tbuckley/cabot-search huggingface dataset:
Changes in Connexin Expression and the Atrial Fibrillation Substrate in Congestive Heart Failure
Authors: Brett Burstein, Philippe Comtois, Georghia Michael, Kunihiro Nishida, Louis Villeneuve, Yung-Hsin Yeh, Stanley Nattel
Journal: Circulation Research (2009)

Rationale: Although connexin changes are important for the ventricular arrhythmic substrate in congestive heart failure (CHF), connexin alterations during CHF-related atrial arrhythmogenic remodeling have received limited attention. Objective: To analyze connexin changes and their potential contribution to the atrial fibrillation (AF) substrate during the development and reversal of CHF. Methods and Results: Three groups of dogs were studied: CHF induced by 2-week ventricular tachypacing (240 bpm, n=15); CHF dogs allowed a 4-week nonpaced recovery interval after 2-week tachypacing (n=16); and nonpaced sham controls (n=19). Left ventricular (LV) end-diastolic pressure and atrial refractory periods increased with CHF and normalized on CHF recovery. CHF caused abnormalities in atrial conduction indexes and increased the duration of burst pacing-induced AF (DAF, from 22±7 seconds in control to 1100±171 seconds, P &lt;0.001). CHF did not significantly alter overall atrial connexin (Cx)40 and Cx43 mRNA and protein expression levels, but produced Cx43 dephosphorylation, increased Cx40/Cx43 protein expression ratio and caused Cx43 redistribution toward transverse cell-boundaries. All of the connexin-alterations reversed on CHF recovery, but CHF-induced conduction abnormalities and increased DAF (884±220 seconds, P &lt;0.001 versus control) remained. The atrial fibrous tissue content increased from 3.6±0.7% in control to 14.7±1.5% and 13.3±2.3% in CHF and CHF recovery, respectively (both P &lt;0.01 versus control), with transversely running zones of fibrosis physically separating longitudinally directed muscle bundles. In an ionically based action potential/tissue model, fibrosis was able to account for conduction abnormalities associated with CHF and recovery. Conclusions: CHF causes atrial connexin changes, but these are not essential for CHF-related conduction disturbances and AF promotion, which are rather related primarily to fibrotic interruption of muscle bundle continuity.
Conscious rabbits become tolerant to multiple episodes of ischemic preconditioning.
Authors: M V Cohen, X M Yang, J M Downey
Journal: Circulation Research (1994)

Although ischemic preconditioning protects myocardium from infarction in isolated hearts and in anesthetized open-chest animals, its effects have not been examined in unanesthetized animals. Furthermore, it is unknown whether animals become tolerant to multiple episodes of ischemic preconditioning. Rabbits were chronically instrumented with a balloon occluder around a major branch of the left coronary artery for reversible coronary occlusion, a left atrial catheter for radioactive microsphere injections, ECG electrodes for monitoring of myocardial ischemia, and, in some cases, a carotid artery catheter for pressure measurements and timed withdrawal of reference arterial blood samples. Eight control rabbits underwent a 30-minute coronary occlusion and then 180 minutes of reperfusion. Five of the eight rabbits developed ventricular tachycardia or fibrillation during ischemia, and infarct size averaged 37.7 +/- 2.6% of the risk area. Eight rabbits experienced a 5-minute coronary occlusion and 10 minutes of reperfusion before the 30-minute occlusion. In these preconditioned animals, potentially fatal arrhythmias during ischemia were significantly reduced (one of eight, P &lt; .05), and infarct size was much smaller (5.6 +/- 1.1%, P &lt; .0001). The difference could not be explained by hemodynamics or collateral blood flow, which were nearly identical in the two groups. But when the 30-minute coronary occlusion was preceded by 40 to 65 five-minute occlusions during a 3- to 4-day period in seven animals, protection was markedly attenuated. Potentially lethal arrhythmias were very common, and infarct size averaged 26.5 +/- 2.9%, substantially larger than in rabbits with only one preconditioning occlusion (P &lt; .0001).(ABSTRACT TRUNCATED AT 250 WORDS)
Hepatic cannabinoid-1 receptors mediate diet-induced insulin resistance by increasing<i>de novo</i>synthesis of long-chain ceramides
Authors: Resat Cinar, Grzegorz Godlewski, Jie Liu, Joseph Tam, Tony Jourdan, Bani Mukhopadhyay, Judith Harvey-White, George Kunos
Journal: Hepatology (2013)

Obesity is associated with increased activity of two lipid signaling systems (endocannabinoids [ECs] and ceramides), with both being implicated in insulin resistance. Cannabinoid-1 receptor (CB1R) antagonists reverse obesity and insulin resistance, but have psychiatric side effects. Here we analyzed the role of ceramide in CB1R-mediated insulin resistance in C57Bl6/J mice with high-fat diet-induced obesity (DIO), using JD5037, a peripherally restricted CB1R inverse agonist. Chronic JD5037 treatment of DIO mice reduced body weight and steatosis and improved glucose tolerance and insulin sensitivity. Peripheral CB1R blockade also attenuated the diet-induced increase in C14:0, C16:0, C18:0, and C20:0 ceramide species with either C16 or C18 sphingosine-base in the liver. Decreased ceramide levels reflected their reduced de novo synthesis, due to inhibition of the activity of serine-palmitoyl transferase (SPT) and the expression of its SPTLC3 catalytic subunit, as well as reduced ceramide synthase (CerS) activity related to reduced expression of CerS1 and CerS6. JD5037 treatment also increased ceramide degradation due to increased expression of ceramidases. In primary cultured mouse hepatocytes and HepG2 cells, the EC anandamide increased ceramide synthesis in an eIF2α-dependent manner, and inhibited insulin-induced akt phosphorylation by increased serine phosphorylation of IRS1 and increased expression of the serine/threonine phosphatase Phlpp1. These effects were abrogated by JD5037 or the SPT inhibitor myriocin. Chronic treatment of DIO mice with myriocin or JD5037 similarly reversed hepatic insulin resistance, as verified using a euglycemic/hyperinsulinemic clamp. Conclusion: ECs induce CB1R-mediated, endoplasmic reticulum stress-dependent synthesis of specific ceramide subspecies in the liver, which plays a key role in obesity-related hepatic insulin resistance. (Hepatology 2014;58:143–153)
New advances in the molecular biology of hepatitis C virus infection: towards the identification of new treatment targets
Authors: Alexander Ploss, Jean Dubuisson
Journal: Gut (2012)

Hepatitis C virus (HCV) causes chronic infection in almost 2% of the world's population. If untreated, chronic carriers can develop severe liver disease including fibrosis, cirrhosis and hepatocellular carcinoma. Until recently, hepatitis C was treated with a combination of pegylated interferon and ribavirin, a treatment which was only partially effective and was plagued with side effects. In 2011 two inhibitors of the virally encoded NS3/4 protease have become part of standard therapy, which have improved treatment rates but can exacerbate the problematic side effects. While the addition of these first directly acting antivirals (DAAs) marks a milestone in anti-HCV therapy, new and improved combinations of drugs are desperately needed. New generations of drugs will have to address genetic variability of HCV and issues of viral resistance. Furthermore, combination therapies have to be tailored to effectively cure patient populations that have traditionally been hardest to treat, including patients with cirrhosis, those receiving liver transplants and individuals who are co-infected with HIV or hepatitis B virus. Since the discovery of HCV a plethora of experimental tools have been developed which enabled detailed analysis of various aspects of the viral life cycle and the interaction of HCV with its human host. Such studies have revealed a growing list of targets for therapeutic intervention, some of which will be discussed in this review.
T-helper and regulatory T-cell cytokines in the peripheral blood of patients with active alopecia areata
Authors: M.K. Tembhre, V.K. Sharma
Journal: British Journal of Dermatology (2013)

Alteration in T‐lymphocyte function and cytokines secreted by T‐cell subsets has been proposed in the immunopathogenesis of alopecia areata (AA). The role of T‐helper and regulatory T‐cell cytokines in the pathogenesis of active AA has not been established. To assess the role of hallmark cytokines of T‐helper cells (Th1, Th2 and Th17) and regulatory T cells (Tregs) in the pathogenesis of AA, and its clinical correlation. Fifty‐one patients with AA and 45 age‐ and sex‐matched healthy control subjects were included in the study. Serum interleukin (IL)‐2, interferon (IFN)‐γ, IL‐10, IL‐13, IL‐17A and transforming growth factor (TGF)‐β1 were measured by enzyme‐linked immunosorbent assay in both groups. Correlation of serum cytokine levels with age, sex, disease subtype and duration, number of patches on the scalp, associated autoimmune disorders and atopy was studied. The serum cytokine levels of IL‐2, IFN‐γ, IL‐13 and IL‐17A were significantly increased, and serum TGF‐β1 levels were significantly decreased (P <0·05) in patients with AA compared with controls. Serum IL‐2 levels were significantly different among AA subgroups (P <0·05). IL‐2 levels were positively correlated with the total disease duration and the number of patches on the scalp. The increased levels of serum IL‐2, IFN‐γ, IL‐13 and IL‐17A suggested altered T‐helper cell function, and reduced serum TGF‐β1 levels suggested a defect in Treg function. Therefore, enhanced T‐cell‐mediated immunity and breakdown of immune tolerance due to deficiency in Tregs may facilitate the occurrence of AA.
Effect of Different Levels of Dietary Corn Oil and Lard During the Initiation Phase of Colon Carcinogenesis in F344 Rats23
Authors: Bandaru S. Reddy, Hiroshi Maruyama
Journal: JNCI Journal of the National Cancer Institute (1986)

The effect of various levels of polyunsaturated fat (corn oil) and saturated fat (lard) fed during the initiation stage of colon carcinogenesis was studied in male F344 rats. The animals were fed the diets containing 5, 13.6, and 23.5% corn oil or lard 2 weeks before, during, and until 1 week after sc injection of 15 mg azoxymethane [(AOM) CAS: 25843-45-2]/kg body weight, once weekly for 2 weeks (designated as initiation). One week after AOM treatment, groups of animals were transferred to their respective 5% corn oil or lard diets. Additional groups consuming 5% corn oil or lard were transferred to 23.5% corn oil or lard, respectively (post-initiation stage). All animals were fed these diets until the termination of the experiment. Fecal bile acids and colonic mucosal ornithine decarboxylase activity were measured in vehicle-treated animals fed the experimental diets for 14 weeks. Body weights and intakes of total calories, protein, nonnutritive fiber, and micronutrients were comparable among the various dietary groups. The animals fed the 23.5% corn oil diet during the postinitiation stage had a higher incidence of colon tumors than did those fed the 5% corn oil diet, whereas feeding of 23.5 and 13.6% corn oil diets during the initiation stage had no effect. In contrast, animals fed the 23.5 and 13.6% lard diet during the initiation stage and 23.5% lard diet during the postinitiation stage developed more colon adenocarcinomas than did those fed the 5% lard diet. The excretion of fecal deoxycholic acid, lithocholic acid, and 12-ketolithocholic acid and the activity of colonic mucosal ornithine decarboxylase activity were higher in animals fed the 23.5% corn oil or lard diet during the postinitiation compared to the levels in animals fed the 5% corn oil or lard diet.
Postprandial hemodynamic responses in patients with cirrhosis
Authors: Samuel S. Lee, Antoine Hadengue, Richard Moreau, Raymond Sayegh, Patrick Hillon, Didier Lebrec
Journal: Hepatology (1988)

The hemodynamic response to a 800 kcal liquid meal was investigated in 24 patients (study group) with cirrhosis and two control groups. One control group of six cirrhotic patients (volume control) had a calorie-free equivolumic electrolyte solution. The second control group (normal control) of six patients with normal hepatic function had the same test meal. Cardiac index, mean arterial pressure, heart rate, hepatic venous pressures, hepatic blood flow and azygos blood flow (only measured in the study group) were measured before and 30 and 60 min after the meal. Systemic circulatory responses were generally absent. Hepatic blood flow and wedged hepatic venous pressure increased significantly in both cirrhotic patients and normal controls; however, cirrhotic patients tended to have a quicker response (peaks at 30 min) than normals (peaks at 60 min). Azygos blood flow showed large postprandial variability, but overall did not change significantly. These results demonstrate that the splanchnic circulation of the patient with cirrhosis reacts differently from normals to the physiologic stimulus of a meal, and in particular appears to have precocious vasoactive reactivity.
Estrogen Receptor: Methodology Matters
Authors: Mitch Dowsett
Journal: Journal of Clinical Oncology (2006)

The estrogen receptor (ER) has been our most important biomarker in breast cancer for more than 30 years, largely because of its role in indicating the potential of patients to benefit from endocrine therapy. The substantial survival benefit from tamoxifeninER-positivebutnotER-negativetumors, 1 andtheextension of this benefit with aromatase inhibitors in postmenopausal patients, has made treatment with one of these well-tolerated endocrine agents mandatory in ER-positive disease; therefore, ER measurement has been rendered essential for all invasive primary breast carcinomas. ER-positive tumors have a better prognosis in the early years after diagnosis, which is at least partly due to their slower proliferation, although it has become clear that recurrencefree survival curves come together after about 15 years, 1 which
Targeting of Urokinase Plasminogen Activator Receptor in Human Pancreatic Carcinoma Cells Inhibits c-Met– and Insulin-like Growth Factor-I Receptor–Mediated Migration and Invasion and Orthotopic Tumor Growth in Mice
Authors: Todd W. Bauer, Wenbiao Liu, Fan Fan, Ernest R. Camp, Anthony Yang, Ray J. Somcio, Corazon D. Bucana, Jennifer Callahan, Graham C. Parry, Douglas B. Evans, Douglas D. Boyd, Andrew P. Mazar, Lee M. Ellis
Journal: Cancer Research (2005)

Abstract Pancreatic carcinomas express high levels of urokinase-type plasminogen activator (uPA) and its receptor (uPAR), both of which mediate cell migration and invasion. We investigated the hypotheses that (a) insulin-like growth factor-I (IGF-I)– and hepatocyte growth factor (HGF)–mediated migration and invasion of human pancreatic carcinoma cells require uPA and uPAR function and (b) inhibition of uPAR inhibits tumor growth, retroperitoneal invasion, and hepatic metastasis of human pancreatic carcinomas in mice. Using transwell assays, we investigated the effect of IGF-I and HGF on L3.6pl migration and invasion. We measured the induction of uPA and uPAR following treatment of cells with IGF-I and HGF using immunoprecipitation and Western blot analysis. The importance of uPA and uPAR on L3.6pl cell migration and invasion was studied by inhibiting their activities with amiloride and antibodies before cytokine treatment. In an orthotopic mouse model of human pancreatic carcinoma, we evaluated the effect of anti-uPAR monoclonal antibodies with and without gemcitabine on primary tumor growth, retroperitoneal invasion, and hepatic metastasis. IGF-I and HGF mediated cell migration and invasion in L3.6pl cells. In addition, IGF-I and HGF induced uPA and uPAR expression in L3.6pl cells. In vitro, blockade of uPA and uPAR activity inhibited IGF-I– and HGF-mediated cell migration and invasion. Treatment of mice with anti-uPAR monoclonal antibody significantly decreased pancreatic tumor growth and hepatic metastasis and completely inhibited retroperitoneal invasion. Our study shows the importance of the uPA/uPAR system in pancreatic carcinoma cell migration and invasion. These findings suggest that uPAR is a potential target for therapy in patients with pancreatic cancer.
Survival of Older Patients With Cancer in the Veterans Health Administration Versus Fee-for-Service Medicare
Authors: Mary Beth Landrum, Nancy L. Keating, Elizabeth B. Lamont, Samuel R. Bozeman, Steven H. Krasnow, Lawrence Shulman, Jennifer R. Brown, Craig C. Earle, Michael Rabin, Barbara J. McNeil
Journal: Journal of Clinical Oncology (2012)

Purpose The Veterans Health Administration (VHA) provides high-quality preventive chronic care and cancer care, but few studies have documented improved patient outcomes that result from this high-quality care. We compared the survival rates of older patients with cancer in the VHA and fee-for-service (FFS) Medicare and examined whether differences in the stage at diagnosis, receipt of guideline-recommended therapies, and unmeasured characteristics explain survival differences. Patients and Methods We used propensity-score methods to compare all-cause and cancer-specific survival rates for men older than age 65 years who were diagnosed or received their first course of treatment for colorectal, lung, lymphoma, or multiple myeloma in VHA hospitals from 2001 to 2004 to similar FFS-Medicare enrollees diagnosed in Surveillance, Epidemiology, and End Results (SEER) areas in the same time frame. We examined the role of unmeasured factors by using sensitivity analyses. Results VHA patients versus similar FFS SEER-Medicare patients had higher survival rates of colon cancer (adjusted hazard ratio [HR], 0.87; 95% CI, 0.82 to 0.93) and non–small-cell lung cancer (NSCLC; HR, 0.91; 95% CI, 0.88 to 0.95) and similar survival rates of rectal cancer (HR, 1.05; 95% CI, 0.95 to 1.16), small-cell lung cancer (HR, 0.99; 95% CI, 0.93 to 1.05), diffuse large–B-cell lymphoma (HR, 1.02; 95% CI, 0.89 to 1.18), and multiple myeloma (HR, 0.92; 95% CI, 0.83 to 1.03). The diagnosis of VHA patients at earlier stages explained much of the survival advantages for colon cancer and NSCLC. Sensitivity analyses suggested that additional adjustment for the severity of comorbid disease or performance status could have substantial effects on estimated differences. Conclusion The survival rate for older men with cancer in the VHA was better than or equivalent to the survival rate for similar FFS-Medicare beneficiaries. The VHA provision of high-quality care, particularly preventive care, can result in improved patient outcomes.
Overexpression of Angiotensinogen Increases Tubular Apoptosis in Diabetes
Authors: Fang Liu, Marie-Luise Brezniceanu, Chih-Chang Wei, Isabelle Che[Combining Acute Accent]nier, Se[Combining Acute Accent]bastien Sachetelli, Shao-Ling Zhang, Janos G. Filep, Julie R. Ingelfinger, John S.D. Chan
Journal: Journal of the American Society of Nephrology (2007)

The intrarenal renin-angiotensin system (RAS) plays an important role in the progression of diabetic nephropathy. We have previously reported that mice overexpressing angiotensinogen in renal proximal tubular cells (RPTC) develop hypertension, albuminuria, and renal injury. Here, we investigated whether activation of the intrarenal RAS contributes to apoptosis of RPTC in diabetes. Induction of diabetes with streptozotocin in these transgenic mice led to significant increases in BP, albuminuria, RPTC apoptosis, and proapoptotic gene expression compared with diabetic nontransgenic littermates. Insulin and/or RAS blockers markedly attenuated these changes. Hydralazine prevented hypertension but not albuminuria, RPTC apoptosis, or proapoptotic gene expression. In vitro, high-glucose medium significantly increased apoptosis and caspase-3 activity in rat immortalized RPTC overexpressing angiotensinogen compared with control cells, and these changes were prevented by insulin and/or RAS blockers. In conclusion, intrarenal RAS activation and high glucose may act in concert to increase tubular apoptosis in diabetes, independent of systemic hypertension.
The Efficacy of Self-Help Group Treatment and Therapist-Led Group Treatment for Binge Eating Disorder
Authors: Carol B. Peterson, James E. Mitchell, Scott J. Crow, Ross D. Crosby, Stephen A. Wonderlich
Journal: American Journal of Psychiatry (2009)

The purpose of this investigation was to compare three types of treatment for binge eating disorder to determine the relative efficacy of self-help group treatment compared to therapist-led and therapist-assisted group cognitive-behavioral therapy.A total of 259 adults diagnosed with binge eating disorder were randomly assigned to 20 weeks of therapist-led, therapist-assisted, or self-help group treatment or a waiting list condition. Binge eating as measured by the Eating Disorder Examination was assessed at baseline, at end of treatment, and at 6 and 12 months, and outcome was assessed using logistic regression and analysis of covariance (intent-to-treat).At end of treatment, the therapist-led (51.7%) and the therapist-assisted (33.3%) conditions had higher binge eating abstinence rates than the self-help (17.9%) and waiting list (10.1%) conditions. However, no between-group differences in abstinence rates were observed at either of the follow-up assessments. The therapist-led condition also showed more reductions in binge eating at end of treatment and follow-up assessments compared to the self-help condition, and treatment or waiting period completion rates were higher in the therapist-led (88.3%) and waiting list (81.2%) conditions than in the therapist-assisted (68.3%) and self-help (59.7%) conditions.Therapist-led group cognitive-behavioral treatment for binge eating disorder led to higher binge eating abstinence rates, greater reductions in binge eating frequency, and lower attrition compared to group self-help treatment. Although these findings indicate that therapist delivery of group treatment is associated with better short-term outcome and less attrition than self-help treatment, the lack of group differences at follow-up suggests that self-help group treatment may be a viable alternative to therapist-led interventions.
Injury prophylaxis in paragliding
Authors: W Schulze, J Richter, B Schulze, S A Esenwein, K Büttner-Janz
Journal: British Journal of Sports Medicine (2002)

To show trends in paragliding injuries and derive recommendations for safety precautions for paraglider pilots on the basis of accident statistics, interviews, questionnaires, medical reports, and current stage of development of paragliding equipment.All paragliding accidents in Germany have to be reported. Information on 409 accidents was collected and analysed for the period 1997-1999.There was a substantial decrease in reported accidents (166 in 1997; 127 in 1998; 116 in 1999). The number of accidents resulting in spinal injuries was 62 in 1997, 42 in 1998, and 38 in 1999. The most common cause of accident was deflation of the glider (32.5%), followed by oversteering (13.9%), collision with obstacles (12.0%), take off errors (10.3%), landing errors (13.7%), misjudgment of weather conditions (4.9%), unsatisfactory preflight checks (4.9%), mid-air collisions with other flyers (2.2%), accidents during winching (2.2%), and defective equipment (0.5%). Accidents predominantly occurred in mountain areas. Fewer than 100 flights had been logged for 40% of injured pilots. In a total of 39 accidents in which emergency parachutes were used, 10 pilots were seriously injured (26%) and an additional three were killed (8%).Injuries in paragliding caused by unpredictable situations can be minimised by (a) using safer gliders in the beginner or intermediate category, (b) improving protection systems, such as padded back protection, and (c) improving pilot skills through performance and safety training.