db mice had decreased survival compared with WT mice. We conclude that leptin-deficient and leptin-resistant mice demonstrate increased apoptosis, DNA damage, and mortality compared with WT mice, suggesting that normal leptin signaling is necessary to prevent excess age-associated DNA damage and premature mortality. These data offer novel insights into potential mechanisms of myocardial dysfunction and early mortality in obesity.
Structural and functional hepatocyte polarity and liver disease
Authors: Paul Gissen, Irwin M. Arias
Journal: Journal of Hepatology (2015)

SummaryHepatocytes form a crucially important cell layer that separates sinusoidal blood from the canalicular bile. They have a uniquely organized polarity with a basal membrane facing liver sinusoidal endothelial cells, while one or more apical poles can contribute to several bile canaliculi jointly with the directly opposing hepatocytes. Establishment and maintenance of hepatocyte polarity is essential for many functions of hepatocytes and requires carefully orchestrated cooperation between cell adhesion molecules, cell junctions, cytoskeleton, extracellular matrix and intracellular trafficking machinery. The process of hepatocyte polarization requires energy and, if abnormal, may result in severe liver disease.A number of inherited disorders affecting tight junction and intracellular trafficking proteins have been described and demonstrate clinical and pathophysiological features overlapping those of the genetic cholestatic liver diseases caused by defects in canalicular ABC transporters. Thus both structural and functional components contribute to the final hepatocyte polarity phenotype. Many acquired liver diseases target factors that determine hepatocyte polarity, such as junctional proteins. Hepatocyte depolarization frequently occurs but is rarely recognized because hematoxylin-eosin staining does not identify the bile canaliculus. However, the molecular mechanisms underlying these defects are not well understood. Here we aim to provide an update on the key factors determining hepatocyte polarity and how it is affected in inherited and acquired diseases.