tbuckley/cabot-search huggingface dataset:
Phosphatidylinositol 3-Kinase–Akt Pathway Plays a Critical Role in Early Cardiomyogenesis by Regulating Canonical Wnt Signaling
Authors: Atsuhiko T. Naito, Hiroshi Akazawa, Hiroyuki Takano, Tohru Minamino, Toshio Nagai, Hiroyuki Aburatani, Issei Komuro
Journal: Circulation Research (2005)

We have recently reported that activation of phosphatidylinositol 3-kinase (PI3K) plays a critical role in the early stage of cardiomyocyte differentiation of P19CL6 cells. We here examined molecular mechanisms of how PI3K is involved in cardiomyocyte differentiation. DNA chip analysis revealed that expression levels of Wnt-3a were markedly increased and that the Wnt/beta-catenin pathway was activated temporally during the early stage of cardiomyocyte differentiation of P19CL6 cells. Activation of the Wnt/beta-catenin pathway during this period was required and sufficient for cardiomyocyte differentiation of P19CL6 cells. Inhibition of the PI3K/Akt pathway suppressed the Wnt/beta-catenin pathway by activation of glycogen synthase kinase-3beta (GSK-3beta) and degradation of beta-catenin. Suppression of cardiomyocyte differentiation by inhibiting the PI3K/Akt pathway was rescued by forced expression of a nonphosphorylated, constitutively active form of beta-catenin. These results suggest that the PI3K pathway regulates cardiomyocyte differentiation through suppressing the GSK-3beta activity and maintaining the Wnt/beta-catenin activity.
Telomere length in circulating leukocytes is associated with lung function and disease
Authors: Eva Albrecht, Elina Sillanpää, Stefan Karrasch, Alexessander Couto Alves, Veryan Codd, Iiris Hovatta, Jessica L. Buxton, Christopher P. Nelson, Linda Broer, Sara Hägg, Massimo Mangino, Gonneke Willemsen, Ida Surakka, Manuel A.R. Ferreira, Najaf Amin, Ben A. Oostra, Heli M. Bäckmand, Markku Peltonen, Seppo Sarna, Taina Rantanen, Sarianna Sipilä, Tellervo Korhonen, Pamela A.F. Madden, Christian Gieger, Rudolf A. Jörres, Joachim Heinrich, Jürgen Behr, Rudolf M. Huber, Annette Peters, Konstantin Strauch, H. Erich Wichmann, Melanie Waldenberger, Alexandra I.F. Blakemore, Eco J.C. de Geus, Dale R. Nyholt, Anjali K. Henders, Päivi L. Piirilä, Aila Rissanen, Patrik K.E. Magnusson, Ana Viñuela, Kirsi H. Pietiläinen, Nicholas G. Martin, Nancy L. Pedersen, Dorret I. Boomsma, Tim D. Spector, Cornelia M. van Duijn, Jaakko Kaprio, Nilesh J. Samani, Marjo-Riitta Jarvelin, Holger Schulz
Journal: European Respiratory Journal (2013)

Several clinical studies suggest the involvement of premature ageing processes in chronic obstructive pulmonary disease (COPD). Using an epidemiological approach, we studied whether accelerated ageing indicated by telomere length, a marker of biological age, is associated with COPD and asthma, and whether intrinsic age-related processes contribute to the interindividual variability of lung function. Our meta-analysis of 14 studies included 934 COPD cases with 15 846 controls defined according to the Global Lungs Initiative (GLI) criteria (or 1189 COPD cases according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria), 2834 asthma cases with 28 195 controls, and spirometric parameters (forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC) of 12 595 individuals. Associations with telomere length were tested by linear regression, adjusting for age, sex and smoking status. We observed negative associations between telomere length and asthma (β= -0.0452, p=0.024) as well as COPD (β= -0.0982, p=0.001), with associations being stronger and more significant when using GLI criteria than those of GOLD. In both diseases, effects were stronger in females than males. The investigation of spirometric indices showed positive associations between telomere length and FEV1 (p=1.07×10(-7)), FVC (p=2.07×10(-5)), and FEV1/FVC (p=5.27×10(-3)). The effect was somewhat weaker in apparently healthy subjects than in COPD or asthma patients. Our results provide indirect evidence for the hypothesis that cellular senescence may contribute to the pathogenesis of COPD and asthma, and that lung function may reflect biological ageing primarily due to intrinsic processes, which are likely to be aggravated in lung diseases.
Regulation of Human Nitric Oxide Synthase 2 Expression by Wnt β-Catenin Signaling
Authors: Qiang Du, Kyung Soo Park, Zhong Guo, Peijun He, Makoto Nagashima, Lifang Shao, Rohit Sahai, David A. Geller, S. Perwez Hussain
Journal: Cancer Research (2006)

Abstract Nitric oxide (NO·), an important mediator of inflammation, and β-catenin, a component of the Wnt–adenomatous polyposis coli signaling pathway, contribute to the development of cancer. We have identified two T-cell factor 4 (Tcf-4)-binding elements (TBE1 and TBE2) in the promoter of human inducible NO synthase 2 (NOS2). We tested the hypothesis that β-catenin regulates human NOS2 gene. Mutation in either of the two TBE sites decreased the basal and cytokine-induced NOS2 promoter activity in different cell lines. The promoter activity was significantly reduced when both TBE1 and TBE2 sites were mutated (P &amp;lt; 0.01). Nuclear extract from HCT116, HepG2, or DLD1 cells bound to NOS2 TBE1 or TBE2 oligonucleotides in electrophoretic mobility shift assays and the specific protein-DNA complexes were supershifted with anti-β-catenin or anti-Tcf-4 antibody. Overexpression of β-catenin and Tcf-4 significantly increased both basal and cytokine-induced NOS2 promoter activity (P &amp;lt; 0.01), and the induction was dependent on intact TBE sites. Overexpression of β-catenin or Tcf-4 increased NOS2 mRNA and protein expression in HCT116 cells. Lithium chloride (LiCl), an inhibitor of glycogen synthase kinase-3β, increased cytosolic and nuclear β-catenin level, NOS2 expression, and NO· production in primary human and rat hepatocytes and cancer cell lines. Treatment with Wnt-3A-conditioned medium increased β-catenin and NOS2 expression in fetal human hepatocytes. When administered in vivo, LiCl increased hepatic β-catenin level in a dose-dependent manner with simultaneous increase in NOS2 expression. These data are consistent with the hypothesis that β-catenin up-regulates NOS2 and suggest a novel mechanism by which the Wnt/β-catenin signaling pathway may contribute to cancer by increasing NO· production. (Cancer Res 2006; 66(14): 7024-31)
Expression of synaptic vesicle protein 2A in epilepsy-associated brain tumors and in the peritumoral cortex
Authors: M. de Groot, S. T. Toering, K. Boer, W. G.M. Spliet, J. J. Heimans, E. Aronica, J. C. Reijneveld
Journal: Neuro-Oncology (2010)

Synaptic vesicle protein 2A (SV2A) has been identified as the binding site for the antiepileptic drug levetiracetam and is thought to decrease neuronal excitability. Since knockout of SV2A in mice leads to seizures, we hypothesized that a reduction in SV2A expression promotes seizure generation in epilepsy-associated brain tumors. We compared the SV2A expression and distribution in surgically removed tumor tissue (n = 63) and peritumoral cortex (n = 31) of patients with glial and glioneuronal tumors to normal control cortex obtained at autopsy in nonbrain tumor patients (n = 6). Additionally, we compared the SV2A expression and distribution in tumor patients with epilepsy (n = 39) with SV2A expression in tumor patients without epilepsy (n = 24). Immunohistochemistry in control cortex demonstrated strong and diffuse SV2A immunoreactivity (IR) throughout all cortical layers. Similar strong SV2A IR (with the same diffuse distribution pattern) was observed in the peritumoral cortical specimens in both patients with and without epilepsy. Modest SV2A IR was observed within the tumor area. The SV2A-positive cells detected within the tumor area were mainly entrapped neurons. Oligodendrogliomas and glioneuronal tumors displayed variable SV2A neuropil staining. In ganglioglioma (GG), strong SV2A IR was present along the dysplastic neuronal cell borders and processes. In both GG and dysembryoplastic neuroepithelial tumors, SV2A IR was occasionally observed within the neuronal perikarya. We found no differences in SV2A expression in the peritumoral cortex between the patients with and without epilepsy, which suggests that the role of SV2A in epileptogenesis in patients with glial tumors is questionable. The distinct pattern of SV2A IR in glioneuronal tumors suggests a redistribution of SV2A.
Acute hyperglycemia impairs functional improvement after spinal cord injury in mice and humans
Authors: Kazu Kobayakawa, Hiromi Kumamaru, Hirokazu Saiwai, Kensuke Kubota, Yasuyuki Ohkawa, Junji Kishimoto, Kazuya Yokota, Ryosuke Ideta, Keiichiro Shiba, Hidetoshi Tozaki-Saitoh, Kazuhide Inoue, Yukihide Iwamoto, Seiji Okada
Journal: Science Translational Medicine (2014)

Acute hyperglycemia exacerbates poor functional outcomes after spinal cord injury through overactivation of microglia in mice and in a human cohort.
Hepatic enzyme activity is the major factor determining elimination rate of high-clearance drugs in cirrhosis
Authors: Richard Callaghan, Paul V. Desmond, Phillip Paull, Maurice L. Mashfor
Journal: Hepatology (1993)

The relative importance of alterations in hepatic enzyme activity, blood flow and drug binding to drug elimination in patients with liver disease remains controversial. In addition, liver disease appears to selectively impair drug oxidation pathways while leaving glucuronidation preserved. These studies using isolated perfused rat livers were designed to examine the effects of liver disease on the hepatic extraction and clearance and intrinsic clearance of morphine, a glucuronidated drug, and meperidine, an oxidized drug, under controlled blood flow and drug-binding conditions. We chose chronic carbon tetrachloride-induced cirrhosis as the liver disease. At a flow rate of 12 ml/min, the extraction of meperidine was reduced from 0.91 +/- 0.02 ml/min in controls to 0.76 +/- 0.04 ml/min (p < 0.05) in cirrhosis, hepatic clearance was reduced from 10.9 +/- 0.3 ml/min in controls to 9.15 +/- 0.48 ml/min (p < 0.05) in cirrhosis and intrinsic hepatic clearance was reduced from 179 +/- 35 ml/min in controls to 69 +/- 14 ml/min (p < 0.05) in cirrhosis. In contrast, for morphine we saw no significant changes: extraction ratio, 0.59 +/- 0.02 in controls and 0.49 +/- 0.04 in cirrhosis; hepatic clearance, 7.02 +/- 0.26 ml/min in controls and 6.04 +/- 0.42 ml/min in cirrhosis; and hepatic intrinsic clearance, 15.4 +/- 1.2 ml/min in controls and 13.9 +/- 2.3 ml/min in cirrhosis. Regression analysis of hepatic clearance vs. hepatic blood flow and hepatic clearance vs. hepatic intrinsic clearance demonstrate that in normal livers the elimination of both morphine and meperidine is mainly dependent on blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)
Sex-Specific Differences In Disease Severity In Patients With Chronic Rhinosinusitis With Nasal Polyps
Authors: Kathryn E. Hulse, Whitney Wyatt Stevens, Bruce K. Tan, James Norton, Lydia Suh, Robert C. Kern, David Conley, Rakesh Chandra, Anju T. Peters, Leslie C. Grammer, Kathleen E. Harris, Roderick Carter, Atsushi Kato, Margrit Urbanek, Robert P. Schleimer
Journal: Journal of Allergy and Clinical Immunology (2014)
Gastric metaplasia and duodenal ulcer disease in children infected by Helicobacter pylori.
Authors: S M Gormally, B M Kierce, L E Daly, B Bourke, R Carroll, M T Durnin, B Drumm
Journal: Gut (1996)

Helicobacter pylori infection of the gastric mucosa is vital in the pathogenesis of duodenal ulcer disease. H pylori will only colonise gastric epithelium and its association with duodenal disease is therefore not easily explained.To determine if gastric metaplasia in the duodenum increases the risk of duodenal ulcer disease in children infected with H pylori.All children undergoing upper endoscopy over a 20 month period in a children's hospital in Ireland.Two biopsy specimens were obtained from the antral mucosa and two from the first part of the duodenum. One antral biopsy specimen was used in a rapid urease test (Clo Test). Biopsy sections were stained with haematoxylin and eosin and also with cresyl violet for identification of H pylori. Periodic acid Schiff (PAS) stain was performed to identify areas of gastric metaplasia.Gastric and duodenal biopsy specimens were obtained from 148 patients (M:F 1:2:1). Twenty five children (17%) had H pylori positive gastritis. Thirty four children (23%) had gastric metaplasia in the duodenum. Nine per cent of children under the age of 8 years had gastric metaplasia compared with 38% in those 12 years of age or over (p < 0.005). Seven children had duodenal ulcer disease. Gastric metaplasia was present in six of seven (86%) children with duodenal ulcer disease compared with 28 of 141 (20%) without ulceration (p < 0.001). While both H pylori and gastric metaplasia were each significant risk factors for duodenal ulcer disease, the combined presence of both factors was associated with a pronounced increase in duodenal ulcer disease. Duodenal ulcer disease occurred in over 50% of children with both H pylori infection and gastric metaplasia. In contrast duodenal disease did not occur in children (0 of 100) when both were absent.The presence of gastric metaplasia in the duodenum is the major risk factor for duodenal ulcer disease in patients colonised by H pylori.
Enterohepatic circulation of bile acids after cholecystectomy.
Authors: E Roda, R Aldini, G Mazzella, A Roda, C Sama, D Festi, L Barbara
Journal: Gut (1978)

Bile acid metabolism was investigated in 10 patients after cholecystectomy, 10 gallstone patients, and 10 control subjects. Diurnal variations of serum levels of cholic and chenodeoxycholic acid conjugates were not abolished by cholecystectomy. Cholic acid pool size was significantly reduced in cholecystectomised patients and the fractional turnover rate and the rate of intestinal degradation of bile acid showed a significant increase. In cholecystectomised patients fasting bile was supersaturated in cholesterol, though less than in gallstone patients, but, in both, feeding resulted in improvement of cholesterol solubility in bile. These data suggest that after cholecystectomy the small intestine alone acts as a pump in regulating the dynamics of the enterohepatic circulation of bile acids and that the improvement of cholesterol solubility in bile is due to a more rapid circulation of the bile acid pool in fasting cholecystectomised patients.
Purification of human angiotensinogen.
Authors: D A Tewksbury, M R Premeau, M L Dumas, W L Frome
Journal: Circulation Research (1977)

A four-step method for the purification of human angiotensinogen has been devised. The four steps are: (1) removal of albumin by affinity chromatography on blue dextran-Sepharose, (2) chromatography on DEAE-Sephadex, (3) chromatography on hydroxylapatite, and (4) chromatography on DEAE-cellulose. This method is capable of producing 8 mg of purified angiotensinogen from 150 ml of plasma with 33% overall recovery of renin-releasable angiotensin I. The angiotensinogen appears homogeneous by immunochemical and ultracentrifugal techniques. The N-terminal amino acids have been determined to be alanine and aspartic acid or asparagine.
Effects of vitamin E on chronic and acute endothelial dysfunction in smokers
Authors: Thomas Neunteufl, Ute Priglinger, Sandra Heher, Manfred Zehetgruber, Gabor Söregi, Stephan Lehr, Kurt Huber, Gerald Maurer, Franz Weidinger, Karam Kostner
Journal: Journal of the American College of Cardiology (2000)
From research to clinical practice an interdisciplinary project of day surgery anaesthesiological course: From preoperative evaluation to patient discharge
Authors: Giuseppe Tomassini, Elisa Bernasconi, Giuseppe Giudice
Journal: International Journal of Surgery (2008)

This paper describes the anaesthesiological course of patients cared by an independent multi skills Day Surgery Unit during four years activity from 2004 to 2007. This method of caring surgical patients, continuously expanding, calls for regular audits where the anaesthetist plays a major role in selecting patients, in choosing and applying the most suitable anaesthesia technique, in managing any postoperative complications, and discharging the patient. All this contributes to minimising the patient's discomfort, to a quick recovery, and to minimise all inconvenience that may invalidate the service provided. Our experience includes 13,014 surgical procedures performed by seven specialised Operative Units. The analysis of our case records shows we have established an adequate organisation model and achieved a high quality standard of care in connection with high volumes of activity.
Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice
Authors: Eric D. Berglund, Claudia R. Vianna, Jose Donato, Mi Hwa Kim, Jen-Chieh Chuang, Charlotte E. Lee, Danielle A. Lauzon, Peagan Lin, Laura J. Brule, Michael M. Scott, Roberto Coppari, Joel K. Elmquist
Journal: Journal of Clinical Investigation (2012)

Leptin action on its receptor (LEPR) stimulates energy expenditure and reduces food intake, thereby lowering body weight. One leptin-sensitive target cell mediating these effects on energy balance is the proopiomelano-cortin (POMC) neuron. Recent evidence suggests that the action of leptin on POMC neurons regulates glucose homeostasis independently of its effects on energy balance. Here, we have dissected the physiological impact of direct leptin action on POMC neurons using a mouse model in which endogenous LEPR expression was prevented by a LoxP-flanked transcription blocker (loxTB), but could be reactivated by Cre recombinase. Mice homozygous for the Lepr(loxTB) allele were obese and exhibited defects characteristic of LEPR deficiency. Reexpression of LEPR only in POMC neurons in the arcuate nucleus of the hypothalamus did not reduce food intake, but partially normalized energy expenditure and modestly reduced body weight. Despite the moderate effects on energy balance and independent of changes in body weight, restoring LEPR in POMC neurons normalized blood glucose and ameliorated hepatic insulin resistance, hyperglucagonemia, and dyslipidemia. Collectively, these results demonstrate that direct leptin action on POMC neurons does not reduce food intake, but is sufficient to normalize glucose and glucagon levels in mice otherwise lacking LEPR.
Blockade of Vascular Endothelial Growth Factor Signaling Ameliorates Diabetic Albuminuria in Mice
Authors: Sun Hee Sung, Fuad N. Ziyadeh, Amy Wang, Petr E. Pyagay, Yashpal S. Kanwar, Sheldon Chen
Journal: Journal of the American Society of Nephrology (2006)

For investigation of how the vascular endothelial growth factor (VEGF) system participates in the pathogenesis of diabetic kidney disease, type 2 diabetic db/db and control db/m mice were treated intraperitoneally with vehicle or 2 mg/kg of a pan-VEGF receptor tyrosine kinase inhibitor, SU5416, twice a week for 8 wk. Efficacy of SU5416 treatment in the kidney was verified by the inhibition of VEGF receptor-1 phosphorylation. Glomerular VEGF immunostaining, normally increased in diabetes, was unaffected by SU5416. Plasma creatinine did not change with diabetes or SU5416 treatment. The primary end point of albuminuria increased approximately four-fold in the diabetic db/db mice but was significantly ameliorated by SU5416. Correlates of albuminuria were investigated. Diabetic glomerular basement membrane thickening was prevented in the SU5416-treated db/db mice, whereas mesangial matrix expansion remained unchanged by treatment. The density of open slit pores between podocyte foot processes was decreased in db/db diabetes but was partly increased toward normal by SU5416. Finally, nephrin protein by immunofluorescence was decreased in the db/db mice but was significantly restored by SU5416. Paradoxically, total nephrin protein by immunoblotting was increased in diabetes, pointing toward a possible dysregulation of nephrin trafficking. Diabetic albuminuria is partially a function of VEGF receptor signaling overactivity. VEGF signaling was found to affect a number of podocyte-driven manifestations such as GBM thickening, slit pore density, and nephrin quantity, all of which are associated with the extent of diabetic albuminuria. By impeding these pathophysiologic processes, VEGF receptor inhibition by SU5416 might become a useful adjunct to anti-albuminuria therapy in diabetic nephropathy.
Low Maternal Vitamin E Intake during Pregnancy Is Associated with Asthma in 5-Year-Old Children
Authors: Graham Devereux, Stephen W. Turner, Leone C. A. Craig, Geraldine McNeill, Sheelagh Martindale, Paul J. Harbour, Peter J. Helms, Anthony Seaton
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

We have previously reported an association between reduced maternal vitamin E intake during pregnancy and wheezing in 2-yr-old children.To assess whether maternal nutrient intake during pregnancy is associated with asthma-related outcomes in children aged 5 yr.A longitudinal cohort study of 1,861 children born to women recruited during pregnancy and followed up at 5 yr.Maternal nutrient status was assessed by a food frequency questionnaire and plasma levels. Respiratory and food frequency questionnaires were completed at 5 yr and children were invited for measurement of spirometry and skin-prick testing.Symptom and food frequency questionnaire data were available for 1,253 and 1,120 children, respectively; 700 children were skin prick tested, and FEV(1) was measured in 478 and exhaled nitric oxide in 167 children. In 5-yr-old children, maternal vitamin E intake during pregnancy was negatively associated with wheeze in previous year (odds ratio per intake quintile, 0.82; 95% confidence interval, 0.71-0.95), asthma ever (0.84, 0.72-0.98), asthma and wheeze in previous year (0.79, 0.65-0.95), and persistent wheezing (0.77, 0.63-0.93). Maternal plasma alpha-tocopherol during pregnancy was positively associated with post-bronchodilator FEV(1) at 5 yr, with a 7-ml (95% confidence interval, 0-14; p = 0.04) increase in FEV(1) per microg/ml alpha-tocopherol. Maternal zinc intake during pregnancy was negatively associated with asthma ever (0.83, 0.71-0.78) and active asthma (0.72, 0.59-0.89). There were no associations between children's nutrient intake and respiratory outcomes.Maternal intake of foods containing vitamin E and zinc during pregnancy is associated with differences in the risks of developing childhood wheeze and asthma.