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  1. Combinatorial gene therapy renders increased survival in cirrhotic rats

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    Armendáriz-Borunda Juan S

    2010-05-01

    Full Text Available Abstract Background Liver fibrosis ranks as the second cause of death in México's productive-age population. This pathology is characterized by acummulation of fibrillar proteins in hepatic parenchyma causing synthetic and metabolic disfunction. Remotion of excessive fibrous proteins might result in benefit for subjects increasing survival index. The goal of this work was to find whether the already known therapeutical effect of human urokinase Plasminogen Activator and human Matrix Metalloprotease 8 extends survival index in cirrhotic animals. Methods Wistar rats (80 g underwent chronic intoxication with CCl4: mineral oil for 8 weeks. Cirrhotic animals were injected with a combined dose of Ad-delta-huPA plus Ad-MMP8 (3 × 1011 and 1.5 × 1011 vp/Kg, respectively or with Ad-beta-Gal (4.5 × 1011 and were killed after 2, 4, 6, 8 and 10 days. Then, liver and serum were collected. An additional set of cirrhotic animals injected with combined gene therapy was also monitored for their probability of survival. Results Only the cirrhotic animals treated with therapeutical genes (Ad-delta-huPA+Ad-MMP-8 showed improvement in liver fibrosis. These results correlated with hydroxyproline determinations. A significant decrement in alpha-SMA and TGF-beta1 gene expression was also observed. Cirrhotic rats treated with Ad-delta-huPA plus Ad-MMP8 had a higher probability of survival at 60 days with respect to Ad-beta-Gal-injected animals. Conclusion A single administration of Ad-delta-huPA plus Ad-MMP-8 is efficient to induce fibrosis regression and increase survival in experimental liver fibrosis.

  2. Chronic nitric oxide synthase inhibition exacerbates renal dysfunction in cirrhotic rats

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    Graebe, M.; Brond, L.; Christensen, S.

    2004-01-01

    The present study investigated sodium balance and renal tubular function in cirrhotic rats with chronic blockade of the nitric oxide (NO) system. Rats were treated with the nonselective NO synthase inhibitor NG-nitro-l-arginine methyl ester (l-NAME) starting on the day of common bile duct ligation...... (CBL). Three weeks of daily sodium balance studies showed that CBL rats developed sodium retention compared with sham-operated rats and that l-NAME treatment dose dependently deteriorated cumulative sodium balance by reducing urinary sodium excretion. Five weeks after CBL, renal clearance studies were...

  3. Metformin reduces intrahepatic fibrosis and intrapulmonary shunts in biliary cirrhotic rats

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    Mu-Tzu Ko

    2017-08-01

    Conclusion: Metformin reduced liver injury and improved hepatic fibrosis in cirrhotic rats. It also attenuated the intrapulmonary shunts. However, the effects of metformin on pulmonary angiogenesis and hypoxia were insignificant.

  4. Hepatic regeneration after sublethal partial liver irradiation in cirrhotic rats

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    Gu Ke; Lai Songtao; Ma Ningyi; Zhao Jiandong; Ren Zhigang; Wang Jian; Liu Jin; Jiang Guoliang

    2011-01-01

    Our previous animal study had demonstrated that partial liver irradiation (IR) could stimulate regeneration in the protected liver, which supported the measurements adopted in radiotherapy planning for hepatocellular carcinoma. The purpose of this present study is to investigate whether cirrhotic liver repopulation could be triggered by partial liver IR. The cirrhosis was induced by thioacetamide (TAA) in rats. After cirrhosis establishment, TAA was withdrawn. In Experiment 1, only right-half liver was irradiated with single doses of 5 Gy, 10 Gy and 15 Gy, respectively. In Experiment 2, right-half liver was irradiated to 15 Gy, and the left-half to 2.5 Gy, 5 Gy and 7.5 Gy, respectively. The regeneration endpoints, including liver index (LI); mitotic index (MI); liver proliferation index (LPI); proliferating cell nuclear antigen-labeling index (PCNA-LI); serum hepatic growth factor (HGF), vascular endothelial growth factor (VEGF), transforming growth factor (TGF)-α and interleukin (IL)-6, were evaluated on 0 day, 30-day, 60-day, 90-day, 120-day and 150-day after IR. Serum and in situ TGF-β1 were also measured. In both experimental groups, the IR injuries were sublethal, inducing no more than 9% animal deaths. Upon TAA withdrawal, hepatic regeneration decelerated in the controls. In Experiment 1 except for LI, all other regeneration parameters were significantly higher than those in controls for both right-half and left-half livers. In Experiment 2 all regeneration parameters were also higher compared with those in controls for both half livers. Serum HGF and VEGF were increased compared with that of controls. Both unirradiated and low dose-irradiated cirrhotic liver were able to regenerate triggered by sublethal partial liver IR and higher doses and IR to both halves liver triggered a more enhanced regeneration. (author)

  5. Renal sodium retention in cirrhotic rats depends on glucocorticoid-mediated activation of mineralocorticoid receptor due to decreased renal 11beta-HSD-2 activity

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    Thiesson, Helle; Jensen, Boye L; Bistrup, Claus

    2007-01-01

    Downregulation of the renal glucocorticoid-metabolizing enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD-2) during liver cirrhosis may allow activation of the mineralocorticoid receptor (MR) by glucocorticoids and contribute to sodium retention. We tested this hypothesis in male Wistar...... rats with decompensated liver cirrhosis and ascites 7 wk after bile duct ligation (BDL). Renal 11beta-HSD-2 mRNA, protein, and activity were significantly decreased in decompensated rats. The urinary Na(+)/K(+) ratio was reduced by 40%. Renal epithelial sodium channel (ENaC) mRNA and immunostaining...... were only slightly affected. Complete metabolic studies, including fecal excretion, showed that the BDL rats had avid renal sodium retention. Treatment of the BDL rats with dexamethasone suppressed endogenous glucocorticoid production, normalized total sodium balance and renal sodium excretion...

  6. Insulin resistance and delayed clearance of peptide hormones in cirrhotic rat liver

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    Shankar, T.P.; Drake, S.; Solomon, S.S.

    1987-01-01

    Clearance of porcine insulin, glucagon, and human growth hormone was measured in intact perfused cirrhotic and normal rat livers. Binding and degradation of 125 I-insulin by hepatocytes isolated from cirrhotic and normal livers were also studied. The half-lives (t/sub 1/2/) of immunoreactive insulin and glucagon were 14.0 +/- 3.1 and 9.6 +/- 2.1 min in normal livers and 26.0 +/- 6.1 and 25.0 +/- 7.1 min in cirrhotic livers. Insulin binding and degradation by hepatocytes from control and cirrhotic livers showed no significant differences. Intraportal insulin infusion in perfusion studies suppressed glucagon-stimulated increases in glucose output from control livers but failed to suppress glucose production by cirrhotic livers, suggesting the presence of hepatic insulin resistance in cirrhosis. Impaired clearance of insulin and glucagon by the intact cirrhotic liver and normal binding and degradation of insulin by isolated hepatocytes suggest that factors such as intrahepatic fibrosis and shunting and postbinding defects may be responsible for the impaired hormone clearance and hepatic insulin resistance

  7. Role of the heme oxygenases in abnormalities of the mesenteric circulation in cirrhotic rats.

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    Sacerdoti, David; Abraham, Nader G; Oyekan, Adebayo O; Yang, Liming; Gatta, Angelo; McGiff, John C

    2004-02-01

    Carbon monoxide (CO), a product of heme metabolism by heme-oxygenase (HO), has biological actions similar to those of nitric oxide (NO). The role of CO in decreasing vascular responses to constrictor agents produced by experimental cirrhosis induced by carbon tetrachloride was evaluated before and after inhibition of HO with tin-mesoporphyrin (SnMP) in the perfused superior mesenteric vasculature (SMV) of cirrhotic and normal rats and in normal rats transfected with the human HO-1 (HHO-1) gene. Perfusion pressure and vasoconstrictor responses of the SMV to KCl, phenylephrine (PE), and endothelin-1 (ET-1) were decreased in cirrhotic rats. SnMP increased SMV perfusion pressure and restored the constrictor responses of the SMV to KCl, PE, and ET-1 in cirrhotic rats. The relative roles of NO and CO in producing hyporeactivity of the SMV to PE in cirrhotic rats were examined. Vasoconstrictor responses to PE were successively augmented by stepwise inhibition of CO and NO production, suggesting a complementary role for these gases in the regulation of reactivity of the SMV. Expression of constitutive but not of inducible HO (HO-1) was increased in the SMV of cirrhotic rats as was HO activity. Administration of adenovirus containing HHO-1 gene produced detection of HHO-1 RNA and increased HO activity in the SMV within 7 days. Rats transfected with HO-1 demonstrated reduction in both perfusion pressure and vasoconstrictor responses to PE in the SMV. We propose that HO is an essential component in mechanisms that modulate reactivity of the mesenteric circulation in experimental hepatic cirrhosis in rats.

  8. Selective cyclooxygenase-1 inhibition improves collateral vascular reactivity in biliary cirrhotic rats

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    Ching-Chih Chang

    2013-10-01

    Conclusion: There was no significant hemodynamic change and renal toxicity after acute administration of COX inhibitor in the FBDL-induced cirrhotic rats. Preincubation of selective COX-1, but not COX-2, inhibitor could enhance collateral vascular response to AVP, indicating that COX-1 plays a major role in the collateral vascular reactivity.

  9. Improved hepatocyte function of future liver remnant of cirrhotic rats after portal vein ligation: a bonus other than volume shifting.

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    Lin, Kun-Ju; Liao, Chien-Hung; Hsiao, Ing-Tsung; Yen, Tzu-Chen; Chen, Tse-Ching; Jan, Yi-Yin; Chen, Miin-Fu; Yeh, Ta-Sen

    2009-02-01

    Preoperative portal vein embolization is increasingly employed for those with hepatocellular carcinoma and cirrhosis to gain a volume-shifting effect. However, the alterations of histologic architecture and hepatocyte function of future liver remnant (FLR) remain unexplored. Portal vein ligation (PVL) was performed in cirrhotic and noncirrhotic rats. Regeneration indices that include the DNA synthesis index, restituted liver mass, and the redistributed volume ratio were measured. The indocyanine green 15' retention test (ICG-R15), histologic changes, total Knodell score, and activated hepatic stellate cells (HSCs) were measured before and after PVL. Tc-99m sulfur-colloid liver single photon emission computed tomography (SPECT) and diisopropyl iminoacetic acid (DISIDA) SPECT were conducted. The redistributed volume ratio of cirrhotic rats was less than noncirrhotic rats (63% vs 80%, P baseline (6.0 +/- 4.1% vs 15.8 +/- 4.6%, P baseline. The redistributed volume ratio of noncirrhotic and cirrhotic rats based on 99mTc sulfur-colloid SPECT were 79% and 64%, respectively. The clearance T(1/2) of FLR in cirrhotic rats based on DISIDA SPECT was decreased compared with baseline (5.2 +/- 1.9 min vs 8.6 +/- 3.1 min). The regenerated functional liver mass of cirrhotic rats after PVL is less than noncirrhotic rats, whereas the hepatocyte function of FLR in cirrhotic rats is improved relevant to tissue remodeling.

  10. Mitochondria-targeted antioxidant mitoquinone deactivates human and rat hepatic stellate cells and reduces portal hypertension in cirrhotic rats.

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    Vilaseca, Marina; García-Calderó, Héctor; Lafoz, Erica; Ruart, Maria; López-Sanjurjo, Cristina Isabel; Murphy, Michael P; Deulofeu, Ramon; Bosch, Jaume; Hernández-Gea, Virginia; Gracia-Sancho, Jordi; García-Pagán, Juan Carlos

    2017-07-01

    In cirrhosis, activated hepatic stellate cells (HSC) play a major role in increasing intrahepatic vascular resistance and developing portal hypertension. We have shown that cirrhotic livers have increased reactive oxygen species (ROS), and that antioxidant therapy decreases portal pressure. Considering that mitochondria produce many of these ROS, our aim was to assess the effects of the oral mitochondria-targeted antioxidant mitoquinone on hepatic oxidative stress, HSC phenotype, liver fibrosis and portal hypertension. Ex vivo: Hepatic stellate cells phenotype was analysed in human precision-cut liver slices in response to mitoquinone or vehicle. In vitro: Mitochondrial oxidative stress was analysed in different cell type of livers from control and cirrhotic rats. HSC phenotype, proliferation and viability were assessed in LX2, and in primary human and rat HSC treated with mitoquinone or vehicle. In vivo: CCl 4 - and thioacetamide-cirrhotic rats were treated with mitoquinone (5 mg/kg/day) or the vehicle compound, DecylTPP, for 2 weeks, followed by measurement of oxidative stress, systemic and hepatic haemodynamic, liver fibrosis, HSC phenotype and liver inflammation. Mitoquinone deactivated human and rat HSC, decreased their proliferation but with no effects on viability. In CCl 4 -cirrhotic rats, mitoquinone decreased hepatic oxidative stress, improved HSC phenotype, reduced intrahepatic vascular resistance and diminished liver fibrosis. These effects were associated with a significant reduction in portal pressure without changes in arterial pressure. These results were further confirmed in the thioacetamide-cirrhotic model. We propose mitochondria-targeted antioxidants as a novel treatment approach against portal hypertension and cirrhosis. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Effects of raloxifene on portal hypertension and hepatic encephalopathy in cirrhotic rats.

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    Chang, Ching-Chih; Lee, Wen-Shin; Chuang, Chiao-Lin; Hsin, I-Fang; Hsu, Shao-Jung; Chang, Ting; Huang, Hui-Chun; Lee, Fa-Yauh; Lee, Shou-Dong

    2017-05-05

    Raloxifene, a selective estrogen receptor modulator, has been used extensively for osteoporosis. In addition to the effect of osteoporosis treatment, emerging evidences show that raloxifene affects the vascular function in different tissues. Cirrhosis is characterized with portal hypertension and complicated with hepatic encephalopathy. Portal hypertension affects portal-systemic shunt which leads to hepatic encephalopathy that the vascular modulation might influence severity of hepatic encephalopathy. Herein, we evaluated the impact of raloxifene on bile duct ligation (BDL)-induced cirrhotic rats. The female Sprague-Dawley rats received BDL plus ovariectomy or sham-operation. Four weeks later, rats were divided into 2 subgroups respectively to receive of raloxifene (10mg/kg/day) or saline (vehicle) for 14 days. On the 43th day, motor activities and hemodynamic parameters were measured. Hepatic and vascular mRNA and protein expressions were determined. The histopathological change of liver was examined. We found that the liver biochemistry, ammonia level and motor activity were similar between cirrhotic rats with or without raloxifene administration. The hemodynamic parameters were not significantly different except that raloxifene reduced portal venous inflow. Raloxifene exacerbated hepatic fibrosis and up-regulated hepatic endothelin-1 and cyclooxygenase 2 protein expressions. In addition, raloxifene modulated the mRNA expressions of endothelial nitric oxide synthase, cyclooxygenase and endothelin-1 in the superior mesenteric artery and collateral vessel. In conclusion, raloxifene aggravates hepatic fibrosis and decreases portal venous inflow in cirrhotic rats without adversely affecting portal hypertension and hepatic encephalopathy. The modulation of hepatic and vascular endothelin-1, endothelial nitric oxide synthase and cyclooxygenase expressions may play a role in the mechanism. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Novel Rat Model of Repetitive Portal Venous Embolization Mimicking Human Non-Cirrhotic Idiopathic Portal Hypertension

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    Klein, Sabine; Hinüber, Christian; Hittatiya, Kanishka

    2016-01-01

    BACKGROUND: Non-cirrhotic idiopathic portal hypertension (NCIPH) is characterized by splenomegaly, anemia and portal hypertension, while liver function is preserved. However, no animal models have been established yet. This study assessed a rat model of NCIPH and characterized the hemodynamics......, and compared it to human NCIPH. METHODS: Portal pressure (PP) was measured invasively and coloured microspheres were injected in the ileocecal vein in rats. This procedure was performed weekly for 3 weeks (weekly embolization). Rats without and with single embolization served as controls. After four weeks (one...... in the weekly embolization group. Fibrotic markers αSMA and Desmin were upregulated in weekly embolized rats. DISCUSSION: This study establishes a model using repetitive embolization via portal veins, comparable with human NCIPH and may serve to test new therapies....

  13. Celecoxib and octreotide synergistically ameliorate portal hypertension via inhibition of angiogenesis in cirrhotic rats.

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    Gao, Jin-Hang; Wen, Shi-Lei; Feng, Shi; Yang, Wen-Juan; Lu, Yao-Yao; Tong, Huan; Liu, Rui; Tang, Shi-Hang; Huang, Zhi-Yin; Tang, Ying-Mei; Yang, Jin-Hui; Xie, Hui-Qi; Tang, Cheng-Wei

    2016-10-01

    Abnormal angiogenesis is critical for portal hypertension in cirrhosis. Except for etiological treatment, no efficient medication or regime has been explored to treat the early stage of cirrhosis when angiogenesis is initiated or overwhelming. In this study, we explored an anti-angiogenesis effort through non-cytotoxic drugs octreotide and celecoxib to treat early stage of cirrhotic portal hypertension in an animal model. Peritoneal injection of thioacetamide (TAA) was employed to induce liver cirrhosis in rats. A combination treatment of celecoxib and octreotide was found to relieve liver fibrosis, portal venous pressure, micro-hepatic arterioportal fistulas, intrahepatic and splanchnic angiogenesis. Celecoxib and octreotide exerted their anti-angiogenesis effect via an axis of cyclooxygenase-2/prostaglandin E2/EP-2/somatostatin receptor-2, which consequently down-regulated phosphorylation of extracellular signal-regulated kinase (p-ERK)-hypoxia-inducible factor-1α (HIF-1α)-vascular endothelial growth factor (VEGF) integrated signaling pathways. In conclusions, combination of celecoxib and octreotide synergistically ameliorated liver fibrosis and portal hypertension of the cirrhotic rats induced by TAA via the inhibition of intrahepatic and extrahepatic angiogenesis. The potential mechanisms behind the regimen may due to the inactivation of p-ERK-HIF-1α-VEGF signaling pathway.

  14. Novel Rat Model of Repetitive Portal Venous Embolization Mimicking Human Non-Cirrhotic Idiopathic Portal Hypertension.

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    Klein, Sabine; Hinüber, Christian; Hittatiya, Kanishka; Schierwagen, Robert; Uschner, Frank Erhard; Strassburg, Christian P; Fischer, Hans-Peter; Spengler, Ulrich; Trebicka, Jonel

    2016-01-01

    Non-cirrhotic idiopathic portal hypertension (NCIPH) is characterized by splenomegaly, anemia and portal hypertension, while liver function is preserved. However, no animal models have been established yet. This study assessed a rat model of NCIPH and characterized the hemodynamics, and compared it to human NCIPH. Portal pressure (PP) was measured invasively and coloured microspheres were injected in the ileocecal vein in rats. This procedure was performed weekly for 3 weeks (weekly embolization). Rats without and with single embolization served as controls. After four weeks (one week after last embolization), hemodynamics were investigated, hepatic fibrosis and accumulation of myofibroblasts were analysed. General characteristics, laboratory analyses and liver histology were collected in patients with NCIPH. Weekly embolization induced a hyperdynamic circulation, with increased PP. The mesenteric flow and hepatic hydroxyproline content was significantly higher in weekly embolized compared to single embolized rats (mesenteric flow +54.1%, hydroxyproline +41.7%). Mesenteric blood flow and shunt volumes increased, whereas splanchnic vascular resistance was decreased in the weekly embolization group. Fibrotic markers αSMA and Desmin were upregulated in weekly embolized rats. This study establishes a model using repetitive embolization via portal veins, comparable with human NCIPH and may serve to test new therapies.

  15. Glycogen content in hepatocytes is related with their size in normal rat liver but not in cirrhotic one.

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    Bezborodkina, Natalia N; Chestnova, Anna Yu; Vorobev, Mikhail L; Kudryavtsev, Boris N

    2016-04-01

    Hepatocytes differ from one another by the degree of the ploidy, size, position in the liver lobule, and level of the DNA-synthetic processes. It is believed, that the cell size exerts substantial influence on the metabolism of the hepatocytes and the glycogen content in them. The aim of the present study was to test this hypothesis. Dry weight of hepatocytes, their ploidy and glycogen content were determined in the normal and the cirrhotic rat liver. Liver cirrhosis in rats was produced by chronic inhalation of CCl4 vapours in the course of 6 months. A combined cytophotometric method was used. Dry weight of the cell, its glycogen and DNA content were successively measured on a mapped preparation. Hepatocytes of each ploidy class in the normal and the cirrhotic rat liver accumulated glycogen at the same rate. In the normal liver, there was a distinct correlation between the size of hepatocytes and glycogen content in them. This correlation was observed in each ploidy class, and was especially pronounced in the class of mononucleate tetraploid hepatocytes. In the cirrhotic liver, there was no correlation between the size of the cells and their glycogen content. The impairment of liver lobular structure probably explains the observed lack of correlation between hepatocyte size and their glycogen content in the cirrhotic liver. © 2016 International Society for Advancement of Cytometry. © 2016 International Society for Advancement of Cytometry.

  16. Intrahepatic upregulation of MRTF-A signaling contributes to increased hepatic vascular resistance in cirrhotic rats with portal hypertension.

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    Zheng, Lei; Qin, Jun; Sun, Longci; Gui, Liang; Zhang, Chihao; Huang, Yijun; Deng, Wensheng; Huang, An; Sun, Dong; Luo, Meng

    2017-06-01

    Portal hypertension in cirrhosis is mediated, in part, by increased intrahepatic resistance, reflecting massive structural changes associated with fibrosis and intrahepatic vasoconstriction. Activation of the Rho/MRTF/SRF signaling pathway is essential for the cellular regulatory network of fibrogenesis. The aim of this study was to investigate MRTF-A-mediated regulation of intrahepatic fibrogenesis in cirrhotic rats. Portal hypertension was induced in rats via an injection of CCl 4 oil. Hemodynamic measurements were obtained using a polyethylene PE-50 catheter and pressure transducers. Expression of hepatic fibrogenesis was measured using histological staining. Expression of protein was measured using western blotting. Upregulation of MRTF-A protein expression in the livers of rats with CCl 4 -induced cirrhosis was relevant to intrahepatic resistance and hepatic fibrogenesis in portal hypertensive rats with increased modeling time. Inhibition of MRTF-A by CCG-1423 decelerated hepatic fibrosis, decreased intrahepatic resistance and portal pressure, and alleviated portal hypertension. Increased intrahepatic resistance in rats with CCl 4 -induced portal hypertension is associated with an upregulation of MRTF-A signaling. Inhibition of this pathway in the liver can decrease hepatic fibrosis and intrahepatic resistance, as well as reduce portal pressure in cirrhotic rats with CCl 4 -induced portal hypertension. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  17. Transplantation of endothelial progenitor cells ameliorates vascular dysfunction and portal hypertension in carbon tetrachloride-induced rat liver cirrhotic model.

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    Sakamoto, Masaharu; Nakamura, Toru; Torimura, Takuji; Iwamoto, Hideki; Masuda, Hiroshi; Koga, Hironori; Abe, Mitsuhiko; Hashimoto, Osamu; Ueno, Takato; Sata, Michio

    2013-01-01

    In cirrhosis, sinusoidal endothelial cell injury results in increased endothelin-1 (ET-1) and decreased nitric oxide synthase (NOS) activity, leading to portal hypertension. However, the effects of transplanted endothelial progenitor cells (EPCs) on the cirrhotic liver have not yet been clarified. We investigated whether EPC transplantation reduces portal hypertension. Cirrhotic rats were created by the administration of carbon tetrachloride (CCl(4) ) twice weekly for 10 weeks. From week 7, rat bone marrow-derived EPCs were injected via the tail vein in this model once a week for 4 weeks. Endothelial NOS (eNOS), vascular endothelial growth factor (VEGF) and caveolin expressions were examined by Western blots. Hepatic tissue ET-1 was measured by a radioimmunoassay (RIA). Portal venous pressure, mean aortic pressure, and hepatic blood flow were measured. Endothelial progenitor cell transplantation reduced liver fibrosis, α-smooth muscle actin-positive cells, caveolin expression, ET-1 concentration and portal venous pressure. EPC transplantation increased hepatic blood flow, protein levels of eNOS and VEGF. Immunohistochemical analyses of eNOS and isolectin B4 demonstrated that the livers of EPC-transplanted animals had markedly increased vascular density, suggesting reconstitution of sinusoidal blood vessels with endothelium. Transplantation of EPCs ameliorates vascular dysfunction and portal hypertension, suggesting this treatment may provide a new approach in the therapy of portal hypertension with liver cirrhosis. © 2012 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

  18. Inhibition of soluble epoxide hydrolase lowers portal hypertension in cirrhotic rats by ameliorating endothelial dysfunction and liver fibrosis.

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    Deng, Wensheng; Zhu, Yiming; Lin, Jiayun; Zheng, Lei; Zhang, Chihao; Luo, Meng

    2017-07-01

    Epoxyeicostrienoic acids (EETs) are arachidonic acid derived meditators which are catalyzed by soluble epoxide hydrolase (sEH) to less active dihydroeicostrienoics acids (DHETS). The aim of our study is to investigate the effects of sEH inhibition on hepatic and systemic hemodynamics, hepatic endothelial dysfunction, and hepatic fibrosis in CCl4 cirrhotic rats. The sEH inhibitor,trans-4-{4-[3-(4-trifluoromethoxyphenyl)-ureido]cyclohexyloxy}benzoic acid (t-TUCB) was administered to stabilize hepatic EETs by gavage at a dose of 1mg/kg/d. Our results showed that hepatic sEH expression was markedly increased in portal hypertension, and led to a lower ratio of EETs/DHETs which was effectively reversed by t-TUCB administration. t-TUCB significantly decreased portal pressure without significant changes in systemic hemodynamics, which was associated with the attenuation of intrahepatic vascular resistance (IHVR) and liver fibrosis. t-TUCB ameliorated endothelial dysfunction, increased hepatic endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production. In addition, t-TUCB significantly reduced alpha-Smooth Muscle Actin (α-SMA) expression and liver fibrosis, which was associated with a decrease in NF-κB signaling. Taken together, inhibition of sEH reduces portal pressure, liver fibrosis and attenuates hepatic endothelial dysfunction in cirrhotic rats. Our results indicate that sEH inhbitors may be useful in the treatment of portal hypertension in patients with cirrhosis. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Regulation of collagen production in freshly isolated cell populations from normal and cirrhotic rat liver: Effect of lactate

    International Nuclear Information System (INIS)

    Cerbon-Ambriz, J.; Cerbon-Solorzano, J.; Rojkind, M.

    1991-01-01

    Previous work has shown that lactic acid, and to a lesser extent pyruvic acid, is able to increase collagen synthesis significantly in liver slices of CCl4-treated rats but not normal rats. The purpose of this report is to document which cells in the cirrhotic liver are responsible for the lactate-stimulated increase in collagen synthesis. It was found that (a) incorporation of 3H-proline into protein-bound 3H-hydroxyproline is increased threefold to fourfold in hepatocytes from CCl4-treated rats as compared with normal rat hepatocytes; (b) neither the hepatocytes from normal nor those from CCl4-treated rats modify their collagen synthesizing capacity when 30 mmol/L lactic acid was added to the incubation medium; (c) nonparenchymal cells obtained from livers of CCl4-treated rats synthesize much less collagen than hepatocytes, but their synthesis is stimulated twofold by lactic acid; (d) from the different nonparenchymal cells, only fat-storing (Ito) cells increase collagen synthesis when lactic acid is present in the incubation medium. These results suggest that the increased lactic acid levels observed in patients with alcoholic hepatic cirrhosis may play an important role in the development of fibrosis by stimulating collagen production by fat-storing (Ito) cells

  20. Celecoxib ameliorates portal hypertension of the cirrhotic rats through the dual inhibitory effects on the intrahepatic fibrosis and angiogenesis.

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    Gao, Jin-Hang; Wen, Shi-Lei; Yang, Wen-Juan; Lu, Yao-Yao; Tong, Huan; Huang, Zhi-Yin; Liu, Zhang-Xu; Tang, Cheng-Wei

    2013-01-01

    Increased intra-hepatic resistance to portal blood flow is the primary factor leading to portal hypertension in cirrhosis. Up-regulated expression of cyclooxygenase-2 (COX-2) in the cirrhotic liver might be a potential target to ameliorate portal hypertension. To verify the effect of celecoxib, a selective inhibitor of COX-2, on portal hypertension and the mechanisms behind it. Cirrhotic liver model of rat was established by peritoneal injection of thiacetamide (TAA). 36 rats were randomly assigned to control, TAA and TAA+celecoxib groups. Portal pressures were measured by introduction of catheters into portal vein. Hepatic fibrosis was assessed by the visible hepatic fibrotic areas and mRNAs for collagen III and α-SMA. The neovasculature was determined by hepatic vascular areas, vascular casts and CD31 expression. Expressions of COX-2, vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR-2) and related signal molecules were quantitated. Compared with TAA group, the portal pressure in TAA+celecoxib group was significantly decreased by 17.8%, pportal venules. The data of fibrotic areas, CD31expression, mRNA levels of α-SMA and collagen III in TAA+celecoxib group were much lower than those in TAA group, pprotein levels of VEGF, VEGFR-2 and COX-2 induced by TAA was significantly inhibited after celecoxib treatment. The expressions of prostaglandin E2 (PGE2), phosphorylated extracellular signal-regulated kinase (p-ERK), hypoxia-inducible factor-1α (HIF-1α), and c-fos were also down-regulated after celecoxib treatment. Long term administration of celecoxib can efficiently ameliorate portal hypertension in TAA rat model by its dual inhibitory effects on the intrahepatic fibrosis and angiogenesis. The anti-angiogenesis effect afforded by celecoxib may attribute to its modulation on VEGF/VEGFR-2 through the down-regulation of integrated signal pathways involving PGE2- HIF-1α- VEGF and p-ERK- c-fos- VEGFR-2.

  1. Celecoxib ameliorates portal hypertension of the cirrhotic rats through the dual inhibitory effects on the intrahepatic fibrosis and angiogenesis.

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    Jin-Hang Gao

    Full Text Available BACKGROUND: Increased intra-hepatic resistance to portal blood flow is the primary factor leading to portal hypertension in cirrhosis. Up-regulated expression of cyclooxygenase-2 (COX-2 in the cirrhotic liver might be a potential target to ameliorate portal hypertension. OBJECTIVE: To verify the effect of celecoxib, a selective inhibitor of COX-2, on portal hypertension and the mechanisms behind it. METHODS: Cirrhotic liver model of rat was established by peritoneal injection of thiacetamide (TAA. 36 rats were randomly assigned to control, TAA and TAA+celecoxib groups. Portal pressures were measured by introduction of catheters into portal vein. Hepatic fibrosis was assessed by the visible hepatic fibrotic areas and mRNAs for collagen III and α-SMA. The neovasculature was determined by hepatic vascular areas, vascular casts and CD31 expression. Expressions of COX-2, vascular endothelial growth factor (VEGF, VEGF receptor-2 (VEGFR-2 and related signal molecules were quantitated. RESULTS: Compared with TAA group, the portal pressure in TAA+celecoxib group was significantly decreased by 17.8%, p<0.01. Celecoxib treatment greatly reduced the tortuous hepatic portal venules. The data of fibrotic areas, CD31expression, mRNA levels of α-SMA and collagen III in TAA+celecoxib group were much lower than those in TAA group, p<0.01. Furthermore, the up-regulation of hepatic mRNA and protein levels of VEGF, VEGFR-2 and COX-2 induced by TAA was significantly inhibited after celecoxib treatment. The expressions of prostaglandin E2 (PGE2, phosphorylated extracellular signal-regulated kinase (p-ERK, hypoxia-inducible factor-1α (HIF-1α, and c-fos were also down-regulated after celecoxib treatment. CONCLUSIONS: Long term administration of celecoxib can efficiently ameliorate portal hypertension in TAA rat model by its dual inhibitory effects on the intrahepatic fibrosis and angiogenesis. The anti-angiogenesis effect afforded by celecoxib may attribute to its

  2. Effects of a high protein diet on cognition and brain metabolism in cirrhotic rats.

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    Méndez-López, M; Méndez, M; Arias, J; Arias, J L

    2015-10-01

    Hepatic encephalopathy (HE) is a neurological complication observed in patients with liver disease. Patients who suffer from HE present neuropsychiatric, neuromuscular and behavioral symptoms. Animal models proposed to study HE resulting from cirrhosis mimic the clinical characteristics of cirrhosis and portal hypertension, and require the administration of hepatotoxins such as thioacetamide (TAA). The aim of this study was to assess the effects of a high protein diet on motor function, anxiety and memory processes in a model of cirrhosis induced by TAA administration. In addition, we used cytochrome c-oxidase (COx) histochemistry to assess the metabolic activity of the limbic system regions. Male rats were distributed into groups: control, animals with cirrhosis, Control rats receiving a high protein diet, and animals with cirrhosis receiving a high protein diet. Results showed preserved motor function and normal anxiety levels in all the groups. The animals with cirrhosis showed an impairment in active avoidance behavior and spatial memory, regardless of the diet they received. However, the animals with cirrhosis and a high protein diet showed longer escape latencies on the spatial memory task. The model of cirrhosis presented an under-activation of the dentate gyrus and CA3 hippocampal subfields and the medial part of the medial mammillary nucleus. The results suggest that a high protein intake worsens spatial memory deficits shown by the TAA-induced model of cirrhosis. However, high protein ingestion has no influence on the COx hypoactivity associated with the model. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Child-Pugh classification dependent alterations in serum leptin levels among cirrhotic patients: a case controlled study

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    Zeyrek Fadile

    2004-09-01

    Full Text Available Abstract Background As anorexia and hypermetabolism are common in cirrhosis, leptin levels may be increased in this disease. In this study, we investigated the relation between the severity of disease and serum leptin levels in post-hepatitis cirrhosis and the role of body composition, gender and viral aetiology of cirrhosis in this association. Methods Thirty-five cases with post-hepatitis cirrhosis and 15 healthy controls were enrolled in this study. Body composition including body mass index, body fat percentage and body fat mass were determined. Serum leptin levels were assayed. Results Leptin levels were significantly higher among cirrhotic patients independent of sex compared to controls (p = 0.001. Female patients in both groups have had higher leptin levels than males (in cirrhotics p = 0.029, in controls p = 0.02. Cirrhotic patients in each of A, B and C subgroups according to the Child- Pugh classification revealed significantly different levels compared to controls (p = 0.046, p = 0.004, p = 0.0001, respectively. Male cirrhotics in Child-Pugh Class B and C subgroups had significantly higher leptin levels compared to male controls (p = 0.006, p = 0.008. On the other hand, female patients only in Child Pugh class C subgroup have had higher levels of serum leptin compared to controls (p = 0.022. Child-Pugh classification has been found to be the sole discriminator in determination of leptin levels in cirrhotics by linear regression (beta: 0.435 p = 0.015. Conclusion Serum leptin levels increase in advanced liver disease independently of gender, body composition in posthepatitic cirrhosis. The increase is more abundant among patients that belong to C subgroup according to the Child- Pugh classification.

  4. IGF-1 decreases portal vein endotoxin via regulating intestinal tight junctions and plays a role in attenuating portal hypertension of cirrhotic rats.

    Science.gov (United States)

    Zhao, Tian-Yu; Su, Li-Ping; Ma, Chun-Ye; Zhai, Xiao-Han; Duan, Zhi-Jun; Zhu, Ying; Zhao, Gang; Li, Chun-Yan; Wang, Li-Xia; Yang, Dong

    2015-07-08

    Intestinal barrier dysfunction is not only the consequence of liver cirrhosis, but also an active participant in the development of liver cirrhosis. Previous studies showed that external administration of insulin-like growth factor 1 (IGF-1) improved intestinal barrier function in liver cirrhosis. However, the mechanism of IGF-1 on intestinal barrier in liver cirrhosis is not fully elucidated. The present study aims to investigate the mechanisms of IGF-1 improving intestinal barrier function via regulating tight junctions in intestines. We used carbon tetrachloride induced liver cirrhotic rats to investigate the effect of IGF-1 on intestinal claudin-1 and occludin expressions, serum alanine transaminase (ALT) and aspartate transaminase (AST) levels, severity of liver fibrosis, portal pressures, enterocytic apoptosis and lipopolysaccharides (LPS) levels in portal vein. The changes of IGF-1 in serum during the development of rat liver cirrhosis were also evaluated. Additionally, we assessed the effect of IGF-1 on claudin-1 and occludin expressions, changes of transepithelial electrical resistance (TEER) and apoptosis in Caco-2 cells to confirm in vivo findings. Serum IGF-1 levels were decreased in the development of rat liver cirrhosis, and external administration of IGF-1 restored serum IGF-1 levels. External administration of IGF-1 reduced serum ALT and AST levels, severity of liver fibrosis, LPS levels in portal vein, enterocytic apoptosis and portal pressure in cirrhotic rats. External administration of IGF-1 increased the expressions of claudin-1 and occludin in enterocytes, and attenuated tight junction dysfunction in intestines of cirrhotic rats. LPS decreased TEER in Caco-2 cell monolayer. LPS also decreased claudin-1 and occludin expressions and increased apoptosis in Caco-2 cells. Furthermore, IGF-1 attenuated the effect of LPS on TEER, claudin-1 expression, occludin expression and apoptosis in Caco-2 cells. Tight junction dysfunction develops during the

  5. Uso de quercetina a longo prazo em ratos cirróticos The long term use of quercetin in cirrhotic rats

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    Aline Miltersteiner

    2003-06-01

    Full Text Available OBJETIVO: Avaliar o uso a longo prazo do flavonóide quercetina em ratos cirróticos por ligadura de ducto biliar comum (LDB. MÉTODOS: Foram utilizados 32 ratos machos Wistar, sendo submetidos à LDB ou simulação, e distribuídos em 4 grupos: 1 controle, 2 cirróticos, 3 cirróticos tratados com quercetina 50mg/kg, intraperitonealmente, desde o segundo dia após o procedimento cirúrgico; e 4 cirróticos tratados após o décimo quarto dia do procedimento cirúrgico. Analisou-se a função hepática por meio de testes bioquímicos (BT e BD e atividade enzimática (ALT, AST, FA e GGT. Na análise anatomopatológica, utilizou-se a coloração de Hematoxilina & Eosina (H&E e de Picrosírius para fibrose. A análise estatística para avaliação de sobrevivência foi realizada pelo teste Kaplan-Meier. RESULTADOS: Os resultados de sobrevivência dos oito animais de cada grupo foram: Grupo 1 = 200 dias de sobrevivência; Grupo 2 = 46 dias; Grupo 3 = 71 dias; e o Grupo 4 = 90 dias. Nos animais com ligadura de ducto biliar comum houve aumento das provas de função hepática e enzimáticas que se reduziu hipoteticamente com o tratamento com quercetina. Foram identificadas cirrose, congestão vascular porta e centrolobular na análise histopatológica por H&E e Picrosírius. CONCLUSÃO: O uso da quercetina diminuiu de maneira significante as alterações bioquímicas provocadas pela cirrose, aumentando o tempo de sobrevivência dos animais com cirrose biliar secundária à LDB, como verificado pelo teste de análise de sobrevivência.PURPOSE: The long term use of quercetin flavonoid was evaluated in cirrhotic rats by common biliary duct bondage (LDB. METHODS: 32 male Wistar rats were submitted to LDB or simulation, and distributed in 4 groups: 1 control, 2 cirrhotic, 3 cirrhotic treated with quercetin the second day after the surgical procedure; and 4 cirrhotic treated with quercetin after the fourteenth day of the surgical procedure. The hepatic

  6. Diabetes diminishes the portal-systemic collateral vascular response to vasopressin via vasopressin receptor and Gα proteins regulations in cirrhotic rats.

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    Jing-Yi Lee

    Full Text Available Liver cirrhosis may lead to portal-systemic collateral formation and bleeding. The hemostatic effect is influenced by the response of collateral vessels to vasoconstrictors. Diabetes and glucose also influence vasoresponsiveness, but their net effect on collaterals remains unexplored. This study investigated the impact of diabetes or glucose application on portal-systemic collateral vasoresponsiveness to arginine vasopressin (AVP in cirrhosis. Spraque-Dawley rats with bile duct ligation (BDL-induced cirrhosis received vehicle (citrate buffer or streptozotocin (diabetic, BDL/STZ. The in situ collateral perfusion was done after hemodynamic measurements: Both were perfused with Krebs solution, D-glucose, or D-glucose and NaF, with additional OPC-31260 for the BDL/STZ group. Splenorenal shunt vasopressin receptors and Gα proteins mRNA expressions were evaluated. The survival rate of cirrhotic rats was decreased by STZ injection. The collateral perfusion pressure changes to AVP were lower in STZ-injected groups, which were reversed by OPC-31260 (a V2R antagonist and overcome by NaF (a G protein activator. The splenorenal shunt V2R mRNA expression was increased while Gα proteins mRNA expressions were decreased in BDL/STZ rats compared to BDL rats. The Gαq and Gα11 mRNA expressions also correlated with the maximal perfusion pressure changes to AVP. Diabetes diminished the portal-systemic collateral vascular response to AVP in rats with BDL-induced cirrhosis, probably via V2 receptor up-regulation and Gα proteins down-regulation.

  7. Portal hypertension and liver cirrhosis in rats: effect of the β3-adrenoceptor agonist SR58611A

    Science.gov (United States)

    Vasina, Valentina; Giannone, Ferdinando; Domenicali, Marco; Latorre, Rocco; Berzigotti, Annalisa; Caraceni, Paolo; Zoli, Marco; De Ponti, Fabrizio; Bernardi, Mauro

    2012-01-01

    BACKGROUND AND PURPOSE β3-Adrenoceptors participate in the regulation of vascular tone in physiological and pathological conditions. We aimed to assess the effect of pharmacological modulation of β3-adrenoceptors on portal pressure (PP) and systemic haemodynamics and their expression in the liver and mesenteric vessels of cirrhotic rats. EXPERIMENTAL APPROACH PP, central venous pressure (CVP) and systemic haemodynamics were invasively assessed in control and CCl4-treated cirrhotic rats before and during infusion of the selective β3-adrenoceptor agonist, SR58611A. Tissue samples were also collected from liver, heart, portal vein and mesenteric artery for immunohistochemistry and molecular biology analysis. The effect of SR58611A on isolated portal vein was assessed. KEY RESULTS At baseline, cirrhotic rats showed portal hypertension, reduced CVP and hyperdynamic circulation. SR58611A induced a significant, dose-dependent decrease in PP in cirrhotic rats, but not in controls. Although both groups manifested a dose-dependent reduction in mean arterial pressure, this effect was associated with decreased cardiac index (CI) and unchanged indicized peripheral vascular resistance (PVRI) in cirrhotic rats and increased CI and decreased PVRI in control animals. Pretreatment with the selective β3-adrenoceptor antagonist SR59230 prevented all SR58611A-induced changes in cirrhotic rats. SR58611A concentration-dependently relaxed portal vein in cirrhotic rats to a significantly greater extent than in healthy rats; pretreatment with SR59230A completely prevented SR58611A-induced cirrhotic portal vein relaxation. Finally, β3-adrenoceptors were identified in the liver, heart and portal vein of cirrhotic and control animals; their expression was increased in cirrhotic rats. CONCLUSIONS AND IMPLICATIONS β3-Adrenoceptors are altered in portal hypertension of experimental cirrhosis and may represent a novel therapeutic target. PMID:22708587

  8. Management of cirrhotic ascites

    DEFF Research Database (Denmark)

    Pedersen, Julie Steen; Bendtsen, Flemming; Møller, Søren

    2015-01-01

    The most common complication to chronic liver failure is ascites. The formation of ascites in the cirrhotic patient is caused by a complex chain of pathophysiological events involving portal hypertension and progressive vascular dysfunction. Since ascites formation represents a hallmark in the na......The most common complication to chronic liver failure is ascites. The formation of ascites in the cirrhotic patient is caused by a complex chain of pathophysiological events involving portal hypertension and progressive vascular dysfunction. Since ascites formation represents a hallmark...... in the natural history of chronic liver failure it predicts a poor outcome with a 50% mortality rate within 3 years. Patients with ascites are at high risk of developing complications such as spontaneous bacterial peritonitis, hyponatremia and progressive renal impairment. Adequate management of cirrhotic...

  9. Erythrocytes Membrane Alterations Reflecting Liver Damage in CCl₄-Induced Cirrhotic Rats: The Ameliorative Effect of Naltrexone

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    Fatemeh Sarhadi Kholari

    2016-11-01

    Full Text Available Cirrhosis is the consequence of chronic liver disease. Deleterious effects of oxidative stress on hepatocytes may be reflected in the erythrocyte membrane. Naltrexone (NTX has been shown to attenuate hepatocellular injury in fibrotic animal models. The aim of this study was to investigate the progressive effect of CCl4 on the liver and whether the improvement of liver cirrhosis can be monitored through alterations in the erythrocyte membrane. In this study, 84 male Wistar rats were divided into 4 groups and received reagents (i.p. as follows: 1- CCl₄, 2- NTX + CCl₄, 3- Mineral Oil (M, and 4- NTX + M. After 2, 6 and 8 weeks, the blood and liver tissue samples were collected. Plasma enzyme activities, the content of erythrocyte GSH and some membrane compositions, including protein carbonyl, protein sulfhydryl, and malondialdehyde were assessed. After 6 and 8 weeks, plasma enzyme activities and the content of protein carbonyl were higher in CCl4 group significantly, as compared to other groups (P<0.001. NTX significantly diminished protein carbonyl and plasma enzyme activities (P<0.001. GSH did not change until the 6th week. However, CCl4+NTX increased it significantly as compared to CCl₄ group (P<0.05. Protein sulfhydryl showed changes in NTX+CCl₄ group which indicated a significant increase in protein sulfhydryl content in a 6th week compared to CCl4 group (P<0.05. MDA did not show any significant alteration. CCl₄-induced cirrhosis is accompanied by increased content of oxidative stress markers, especially protein carbonyl of RBC membrane and plasma enzyme activities. This study shows that the progression of liver cirrhosis and the ameliorative effect of NTX can be followed through alterations of these markers.

  10. Alpha-2A Adrenoceptor Agonist Guanfacine Restores Diuretic Efficiency in Experimental Cirrhotic Ascites: Comparison with Clonidine.

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    Giovanni Sansoè

    Full Text Available In human cirrhosis, adrenergic hyperfunction causes proximal tubular fluid retention and contributes to diuretic-resistant ascites, and clonidine, a sympatholytic drug, improves natriuresis in difficult-to-treat ascites.To compare clonidine (aspecific α2-adrenoceptor agonist to SSP-002021R (prodrug of guanfacine, specific α2A-receptor agonist, both associated with diuretics, in experimental cirrhotic ascites.Six groups of 12 rats were studied: controls (G1; controls receiving furosemide and potassium canrenoate (G2; rats with ascitic cirrhosis due to 14-week CCl4 treatment (G3; cirrhotic rats treated (over the 11th-14th CCl4 weeks with furosemide and canrenoate (G4, furosemide, canrenoate and clonidine (G5, or diuretics and SSP002021R (G6. Three rats of each group had their hormonal status and renal function assessed at the end of 11th, 12th, 13th, and 14th weeks of respective treatments.Cirrhotic rats in G3 and G4 gained weight over the 12th-14th CCl4 weeks. In G4, brief increase in sodium excretion over the 11th-12th weeks preceded worsening of inulin clearance and natriuresis (diuretic resistance. In comparison with G4, the addition of clonidine (G5 or guanfacine (G6 to diuretics improved, respectively, sodium excretion over the 11th-12th CCl4 weeks, or GFR and electrolytes excretion over the 13th-14th CCl4 weeks. Natriuretic responses in G5 and G6 were accompanied by reduced catecholamine serum levels.α2A-receptor agonists restore glomerular filtration rate and natriuresis, and delay diuretic-resistant ascites in experimental advanced cirrhosis. Clonidine ameliorates diuretic-dependent natriuresis just for a short time.

  11. Cirrhotic Multiorgan Syndrome

    DEFF Research Database (Denmark)

    Møller, Søren; Bendtsen, Flemming

    2015-01-01

    Patients with cirrhosis and portal hypertension are at an increased risk of the development of circulatory dysfunction that may potentially result in multiple organ failure. Apart from the liver, this may involve the heart, lungs, kidneys, the immune system, the adrenal glands, and other organ...... systems. As the disease progresses, the circulation becomes hyperdynamic, and signs of cardiac, pulmonary, and renal dysfunction are observed, in addition to reduced survival. Infections and an altered cardiac function known as cirrhotic cardiomyopathy may be precipitators for the development of other...

  12. Polyphenol-Rich Blackcurrant Juice Prevents Endothelial Dysfunction in the Mesenteric Artery of Cirrhotic Rats with Portal Hypertension: Role of Oxidative Stress and the Angiotensin System.

    Science.gov (United States)

    Rashid, Sherzad; Idris-Khodja, Noureddine; Auger, Cyril; Kevers, Claire; Pincemail, Joël; Alhosin, Mahmoud; Boehm, Nelly; Oswald-Mammosser, Monique; Schini-Kerth, Valérie B

    2018-04-01

    Chronic liver diseases with portal hypertension are characterized by a progressive vasodilatation, endothelial dysfunction, and NADPH oxidase-derived vascular oxidative stress, which have been suggested to involve the angiotensin system. This study evaluated the possibility that oral intake of polyphenol-rich blackcurrant juice (PRBJ), a rich natural source of antioxidants, prevents endothelial dysfunction in a rat model of cirrhosis induced by chronic bile duct ligation (CBDL), and, if so, determined the underlying mechanism. Male Wistar rats received either control drinking water or water containing 60 mg/kg gallic acid equivalents of PRBJ for 3 weeks before undergoing surgery with CBDL or sham surgery. After 4 weeks, vascular reactivity was assessed in mesenteric artery rings using organ chambers. Both the acetylcholine-induced nitric oxide (NO)- and endothelium-dependent hyperpolarization (EDH)-mediated relaxations in mesenteric artery rings were significantly reduced in CBDL rats compared to sham rats. An increased level of oxidative stress and expression of NADPH oxidase subunits, COX-2, NOS, and of the vascular angiotensin system are observed in arterial sections in the CBDL group. Chronic intake of PRBJ prevented the CBDL-induced impaired EDH-mediated relaxation, oxidative stress, and expression of the different target proteins in the arterial wall. In addition, PRBJ prevented the CBDL-induced increase in the plasma level of proinflammatory cytokines (interleukin [IL]-1α, monocyte chemotactic protein 1, and tumor necrosis factor α) and the decrease of the anti-inflammatory cytokine, IL-4. Altogether, these observations indicate that regular ingestion of PRBJ prevents the CBDL-induced endothelial dysfunction in the mesenteric artery most likely by normalizing the level of vascular oxidative stress and the angiotensin system.

  13. New insights into cirrhotic cardiomyopathy

    DEFF Research Database (Denmark)

    Møller, Søren; Hove, Jens D; Dixen, Ulrik

    2013-01-01

    beta-receptor function seem involved in the autonomic and cardiac dysfunction. Cirrhotic cardiomyopathy can be revealed by tissue Doppler imaging but is best demasked by physical or pharmacological stress. Liver transplantation may revert cardiac dysfunction but surgery and shunt insertion may also...

  14. Diastolic dysfunction characterizes cirrhotic cardiomyopathy

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    Piyush O. Somani

    2014-11-01

    Conclusions: Present study shows that although diastolic dysfunction is a frequent event in cirrhosis, it is usually of mild degree and does not correlate with severity of liver dysfunction. There are no significant differences in echocardiographic parameters between alcoholic and non-alcoholic cirrhosis. HRS is not correlated to diastolic dysfunction in cirrhotic patients. There is no difference in survival at one year between patients with or without diastolic dysfunction. Diastolic dysfunction in cirrhosis is unrelated to circulatory dysfunction, ascites and HRS.

  15. Intrarenal octreotide treatment prevents sodium retention in liver cirrhotic rats: evidence for direct effects within the thick ascending limb of Henle's loop

    DEFF Research Database (Denmark)

    Jonassen, Thomas; Christensen, Sten; Marcussen, Niels

    2006-01-01

    not affect the abundance of NCKK2 within the outer medulla. Together with the histological findings, these results indicate that IROA reduces the total number of NKCC2 within the outer medulla. In conclusion, the results indicate a direct intrarenal effect of octreotide on TAL function and morphology......We have previously shown that systemic treatment with the somatostatin analog octreotide has marked beneficial effects on renal function in rats with liver cirrhosis induced by common bile duct ligation (CBL; Jonassen TEN, Christensen S, Sørensen AM, Marcussen N, Flyvbjerg A, Andreasen F......, and Petersen JS. Hepatology 29: 1387-1395, 1999). In the present study, we tested the hypothesis that octreotide has a direct effect on renal tubular function. Rats (CBL or Sham-CBL) were intrarenally treated with low-dose octreotide in a long-acting release formulation, which had no systemic actions (100...

  16. Delay discounting of oral morphine and sweetened juice rewards in dependent and non-dependent rats.

    Science.gov (United States)

    Harvey-Lewis, Colin; Perdrizet, Johnna; Franklin, Keith B J

    2014-07-01

    Opioid-dependent humans are reported to show accelerated delay discounting of opioid rewards when compared to monetary rewards. It has been suggested that this may reflect a difference in discounting of consumable and non-consumable goods not specific to dependent individuals. Here, we evaluate the discounting of similar morphine and non-morphine oral rewards in dependent and non-dependent rats We first tested the analgesic and rewarding effects of our morphine solution. In a second experiment, we assigned rats randomly to either dependent or non-dependent groups that, 30 min after daily testing, received 30 mg/kg subcutaneous dose of morphine, or saline, respectively. Delay discounting of drug-free reward was examined prior to initiation of the dosing regimen. We tested discounting of the morphine reward in half the rats and retested the discounting of the drug-free reward in the other half. All tests were run 22.5 h after the daily maintenance dose. Rats preferred the morphine cocktail to the drug-free solution and consumed enough to induce significant analgesia. The control quinine solution did not produce these effects. Dependent rats discounted morphine rewards more rapidly than before dependence and when compared to discounting drug-free rewards. In non-dependent rats both reward types were discounted similarly. These results show that morphine dependence increases impulsiveness specifically towards a drug reward while morphine experience without dependence does not.

  17. Esophageal varices in cirrhotics on dynamic computed tomography

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    Miyazaki, Masaru; Takahashi, Osamu; Shimura, Tadanori

    1985-07-01

    Dynamic CT was performed on fifteen cirrhotics. The cirrhotics with esophageal varices were compared with those without esophageal varices in regard to the enhanced capacity of the liver and the spleen and the declining ratio of the spleen following the enhancement. Both the liver and the spleen in cirrhotics were enhanced less than non-cirrhotics, especially in those with esophageal varices (p<0.01). Splenic declining ratio following splenic enhancement clearly distinguish cirrhotics with esophageal varices from those without esophageal varices (p<0.01). These parameters on dynamic CT could be useful for the diagnosis of portal hypertension in cirrhotics.

  18. Age dependence of rat liver function measurements

    DEFF Research Database (Denmark)

    Fischer-Nielsen, A; Poulsen, H E; Hansen, B A

    1989-01-01

    Changes in the galactose elimination capacity, the capacity of urea-N synthesis and antipyrine clearance were studied in male Wistar rats at the age of 8, 20 and 44 weeks. Further, liver tissue concentrations of microsomal cytochrome P-450, microsomal protein and glutathione were measured. All...... liver function measurements increased from the age of 8 to 44 weeks when expressed in absolute values. In relation to body weight, these function measurements were unchanged or reduced from week 8 to week 20. At week 44, galactose elimination capacity and capacity of urea-N synthesis related to body...... weight were increased by 10% and 36%, respectively, and antipyrine plasma clearance was reduced to 50%. Liver tissue concentrations of microsomal cytochrome P-450 and microsomal protein increased with age when expressed in absolute values, but were unchanged per g liver, i.e., closely related to liver...

  19. Idiopathic non-cirrhotic portal hypertension

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    CHEN Jie

    2013-07-01

    Full Text Available The pathogenesis of idiopathic non-cirrhotic portal hypertension (INCPH remains unknown and the disease is diagnosed by the absence of recognized clinical indicators of cirrhosis and of any other known etiologies of portal hypertension. To promote understanding of this disease, a comprehensive overview of potential etiologies, clinical manifestations, histopathological features, methods of diagnosis and potential differential diagnoses, and outcome of clinical management is presented in this review. In particular, we discuss the findings from INCPH studies and their implications in regards to each of the above-mentioned categories. For example, associations with various comorbidities have suggested a possible immune system component to INCPH development and/or progression. In addition, the common clinical characteristics of patients upon presentation can not only help to recognize disease suspects but may also provide insights into the pathogenesis and prognosis. Finally, prognosis following the various intervention strategies appears to depend mainly on severity of the portal hypertension, as well as its various accompanying complications.

  20. Effect of liver ischemic preconditioning in cirrhotic rats submitted to hepatic ischemia/reperfusion injury Efeito do pré-condicionamento isquêmico hepático submetidos a lesão de isquemia/reperfusão do fígado

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    Eduardo Garcia Pacheco

    2006-01-01

    Full Text Available PURPOSE: The main aim of this study was to determine the influence of ischemic preconditioning (IPC on rat liver cirrhosis. METHODS: Cirrhosis was induced in Wistar rats by occlusion of the hepatic duct. The animals were divided into four groups of six animals each: non-cirrhotic group (simulated operation only, cirrhotic control group (simulated operation in cirrhotic rats, I/R group (40-minute ischemia without IPC, and IPC group (cirrhotic rats with ischemia, previously submitted to IPC. The IPC procedure consisted of partial hepatic ischemia for five minutes, followed by 10 minutes of reperfusion. In the case of the IPC group, the animals were submitted to liver ischemia for 40 minutes after the preconditioning procedure, followed by 2 hours of reperfusion. Blood samples were collected for measurement of serum aminotransferases (ALT and AST. The respiratory control ratio (RCR, the mitochondrial membrane potential (MMP, and malondialdehyde (MDA values in the hepatic tissue were analyzed. Nonparametric statistical analysis was used and a value of pOBJETIVO: O objetivo deste estudo foi determinar a influência do pré-condicionamento isquêmico (IPC em fígados de ratos cirróticos. MÉTODOS: A cirrose hepática foi induzida em ratos Wistar machos (250 a 300g por oclusão, durante 30 dias, do ducto hepático comum.A seguir, os animais cirróticos foram divididos em três grupos de seis; Grupo controle cirrótico (operação simulada para isquemia/reperfusão/pré-condicionamento, Grupo I/R, isquemia de 40 minutos sem pré-condicionamento (IPC e grupo IPC com isquemia precedida por IPC. O IPC consistiu de uma isquemia parcial por cinco minutos, seguida por 10 minutos de reperfusão. No grupo IPC, após o pré-condicionamento, os animais foram submetidos à isquemia hepática de 40 minutos seguida de 2 horas de reperfusão. Foram colhidas amostras de sangue para dosagem sérica de aminotransferases (ALT e AST. Razão de controle respiratório (RCR

  1. Caffeine dependence in rats: effects of exposure duration and concentration.

    Science.gov (United States)

    Dingle, Rachel N; Dreumont-Boudreau, Sarah E; Lolordo, Vincent M

    2008-09-03

    Groups of rats were chronically exposed to a 1.0-g/L caffeine solution for 5, 10, 15 or 20 days. Upon removal of caffeine, rats were given brief exposure to a novel flavour CS (withdrawal CS) followed by 12 days of plain water and then brief exposure to a second flavour CS (neutral CS). Only rats exposed to 20 days of caffeine strongly preferred the neutral CS to the withdrawal CS in a 2-bottle test. In Experiment 2, groups of rats were chronically exposed to caffeine at one of four concentrations (1.0, 0.5, 0.25, or 0.125 g/L) for 21 days, after which withdrawal and neutral CSs were established. Only rats that drank the highest caffeine concentration, 1.0 g/L, preferred the neutral CS to the withdrawal CS. This suggests that long exposure to a strong caffeine solution is required in order to induce dependence in rats such that a CS associated with the withdrawal of caffeine becomes avoided.

  2. Increased glucose dependence in resting, iron-deficient rats

    International Nuclear Information System (INIS)

    Brooks, G.A.; Henderson, S.A.; Dallman, P.R.

    1987-01-01

    Rates of blood glucose and lactate turnover were assessed in resting iron-deficient and iron-sufficient (control) rats to test the hypothesis that dependence on glucose metabolism is increased in iron deficiency. Male Sprague-Dawley rats, 21 days old, were fed a diet containing either 6 mg iron/kg feed (iron-deficient group) or 50 mg iron/kg feed (iron-sufficient group) for 3-4 wk. The iron-deficient group became anemic, with hemoglobin levels of 6.4 ± 0.2 compared with 13.8 ± 0.3 g/dl for controls. Rats received a 90-min primed continuous infusion of D-[6- 3 H]glucose and sodium L-[U- 14 C]lactate via a jugular catheter. Serial samples were taken from a carotid catheter for concentration and specific activity determinations. Iron-deficient rats had significantly higher blood glucose and lactate concentrations than controls. The iron-deficient group had a significantly higher glucose turnover rate than the control group. Significantly more metabolite recycling in iron-deficient rats was indicated by greater incorporation of 14 C into blood glucose. Assuming a carbon crossover correction factor of 2, half of blood glucose arose from lactate in deficient animals. By comparison, only 25% of glucose arose from lactate in controls. Lack of a difference in lactate turnover rates between deficient rats and controls was attributed to 14 C recycling. The results indicate a greater dependence on glucose metabolism in iron-deficient rats

  3. Swimming reduces the severity of physical and psychological dependence and voluntary morphine consumption in morphine dependent rats.

    Science.gov (United States)

    Fadaei, Atefeh; Gorji, Hossein Miladi; Hosseini, Shahrokh Makvand

    2015-01-15

    Previous studies have indicated that voluntary exercise decreases the severity of the anxiogenic-like behaviors in both morphine-dependent and withdrawn rats. This study examined the effects of regular swimming exercise during the development of dependency and spontaneous morphine withdrawal on the anxiety-depression profile and voluntary morphine consumption in morphine dependent rats. The rats were chronically treated with bi-daily doses (10 mg/kg, at 12h intervals) of morphine over a period of 14 days. The exercising rats were allowed to swim (45 min/d, five days per a week, for 14 or 21 days) during the development of morphine dependence and withdrawal. Then, rats were tested for the severity of morphine dependence, the elevated plus-maze (EPM), sucrose preference test (SPT) and voluntary morphine consumption using a two-bottle choice paradigm in animal models of craving. The results showed that withdrawal signs were decreased in swimmer morphine dependent rats than sedentary rats (Pmorphine-dependent and withdrawn rats exhibited an increase in EPM open arm time and entries (Pmorphine was less in the swimmer morphine-withdrawn rats than the sedentary groups during four periods of the intake of drug (Pmorphine dependence and voluntary morphine consumption with reducing anxiety and depression in morphine-dependent and withdrawn rats. Thus, swimming exercise may be a potential method to ameliorate some of the deleterious behavioral consequences of morphine dependence. Copyright © 2014 Elsevier B.V. All rights reserved.

  4. Mechanisms underlying epithelium-dependent relaxation in rat bronchioles

    DEFF Research Database (Denmark)

    Kroigaard, Christel; Dalsgaard, Thomas; Simonsen, Ulf

    2010-01-01

    This study investigated the mechanisms underlying epithelium-derived hyperpolarizing factor (EpDHF)-type relaxation in rat bronchioles. Immunohistochemistry was performed, and rat bronchioles and pulmonary arteries were mounted in microvascular myographs for functional studies. An opener of small...... (SK(Ca)) and intermediate (IK(Ca))-conductance calcium-activated potassium channels, NS309 (6,7-dichloro-1H-indole-2,3-dione 3-oxime) was used to induce EpDHF-type relaxation. IK(Ca) and SK(Ca)3 positive immunoreactions were observed mainly in the epithelium and endothelium of bronchioles and arteries......, respectively. In 5-hydroxytryptamine (1 microM)-contracted bronchioles (828 +/- 20 microm, n = 84) and U46619 (0.03 microM)-contracted arteries (720 +/- 24 microm, n = 68), NS309 (0.001-10 microM) induced concentration-dependent relaxations that were reduced by epithelium/endothelium removal and by blocking IK...

  5. Alcohol dependence induced in rats by semivoluntary intermittent intake

    Directory of Open Access Journals (Sweden)

    M.S. Macieira

    1997-09-01

    Full Text Available The objective of the present experiment was to assess ethyl alcohol (ETOH dependence brought about by a semivoluntary intermittent intake regimen in rats. Male Wistar rats weighing 150-250 g at the onset of the experiment were assigned to the following groups: 0% ETOH (N = 11, 5% ETOH (N = 20, 20% ETOH (N = 20 and 40% ETOH (N = 18. ETOH solutions were offered at the end of the day and overnight from Monday to Friday, and throughout weekends, for 90 days. The concentration of the ETOH solutions was increased in a stepwise fashion allowing the rats to get used to the taste of alcohol. Reposition of pure water was permitted during 1-h water drinking periods in the morning. Daily volume intake (± SEM averaged 25.4 ± 0.4 ml (0% ETOH, 23.8 ± 0.6 ml (5% ETOH, 17.6 ± 0.7 ml (20% ETOH and 17.5 ± 0.6 ml (40% ETOH. ETOH consumption differed significantly (P<0.05 among groups, averaging 4.4 ± 0.2 g kg-1 day-1 (5% ETOH, 10.3 ± 0.3 g kg-1 day-1 (20% ETOH and 26 ± 1.2 g kg-1 day-1 (40% ETOH. Furthermore, ETOH detection in plasma 10-12 h after offering the solution indicated that its consumption in the 40% ETOH group was sufficient to override its metabolism. Overt signs of ETOH dependence, such as increased thirst, hyperactivity, puffing, hair ruffling and startle responsiveness as well as reduced drowsiness, were significantly increased in the 20% and 40% ETOH groups compared to the 0% and 5% groups. Accordingly, the model described here proved to be a useful tool for the evaluation of subtle or moderate behavioral and physical consequences of long-term ETOH intake

  6. RANTES: a new prostaglandin dependent endogenous pyrogen in the rat.

    Science.gov (United States)

    Tavares, E; Miñano, F J

    2000-09-01

    Fever, a hallmark of disease, is a highly complex process initiated by the action of a number of endogenous pyrogens on the thermosensitive cells of the brain. We describe the activity of RANTES, a chemotactic cytokine, as intrinsically pyrogenic in the rat, when it is delivered directly to the thermosensitive region of the rat's anterior hypothalamic, pre-optic area (AH/POA). RANTES, microinjected into the AH/POA in a dose of 1, 5, 10, 15, 25 or 50 pg, produces an immediate and intense dose-related fever following injection. Increasing the dose to 100 pg did not result in a further increase in the febrile response. No significant change in body temperature was produced by heat-inactivated RANTES. The intrahypothalamic injection of antibodies against RANTES (2.0 microg, 15 min prior to RANTES) significantly blocked the fever induced by this chemokine. Pretreatment with ibuprofen blocked the fever induced by RANTES. In order of potency, the magnitude of the febrile response induced by RANTES was greater than that produced with equipotent doses of either macrophage inflammatory protein-1beta or interleukin-6. The results thus demonstrate that RANTES is the most potent endopyrogen discovered thus far and exerts its action directly on pyrogen-sensitive cells of the AH/POA through a prostaglandin-dependent pathway.

  7. Effect of biliary cirrhosis on nonadrenergic noncholinergic-mediated relaxation of rat corpus cavernosum: Role of nitric oxide pathway and endocannabinoid system

    Directory of Open Access Journals (Sweden)

    Dehpour A.R.

    2008-06-01

    Full Text Available Background: Relaxation of the corpus cavernosum plays a major role in penile erection. Nitric oxide (NO is known to be the most important factor mediating relaxation of corpus cavernosum, which is mainly derived from nonadrenergic noncholinergic (NANC nerves. The aim of the present study was to investigate the effect of biliary cirrhosis on nonadrenergic noncholinergic (NANC-mediated relaxation of rat corpus cavernosum as well as the possible relevant roles of endocannabinoid and nitric oxide systems.Methods: Corporal strips from sham-operated and biliary cirrhotic rats were mounted under tension in a standard oxygenated organ bath with guanethidine sulfate (5 µM and atropine (1 µM to induce adrenergic and cholinergic blockade. The strips were precontracted with phenylephrine hydrochloride (7.5 µM and electrical field stimulation was applied at different frequencies (2, 5, 10, 15 Hz to obtain NANC-mediated relaxation. In separate precontracted strips of the sham and cirrhotic groups, the concentration-dependent relaxant responses to sodium nitroprusside (10 nM-1mM, as an NO donor, were assessed.  Results: The NANC-mediated relaxation was significantly enhanced in cirrhotic animals (P<0.01. Anandamide potentiated the relaxations in both groups (P<0.05. The cannabinoid CB1 receptor antagonist AM251 (10 µM and the vanilloid receptor antagonist capsazepine (10 µM each significantly prevented the enhanced relaxations in cirrhotic rats (P<0.01. The CB2 receptor antagonist AM630 had no effect on relaxations in the cirrhotic group. In a concentration-dependent manner, L-NAME (30-1000 nM inhibited relaxations in both the sham and cirrhotic groups, although cirrhotic groups were more resistant to the inhibitory effects of L-NAME. The degree of relaxation induced by sodium nitroprusside (10 nM-1 mM was similar in the two groups.Conclusions: Biliary cirrhosis enhances the neurogenic relaxation in rat corpus cavernosum probably via the NO pathway and

  8. Parathyroid hormone dependent T cell proliferation in uremic rats

    DEFF Research Database (Denmark)

    Lewin, E; Ladefoged, Jens; Brandi, L

    1993-01-01

    Chronic renal failure (CRF) is combined with an impairment of the immune system. The T cell may be a target for the action of parathyroid hormone (PTH). Rats with CRF have high blood levels of PTH. Therefore, the present investigation examined some aspects of the T cell function in both normal...... and CRF rats before and after parathyroidectomy and after an isogenic kidney transplantation. The T cell proliferative response to phytohemagglutinin (PHA) stimulation was significantly higher in peripheral blood mononuclear cell (PBMC) cultures obtained from CRF rats than from normal rats. After...... parathyroidectomy the T cells of normal as well as of uremic rats could still be significantly stimulated by PHA, but now no significant difference was seen. When CRF was reversed after an isogenic kidney transplantation and PTH reversed to levels in the normal range, the T cell proliferative response to PHA...

  9. Laparoscopic cholecystectomy in cirrhotic patients: the role of subtotal cholecystectomy and its variants.

    Science.gov (United States)

    Palanivelu, Chinnasamy; Rajan, Pidigu Seshiyer; Jani, Kalpesh; Shetty, Alangar Roshan; Sendhilkumar, Karuppasamy; Senthilnathan, Palanisamy; Parthasarthi, Ramakrishnan

    2006-08-01

    Open cholecystectomy is associated with considerable morbidity and mortality in cirrhotic patients. Laparoscopic cholecystectomy may offer a better option because of the magnification available and the availability of newer instruments like the ultrasonic shears. We present our experience of 265 laparoscopic cholecystectomies and attempt to identify the difficulties encountered in this group of patients. Between 1991 and 2005, 265 cirrhotic patients of Child-Pugh Classification A and B, with symptomatic gallstones, were subjected to laparoscopic cholecystectomy. We describe here our tailored approach and our techniques of subtotal cholecystectomy. Features of acute cholecystitis were present in 35.1% of the patients, and 64.9% presented with chronic cholecystitis. In 81.5% of the patients, the diagnosis of cirrhosis was established preoperatively. In 8.3% of the patients, a fundus first method was adopted when the hilum could not be approached despite additional ports. Modified subtotal cholecystectomy was performed in a total of 206 patients. Mean operative time in the subtotal cholecystectomy group was 72 minutes; in the standard group, it was 41 minutes. There was no mortality. In 15% of patients, postoperative deterioration in liver function occurred. Worsening of ascites, port site infection, port site bleeding, intraoperative hemorrhage, bilious drainage, and stone formation in the remnant were the other complications encountered. Laparoscopic cholecystectomy is a safe and effective treatment for calculous cholecystitis in cirrhotic patients. Appropriate modification of subtotal cholecystectomy should be practiced, depending on the risk factors present, to avoid complications.

  10. High mortality in cirrhotic patients following hemorrhagic stroke.

    Science.gov (United States)

    Hung, Tsung-Hsing; Hsieh, Yu-Hsi; Tseng, Kuo-Chih; Tseng, Chih-Wei; Lee, Hsing-Feng; Tsai, Chih-Chun; Tsai, Chen-Chi

    2015-06-01

    The impact of hemorrhagic stroke (HS) on the mortality of cirrhotic patients is unknown. To evaluate the morality risk of HS in cirrhotic patients, we used the Taiwan National Health Insurance Database to evaluate cirrhotic patients with HS who were discharged between 1 January and 31 December 2007. In total, there were 321 cirrhotic patients with HS. We randomly selected 3210 cirrhotic patients without HS as a comparison group. The 30 and 90 day mortality rates were 29.6% and 43.0% in the HS group, and 9.1% and 17.7% in the comparison group, respectively (pmortality in the HS group was 3.89 (95% confidence interval [CI] 3.20-4.71, pmortality in the subarachnoid hemorrhage and other HS groups were 7.93 (95% CI 5.23-12.0, pmortality risk in cirrhotic patients, in whom subarachnoid hemorrhage can also increase the risk of mortality eight-fold. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. Age, Dose, and Time-Dependency of Plasma and Tissue Distribution of Deltamethrine in Immature Rats

    Science.gov (United States)

    The major objective of this project was to characterize the systemic disposition of the pyrethroid, deltamethrin (DLT), in immature rats, with emphasis on the age-dependence of target organ (brain) dosimetry. Postnatal day (PND) 10, 21, and 40 male Sprague-Dawley rats received 0...

  12. Myoelectric activity of the small intestine during morphine dependence and withdrawal in rats

    International Nuclear Information System (INIS)

    Kuperman, D.A.; Sninsky, C.A.; Lynch, D.F.

    1987-01-01

    The authors investigated (1) the effect of morphine dependence on the migrating myoelectric complex (MMC) of the small intestine, (2) whether bacterial overgrowth developed in morphine-dependent rats, and (3) the effect of naloxone and methylbromide naltrexone, a peripheral opioid antagonist, on the MMC in morphine-naive and morphine-dependent rats. They also evaluated intestinal motility during naloxone-induced withdrawal in animals pretreated with clonidine. Intestinal myoelectric activity was monitored by four indwelling electrodes in unanesthetized, fasted rats. D-[ 14 C]xylose breath tests were performed before and after morphine-pellet implantation to evaluate the presence of bacterial overgrowth of the small intestine. Naloxone had no effect on myoelectric activity of the small intestine in morphine-naive rats. Cycling activity fronts were present in morphine-dependent animals, but there was a significant prolongation of activity front periodicity and slowing of the propagation velocity. No significant increase in 14 CO 2 excretion was noted in the morphine-dependent rats. They conclude from their studies that (1) myoelectric activity of the small intestine develops incomplete tolerance to morphine; (2) bacterial overgrowth is not a feature of morphine dependence in the rat; (3) alterations of intestinal myoelectric activity are a component of the opiate withdrawal syndrome, and they appear at least partially mediated by a peripheral mechanism that can be suppressed by an α 2 -adrenergic agonist

  13. Myoelectric activity of the small intestine during morphine dependence and withdrawal in rats

    Energy Technology Data Exchange (ETDEWEB)

    Kuperman, D.A.; Sninsky, C.A.; Lynch, D.F.

    1987-04-01

    The authors investigated (1) the effect of morphine dependence on the migrating myoelectric complex (MMC) of the small intestine, (2) whether bacterial overgrowth developed in morphine-dependent rats, and (3) the effect of naloxone and methylbromide naltrexone, a peripheral opioid antagonist, on the MMC in morphine-naive and morphine-dependent rats. They also evaluated intestinal motility during naloxone-induced withdrawal in animals pretreated with clonidine. Intestinal myoelectric activity was monitored by four indwelling electrodes in unanesthetized, fasted rats. D-(/sup 14/C)xylose breath tests were performed before and after morphine-pellet implantation to evaluate the presence of bacterial overgrowth of the small intestine. Naloxone had no effect on myoelectric activity of the small intestine in morphine-naive rats. Cycling activity fronts were present in morphine-dependent animals, but there was a significant prolongation of activity front periodicity and slowing of the propagation velocity. No significant increase in /sup 14/CO/sub 2/ excretion was noted in the morphine-dependent rats. They conclude from their studies that (1) myoelectric activity of the small intestine develops incomplete tolerance to morphine; (2) bacterial overgrowth is not a feature of morphine dependence in the rat; (3) alterations of intestinal myoelectric activity are a component of the opiate withdrawal syndrome, and they appear at least partially mediated by a peripheral mechanism that can be suppressed by an ..cap alpha../sub 2/-adrenergic agonist.

  14. [Evaluation and treatment of the critically ill cirrhotic patient].

    Science.gov (United States)

    Fernández, Javier; Aracil, Carles; Solà, Elsa; Soriano, Germán; Cinta Cardona, Maria; Coll, Susanna; Genescà, Joan; Hombrados, Manoli; Morillas, Rosa; Martín-Llahí, Marta; Pardo, Albert; Sánchez, Jordi; Vargas, Victor; Xiol, Xavier; Ginès, Pere

    2016-11-01

    Cirrhotic patients often develop severe complications requiring ICU admission. Grade III-IV hepatic encephalopathy, septic shock, acute-on-chronic liver failure and variceal bleeding are clinical decompensations that need a specific therapeutic approach in cirrhosis. The increased effectiveness of the treatments currently used in this setting and the spread of liver transplantation programs have substantially improved the prognosis of critically ill cirrhotic patients, which has facilitated their admission to critical care units. However, gastroenterologists and intensivists have limited knowledge of the pathogenesis, diagnosis and treatment of these complications and of the prognostic evaluation of critically ill cirrhotic patients. Cirrhotic patients present alterations in systemic and splanchnic hemodynamics, coagulation and immune dysfunction what further increase the complexity of the treatment, the risk of developing new complications and mortality in comparison with the general population. These differential characteristics have important diagnostic and therapeutic implications that must be known by general intensivists. In this context, the Catalan Society of Gastroenterology and Hepatology requested a group of experts to draft a position paper on the assessment and treatment of critically ill cirrhotic patients. This article describes the recommendations agreed upon at the consensus meetings and their main conclusions. Copyright © 2015 Elsevier España, S.L.U. y AEEH y AEG. All rights reserved.

  15. Neonatal Handling Produces Sex Hormone-Dependent Resilience to Stress-Induced Muscle Hyperalgesia in Rats.

    Science.gov (United States)

    Alvarez, Pedro; Green, Paul G; Levine, Jon D

    2018-06-01

    Neonatal handling (NH) of male rat pups strongly attenuates stress response and stress-induced persistent muscle hyperalgesia in adults. Because female sex is a well established risk factor for stress-induced chronic muscle pain, we explored whether NH provides resilience to stress-induced hyperalgesia in adult female rats. Rat pups underwent NH, or standard (control) care. Muscle mechanical nociceptive threshold was assessed before and after water avoidance (WA) stress, when they were adults. In contrast to male rats, NH produced only a modest protection against WA stress-induced muscle hyperalgesia in female rats. Gonadectomy completely abolished NH-induced resilience in male rats but produced only a small increase in this protective effect in female rats. The administration of the antiestrogen drug fulvestrant, in addition to gonadectomy, did not enhance the protective effect of NH in female rats. Finally, knockdown of the androgen receptor by intrathecal antisense treatment attenuated the protective effect of NH in intact male rats. Together, these data indicate that androgens play a key role in NH-induced resilience to WA stress-induced muscle hyperalgesia. NH induces androgen-dependent resilience to stress-induced muscle pain. Therefore, androgens may contribute to sex differences observed in chronic musculoskeletal pain and its enhancement by stress. Copyright © 2018 The American Pain Society. Published by Elsevier Inc. All rights reserved.

  16. Prevalence of simple liver cysts and hemangiomas in cirrhotic and non-cirrhotic patients submitted to magnetic resonance imaging

    Directory of Open Access Journals (Sweden)

    Breno Victor Tomaz Galvao

    2013-07-01

    Full Text Available Objective To determine the prevalence of liver cysts and hemangiomas in the general population and in cirrhotic patients. Materials and Methods Retrospective, observational, and cross-sectional study selecting consecutive magnetic resonance imaging studies performed in the period from February to July 2011. A total of 303 patients (187 women and 116 men with mean age of 53.3 years were included in the present study. Patients with previously known liver lesions were excluded. The images were consensually analyzed by two observers in the search for simple liver cysts and typical liver hemangiomas, according to universally accepted imaging criteria. Lesions prevalence, diameters and location were determined in both cirrhotic and non-cirrhotic individuals. Results The authors observed prevalence of 8.6% for hemangiomas and 14.5% for simple cysts. No statistically significant difference was observed in relation to prevalence of hemangiomas and cysts among cirrhotic and non-cirrhotic patients (p = 0.954; p = 0.472. Conclusion In the present study, the prevalence of cysts and hemangiomas was higher than the prevalence reported by autopsy series. No influence of cirrhosis was observed on the prevalence and appearance of such incidental lesions.

  17. Dose and time dependent ototoxicity of aspartame in rats.

    Science.gov (United States)

    Ozturan, Orhan; Dogan, Remzi; Tugrul, Selahattin; Gedik, Ozge; Sjostrand, Alev Pektas; Yildirim, Yavuz Selim

    2017-04-01

    Low-dose administration of Aspartame (Ap) did not produce a significant ototoxic effect at the end of the 6th month. However, duration of the ototoxic effect is shortened and severity of the effect is increased as dose and duration of Ap administration is increased. While Ap toxicity has been studied in short- and long-term studies, its effects on hearing have not been investigated. This study was conducted to evaluate the effects of long-term consumption of Ap administered in various doses on hearing status of rats. The study included 54 female Wistar Albino rats. Ap was given for 6 months to the rats. The groups were assigned according to levels of Ap dosage. DPOAE and ABR tests were utilized for serial hearing evaluations. Serial hearing measurement times were designed as baseline, 1st week, 2nd week, 1st, 2nd, 3rd, and 6th months. While audiological parameters deteriorated with 100 mg/kg/day dose after the 3rd month, ABR thresholds were elevated and DPOAE values were significantly decreased in 500 mg/kg/day and 1000 mg/kg/day applications after the 2nd month. In 2000 mg/kg/day and 4000 mg/kg/day applications, deteriorations in audiological parameters were detected as early as the first and second months; respectively.

  18. Free radical activity during development of insulin-dependent diabetes mellitus in the rat

    Energy Technology Data Exchange (ETDEWEB)

    Pitkaenen, O.M.; Akerblom, H.K.; Sariola, H.; Andersson, S.M. (Univ. of Helsinki (Finland)); Martin, J.M. (Hospital for Sick Children, Toronto, Ontario (Canada)); Hallman, M. (Univ. of California, Irvine (United States))

    1991-01-01

    Free radical-induced lipid peroxidation was quantified by measuring expired pentane from diabetic prone BB Wistar rats of 45-90 d of age. Insulin-dependent diabetes mellitus was manifest at the age of 71 {plus minus} 8 d. Expired pentane increased from 2.1 {plus minus} 0.7 to 5.0 {plus minus}3.0 pmol/100g/min (p <0.01) at manifestation of the disease and remained high throughout the test period. In healthy age-matched control rats it persisted low. In rats made diabetic with streptozotocin, expired pentane remained low. The changes in expired pentane suggest that the development of endogenous insulin-dependent diabetes mellitus in BB rats is associated with increased free radical activity. This is not due to hyperglycemia or ketosis per se, and reflects a fundamental difference in the free radical activity between the spontaneously diabetic BB rats and the disease produced by streptozotocin. Development of spontaneous insulin-dependent diabetes in BB rats is associated with increased free radical activity that persists after the manifestation of the disease.

  19. Development of mechanical hypersensitivity in rats during heroin and ethanol dependence: alleviation by CRF₁ receptor antagonism.

    Science.gov (United States)

    Edwards, Scott; Vendruscolo, Leandro F; Schlosburg, Joel E; Misra, Kaushik K; Wee, Sunmee; Park, Paula E; Schulteis, Gery; Koob, George F

    2012-02-01

    Animal models of drug dependence have described both reductions in brain reward processes and potentiation of stress-like (or anti-reward) mechanisms, including a recruitment of corticotropin-releasing factor (CRF) signaling. Accordingly, chronic exposure to opiates often leads to the development of mechanical hypersensitivity. We measured paw withdrawal thresholds (PWTs) in male Wistar rats allowed limited (short access group: ShA) or extended (long access group: LgA) access to heroin or cocaine self-administration, or in rats made dependent on ethanol via ethanol vapor exposure (ethanol-dependent group). In heroin self-administering animals, after transition to LgA conditions, thresholds were reduced to around 50% of levels observed at baseline, and were also significantly lower than thresholds measured in animals remaining on the ShA schedule. In contrast, thresholds in animals self-administering cocaine under either ShA (1 h) or LgA (6 h) conditions were unaltered. Similar to heroin LgA rats, ethanol-dependent rats also developed mechanical hypersensitivity after eight weeks of ethanol vapor exposure compared to non-dependent animals. Systemic administration of the CRF1R antagonist MPZP significantly alleviated the hypersensitivity observed in rats dependent on heroin or ethanol. The emergence of mechanical hypersensitivity with heroin and ethanol dependence may thus represent one critical drug-associated negative emotional state driving dependence on these substances. These results also suggest a recruitment of CRF-regulated nociceptive pathways associated with escalation of intake and dependence. A greater understanding of relationships between chronic drug exposure and pain-related states may provide insight into mechanisms underlying the transition to drug addiction, as well as reveal new treatment opportunities. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'. Copyright © 2011 Elsevier Ltd. All rights reserved.

  20. Spinal cord thyrotropin releasing hormone receptors of morphine tolerant-dependent and abstinent rats

    Energy Technology Data Exchange (ETDEWEB)

    Rahmani, N.H.; Gulati, A.; Bhargava, H.N. (Univ. of Illinois, Chicago (USA))

    1990-07-01

    The effect of chronic administration of morphine and its withdrawal on the binding of 3H-(3-MeHis2)thyrotropin releasing hormone (3H-MeTRH) to membranes of the spinal cord of the rat was determined. Male Sprague-Dawley rats were implanted with either 6 placebo or 6 morphine pellets (each containing 75-mg morphine base) during a 7-day period. Two sets of animals were used. In one, the pellets were left intact at the time of sacrificing (tolerant-dependent) and in the other, the pellets were removed 16 hours prior to sacrificing (abstinent rats). In placebo-pellet-implanted rats, 3H-MeTRH bound to the spinal cord membranes at a single high affinity binding site with a Bmax of 21.3 +/- 1.6 fmol/mg protein, and an apparent dissociation constant Kd of 4.7 +/- 0.8 nM. In morphine tolerant-dependent or abstinent rats, the binding constants of 3H-MeTRH to spinal cord membranes were unaffected. Previous studies from this laboratory indicate that TRH can inhibit morphine tolerance-dependence and abstinence processes without modifying brain TRH receptors. Together with the present results, it appears that the inhibitory effect of TRH on morphine tolerance-dependence and abstinence is probably not mediated via central TRH receptors but may be due to its interaction with other neurotransmitter systems.

  1. Dose dependent disposition of gallium-67 in rats

    International Nuclear Information System (INIS)

    Gautam, S.R.

    1982-01-01

    Radioactive gallium-67 has been employed as a diagnostic and follow-up agent for cancer therapy. Currently gallium nitrate is undergoing Phase I clinical studies. A million fold increase in the concentration of the carrier gallium citrate over the range of carrier-free gallium-67 (pgm) to 1.0 μg caused no significant alteration in the disposition of gallium-67 in rats.Gallium-67 was eliminated from blood with a biological t1/2 of 4.1 days. A linear tissue binding profile was observed for gallium-67 over this concentration range. A multi-compartment pharmacokinetic model was developed in which all the tissues studied were treated as separate compartments. At 1.0 mg dose level, significant alteration in the disposition of gallium-67 was observed in rats, > 95% of the initial radioactivity was characteristic reappearance of the radioactivity in the blood approximately 4 hours after dosing leading to a ''hump'' in the blood concentration-time profiles. Following the 1.0 mg dose low tissue levels were observed, except for the kidneys, which contained about 8% of the administered dose per gram of the tissue one-half hour after dosing. A non-linear tissue binding profile was observed to be associated with gallium at high doses. It was hypothesized that the rapid loss of gallium-67 from the vascular system following the high doses of gallium citrate was due to the accumulation of the drug in the kidneys where it was eventually eliminated via urine. The kidneys thus would act as a temporary storage site for gallium. It was concluded that the dose-related renal toxicity associated with gallium therapy may be attributed to the kidney's role as a temporary storage site following high doses

  2. Liver resection for non-cirrhotic hepatocellular carcinoma in south ...

    African Journals Online (AJOL)

    Background. We describe the clinicopathologic features and outcome of South African patients who have undergone hepatic resection for hepatocellular carcinoma (HCC) arising in a non-cirrhotic liver. Methods. We utilised the prospective liver resection database in the Surgical Gastroenterology Unit at Groote Schuur ...

  3. Idiopathic non-cirrhotic portal hypertension: a review

    NARCIS (Netherlands)

    Schouten, Jeoffrey N. L.; Verheij, Joanne; Seijo, Susana

    2015-01-01

    Idiopathic non-cirrhotic portal hypertension (INCPH) is a rare disease characterized of intrahepatic portal hypertension in the absence of cirrhosis or other causes of liver disease and splanchnic venous thrombosis. The etiology of INCPH can be classified in five categories: 1) immunological

  4. Pathology of idiopathic non-cirrhotic portal hypertension.

    Science.gov (United States)

    Guido, Maria; Sarcognato, Samantha; Sacchi, Diana; Colloredo, Guido

    2018-04-12

    Idiopathic non-cirrhotic portal hypertension is an under-recognized vascular liver disease of unknown etiology, characterized by clinical signs of portal hypertension in the absence of cirrhosis. By definition, any disorder known to cause portal hypertension in the absence of cirrhosis and any cause of chronic liver disease must be excluded to make a diagnosis of idiopathic non-cirrhotic portal hypertension. However, the diagnosis is often difficult because the disease resembles cirrhosis and there is no gold standard test. Liver biopsy is an essential tool: it is able to exclude cirrhosis and other causes of portal hypertension and it allows the identification of the characteristic lesions. Nonetheless, the histological diagnosis of idiopathic non-cirrhotic portal hypertension is not always straightforward, in particular by needle biopsy samples, because there is no pathognomonic lesion, but rather a variety of vascular changes which are unevenly distributed, very subtle, and not all necessarily identified in a single specimen. Pathologists should be able to recognize several patterns of injury, involving portal/periportal areas as well as parenchymal structures.The histological features of idiopathic non-cirrhotic portal hypertension are described in this review, focusing on their interpretation in needle biopsy specimens.

  5. Ghrelin, leptin and insulin in cirrhotic children and adolescents: relationship with cirrhosis severity and nutritional status.

    Science.gov (United States)

    Dornelles, Cristina T L; Goldani, Helena A S; Wilasco, Maria Inês A; Maurer, Rafael L; Kieling, Carlos O; Porowski, Marilene; Ferreira, Cristina T; Santos, Jorge L; Vieira, Sandra M G; Silveira, Themis R

    2013-01-10

    Ghrelin, leptin, and insulin concentrations are involved in the control of food intake and they seem to be associated with anorexia-cachexia in cirrhotic patients. The present study aimed to investigate the relationship between the nutritional status and fasting ghrelin, leptin and insulin concentrations in pediatric cirrhotic patients. Thirty-nine patients with cirrhosis and 39 healthy controls aged 0-15 years matched by sex and age were enrolled. Severity of liver disease was assessed by Child-Pugh classification, and Pediatric for End Stage Liver Disease (PELD) or Model for End-stage Liver Disease (MELD) scores. Blood samples were collected from patients and controls to assay total ghrelin, acyl ghrelin, leptin and insulin by using a commercial ELISA kit. Anthropometry parameters used were standard deviation score of height-for-age and triceps skinfold thickness-for-age ratio. A multiple linear regression analysis was used to determine the correlation between dependent and independent variables. Acyl ghrelin was significantly lower in cirrhotic patients than in controls [142 (93-278) pg/mL vs 275 (208-481) pg/mL, P=0.001]. After multiple linear regression analysis, total ghrelin and acyl ghrelin showed an inverse correlation with age; acyl ghrelin was associated with the severity of cirrhosis and des-acyl ghrelin with PELD or MELD scores ≥15. Leptin was positively correlated with gender and anthropometric parameters. Insulin was not associated with any variable. Low acyl ghrelin and high des-acyl ghrelin concentrations were associated with cirrhosis severity, whereas low leptin concentration was associated with undernourishment in children and adolescents with cirrhosis. Copyright © 2012 Elsevier B.V. All rights reserved.

  6. Incidence of bacteremia in cirrhotic patients undergoing upper endoscopic ultrasonography.

    Science.gov (United States)

    Fernández-Esparrach, Gloria; Sendino, Oriol; Araujo, Isis; Pellisé, Maria; Almela, Manel; González-Suárez, Begoña; López-Cerón, María; Córdova, Henry; Sanabria, Erwin; Uchima, Hugo; Llach, Josep; Ginès, Àngels

    2014-01-01

    The incidence of bacteremia after endoscopic ultrasonography (EUS) or EUS-guided fine-needle aspiration (EUS-FNA) is between 0% and 4%, but there are no data on this topic in cirrhotic patients. To prospectively assess the incidence of bacteremia in cirrhotic patients undergoing EUS and EUS-FNA. We enrolled 41 cirrhotic patients. Of these, 16 (39%) also underwent EUS-FNA. Blood cultures were obtained before and at 5 and 30 min after the procedure. When EUS-FNA was used, an extra blood culture was obtained after the conclusion of radial EUS and before the introduction of the sectorial echoendoscope. All patients were clinically followed up for 7 days for signs of infection. Blood cultures were positive in 16 patients. In 10 patients, blood cultures grew coagulase-negative Staphylococcus, Corynebacterium species, Propionibacterium species or Acinetobacterium Lwoffii, which were considered contaminants (contamination rate 9.8%, 95% CI: 5.7-16%). The remaining 6 patients had true positive blood cultures and were considered to have had true bacteremia (15%, 95% CI: 4-26%). Blood cultures were positive after diagnostic EUS in five patients but were positive after EUS-FNA in only one patient. Thus, the frequency of bacteremia after EUS and EUS-FNA was 12% and 6%, respectively (95% CI: 2-22% and 0.2-30%, respectively). Only one of the patients who developed bacteremia after EUS had a self-limiting fever with no other signs of infection. Asymptomatic Gram-positive bacteremia developed in cirrhotic patients after EUS and EUS-FNA at a rate higher than in non-cirrhotic patients. However, this finding was not associated with any clinically significant infections. Copyright © 2013 Elsevier España, S.L. and AEEH y AEG. All rights reserved.

  7. Pubertal dependent effects of cadmium on episodic prolactin secretion in male rats

    Energy Technology Data Exchange (ETDEWEB)

    Lafuente, A.; Alvarez-Demanuel, E.; Marquez, N. [Fac. de Cienicas, Orense (Spain). Lab. de Toxicologia; Esquifino, A.I. [Dept. Bioquimica, Facultad de Medicina, Universidad Complutense, 28040-Madrid (Spain)

    1999-02-01

    This work was undertaken to assess if exposure to cadmium related to puberty may affect the episodic pattern of prolactin. Male rats were submitted to cadmium exposure, from day 30 to 60 or from day 60 to 90 of life respectively, at a dose of 50 ppm in the drinking water. Control age-matched rats received cadmium-free water. Prepubertal cadmium administration decreased mean serum prolactin levels and the absolute amplitude of the prolactin pulses. Subchronic exposure to cadmium of adult rats decreased mean serum prolactin levels, the absolute amplitude of the prolactin pulses and their duration, and the mean half-life of the hormone. These results suggest that subchronic cadmium exposure changes the secretory pattern of prolactin in adult male rats in a puberty-dependent way. (orig.) With 1 fig., 1 tab., 37 refs.

  8. Effect of environmental enrichment on physical and psychological dependence signs and voluntary morphine consumption in morphine-dependent and morphine-withdrawn rats.

    Science.gov (United States)

    Hammami-Abrand Abadi, Arezoo; Miladi-Gorji, Hossein; Bigdeli, Imanollah

    2016-04-01

    This study was designed to examine the effect of environmental enrichment during morphine dependency and withdrawal on the severity of naloxone-precipitated withdrawal signs, anxiety, and depressive-like behaviors and voluntary morphine consumption in morphine-dependent rats. The rats were injected with bi-daily doses (10 mg/kg, 12 h intervals) of morphine for 14 days following rearing in a standard environment (SE) or enriched environment (EE) during the development of morphine dependence and withdrawal. Then, rats were tested for withdrawal signs after naloxone injection, anxiety (the elevated plus maze) and depression-related behavior (sucrose preference test), and voluntary consumption of morphine using a two-bottle choice paradigm, in morphine-dependent and morphine-withdrawn rats. The results showed that EE decreased naloxone-precipitated withdrawal signs, but not anxiety or sucrose preference during dependence on morphine. The EE-withdrawn rats showed an increase in the elevated plus maze open arm time and entries and higher levels of sucrose preference than SE rats. Voluntary consumption of morphine was lower in the EE-withdrawn rats than in the SE groups in the second period of drug intake. Thus, exposure to EE reduced the severity of morphine dependence and voluntary consumption of morphine, alongside reductions in anxiety and depression-related behavior in morphine-withdrawn rats.

  9. Fluoxetine Exerts Age-Dependent Effects on Behavior and Amygdala Neuroplasticity in the Rat

    Science.gov (United States)

    Homberg, Judith R.; Olivier, Jocelien D. A.; Blom, Tom; Arentsen, Tim; van Brunschot, Chantal; Schipper, Pieter; Korte-Bouws, Gerdien; van Luijtelaar, Gilles; Reneman, Liesbeth

    2011-01-01

    The selective serotonin reuptake inhibitor (SSRI) Prozac® (fluoxetine) is the only registered antidepressant to treat depression in children and adolescents. Yet, while the safety of SSRIs has been well established in adults, serotonin exerts neurotrophic actions in the developing brain and thereby may have harmful effects in adolescents. Here we treated adolescent and adult rats chronically with fluoxetine (12 mg/kg) at postnatal day (PND) 25 to 46 and from PND 67 to 88, respectively, and tested the animals 7–14 days after the last injection when (nor)fluoxetine in blood plasma had been washed out, as determined by HPLC. Plasma (nor)fluoxetine levels were also measured 5 hrs after the last fluoxetine injection, and matched clinical levels. Adolescent rats displayed increased behavioral despair in the forced swim test, which was not seen in adult fluoxetine treated rats. In addition, beneficial effects of fluoxetine on wakefulness as measured by electroencephalography in adults was not seen in adolescent rats, and age-dependent effects on the acoustic startle response and prepulse inhibition were observed. On the other hand, adolescent rats showed resilience to the anorexic effects of fluoxetine. Exploratory behavior in the open field test was not affected by fluoxetine treatment, but anxiety levels in the elevated plus maze test were increased in both adolescent and adult fluoxetine treated rats. Finally, in the amygdala, but not the dorsal raphe nucleus and medial prefrontal cortex, the number of PSA-NCAM (marker for synaptic remodeling) immunoreactive neurons was increased in adolescent rats, and decreased in adult rats, as a consequence of chronic fluoxetine treatment. No fluoxetine-induced changes in 5-HT1A receptor immunoreactivity were observed. In conclusion, we show that fluoxetine exerts both harmful and beneficial age-dependent effects on depressive behavior, body weight and wakefulness, which may relate, in part, to differential fluoxetine

  10. Fluoxetine exerts age-dependent effects on behavior and amygdala neuroplasticity in the rat.

    Directory of Open Access Journals (Sweden)

    Judith R Homberg

    Full Text Available The selective serotonin reuptake inhibitor (SSRI Prozac® (fluoxetine is the only registered antidepressant to treat depression in children and adolescents. Yet, while the safety of SSRIs has been well established in adults, serotonin exerts neurotrophic actions in the developing brain and thereby may have harmful effects in adolescents. Here we treated adolescent and adult rats chronically with fluoxetine (12 mg/kg at postnatal day (PND 25 to 46 and from PND 67 to 88, respectively, and tested the animals 7-14 days after the last injection when (norfluoxetine in blood plasma had been washed out, as determined by HPLC. Plasma (norfluoxetine levels were also measured 5 hrs after the last fluoxetine injection, and matched clinical levels. Adolescent rats displayed increased behavioral despair in the forced swim test, which was not seen in adult fluoxetine treated rats. In addition, beneficial effects of fluoxetine on wakefulness as measured by electroencephalography in adults was not seen in adolescent rats, and age-dependent effects on the acoustic startle response and prepulse inhibition were observed. On the other hand, adolescent rats showed resilience to the anorexic effects of fluoxetine. Exploratory behavior in the open field test was not affected by fluoxetine treatment, but anxiety levels in the elevated plus maze test were increased in both adolescent and adult fluoxetine treated rats. Finally, in the amygdala, but not the dorsal raphe nucleus and medial prefrontal cortex, the number of PSA-NCAM (marker for synaptic remodeling immunoreactive neurons was increased in adolescent rats, and decreased in adult rats, as a consequence of chronic fluoxetine treatment. No fluoxetine-induced changes in 5-HT(1A receptor immunoreactivity were observed. In conclusion, we show that fluoxetine exerts both harmful and beneficial age-dependent effects on depressive behavior, body weight and wakefulness, which may relate, in part, to differential

  11. The endocannabinoid transport inhibitor AM404 differentially modulates recognition memory in rats depending on environmental aversiveness

    Directory of Open Access Journals (Sweden)

    Patrizia eCampolongo

    2012-03-01

    Full Text Available Cannabinoid compounds may influence both emotional and cognitive processes depending on the level of environmental aversiveness at the time of drug administration. However, the mechanisms responsible for these responses remain to be elucidated. The present experiments investigated the effects induced by the endocannabinoid transport inhibitor AM404 (0.5-5 mg/kg, i.p. on bothemotional and cognitive performances of rats tested in a Spatial Open Field task and subjected to different experimental settings, named High Arousal and Low Arousal conditions. The two different experimental conditions influenced emotional reactivity independently of drug administration. Indeed, vehicle-treated rats exposed to the Low Arousal condition spent more time in the centre of the arena than vehicle-treated rats exposed to the High Arousal context. Conversely, the different arousal conditions did not affect the cognitive performances of vehicle-treated animals such as the capability to discriminate a spatial displacement of the objects or an object substitution.AM404 administration did not alter the locomotor activity of the animals exposed to both environmental conditions. Interestingly, AM404 administration increased the emotional reactivity of rats exposed to the High Arousal condition but did not influence emotionality of rats exposed to the Low Arousal condition. Moreover, AM404 administration influenced the cognitive parameters depending on the level of emotional arousal: it impaired the capability of rats exposed to the High Arousal condition to recognize a novel object while it did not induce any impairing effect in rats exposed to the Low Arousal condition.These findings suggest that drugs which enhance the endocannabinoid signalling induce different effects on recognition memory performance depending on the level of emotional arousal induced by the environmental conditions.

  12. Gravity-dependent ventilation distribution in rats measured with electrical impedance tomography

    International Nuclear Information System (INIS)

    Rooney, Daniel; Fraser, John F; R Dunster, Kimble; Schibler, Andreas; Friese, Marlies

    2009-01-01

    Ventilation in larger animals and humans is gravity dependent and mainly distributed to the dependent lung. Little is known of the effect of gravity on ventilation distribution in small animals such as rodents. The aim of this study was to investigate gravity-dependent ventilation distribution and regional filling characteristics in rats. Ventilation distribution and regional lung filling were measured in six rats using electrical impedance tomography (EIT). Measurements were performed in four body positions (supine, prone, left and right lateral), and all animals were ventilated with increasing tidal volumes from 3 to 8 mL kg −1 . The effect of gravity on regional ventilation distribution was assessed with profiles of relative impedance change and calculation of the geometric centre. Regional filling was measured by calculating the slope of the plot of regional versus global relative impedance change on a breath-by-breath basis. Ventilation was significantly distributed to the non-dependent lung regardless of body position and tidal volume used. The geometric centre was located in the dependent lung in all but prone position. The regional filling characteristics followed an anatomical pattern with the posterior and the right lung generally filling faster. Gravity had little impact on regional filling. Ventilation distribution in rats is gravity dependent, whereas regional filling characteristics are dependent on anatomy

  13. Oxygen dependence of respiration in rat spinotrapezius muscle in situ

    Science.gov (United States)

    Pittman, Roland N.

    2012-01-01

    The oxygen dependence of respiration in striated muscle in situ was studied by measuring the rate of decrease of interstitial Po2 [oxygen disappearance curve (ODC)] following rapid arrest of blood flow by pneumatic tissue compression, which ejected red blood cells from the muscle vessels and made the ODC independent from oxygen bound to hemoglobin. After the contribution of photo-consumption of oxygen by the method was evaluated and accounted for, the corrected ODCs were converted into the Po2 dependence of oxygen consumption, V̇o2, proportional to the rate of Po2 decrease. Fitting equations obtained from a model of heterogeneous intracellular Po2 were applied to recover the parameters describing respiration in muscle fibers, with a predicted sigmoidal shape for the dependence of V̇o2 on Po2. This curve consists of two regions connected by the point for critical Po2 of the cell (i.e., Po2 at the sarcolemma when the center of the cell becomes anoxic). The critical Po2 was below the Po2 for half-maximal respiratory rate (P50) for the cells. In six muscles at rest, the rate of oxygen consumption was 139 ± 6 nl O2/cm3·s and mitochondrial P50 was k = 10.5 ± 0.8 mmHg. The range of Po2 values inside the muscle fibers was found to be 4–5 mmHg at the critical Po2. The oxygen dependence of respiration can be studied in thin muscles under different experimental conditions. In resting muscle, the critical Po2 was substantially lower than the interstitial Po2 of 53 ± 2 mmHg, a finding that indicates that V̇o2 under this circumstance is independent of oxygen supply and is discordant with the conventional hypothesis of metabolic regulation of the oxygen supply to tissue. PMID:22523254

  14. Oxygen dependence of respiration in rat spinotrapezius muscle in situ

    OpenAIRE

    Golub, Aleksander S.; Pittman, Roland N.

    2012-01-01

    The oxygen dependence of respiration in striated muscle in situ was studied by measuring the rate of decrease of interstitial Po2 [oxygen disappearance curve (ODC)] following rapid arrest of blood flow by pneumatic tissue compression, which ejected red blood cells from the muscle vessels and made the ODC independent from oxygen bound to hemoglobin. After the contribution of photo-consumption of oxygen by the method was evaluated and accounted for, the corrected ODCs were converted into the Po...

  15. Rat liver microsomal cytochrome P450-dependent oxidation of 3,5-disubstituted analogues of paracetamol

    NARCIS (Netherlands)

    Bessems, J.G.M.; Koppele, J.M. te; Dijk, P.A. van; Stee, L.L.P. van; Commandeur, J.N.M.; Vermeulen, N.P.E.

    1996-01-01

    1. The cytochrome P450-dependent binding of paracetamol and a series of 3,5-disubstituted paracetamol analogues (R = -F, -Cl, -Br, -I, -C(H)3, -C2H5, -iC3H7) have been determined with β-naphthoflavone (βNF)-induced rat liver microsomes and produced reverse type I spectral changes. K(s,app) varied

  16. WHY DO THE ACUTE BEHAVIORAL EFFECTS OT TOLUENE IN RATS DEPEND ON THE ROUTE OF EXPOSURE?

    Science.gov (United States)

    Despite evidence suggesting that the acute effects of organic solvents are related to their concentration in the brain, we have observed route-dependent differences in the acute behavioral effects of toluene. Whereas inhaled toluene disrupts the performance of rats on a visual si...

  17. Conditioned taste aversion and Ca/calmodulin-dependent kinase II in the parabrachial nucleus of rats

    Czech Academy of Sciences Publication Activity Database

    Křivánek, Jiří

    2001-01-01

    Roč. 76, č. 1 (2001), s. 46-56 ISSN 1074-7427 R&D Projects: GA AV ČR IAA7011706 Institutional research plan: CEZ:AV0Z5011922 Keywords : calcium/calmodulin-dependent kinase II * conditioned taste aversion * parabrachial nucleus of rat Subject RIV: FH - Neurology Impact factor: 1.830, year: 2001

  18. Thyroid status affects the rat cardiac beta-adrenoceptor system transiently and time-dependently

    NARCIS (Netherlands)

    Zwaveling, J.; Batink, H. D.; Taguchi, K.; de Jong, J.; Michel, M. C.; Pfaffendorf, M.; van Zwieten, A.

    1998-01-01

    1. The aim of this study was to investigate the time-dependency of the influence of dysthyroid states on the beta-adrenoceptor system in rat heart left ventricle. Therefore, the influence of acute and chronic hyper- and hypothyroidism on beta-adrenoceptor-induced left ventricular responses,

  19. Age dependent in vitro metabolism of bifenthrin in rat and human hepatic microsomes.

    Science.gov (United States)

    Nallani, Gopinath C; Chandrasekaran, Appavu; Kassahun, Kelem; Shen, Li; ElNaggar, Shaaban F; Liu, Zhiwei

    2018-01-01

    Bifenthrin, a pyrethroid insecticide, undergoes oxidative metabolism leading to the formation of 4'-hydroxy-bifenthrin (4'-OH-BIF) and hydrolysis leading to the formation of TFP acid in rat and human hepatic microsomes. In this study, age-dependent metabolism of bifenthrin in rats and humans were determined via the rates of formation of 4'-OH-BIF and TFP acid following incubation of bifenthrin in juvenile and adult rat (PND 15 and PND 90) and human (18years) liver microsomes. Furthermore, in vitro hepatic intrinsic clearance (CL int ) of bifenthrin was determined by substrate consumption method in a separate experiment. The mean V max (±SD) for the formation of 4'-OH-BIF in juvenile rat hepatic microsomes was 25.0±1.5pmol/min/mg which was significantly lower (pbifenthrin occurs primarily via oxidative pathway with relatively lesser contribution (~30%) from hydrolytic pathway in both rat and human liver microsomes. The CL int values for bifenthrin, determined by monitoring the consumption of substrate, in juvenile and adult rat liver microsomes fortified with NADPH were 42.0±7.2 and 166.7±20.5μl/min/mg, respectively, and the corresponding values for human liver microsomes were 76.0±4.0 and 21.3±1.2μl/min/mg, respectively. The data suggest a major species difference in the age dependent metabolism of bifenthrin. In human liver microsomes, bifenthrin is metabolized at a much higher rate in juveniles than in adults, while the opposite appears to be true in rat liver microsomes. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Effect of opium dependency on secondary intention wound healing in a rat model: an experimental study.

    Science.gov (United States)

    Vahedian, Jalal; Mirshekari, Tooraj-Reza; Nabavizadeh, Fatemeh

    2013-06-01

    Opium dependency is a social and health problem in some middle eastern countries like Iran. Many of these people may require surgery. This study investigates the effects of opium dependency on histological parameters of secondary intention wound healing in rat. A full-thickness wound (2 × 2 cm in diameters) was created on the dorsum of two groups of rats, a normal control group and a second group of rat depended to opium (Badawy's method). Several times during 14 days postwounding, the wound was excised with peripheral margins of normal skin and was evaluated for cellular population, reepithelialisation and revascularisation. Results are presented as the mean ± standard error. Data were compared by an unpaired t-test or analysis of variance. Histological examination of the wound tissue showed evidence of increased population of fibroblasts, decreased recruitment of neutrophile and plateau of macrophage cells in opium depended animals comparing with control group. In the depended animals, reepithelialisation was seen to be enhanced significantly, while prohibiting progression of revascularisation. This study shows that opium dependency enhances reepitheliazation as well as tissue recruitment of fibroblasts; thereby probable enhancement of secondary intention wound healing. © 2012 The Authors. International Wound Journal © 2012 John Wiley & Sons Ltd and Medicalhelplines.com Inc.

  1. Age dependence of organophosphate and carbamate neurotoxicity in the postnatal rat: extrapolation to the human

    International Nuclear Information System (INIS)

    Vidair, Charles A.

    2004-01-01

    One important aspect of risk assessment for the organophosphate and carbamate pesticides is to determine whether their neurotoxicity occurs at lower dose levels in human infants compared to adults. Because these compounds probably exert their neurotoxic effects through the inhibition of acetylcholinesterase (AChE), the above question can be narrowed to whether the cholinesterase inhibition and neurotoxicity they produce is age-dependent, both in terms of the effects produced and potency. The rat is the animal model system most commonly used to address these issues. This paper first discusses the adequacy of the postnatal rat to serve as a model for neurodevelopment in the postnatal human, concluding that the two species share numerous pathways of postnatal neurodevelopment, and that the rat in the third postnatal week is the neurodevelopmental equivalent of the newborn human. Then, studies are discussed in which young and adult rats were dosed by identical routes with organophosphates or carbamates. Four pesticides were tested in rat pups in their third postnatal week: aldicarb, chlorpyrifos, malathion, and methamidophos. The first three, but not methamidophos, caused neurotoxicity at dose levels that ranged from 1.8- to 5.1-fold lower (mean 2.6-fold lower) in the 2- to 3-week-old rat compared to the adult. This estimate in the rat, based on a limited data set of three organophosphates and a single carbamate, probably represents the minimum difference in the neurotoxicity of an untested cholinesterase-inhibiting pesticide that should be expected between the human neonate and adult. For the organophosphates, the greater sensitivity of postnatal rats, and, by analogy, that expected for human neonates, is correlated with generally lower levels of the enzymes involved in organophosphate deactivation

  2. Transjugular local thrombolysis with/without TIPS in patients with acute non-cirrhotic, non-malignant portal vein thrombosis.

    Science.gov (United States)

    Klinger, Christoph; Riecken, Bettina; Schmidt, Arthur; De Gottardi, Andrea; Meier, Benjamin; Bosch, Jaime; Caca, Karel

    2017-12-01

    Therapeutic anticoagulation is the standard treatment in patients with acute non-cirrhotic portal vein thrombosis (PVT). In critically ill patients, anticoagulation only may not suffice to achive rapid and stable recanalization. This study evaluates efficacy and safety of transjugular interventional therapy in acute non-cirrhotic PVT. This retrospective study includes 17 consecutive patients with acute noncirrhotic, non-malignant PVT. Main indication for interventional therapy was imminent intestinal infarction (n=10). Treatment consisted of a combination of transjugular thrombectomy, local fibrinolysis and - depending on thrombus resolution - transjugular intrahepatic portosystemic shunt. Recanalization was successful in 94.1%. One- and two-year secondary PV patency rates were 88.2%. Major complications (n=3) resolved spontaneously in all but one patient (heparin induced thrombocytopenia type 2 with intestinal infarction). Symptoms improved in all patients. However, segmental bowel resection had to be performed in two (11.8%). During a median follow-up of 28.6 months, no patient experienced portal hypertensive complications. Presence of JAK2 V617F mutation predicted both short-term and long-term technical success. Transjugular recanalization is safe and effective in patients with acute non-cirrhotic, non-malignant PVT. It should be considered especially in patients with imminent bowel infarction and low likelihood of recanalization following therapeutic anticoagulation. Patients with JAK2 mutation ought to be followed meticulously. Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  3. Synergistic Effect of Rapamycin and Metformin Against Age-Dependent Oxidative Stress in Rat Erythrocytes.

    Science.gov (United States)

    Singh, Abhishek Kumar; Garg, Geetika; Singh, Sandeep; Rizvi, Syed Ibrahim

    2017-10-01

    Erythrocytes are particularly vulnerable toward age-dependent oxidative stress-mediated damage. Caloric restriction mimetics (CRMs) may provide a novel strategy for the maintenance of redox balance as well as effective treatment of age-associated diseases. Herein, we have investigated the beneficial effect of cotreatment with CRM-candidate drugs, rapamycin (an immunosuppressant drug and inhibitor of mammalian target of rapamycin) and metformin (an antidiabetic biguanide and activator of adenosine monophosphate kinase), against aging-induced oxidative stress in erythrocytes and plasma of aging rats. Male Wistar rats of age 4 (young) and 24 months (old) were coexposed to rapamycin (0.5 mg/kg body weight [b.w.]) and metformin (300 mg/kg b.w.), and data were compared with the response of rats receiving an independent exposure to these chemicals at similar doses. The exposure of individual candidate drugs significantly reversed the age-dependent alterations in the endpoints associated with oxidative stress such as reactive oxygen species, ferric reducing ability of plasma, malondialdehyde, reduced glutathione, plasma membrane redox system, plasma protein carbonyl, and acetyl cholinesterase in erythrocytes and plasma of aging rats. However, the cotreatment with rapamycin and metformin showed a significant augmented effect compared with individual drug interventions on reversal of these age-dependent biomarkers of oxidative stress, suggesting a synergistic response. Thus, the findings open up further possibilities for the design of new combinatorial therapies to prevent oxidative stress- and age-associated health problems.

  4. Flow and volume dependence of rat airway resistance during constant flow inflation and deflation.

    Science.gov (United States)

    Rubini, Alessandro; Carniel, Emanuele Luigi; Parmagnani, Andrea; Natali, Arturo Nicola

    2011-12-01

    The aim of this study was to measure the flow and volume dependence of both the ohmic and the viscoelastic pressure dissipations of the normal rat respiratory system separately during inflation and deflation. The study was conducted in the Respiratory Physiology Laboratory in our institution. Measurements were obtained for Seven albino Wistar rats of both sexes by using the flow interruption method during constant flow inflations and deflations. Measurements included anesthesia induction, tracheostomy and positioning of a tracheal cannula, positive pressure ventilation, constant flow respiratory system inflations and deflations at two different volumes and flows. The ohmic resistance exhibited volume and flow dependence, decreasing with lung volume and increasing with flow rate, during both inflation and deflation. The stress relaxation-related viscoelastic resistance also exhibited volume and flow dependence. It decreased with the flow rate at a constant lung volume during both inflation and deflation, but exhibited a different behavior with the lung volume at a constant flow rate (i.e., increased during inflations and decreased during deflations). Thus, stress relaxation in the rat lungs exhibited a hysteretic behavior. The observed flow and volume dependence of respiratory system resistance may be predicted by an equation derived from a model of the respiratory system that consists of two distinct compartments. The equation agrees well with the experimental data and indicates that the loading time is the critical parameter on which stress relaxation depends, during both lung inflation and deflation.

  5. The role of glucocorticoids in sodium retention in cirrhotic patients

    DEFF Research Database (Denmark)

    Hansen, Martin Højmark; Kristensen, Steffen Skott; Schaffalitzky de Muckadell, Ove B

    2012-01-01

    sodium retention evident in cirrhosis. The aim was to elucidate the role of glucocorticoids in sodium retention in decompensated cirrhotic patients. Methods. A randomized, double-blind, placebo-controlled, crossover study was performed in nine patients with alcoholic cirrhosis of the liver. A washout....... Conclusion. These results indicate that endogenous glucocorticoids contribute to the sodium retention in patients with alcoholic cirrhosis of the liver....

  6. Does hepatocellular carcinoma in non-alcoholic steatohepatitis exist in cirrhotic and non-cirrhotic patients?

    Directory of Open Access Journals (Sweden)

    A.L. Chagas

    2009-10-01

    Full Text Available Non-alcoholic steatohepatitis (NASH has been associated with hepatocellular carcinoma (HCC often arising in histologically advanced disease when steatohepatitis is not active (cryptogenic cirrhosis. Our objective was to characterize patients with HCC and active, histologically defined steatohepatitis. Among 394 patients with HCC detected by ultrasound imaging over 8 years and staged by the Barcelona Clinic Liver Cancer (BCLC criteria, we identified 7 cases (1.7% with HCC occurring in the setting of active biopsy-proven NASH. All were negative for other liver diseases such as hepatitis C, hepatitis B, autoimmune hepatitis, Wilson disease, and hemochromatosis. The patients (4 males and 3 females, age 63 ± 13 years were either overweight (4 or obese (3; 57% were diabetic and 28.5% had dyslipidemia. Cirrhosis was present in 6 of 7 patients, but 1 patient had well-differentiated HCC in the setting of NASH without cirrhosis (fibrosis stage 1 based on repeated liver biopsies, the absence of portal hypertension by clinical and radiographic evaluations and by direct surgical inspection. Among the cirrhotic patients, 71.4% were clinically staged as Child A and 14.2% as Child B. Tumor size ranged from 1.0 to 5.2 cm and 5 of 7 patients were classified as early stage; 46% of all nodules were hyper-echoic and 57% were <3 cm. HCC was well differentiated in 1/6 and moderately differentiated in 5/6. Alpha-fetoprotein was <100 ng/mL in all patients. HCC in patients with active steatohepatitis is often multifocal, may precede clinically advanced disease and occurs without diagnostic levels of alpha-fetoprotein. Importantly, HCC may occur in NASH in the absence of cirrhosis. More aggressive screening of NASH patients may be warranted.

  7. Does hepatocellular carcinoma in non-alcoholic steatohepatitis exist in cirrhotic and non-cirrhotic patients?

    Directory of Open Access Journals (Sweden)

    A.L. Chagas

    Full Text Available Non-alcoholic steatohepatitis (NASH has been associated with hepatocellular carcinoma (HCC often arising in histologically advanced disease when steatohepatitis is not active (cryptogenic cirrhosis. Our objective was to characterize patients with HCC and active, histologically defined steatohepatitis. Among 394 patients with HCC detected by ultrasound imaging over 8 years and staged by the Barcelona Clinic Liver Cancer (BCLC criteria, we identified 7 cases (1.7% with HCC occurring in the setting of active biopsy-proven NASH. All were negative for other liver diseases such as hepatitis C, hepatitis B, autoimmune hepatitis, Wilson disease, and hemochromatosis. The patients (4 males and 3 females, age 63 ± 13 years were either overweight (4 or obese (3; 57% were diabetic and 28.5% had dyslipidemia. Cirrhosis was present in 6 of 7 patients, but 1 patient had well-differentiated HCC in the setting of NASH without cirrhosis (fibrosis stage 1 based on repeated liver biopsies, the absence of portal hypertension by clinical and radiographic evaluations and by direct surgical inspection. Among the cirrhotic patients, 71.4% were clinically staged as Child A and 14.2% as Child B. Tumor size ranged from 1.0 to 5.2 cm and 5 of 7 patients were classified as early stage; 46% of all nodules were hyper-echoic and 57% were <3 cm. HCC was well differentiated in 1/6 and moderately differentiated in 5/6. Alpha-fetoprotein was <100 ng/mL in all patients. HCC in patients with active steatohepatitis is often multifocal, may precede clinically advanced disease and occurs without diagnostic levels of alpha-fetoprotein. Importantly, HCC may occur in NASH in the absence of cirrhosis. More aggressive screening of NASH patients may be warranted.

  8. Toxoplasma gondii influences aversive behaviors of female rats in an estrus cycle dependent manner.

    Science.gov (United States)

    Golcu, Doruk; Gebre, Rahiwa Z; Sapolsky, Robert M

    2014-08-01

    The protozoan Toxoplasma gondii (T. gondii) manipulates the behavior of its rodent intermediate host to facilitate its passage to its feline definitive host. This is accomplished by a reduction of the aversive response that rodents show towards cat odors, which likely increases the predation risk. Females on average show similar changes as males. However, behaviors that relate to aversion and attraction are usually strongly influenced by the estrus cycle. In this study, we replicated behavioral effects of T. gondii in female rats, as well as expanded it to two novel behavioral paradigms. We also characterized the role of the estrus cycle in the behavioral effects of T. gondii on female rats. Uninfected females preferred to spend more time in proximity to rabbit rather than bobcat urine, and in a dark chamber rather than a lit chamber. Infected females lost both of these preferences, and also spent more time investigating social novelty (foreign bedding in their environment). Taken together, these data suggest that infection makes females less risk averse and more exploratory. Furthermore, this effect was influenced by the estrus cycle. Uninfected rats preferred rabbit urine to bobcat urine throughout the cycle except at estrus and metestrus. In contrast, infected rats lost this preference at every stage of the cycle except estrus. Commensurate with the possibility that this was a hormone-dependent effect, infected rats had elevated levels of circulating progesterone, a known anxiolytic. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. Supplier-dependent differences in intermittent voluntary alcohol intake and response to naltrexone in Wistar rats

    Directory of Open Access Journals (Sweden)

    Shima eMomeni

    2015-11-01

    Full Text Available Alcohol use disorder (AUD is a worldwide public health problem and a polygenetic disorder displaying substantial individual variation. This work aimed to study individual differences in behavior and its association to voluntary alcohol intake and subsequent response to naltrexone in a seamless heterogenic group of animals. Thus, by this approach the aim was to more accurately recapitulate the existing heterogeneity within the human population. Male Wistar rats from three different suppliers (Harlan Laboratories B.V., RccHanTM:WI; Taconic Farms A/S, HanTac:WH; and Charles River GmbH, Crl:WI were used to create a heterogenic group for studies of individual differences in behavior, associations to intermittent voluntary alcohol intake and subsequent response to naltrexone. The rats were tested in the open field prior to the Y-maze and then given voluntary intermittent access to alcohol or water in the home cage for six weeks, where after, naltrexone in three different doses or saline was administered in a Latin square design over four weeks and alcohol intake and preference was measured. However, supplier-dependent differences and concomitant skew subgroup formations, primarily in open field behavior and intermittent alcohol intake, resulted in a shifted focus to instead study voluntary alcohol intake and preference, and the ensuing response to naltrexone in Wistar rats from three different suppliers. The results showed that outbred Wistar rats are diverse with regard to voluntary alcohol intake and preference in a supplier-dependent manner; higher in RccHanTM:WI relative to HanTac:WH and Crl:WI. The results also revealed supplier-dependent differences in the effect of naltrexone that were dose- and time-dependent; evident differences in high-drinking RccHanTM:WI rats relative to HanTac:WH and Crl:WI rats. Overall these findings render RccHanTM:WI rats more suitable for studies of individual differences in voluntary alcohol intake and response to

  10. Safety and efficacy of endoscopic retrograde cholangiopancreatography for common bile duct stones in liver cirrhotic patients.

    Science.gov (United States)

    Li, De-min; Zhao, Jie; Zhao, Qiu; Qin, Hua; Wang, Bo; Li, Rong-xiang; Zhang, Min; Hu, Ji-fen; Yang, Min

    2014-08-01

    In order to investigate the safety and efficacy of endoscopic retrograde cholangiopancreatograpy (ERCP) in liver cirrhosis patients with common bile duct stones, we retrospectively analyzed data of 46 common bile duct stones patients with liver cirrhosis who underwent ERCP between 2000 and 2008. There were 12 cases of Child-Pugh A, 26 cases of Child-Pugh B, and 8 cases of Child-Pugh C. 100 common bile duct stones patients without liver cirrhosis were randomly selected. All the patients were subjected to ERCP for biliary stones extraction. The rates of bile duct clearance and complications were compared between cirrhotic and non-cirrhotic patients. The success rate of selective biliary cannulation was 95.6% in liver cirrhotic patients versus 97% in non-cirrhotic patients (P>0.05). The bile duct clearance rate was 87% in cirrhotic patients versus 96% in non-cirrhotic patients, but the difference was not statistically significant. Two liver cirrhotic patients (4.35%, 2/46) who were scored Child-Pugh C had hematemesis and melena 24 h after ERCP. The hemorrhage rate after ERCP in non-cirrhotic patients was 3%. The hemorrhage rate associated with ERCP in Child-Pugh C patients was significantly higher (25%, 2/8) than that (3%, 3/100) in non-cirrhotic patients (Pbile duct stones. Hemorrhage risk in ERCP is higher in Child-Pugh C patients.

  11. Carboxylesterase-dependent cytotoxicity of dibasic esters (DBE) in rat nasal explants.

    Science.gov (United States)

    Trela, B A; Bogdanffy, M S

    1991-02-01

    Dibasic esters (DBE) are a solvent mixture of dimethyl adipate (DMA), dimethyl glutarate (DMG), and dimethyl succinate (DMS) used in the paint and coating industry. Subchronic inhalation toxicity studies have demonstrated that DBE induce a mild degeneration of the olfactory, but not the respiratory, epithelium of the rat nasal cavity. Carboxylesterase-mediated hydrolysis of the individual dibasic esters is more efficient in olfactory than in respiratory mucosal homogenates. In the present study, an in vitro system of cultured rat nasal explants was utilized to determine if DBE toxicity is dependent on a metabolic activation by nonspecific carboxylesterase. Explants from both the olfactory and the respiratory regions of the female rat nasal cavity were incubated for 2 hr in Williams' medium E containing 10-100 mM DMA, DMG, or DMS. DBE caused a dose-related increase in nasal explant acid phosphatase release, a biochemical index of cytotoxicity. HPLC analysis demonstrated parallel increases in the carboxylesterase-mediated formation of monomethyl ester metabolites. Diacid metabolite production in the nasal explant system was not entirely concentration-dependent. Metabolite concentrations and acid phosphatase release were generally greater in olfactory than respiratory tissues. DBE-induced cytotoxicity and acid metabolite production were markedly attenuated in nasal tissue excised from rats which were pretreated with bis(p-nitrophenyl)phosphate, a carboxylesterase inhibitor. This study presents a viable in vitro method for assessing organic ester cytotoxicity in the rat nasal cavity. It was shown that DBE are weak nasal toxicants under the conditions of this system. It was further demonstrated that DBE toxicity is dependent on a carboxylesterase-mediated activation. A similar mechanism was proposed for the nasal toxicity induced by other organic esters following inhalation exposure.

  12. Does exercise deprivation increase the tendency towards morphine dependence in rats?

    Science.gov (United States)

    Nakhaee, Mohammad Reza; Sheibani, Vahid; Ghahraman Tabrizi, Kourosh; Marefati, Hamid; Bahreinifar, Sareh; Nakhaee, Nouzar

    2010-01-01

    Exercise deprivation has been concluded to have some negative effectson psychological well-being. This study was conducted to find outwhether exercise deprivation may lead to morphine dependence in rats. Forty male Wistar rats weighing 162 ± 9 g were housed in clear plasticcages in groups of two under standard laboratory conditions. The studyhad two phases. In phase I, the animals were randomly divided intoexercised (E) and unexercised (UE) groups (n = 20 each) and treadmillrunning was performed based on a standard protocol for three weeks. Atthe end of the training period, plasma β-endorphin levels weredetermined in four rats from each group. In phase II, the animals wereprovided with two bottles, one containing tap water and the other 25mg/l morphine sulfate in tap water for a total of 12 weeks. At the end ofthis phase naloxone was injected intraperitoneally to precipitatemorphine withdrawal. THERE WAS NO SIGNIFICANT DIFFERENCE BETWEEN UE AND E GROUPS INMORPHINE CONSUMPTION (MG/KG/WK) [ F(1,14) = 0.2, P = 0.690; time:F(11,154) =18.72, P exercise does not increasethe tendency of morphine dependence in rats.

  13. Polysaccharide peptide induces a tumor necrosis factor-α-dependent drop of body temperature in rats.

    Science.gov (United States)

    Jedrzejewski, Tomasz; Piotrowski, Jakub; Wrotek, Sylwia; Kozak, Wieslaw

    2014-08-01

    Polysaccharide peptide (PSP) extracted from the Coriolus versicolor mushroom is frequently suggested as an adjunct to the chemo- or radiotherapy in cancer patients. It improves quality of the patients' life by decreasing pain, fatigue, loss of appetite, nausea, and vomiting. However, the effect of PSP on body temperature has not thus far been studied, although it is well known that treatment with other polysaccharide adjuvants, such as lipopolysaccharides, may induce fever. The aim of the present study, therefore, was to investigate the influence of PSP on temperature regulation in rats. We report that intraperitoneal injection of PSP provoked a dose-dependent decrease of temperature in male Wistar rats equipped with biotelemetry devices to monitor deep body temperature (Tb). The response was rapid (i.e., with latency of 15-20min), transient (lasting up to 5h post-injection), and accompanied by a significant elevation of the blood tumor necrosis factor-α (TNF-α) level. Pretreatment of the rats with anti-TNF-α antibody prevented the PSP-induced drop in Tb. Based on these data, we conclude that rats may develop an anapyrexia-like response to the injection of peptidopolysaccharide rather than fever, and the response was TNF-α-dependent. Copyright © 2014 Elsevier Ltd. All rights reserved.

  14. Nitro-oxidative stress, VEGF and MMP-9 in patients with cirrhotic and non-cirrhotic portal hypertension.

    Science.gov (United States)

    Muti, Leon Adrian; Pârvu, Alina Elena; Crăciun, Alexandra M; Miron, Nicolae; Acalovschi, Monica

    2015-01-01

    Nitro-oxidative stress may have pathophysiological consequences. The study aimed to assess the nitro-oxidative stress, the vascular growth factor, and metalloproteinase-9 levels in patients with noncirrohic and cirrhotic portal hypertension. Patients with noncirrhotic portal hypertension (n=50) and cirrhotic portal hypertension (n=50) from the 3rd Medical Clinic in Cluj-Napoca Romania were prospectively enrolled between October 2004 and October 2006. A control group of healthy volunteers (n=50) was also evaluated. Nitro-oxidative stress was assessed by measuring serum concentration of nitrites and nitrate, 3-nitrotyrosine, total oxidative status, total antioxidant reactivity, and oxidative stress index. Serum vascular growth factor and matrix metalloproteinase-9 were also determined. Serum nitrites and nitrate levels significantly increased in both noncirrhotic (pportal hypertension (p=0.057). 3-nitrotyrosine also increased in noncirrhotic (p=0.001) and cirrhotic portal hypertension patients (p=0.014). Total oxidative status showed a significant increase in noncirrhotic (pportal hypertension (pportal hypertension (pportal hypertension a significant systemic nitro-oxidative stress was found, correlated with an increase of VEGF. MMP-9 decreased in noncirrhotic portal hypertension.

  15. Activation of Peripheral κ-Opioid Receptors Normalizes Caffeine Effects Modified in Nicotine-Dependent Rats during Nicotine Withdrawal.

    Science.gov (United States)

    Sudakov, S K; Bogdanova, N G

    2016-10-01

    The study examined the effect of peripheral (intragastric) ICI-204,448, an agonist of gastric κ-opioid receptors, on the psychostimulating and anxiolytic effects of caffeine in nicotinedependent rats at the stage of nicotine withdrawal. In these rats, the effects of caffeine (10 mg/kg) were perverted. In nicotine-dependent rats, caffeine produced an anxiolytic effect accompanied by pronounced stimulation of motor activity, in contrast to anxiogenic effect induced by caffeine in intact rats without nicotine dependence. During nicotine withdrawal, nicotine-dependent rats demonstrated enhanced sensitivity to nicotine. Intragastric administration of κ-opioid receptor agonist ICI-204,448 normalized the effect of caffeine in nicotinedependent rats. We have previously demonstrated that activation of peripheral κ-opioid receptors inhibited central κ-opioid activity and eliminated manifestations of nicotine withdrawal syndrome in nicotine-dependent rats, e.g. metabolism activation, stimulation of motor activity, and enhancement of food consumption. In its turn, inhibition of central κ-opioid structures activates the brain adenosine system, which can attenuate the caffeine-induced effects in nicotine-dependent rats.

  16. Age Dependent Hypothalamic and Pituitary Responses to Novel Environment Stress or Lipopolysaccharide in Rats

    Directory of Open Access Journals (Sweden)

    Sandy Koenig

    2018-03-01

    Full Text Available Previously, we have shown that the transcription factor nuclear factor interleukin (NF-IL6 can be used as an activation marker for inflammatory lipopolysaccharide (LPS-induced and psychological novel environment stress (NES in the rat brain. Here, we aimed to investigate age dependent changes of hypothalamic and pituitary responses to NES (cage switch or LPS (100 μg/kg in 2 and 24 months old rats. Animals were sacrificed at specific time points, blood and brains withdrawn and analyzed using immunohistochemistry, RT-PCR and bioassays. In the old rats, telemetric recording revealed that NES-induced hyperthermia was enhanced and prolonged compared to the young group. Plasma IL-6 levels remained unchanged and hypothalamic IL-6 mRNA expression was increased in the old rats. Interestingly, this response was accompanied by a significant upregulation of corticotropin-releasing hormone mRNA expression only in young rats after NES and overall higher plasma corticosterone levels in all aged animals. Immunohistochemical analysis revealed a significant upregulation of NF-IL6-positive cells in the pituitary after NES or LPS-injection. In another important brain structure implicated in immune-to-brain communication, namely, in the median eminence (ME, NF-IL6-immunoreactivity was increased in aged animals, while the young group showed just minor activation after LPS-stimulation. Interestingly, we found a higher amount of NF-IL6-CD68-positive cells in the posterior pituitary of old rats compared to the young counterparts. Moreover, aging affected the regulation of cytokine interaction in the anterior pituitary lobe. LPS-treatment significantly enhanced the secretion of the cytokines IL-6 and TNFα into supernatants of primary cell cultures of the anterior pituitary. Furthermore, in the young rats, incubation with IL-6 and IL-10 antibodies before LPS-stimulation led to a robust decrease of IL-6 production and an increase of TNFα production by the pituitary

  17. The endocannabinoid transport inhibitor AM404 differentially modulates recognition memory in rats depending on environmental aversiveness

    OpenAIRE

    Campolongo, Patrizia; Ratano, Patrizia; Manduca, Antonia; Scattoni, Maria L.; Palmery, Maura; Trezza, Viviana; Cuomo, Vincenzo

    2012-01-01

    Cannabinoid compounds may influence both emotional and cognitive processes depending on the level of environmental aversiveness at the time of drug administration. However, the mechanisms responsible for these responses remain to be elucidated. The present experiments investigated the effects induced by the endocannabinoid transport inhibitor AM404 (0.5-5 mg/kg, i.p.) on bothemotional and cognitive performances of rats tested in a Spatial Open Field task and subjected to different experimenta...

  18. Age-dependent salt hypertension in Dahl rats: fifty years of research.

    Science.gov (United States)

    Zicha, J; Dobešová, Z; Vokurková, M; Rauchová, H; Hojná, S; Kadlecová, M; Behuliak, M; Vaněčková, I; Kuneš, J

    2012-01-01

    Fifty years ago, Lewis K. Dahl has presented a new model of salt hypertension - salt-sensitive and salt-resistant Dahl rats. Twenty years later, John P. Rapp has published the first and so far the only comprehensive review on this rat model covering numerous aspects of pathophysiology and genetics of salt hypertension. When we summarized 25 years of our own research on Dahl/Rapp rats, we have realized the need to outline principal abnormalities of this model, to show their interactions at different levels of the organism and to highlight the ontogenetic aspects of salt hypertension development. Our attention was focused on some cellular aspects (cell membrane function, ion transport, cell calcium handling), intra- and extrarenal factors affecting renal function and/or renal injury, local and systemic effects of renin-angiotensin-aldosterone system, endothelial and smooth muscle changes responsible for abnormal vascular contraction or relaxation, altered balance between various vasoconstrictor and vasodilator systems in blood pressure maintenance as well as on the central nervous and peripheral mechanisms involved in the regulation of circulatory homeostasis. We also searched for the age-dependent impact of environmental and pharmacological interventions, which modify the development of high blood pressure and/or organ damage, if they influence the salt-sensitive organism in particular critical periods of development (developmental windows). Thus, severe self-sustaining salt hypertension in young Dahl rats is characterized by pronounced dysbalance between augmented sympathetic hyperactivity and relative nitric oxide deficiency, attenuated baroreflex as well as by a major increase of residual blood pressure indicating profound remodeling of resistance vessels. Salt hypertension development in young but not in adult Dahl rats can be attenuated by preventive increase of potassium or calcium intake. On the contrary, moderate salt hypertension in adult Dahl rats is

  19. Penetration of radionuclides across the skin. Rat age dependent promethium permeation through skin in vitro

    International Nuclear Information System (INIS)

    Kassai, Z.; Kassai, A.; Bauerova, K.; Koprda, V.; Harangozo, M.; Bendova, P.; Bujnova, A.

    2003-01-01

    The composition and the permeation properties of the skin are dependent on age. In the animal models for permation studies, age affects the mechanical as well as the permeation properties significantly. The time dependence of permeation of 147 Pm 3+ from aqueous solution was established by the animal skin model and the age dependence of promethium permeation through the skin was examined. The aim was to find the optimum rat skin age model for radionuclide permeation studies and to assess the relative importance of the main permeation pathways: transepidermal and transfollicular permeation. The skin from 5-day-old rats (5DR) was found to represent the optimum animal model to study transepidermal permeation of ions. The skin from 9-day-old rats (9DR) was selected to study transfollicular permeation of ions. Comparison of the permeated amounts of promethium through the skin without hairs (3 DR to 6 DR) and with hairs (7DR to 12DR) showed that the additional permation mode via follicles significantly contributed to the permeation rate and extent. (author)

  20. Aloe vera Aqueous Extract Effect on Morphine Withdrawal Syndrome in Morphine-Dependent Female Rats.

    Science.gov (United States)

    Shahraki, Mohammad Reza; Mirshekari, Hamideh; Sabri, Azame

    2014-09-01

    Aloe vera is a medicinal herb used as an anti-inflammatory and sedative agent. The current study aimed to evaluate the effect of Aloe vera aqueous extract on morphine withdrawal symptoms in morphine-dependent female rats. The current research was performed on 40 female Wista-Albino rats which were made dependent on morphine using Houshyar protocol and were randomly divided into five groups (A, B, C, D, and E). Group A did not receive any agent in the period of handling but other groups (B, C, D and E) received 5, 10, 20 and 40 mg/kg of Aloe vera aqueous extract by gavage, three times daily for a week, respectively. Withdrawal symptoms, stool form, agitation, disparity, floppy eyelids, and body mass variations were checked for 10 days. The obtained data were analyzed using SPSS v.11 software, and Friedman, Kruskal-Wallis, and Mann-Whitney statistical tests. Statistical difference was considered significant (P E were significantly higher than those of others groups; however, these symptoms in group C were significantly lower than those of the other groups. The results of the present study revealed that the Aloe vera aqueous extract had various effects on morphine withdrawal syndrome in morphine-dependent female rats .

  1. Cholecystokinin octapeptide induces endogenous opioid-dependent anxiolytic effects in morphine-withdrawal rats.

    Science.gov (United States)

    Wen, D; Sun, D; Zang, G; Hao, L; Liu, X; Yu, F; Ma, C; Cong, B

    2014-09-26

    Cholecystokinin octapeptide (CCK-8), a brain-gut peptide, plays an important role in several opioid addictive behaviors. We previously reported that CCK-8 attenuated the expression and reinstatement of morphine-induced conditioned place preference. The possible effects of CCK-8 on the negative affective components of drug abstinence are not clear. There are no studies evaluating the effect of CCK-8 on emotional symptoms, such as anxiety, in morphine-withdrawal animals. We investigated the effects of CCK-8 on the anxiety-like behavior in morphine-withdrawal rats using an elevated plus-maze. Morphine withdrawal elicited time-dependent anxiety-like behaviors with peak effects on day 10 (5 days after induction of morphine dependence). Treatment with CCK-8 (0.1 and 1 μg, i.c.v.) blocked this anxiety in a dose-dependent fashion. A CCK1 receptor antagonist (L-364,718, 10 μg, i.c.v.) blocked the effect of CCK-8. Mu-opioid receptor antagonism with CTAP (10 μg, i.c.v.) decreased the 'anxiolytic' effect. CCK-8 inhibited anxiety-like behaviors in morphine-withdrawal rats by up-regulating endogenous opioids via the CCK1 receptor in rats. This study clearly identifies a distinct function of CCK-8 and a potential medication target of central CCK1 receptors for drugs aimed at ameliorating drug addiction. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

  2. Maraviroc attenuates trauma-hemorrhage-induced hepatic injury through PPAR gamma-dependent pathway in rats.

    Directory of Open Access Journals (Sweden)

    Fu-Chao Liu

    Full Text Available Maraviroc is a CC-chemokine receptor 5 (CCR5 antagonist with potent antiviral and cancer preventive effects. Recent evidence suggests that the co-existence of CCR5 in various cell types is involved in inflammation. However, the effects that CCR5 antagonists produce in trauma-hemorrhage remain unknown. The peroxisome proliferator-activated receptor gamma (PPAR(γ pathway exerts anti-inflammatory effects in injury. In this study, we hypothesized that maraviroc administration in male rats, after trauma-hemorrhage, decreases cytokine production and protects against hepatic injury through a PPAR(γ-dependent pathway. Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure maintained at approximately 35-40 mmHg for 90 minutes, followed by fluid resuscitation. During resuscitation, a single dose of maraviroc (3 mg/kg, intravenously with and without a PPAR(γ antagonist GW9662 (1 mg/kg, intravenously, GW9662 or vehicle was administered. Plasma alanine aminotransferase (ALT with aspartate aminotransferase (AST concentrations and various hepatic parameters were measured (n=8 rats/group at 24 hours after resuscitation. The results showed that trauma-hemorrhage increased hepatic myeloperoxidase activity, intercellular adhesion molecule-1 and interleukin-6 levels, and plasma ALT and AST concentrations. These parameters were significantly improved in the maraviroc-treated rats subjected to trauma-hemorrhage. Maraviroc treatment also increased hepatic PPAR(γ expression compared with vehicle-treated trauma-hemorrhaged rats. Co-administration of GW9662 with maraviroc abolished the maraviroc-induced beneficial effects on the above parameters and hepatic injury. These results suggest that the protective effect of maraviroc administration on alleviation of hepatic injury after trauma-hemorrhage, which is, at least in part, through PPAR(γ-dependent pathway.

  3. Studies on the age-dependent proliferation kinetics of the epithelium of the rat small intestine

    International Nuclear Information System (INIS)

    Kranz, D.; Dietze, F.; Laue, R.; Fuhrmann, I.

    1980-01-01

    The small intestine of 244 Wistar rats, aged 6 days, 6 weeks, 6, 12, 23, and 28 months, respectively. were investigated autoradiographically as to their age-dependent cell proliferation kinetics of the mucosal epithelial cells. There were age-dependent differences concerning the hourly regeneration ratio of the crypt cells and the migration velocity of the enterocytes. Both parameters became greater while the existing non growth fraction became smaller with increasing age. The non growth fraction seems to be a reserve being involved into the proliferating pool if required

  4. Ursodeoxycholic Acid Influences the Expression of p27kip1 but Not FoxO1 in Patients with Non-Cirrhotic Primary Biliary Cirrhosis

    Directory of Open Access Journals (Sweden)

    Malgorzata Milkiewicz

    2014-01-01

    Full Text Available Background. Enhanced expression of cell cycle inhibitor p27kip1 suppresses cell proliferation. Ursodeoxycholic acid (UDCA delays progression of primary biliary cirrhosis (PBC but its effect on p27kip1 expression is uncertain. Aims. To analyze the expression of p27kip1 and its transcription modulator FoxO1 in patients with PBC, and to assess the impact of UDCA on this pathway. Materials and Methods. The examined human tissue included explanted livers from patients with cirrhotic PBC (n=23, primary sclerosing cholangitis (PSC; n=9, alcoholic liver disease (ALD; n=9, and routine liver biopsies from patients with non-cirrhotic PBC (n=26. Healthy liver samples served as controls (n=19. Livers of FoxO-deficient mice were also studied. mRNA and protein expressions were analyzed by real-time PCR and Western blot. Results. p27kip1 expression was increased in cirrhotic and non-cirrhotic PBC. FoxO1 mRNA levels were increased in PBC (8.5-fold increase versus controls. FoxO1 protein expression in PBC was comparable to controls, but it was decreased in patients with PSC and ALD (63% and 70% reduction, respectively; both P<0.05 versus control. UDCA-treated non-cirrhotic patients with PBC showed decreased expression of p27kip1 mRNA. Conclusion. PBC progression is characterized by a FoxO1-independent increase of p27kip1 expression. In early PBC, UDCA may enhance liver regeneration via p27kip1-dependent mechanism.

  5. Time-dependent responses of rat troponin I and cardiac injury following isoproterenol administration

    Directory of Open Access Journals (Sweden)

    Sabaheta Hasić

    2011-02-01

    Full Text Available Aim To develop a rat model of myocardial infarction induced by isoproterenol (ISO. We investigated a type of histological myocardial changes and cardiac troponin I (TnI kinetic. Methods The study has used adult, male, Wistar strain rats. Rats were distributed in ISO and control groups. Rats treated with ISO were divided into groups according to the time of cTnI and myocardial lesion analyses: ISO I (30’, ISO II (60’, ISO III (120’ and ISO IV (240’. We determined cTnI (Life Diagnostics Inc. West Chester PA, USA in the serum by ELISA method. We performed histological analysis on the specimens of left ventricular wall stained by hematoxillin-eosin (HE method. Results The irst statistically signiicant rise of cTnI was noted 30 minutes after the ISO administration. There was no statistically signiicant difference between cTnI mean values among the ISO groups. Observed myocardial histological changes were time dependent. Conclusions This model can be suitable for cardioprotective and cardiotoxicity supstance investigations followed by cTnI measurement in blood. The similarity between induced myocardial lesion on animal model in our study and human myocardial lesion in ischemia give us suficient impulse for further preclinical researches of new cardiac markers.

  6. ENDURANCE TRAINING AND GLUTATHIONE-DEPENDENT ANTIOXIDANT DEFENSE MECHANISM IN HEART OF THE DIABETIC RATS

    Directory of Open Access Journals (Sweden)

    Mustafa Atalay

    2003-06-01

    Full Text Available Regular physical exercise beneficially influences cardiac antioxidant defenses in normal rats. The aim of this study was to test whether endurance training can strengthen glutathione-dependent antioxidant defense mechanism and decrease lipid peroxidation in heart of the streptozotocin-induced diabetic rats. Redox status of glutathione in blood of diabetic rats in response to training and acute exercise was also examined. Eight weeks of treadmill training increased the endurance in streptozotocin-induced diabetic rats. It did not affect glutathione level in heart tissue at rest and also after exercise. On the other hand, endurance training decreased glutathione peroxidase activity in heart, while glutathione reductase and glutathione S-transferase activities were not affected either by acute exhaustive exercise or endurance training. Reduced and oxidized glutathione levels in blood were not affected by either training or acute exercise. Conjugated dienes levels in heart tissue were increased by acute exhaustive exercise and also 8 weeks treadmill training. Longer duration of exhaustion in trained group may have contributed to the increased conjugated dienes levels in heart after acute exercise. Our results suggest that endurance type exercise may make heart more susceptible to oxidative stress. Therefore it may be wise to combine aerobic exercise with insulin treatment to prevent its adverse effects on antioxidant defense in heart in patients with diabetes mellitus

  7. Effect of subchronic exposure to mainstream cigarette smoke on endothelium-dependent vasodilation in rat arteries

    Directory of Open Access Journals (Sweden)

    Helena Lenasi

    2005-07-01

    Full Text Available Background: Cigarette smoking is reported to impair endothelium-dependent vasodilation. The aim of the present study was to assess the effect of 30-day exposure to mainstream cigarette smoke on vascular reactivity of rat abdominal aorta, carotid, renal and mesenteric artery. Separately, the NO-mediated and the EDHF-mediated, endothelium-dependent vascular relaxations were determined.Methods: Two groups of »Whistar Kyoto« rats were exposed to mainstream cigarette smoke (2 hours/day, 5 days/week for 30 days and to fresh conditioned air, respectively. Rats were sacrificed on the second day after the last exposition to cigarette smoke. Vascular reactivity studies were performed on isolated, endothelium-intact, phenylephrine-preconstricted rat artery rings. Cumulative concentration-relaxation curves to acetylcholine (ACh were obtained in the absence and presence of the endothelial NO synthase (eNOS inhibitor N ω nitro L-arginine (L-NA and the cyclo-oxygenase (COX inhibitor diclofenac, respectively. After washing period of 1 hour, vessels were exposed either to the intracellular superoxide scavenger tiron, to the cytochrome P450 (CYP inhibitor miconazole or the Na-K-ATPase inhibitor ouabain before being preconstricted with phenylephrine and determining the concentration-response curve to ACh.Results: ACh induced concentration-dependent relaxations. In none of the vessels investigated did we observe a significant difference in the relaxations obtained in arteries from control rats and rats exposed to cigarettee smoke. Although smoking is known to cause an increase in oxidative stress, treatment of the vessels with tiron did not affect the NOmediated relaxations. To evaluate the contribution of EDHF to endothelium-dependent vasodilation rings were preincubated with L-NA. The EDHF-mediated relaxations were significantly attenuated compared to the NO-mediated relaxations in renal and mesenteric artery and almost completely abolished in aorta and

  8. Human urotensin-II is an endothelium-dependent vasodilator in rat small arteries

    Science.gov (United States)

    Bottrill, Fiona E; Douglas, Stephen A; Hiley, C Robin; White, Richard

    2000-01-01

    The possible role of the endothelium in modulating responses to human urotensin-II (U-II) was investigated using isolated segments of rat thoracic aorta, small mesenteric artery, left anterior descending coronary artery and basilar artery.Human U-II was a potent vasoconstrictor of endothelium-intact isolated rat thoracic aorta (EC50=3.5±1.1 nM, Rmax=103±10% of control contraction induced by 60 mM KCl and 1 μM noradrenaline). However the contractile response was not significantly altered by removal of the endothelium or inhibition of nitric oxide synthesis with L-NAME (100 μM). Human U-II did not cause relaxation of noradrenaline-precontracted, endothelium-intact rat aortae.Human U-II contracted endothelium-intact rat isolated left anterior descending coronary arteries (EC50=1.3±0.8 nM, Rmax=20.1±4.9% of control contraction induced by 10 μM 5-HT). The contractile response was significantly enhanced by removal of the endothelium (Rmax=55.4±16.1%). Moreover, human U-II caused concentration-dependent relaxation of 5-HT-precontracted arteries, which was abolished by L-NAME or removal of the endothelium.No contractile effects of human U-II were found in rat small mesenteric arteries. However the peptide caused potent, concentration- and endothelium-dependent relaxations of methoxamine-precontracted vessels. The relaxant responses were potentiated by L-NAME (300 μM) but abolished in the additional presence of 25 mM KCl (which inhibits the actions of endothelium-derived hyperpolarizing factor).The present study is the first to show that human U-II is a potent endothelium-dependent vasodilator in some rat resistance vessels, and acts through release of EDHF as well as nitric oxide. Our findings have also highlighted clear anatomical differences in the responses of different vascular beds to human U-II which are likely to be important in determining the overall cardiovascular activity of this peptide. PMID:10952676

  9. Parameters of Blood Flow in Great Arteries in Hypertensive ISIAH Rats with Stress-Dependent Arterial Hypertension.

    Science.gov (United States)

    Seryapina, A A; Shevelev, O B; Moshkin, M P; Markel', A L

    2016-08-01

    Magnetic resonance angiography was used to examine blood flow in great arteries of hypertensive ISIAH and normotensive Wistar rats. In hypertensive ISIAH rats, increased vascular resistance in the basin of the abdominal aorta and renal arteries as well as reduced fraction of total renal blood flow were found. In contrast, blood flow through both carotid arteries in ISIAH rats was enhanced, which in suggests more intensive blood supply to brain regulatory centers providing enhanced stress reactivity of these rats characterized by stress-dependent arterial hypertension.

  10. Hepatoprotective Effects of Chinese Medicine Herbs Decoction on Liver Cirrhosis in Rats

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    Nor Aziyah Mat-Rahim

    2017-01-01

    Full Text Available Hepatoprotective and curative activities of aqueous extract of decoction containing 10 Chinese medicinal herbs (HPE-XA-08 were evaluated in Sprague–Dawley albino rats with liver damage induced by thioacetamide (TAA. These activities were assessed by investigating the liver enzymes level and also histopathology investigation. Increases in alkaline phosphatase (ALP and gamma-glutamyl transferase (GGT levels were observed in rats with cirrhotic liver. No significant alterations of the liver enzymes were observed following treatment with HPE-XA-08. Histopathology examination of rats treated with HPE-XA-08 at 250 mg/kg body weight, however, exhibited moderate liver protective effects. Reduced extracellular matrix (ECM proteins within the hepatocytes were noted in comparison to the cirrhotic liver. The curative effects of HPE-XA-08 were observed with marked decrease in the level of ALP (more than 3x and level of GGT (more than 2x in cirrhotic rat treated with 600 mg/kg body weight HPE-XA-08 in comparison to cirrhotic rat treated with just water diluent. Reversion of cirrhotic liver to normal liver condition in rats treated with HPE-XA-08 was observed. Results from the present study suggest that HPE-XA-08 treatment assisted in the protection from liver cirrhosis and improved the recovery of cirrhotic liver.

  11. Early rebleeding and death at 6 weeks in alcoholic cirrhotic patients ...

    African Journals Online (AJOL)

    Background. This study evaluated the incidence of rebleeding and death at 6 weeks after a first episode of acute variceal haemorrhage (AVH) treated by emergency endoscopic sclerotherapy in a large cohort of alcoholic cirrhotic patients. Methods. From January 1984 to December 2006, 310 alcoholic cirrhotic patients (242 ...

  12. Reinforcement magnitude modulation of rate dependent effects in pigeons and rats.

    Science.gov (United States)

    Ginsburg, Brett C; Pinkston, Jonathan W; Lamb, R J

    2011-08-01

    Response rate can influence the behavioral effects of many drugs. Reinforcement magnitude may also influence drug effects. Further, reinforcement magnitude can influence rate-dependent effects. For example, in an earlier report, we showed that rate-dependent effects of two antidepressants depended on reinforcement magnitude. The ability of reinforcement magnitude to interact with rate-dependency has not been well characterized. It is not known whether our previous results are specific to antidepressants or generalize to other drug classes. Here, we further examine rate-magnitude interactions by studying effects of two stimulants (d-amphetamine [0.32-5.6 mg/kg] and cocaine [0.32-10 mg/kg]) and two sedatives (chlordiazepoxide [1.78-32 mg/kg] and pentobarbital [1.0-17.8 mg/kg]) in pigeons responding under a 3-component multiple fixed-interval (FI) 300-s schedule maintained by 2-, 4-, or 8-s of food access. We also examine the effects of d-amphetamine [0.32-3.2 mg/kg] and pentobarbital [1.8-10 mg/kg] in rats responding under a similar multiple FI300-s schedule maintained by 2- or 10- food pellet (45 mg) delivery. In pigeons, cocaine and, to a lesser extent, chlordiazepoxide exerted rate-dependent effects that were diminished by increasing durations of food access. The relationship was less apparent for pentobarbital, and not present for d-amphetamine. In rats, rate-dependent effects of pentobarbital and d-amphetamine were not modulated by reinforcement magnitude. In conclusion, some drugs appear to exert rate-dependent effect which are diminished when reinforcement magnitude is relatively high. Subsequent analysis of the rate-dependency data suggest the effects of reinforcement magnitude may be due to a diminution of drug-induced increases in low-rate behavior that occurs early in the fixed-interval. (c) 2011 APA, all rights reserved.

  13. Pituitary glycoprotein hormone a-subunit secretion by cirrhotic patients

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    Oliveira M.C.

    1999-01-01

    Full Text Available Secretion of the a-subunit of pituitary glycoprotein hormones usually follows the secretion of intact gonadotropins and is increased in gonadal failure and decreased in isolated gonadotropin deficiency. The aim of the present study was to determine the levels of the a-subunit in the serum of patients with cirrhosis of the liver and to compare the results obtained for eugonadal cirrhotic patients with those obtained for cirrhotic patients with hypogonadotropic hypogonadism. Forty-seven of 63 patients with cirrhosis (74.6% presented hypogonadism (which was central in 45 cases and primary in 2, 7 were eugonadal, and 9 women were in normal menopause. The serum a-subunit was measured by the fluorimetric method using monoclonal antibodies. Cross-reactivity with LH, TSH, FSH and hCG was 6.5, 1.2, 4.3 and 1.1%, respectively, with an intra-assay coefficient of variation (CV of less than 5% and an interassay CV of 5%, and sensitivity limit of 4 ng/l. The serum a-subunit concentration ranged from 36 to 6253 ng/l, with a median of 273 ng/l. The median was 251 ng/l for patients with central hypogonadism and 198 ng/l for eugonadal patients. The correlation between the a-subunit and basal LH levels was significant both in the total sample (r = 0.48, P<0.01 and in the cirrhotic patients with central hypogonadism (r = 0.33, P = 0.02. Among men with central hypogonadism there was a negative correlation between a-subunit levels and total testosterone levels (r = 0.54, P<0.01 as well as free testosterone levels (r = -0.53, P<0.01. In conclusion, although the a-subunit levels are correlated with LH levels, at present they cannot be used as markers for hypogonadism in patients with cirrhosis of the liver.

  14. Morphometric study on age-dependent pulmonary lesions in rats exposed to nitrogen dioxide

    Energy Technology Data Exchange (ETDEWEB)

    Kyono, H.; Kawai, K.

    1982-01-01

    Electronmicroscopic morphometry was performed on lung of 1, 3, 12 and 21 months-old rats exposed to 0.1, 0.5, 3 and 10 ppm nitrogen dioxide (NO/sub 2/) continuously for one month. The rats used in this experiment were all supplied at one time from one colony and kept under a barrier system until exposure. Effects of aging on the responses of lungs to NO/sub 2/ were studied by comparing the dose-effect reaction patterns among the age groups. A trend of dose-dependent increase of arithmetic mean thickness of air-blood barrier was found in all age groups examined. The response of lung to NO/sub 2/ exposure showed age-related differences. Based on the morphometric index, the response declines from 1 to 12 months, but increases again in 21-months-old rats. The compartmental components of alveolar wall tissue such as type I epithelial cells, type II epithelial cells, interstitial cells, interstitial matrix and capillary endothelium appeared to have various degrees of response due to both age at onset of exposure and NO/sub 2/ concentration, resulting in the appearance of varying stages in impairment or repair. Accordingly, the response of each compartmental component of lung to the concentrations of NO/sub 2/ did not always exhibit a simple dose-dependent increase or decrease but sometimes indicated a multiphasic reaction pattern.

  15. Pharmacokinetic Study of Frusemide in Healthy and Cirrhotic Indian Subjects

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    Dr. Yuvrajsing Dhunnoo

    2008-01-01

    Full Text Available Liver cirrhosis is associated with various complications such as ascites and fluid retention, progressing to development of hepatorenal syndrome, further compromising fluid elimination. Frusemide, a loop diuretic is normally administered to relieve fluid retentions. The kinetics of frusemide has not been conclusively reported in the three types of cirrhosis and among Indian subjects. The aim of the current study was to evaluate the kinetics of frusemide among healthy and Child’s A, B and C cirrhosis and compare with earlier data. 24 cirrhotic were selected and classified according to the Child’s-Pugh classification. 12 healthy male volunteers were screened and included in the study. 40 mg of frusemide was administered orally to both groups and blood samples were withdrawn at various intervals of time for a duration of 8 hrs. The amount of frusemide present in plasma was analyzed using HPLC. The volumes of distribution (Vd, area under curve (AUC, systemic clearance (CL, maximum concentration (Cmax, time for maximum concentration (tmax in healthy volunteers were respectively 4.56 ± 0.15 L, 2258 ± 530.7, 4.97 ± 1.67 L/h, 892 ± 49.4 ng/ml, 85.20± 7.49 mins. Corresponding values in Group A were 5.00 ± 0.31 L, 2471 ± 228.6, 6.60 ± 2.90L/h, 1021 ± 47.97 ng/ml and 88.25 V 2.12 mins; in Group B 7.73 ± 1.10 L, 4038 ± 154.7, 8.84 ± 0.45 L/h, 1448 ± 43.20 ng/ml and 120 ± 1.89 mins; In group C cirrhosis 9.69 ± 1.32 L, 4085 ± 131.75, 3.49 ± 1.40 L/h, 1551± 59.02 ng/ml and 185.7 ± 2.68 mins respectively. Significant differences at 1% and 5% were observed among the cirrhotic groups and between healthy v/s cirrhotic patients. Data from current study do not correlate with earlier reports, carried mainly in Western population, due to possibly differences in instrumentation, etc but a possible genetic interplay should not be ruled out. Data from cirrhotic patients could not be effectively compared with earlier studies as kinetics of frusemide

  16. Splenic embolization in cirrhotic patients with portal hypertension

    International Nuclear Information System (INIS)

    Falappa, P.G.; Cotroneo, A.R.; De Cinque, M.; Maresca, G.; Patane', D.

    1988-01-01

    Over the last four years the authors performed transcatheter embolization of the splenic artery by Gianturco coils in 32 consecutive cirrhotic patients with portal hypertension, splenomegaly, cytopenia and gastro-esophageal varices endoscopically proved. This procedure was especially useful for treatement of splenomegaly and cytopenia because a constant reduction of spleen dimensions and increase in platelet count were registered. The effectiveness of transcatheter embolization and follow-up are based on clinic, hematologic and sonographic findings. Sonographic monitoring is believed to be very useful both to evaluate splenomegaly and signs of portal hypertension and to reveal splenic complications (abscesses). Severe complications have been never registered

  17. Splenic embolization in cirrhotic patients with portal hypertension. US findings

    Energy Technology Data Exchange (ETDEWEB)

    Falappa, P G; Cotroneo, A R; De Cinque, M; Maresca, G; Patane' , D

    1988-01-01

    Over the last four years the authors performed transcatheter embolization of the splenic artery by Gianturco coils in 32 consecutive cirrhotic patients with portal hypertension, splenomegaly, cytopenia and gastro-esophageal varices endoscopically proved. This procedure was especially useful for treatement of splenomegaly and cytopenia because a constant reduction of spleen dimensions and increase in platelet count were registered. The effectiveness of transcatheter embolization and follow-up are based on clinic, hematologic and sonographic findings. Sonographic monitoring is believed to be very useful both to evaluate splenomegaly and signs of portal hypertension and to reveal splenic complications (abscesses). Severe complications have been never registered. 21 refs.

  18. Relevance of plasma malondialdehyde level and severity of portal hypertension in cirrhotic patients.

    Science.gov (United States)

    Wang, Sheng-Lan; Zhu, Xin-Yan; Zhang, Dong-Wei; Zhang, Zhao-Jie; Gao, Heng-Jun; Yang, Chang-Qing

    2015-01-01

    Portal hypertension is one of the death reasons for the liver cirrhosis patients. The oxidative stress is related to the occurrence and development of portal hypertension in cirrhosis. Malondialdehyde (MDA), one of the lipid peroxides, increases substantially in cirrhotic patients. To evaluate the relevance between the MDA level and portal hypertension in cirrhotic patients. 60 liver cirrhotic patients and 30 healthy controls were enrolled. The plasma MDA level and general blood tests including ALT, AST, ALB, total bilirubin, and platelet were measured. All people enrolled accepted endoscopic examination and B-Ultrasound check to evaluate the severity of portal hypertension. The MDA plasma level of cirrhotic patients was significantly higher than the controls (Pportal hypertension (Pportal vein (r=0.652, Pportal hypertension. Plasma MDA level may correlate with the severity of portal hypertension in cirrhotic patients.

  19. Dose-Dependent Effect of Curcumin on Learning and Memory Deficit in Kainate-Epileptic Rats

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    Zahra Kiasalari

    2014-09-01

    Full Text Available Background & objectives : Epileptic seizures accompany disturbances in learning, memory, and cognitive skills. With regard to antiepileptic potential of curcumin and its beneficial effect on memory, the effect of its administration on learning and memory in kainate-epileptic rats was investigated.   Methods: Forty male rats were divided into sham, positive control ( valproate-treated epileptic, epileptic, and two curcumin-treated epileptic groups. Rat model of epilepsy was induced by unilateral intrahippocampal administration of 4 μg of kainate per rat. Rats received intraperitoneal injection of curcumin (50 and 100 mg/kg daily for 1 week before surgery. For evaluation of learning and memory, initial (IL and step-through latencies (STL were determined using passive avoidance test and alternation behavior percentage was obtained according to Y maze test.   Results: Regarding IL, there was no significant difference between the groups. In contrast, STL significantly decreased in curcumin-50-treated epileptic group (p<0.05 (a change from 263.1 to 184.5 s. However, this parameter significantly increased in curcumin-100-treated epileptic group as compared to epileptic group (p<0.01 (a change from 263.1 to 220.3 s. In addition, STL was also significantly higher in valproic acid-treated epileptic group versus epileptic group (p<0.05 (a change from 145.7 to 210.3 s. Alternation percentage was also significantly higher in curcumin-50- and curcumin-100-treated epileptic groups relative to epileptic group (p<0.05 (a change from 60.5 to 77.6 and 80.3%.   Conclusion: Curcumin could dose-dependently enhance the consolidation and recall in epileptic animals and could improve spatial memory in such animals.

  20. Arbutus unedo induces endothelium-dependent relaxation of the isolated rat aorta.

    Science.gov (United States)

    Ziyyat, Abderrahim; Mekhfi, Hassane; Bnouham, Mohamed; Tahri, Abdelhafid; Legssyer, Abdelkhaleq; Hoerter, Jacqueline; Fischmeister, Rodolphe

    2002-09-01

    Arbutus unedo L. (Ericaceae) is used in oriental Morocco to treat arterial hypertension. We studied its vasodilator effect and mechanisms of action in vitro. The root aqueous extract of Arbutus (0.25 mg/mL) produced a relaxation of noradrenaline-precontracted ring preparations of rat aorta with intact endothelium. Relaxation by Arbutus did not occur in specimens without endothelium and was inhibited by pretreatment with 100 microM N(G)-methyl-L-arginine (L-NMA), 10 microM methylene blue or 50 microM 1H-[1,2,4] oxadiazolo [4,3-a] quinoxaline-1-one (ODQ) but not by 10 microM atropine. These results suggest that Arbutus produces an endothelium-dependent relaxation of the isolated rat aorta which may be mediated mainly by a stimulation of the endothelial nitric oxide synthase by mechanisms other than activation of muscarinic receptors. Copyright 2002 John Wiley & Sons, Ltd.

  1. Adrenal and plasma corticosterone changes in continuously irradiated rats. II. Dependence on additional stress factors

    Energy Technology Data Exchange (ETDEWEB)

    Malatova, Z; Ahlers, I; Praslicka, M [Univerzita P.J. Safarika, Kosice (Czechoslovakia). Katedra Vseobecnej Biologie

    1978-01-01

    Adrenal and plasma corticosterone levels were followed in continuously irradiated rats in dependence on additional stress factors - transport of animals, handling and overnight fasting. Rats were gamma irradiated on an open experimental field with a daily dose rate of 15.48x10/sup -3/ C/kg (60 R) continuously up to a total exposure of 387.0x10/sup -3/ C/kg (1500 R) and analyzed after irradiation. The continuous irradiation increased the adrenal and plasma corticosterone concentrations in all groups of animals. The transport and weighing increased mainly adrenal corticosterone in all three groups, irradiated, non-irradiated controls from the field and intact laboratory controls. The scatter of the results made reproducibility difficult. Overnight fasting increased the absolute values in all groups. The radiation effect was evident especially in adrenal corticosterone values of non-handled animals.

  2. Dose dependent effect of progesterone on hypoxic ventilatory response in newborn rats.

    Science.gov (United States)

    Hichri, Oubeidallah; Laurin, Jean-C; Julien, Cécile A; Joseph, Vincent; Bairam, Aida

    2012-01-01

    The effect of progesterone as a respiratory stimulant in newborn subjects is less known than that in adults. This study investigated the dose-response curve (0, 2, 4, and 8 mg/kg, ip) of progesterone on ventilation in non-anesthetized newborn rats at 4- and 12-days old using plethysmography. Progesterone had no effects in the regulation of normoxic ventilation. However, it enhanced the response to moderate hypoxia (FiO(2) 12%, 20 min) in 4- but not in 12-days old pups. This response was similar between the dose of 4 and 8 mg/kg. These observations suggested that progesterone enhances in age- and dose-dependent manner the hypoxic ventilatory response in newborn rats.

  3. The diminished expression of proangiogenic growth factors and their receptors in gastric ulcers of cirrhotic patients.

    Science.gov (United States)

    Luo, Jiing-Chyuan; Peng, Yen-Ling; Hou, Ming-Chih; Huang, Kuang-Wei; Huang, Hui-Chun; Wang, Ying-Wen; Lin, Han-Chieh; Lee, Fa-Yauh; Lu, Ching-Liang

    2013-01-01

    The pathogenesis of the higher occurrence of peptic ulcer disease in cirrhotic patients is complex. Platelets can stimulate angiogenesis and promote gastric ulcer healing. We compared the expressions of proangiogenic growth factors and their receptors in the gastric ulcer margin between cirrhotic patients with thrombocytopenia and those of non-cirrhotic patients to elucidate possible mechanisms. Eligible cirrhotic patients (n = 55) and non-cirrhotic patients (n = 55) who had gastric ulcers were enrolled. Mucosa from the gastric ulcer margin and non-ulcer areas were sampled and the mRNA expressions of the proangiogenic growth factors (vascular endothelial growth factor [VEGF], platelet derived growth factor [PDGF], basic fibroblast growth factor [bFGF]) and their receptors (VEGFR1, VEGFR2, PDGFRA, PDGFRB, FGFR1, FGFR2) were measured and compared. Platelet count and the expressions of these growth factors and their receptors were correlated with each other. The two groups were comparable in terms of gender, ulcer size and infection rate of Helicobacter pylori. However, the cirrhotic group were younger in age, had a lower platelet count than those in the non-cirrhotic group (pexpressions of PDGFB, VEGFR2, FGFR1, and FGFR2 in gastric ulcer margin when compared with those of the non-cirrhotic patients (pexpressions of PDGFB and VEGFR2, FGFR1, and FGFR2 were well correlated with the degree of thrombocytopenia in these cirrhotic patients (ρ>0.5, pimplied that diminished activity of proangiogenic factors and their receptors may contribute to the pathogenesis of gastric ulcers in cirrhotic patients.

  4. Comparison of estrogenic responses in bone and uterus depending on the parity status in Lewis rats.

    Science.gov (United States)

    Keiler, Annekathrin Martina; Bernhardt, Ricardo; Scharnweber, Dieter; Jarry, Hubertus; Vollmer, Günter; Zierau, Oliver

    2013-01-01

    The reproductive transition of women through peri- to postmenopause is characterized by changes in steroid hormone levels due to the cessation of the ovarian function. Beside several complaints associated with these hormonal changes, the deterioration of the trabecular bone micro-architecture and the loss of skeletal mass can cause osteoporosis. At this life stage, women often have a reproductive history of one to several pregnancies. The ovariectomized skeletally mature rat (>10 months old) is one of the most commonly used animal models for postmenopausal osteoporosis research. Despite the fact that mammals can undergo up to several reproductive cycles (primi-/pluriparous), nulliparous animals are often used and the question whether changes in the hormonal milieu subsequently affect the skeleton and influence the outcome of intervention studies is often neglected in study designs. Therefore, the aim of the present study was to compare the estrogen responsiveness of nulliparous and pluriparous rats. For this purpose, one year old virgin or retired breeder Lewis rats were either sham operated or ovariectomized, whereas half of the ovariectomized animals received subcutaneous 17β-estradiol pellets eight weeks after surgery. After another four weeks, the effects on the uterus were determined by expression analysis of estrogen-dependently regulated steroid receptor genes and well-established marker genes. Moreover, trabecular bone parameters in the tibia were analyzed by micro-computed tomography (μCT). Parity-dependency in estrogen responsiveness was observed with respect to the achieved serum E2 levels in response to similar E2 treatment. This led to differences both on the uterus wet weight and on the expression level of uterine target genes. In addition, a reversal of the ovariectomy-induced changes of the bone architecture after 17β-estradiol substitution was only observed among the nulliparous. In conclusion, the observations of this study support parity-dependent

  5. Na+-H+ exchange and Na+-dependent transport systems in streptozotocin diabetic rat kidneys

    International Nuclear Information System (INIS)

    El-Seifi, S.; Freiberg, J.M.; Kinsella, F.J.; Cheng, L.; Sacktor, B.

    1987-01-01

    The streptozotocin-induced diabetic rat was used to test the hypothesis that Na + -H + exchange activity in the proximal tubule luminal membrane would be increased in association with renal hypertrophy, altered glomerular hemodynamics, enhanced filtered load and tubular reabsorption of 22 Na + , and stimulated 22 Na= pump activity in the basolateral membrane, previously reported characteristics of this experimental animal model. Amiloride-sensitive H + gradient-dependent Na + uptake and Na + gradient-dependent H + flux were increased in brush-border membrane vesicles from the streptozotocin-treated animals. Na + gradient-dependent uptakes of phosphate, D-glucose, L-proline, and myoinositol were decreased in the drug-induced diabetic animals. These membrane transport alterations were not found when the streptozotocin-diabetic animals were treated with insulin

  6. Ascitic Fluid Culture In Cirrhotic Patients With Spontaneous Bacterial Peritonitis

    International Nuclear Information System (INIS)

    Sajjad, M.; Khan, Z.A.; Khan, M.S.

    2016-01-01

    Objective: To determine the frequency and compare the culture yield of bacterial isolation by conventional and blood culture BACTEC bottle techniques in cirrhotic patients with spontaneous bacterial peritonitis (SBP). Study Design: Cross-sectional comparative study. Place and Duration of Study: Pathology Department, Bannu Medical College, Bannu, KPK, from January 2012 to December 2013. Methodology: Paracentesis of 20 ml of ascitic fluid tapped from cirrhotic patients with SBP was carried out by a single technologist. The analysis included differential leukocyte count (DLC), while 5 ml each of the fluid was inoculated into conventional culture media and BACTEC blood culture bottle. All the data were analysed on (SPSS) version 16 to determine frequencies with percentages and mean values with standard deviation. Chi-square test was used for comparing the yield of conventional and blood culture bottle methods. P-value was considered significant if < 0.05. Results: In 105 cases of ascitic fluid analyses, 27 (25.72 percent) had positive ascitic fluid culture whereas 78 (74.28 percent) had negative ascitic fluid culture. Ascitic fluid culture was positive in 6 cases by conventional culture media and in 27 cases by BACTEC culture bottle media (p < 0.001). Bacterial isolation was obtained by both culture methods in 6 cases (p < 0.001). Conclusion: Direct bedside inoculation of ascitic fluid by BACTEC culture bottle method has better yield as compared to conventional culture method. (author)

  7. Laparoscopic cholecystectomy in cirrhotic patients: Feasibility in adeveloping country

    International Nuclear Information System (INIS)

    Tayeb, M.; Khan, Muhammad R.; Riaz, N.

    2008-01-01

    Although laparoscopic cholecystectomy (LC) has become the procedure ofchoice for cholelithiasis in the general population, many consider cirrhosisas a relative or absolute contraindication for laparoscopic surgery. The aimof this study was to confirm the safety of LC in cirrhotic patients in ourset-up. This is a retrospective case series including all patients withcirrhosis who underwent LC for gallstones from January 2000 to December2006at our institution. Data were analyzed for Child class, indication forsurgery, hospital stay and procedure-related morbidity and mortality. Resultsare given as +- standard deviation. Thirty patients, including 21 females(median age: 42 years) underwent LC during the study period. There was nooperative mortality. Twenty-four patients belonged to Child class A and 6belonged to Child class B. Mean operative time was 80+-26 min. There was noincident of bile duct injury, but two patients (6.7%) required conversion toopen procedure. Mean hospital stay was 3+-2.7 days. Postoperative morbiditywas observed in 7 patients, including postoperative deterioration of liverfunction in 2, worsening of ascites in 2 and pneumonia and port-siteinfection in 1. Two patients had significant in hemoglobin requiring bloodtransfusion. Cirrhosis is not a contraindication for LC and it can beperformed safely in compensated cirrhotic patients with acceptable morbidityand mortality. (author)

  8. Research advances in non-cirrhotic portal hypertension

    Directory of Open Access Journals (Sweden)

    ZHANG Bojing

    2016-02-01

    Full Text Available Although liver cirrhosis is the most common cause of portal hypertension (PH, about 20% of PH cases are caused by non-cirrhotic reasons, which are referred to as non-cirrhotic portal hypertension (NCPH, with a high incidence rate in developing countries. NCPH is a group of heterogeneous hepatic vascular diseases, including idiopathic portal hypertension (IPH and extrahepatic portal vein obstruction (EHPVO, as well as the rare diseases in clinical practice such as Budd-Chiari syndrome, congenital hepatic fibrosis, and nodular regenerative hyperplasia. The patients with NCPH usually have the symptoms of portal hypertension, such as recurrent variceal bleeding and splenomegaly, but liver function is well preserved in these patients. At present, the diagnosis of NCPH lacks a universally accepted standard and remains a challenge. In clinical practice, the method of exclusion is usually applied for the diagnosis of HCPH, and liver biopsy is performed when necessary to make a confirmed diagnosis. This paper introduces the pathogenesis and pathological manifestations of IPH and EHPVO, as well as the selection of diagnostic methods and therapeutic strategies. If upper gastrointestinal bleeding can be effectively controlled, NCPH is considered to have a relatively good prognosis.

  9. Strain-dependent variations in spatial learning and in hippocampal synaptic plasticity in the dentate gyrus of freely behaving rats

    Directory of Open Access Journals (Sweden)

    Denise eManahan-Vaughan

    2011-03-01

    Full Text Available Hippocampal synaptic plasticity is believed to comprise the cellular basis for spatial learning. Strain-dependent differences in synaptic plasticity in the CA1 region have been reported. However, it is not known whether these differences extend to other synapses within the trisynaptic circuit, although there is evidence for morphological variations within that path. We investigated whether Wistar and Hooded Lister (HL rat strains express differences in synaptic plasticity in the dentate gyrus in vivo. We also explored whether they exhibit differences in the ability to engage in spatial learning in an 8-arm radial maze. Basal synaptic transmission was stable over a 24h period in both rat strains, and the input-output relationship of both strains was not significantly different. Paired-pulse analysis revealed significantly less paired-pulse facilitation in the Hooded Lister strain when pulses were given 40-100 msec apart. Low frequency stimulation at 1Hz evoked long-term depression (>24h in Wistar and short-term depression (<2h in HL rats; 200Hz stimulation induced long-term potentiation (>24h in Wistar, and a transient, significantly smaller potentiation (<1h in HL rats, suggesting that HL rats have higher thresholds for expression of persistent synaptic plasticity. Training for 10d in an 8-arm radial maze revealed that HL rats master the working memory task faster than Wistar rats, although both strains show an equivalent performance by the end of the trial period. HL rats also perform more efficiently in a double working and reference memory task. On the other hand, Wistar rats show better reference memory performance on the final (8-10 days of training. Wistar rats were less active and more anxious than HL rats.These data suggest that strain-dependent variations in hippocampal synaptic plasticity occur in different hippocampal synapses. A clear correlation with differences in spatial learning is not evident however.

  10. Dosing-time-dependent variation in biliary excretion of flomoxef in rats.

    Science.gov (United States)

    Hishikawa, Shuji; Sugimoto, Koh-ichi; Kobayashi, Eiji; Kumagai, Yuji; Fujimura, Akio

    2003-05-01

    We previously reported that the biliary excretion of flomoxef, an oxacephem antibiotic, was greater after dosing at 21:00 than at 09:00 h in diurnally active human subjects. The present study was undertaken to examine whether the biliary excretion of flomoxef is also dependent on its dosing time in rats. Adult male Wistar rats were housed under light on at 07:00 h and off at 19:00 h. Bile fluid was completely drained through a polyethylene catheter from conscious animals. Flomoxef (20 mg/kg) was injected into the tail vein at 09:00 or 21:00 h by a cross-over design, and drained bile fluid was collected for 8 h after each dosing. The maximum concentration of biliary flomoxef was significantly greater and its total excretion tended to be greater after dosing at 09:00 than 21:00 h. These results suggest the biliary excretion of flomoxef is enhanced after dosing at the beginning of the rest period in rats, as it is in humans.

  11. The pH dependence of silicon-iron interaction in rats.

    Science.gov (United States)

    Jia, X; Emerick, R J; Kayongo-Male, H

    1997-01-01

    A 2 x 2 x 3 factorial experiment was conducted to study the pH dependence of a silicon-iron interaction in vivo. The dietary treatments used in the factorial design were the following (mg/kg of diet): silicon, 0 and 500; iron, 35 and 187; acid-base, ammonium chloride as 0.5% of total diet (acidic), sodium bicarbonate as 1.0% of total diet (basic), or no supplementation of acid or base (control). The supplementation of 500 mg silicon/kg of diet increased plasma-iron concentration in rats fed the acidic or control diets, but not in rats fed the basic diet. A high dietary-iron level suppressed copper absorption and utilization and subsequently imposed a negative effect on its own utilization. An increase in the plasma total-cholesterol concentration caused by high dietary-iron level was likely a consequence of the antagonistic effect of iron on copper absorption and utilization. The use of cupric sulfate pentahydrate as the dietary-copper source in this study resulted in plasma copper concentrations that were approximately twice those obtained in a related study using cupric carbonate. Also, a 42% coefficient of variation (C.V.) for plasma-copper concentrations of rats fed cupric sulfate in this study was greatly reduced from the C.V. = 108% previously associated with the dietary cupric carbonate.

  12. Salivary gland ultrastructure and cyclic AMP-dependent reactions in Spacelab 3 rats

    International Nuclear Information System (INIS)

    Mednieks, M.I.; Hand, A.R.

    1987-01-01

    Environmental stimuli influencing catecholamine levels induce changes in cyclic AMP-dependent reactions and cell morphology in the rat parotid. Responses of salivary glands to spaceflight were determined by measurement of cyclic AMP-mediated reactions in fresh-frozen salivary glands and by microscopic evaluation of ultrastructure in fixed parotid glands. Decreased cell-free protein phosphorylation, determined by autoradiography, occurred in parotid glands in three of five flight animals. Protein kinase activity ratios were decreased in the soluble and increased in the particulate fractions of Spacelab 3 (SL-3) rat sublingual glands, compared with ground controls. Biochemical analyses show that effects of space flight on salivary glands are similar to those induced experimentally by physiological manipulation or alteration of catecholamine levels. Morphological evaluation of three SL-3 rat parotid glands showed increased numbers of lysosomes, autophagic vacuoles containing degenerating secretory product, and accumulation of lipid droplets. Since these animals lost weight, consistent with disruption of food and water consumption, morphological changes may in part be due to decreased masticatory stimulation, as occurs with reduced food intake or a liquid diet. The observed changes may reflect physiological responses of the gastrointestinal and autonomic systems to effects of spaceflight

  13. Brain receptors for thyrotropin releasing hormone in morphine tolerant-dependent rats

    Energy Technology Data Exchange (ETDEWEB)

    Bhargava, H.N.; Das, S.

    1986-03-01

    The effect of chronic treatment of rats with morphine and its subsequent withdrawal on the brain receptors for thyrotropin releasing hormone (TRH) labeled with /sup 3/H-(3MeHis/sup 2/)TRH (MeTRH). Male Sprague Dawley rats were implanted with 4 morphine pellets (each containing 75 mg morphine base) during a 3-day period. Placebo pellet implanted rats served as controls. Both tolerance to and dependence on morphine developed as a result of this procedure. For characterization of brain TRH receptors, the animals were sacrificed 72 h after the implantation of first pellet. In another set of animals the pellets were removed and were sacrificed 24 h later. The binding of /sup 3/H-MeTRH to membranes prepared from brain without the cerebellum was determined. /sup 3/H-MeTRH bound to brain membranes prepared from placebo pellet implanted rats at a single high affinity site with a B/sub max/ value of 33.50 +/- 0.97 fmol/mg protein and a K/sub d/ of 5.18 +/- 0.21 nM. Implantation of morphine pellets did not alter the B/sub max/ value of /sup 3/H-MeTRH but decreased the K/sub d/ value significantly. Abrupt or naloxone precipitated withdrawal of morphine did not alter B/sub max/ or the K/sub d/ values. The binding of /sup 3/H-MeTRH to brain areas was also determined. The results suggest that the development of tolerance to morphine is associated with enhanced sensitivity of brain TRH receptors, however abrupt withdrawal of morphine does not change the characteristics of brain TRH receptors.

  14. The role of basolateral amygdala adrenergic receptors in hippocampus dependent spatial memory in rat

    Directory of Open Access Journals (Sweden)

    Vafaei A.L.

    2008-03-01

    Full Text Available Background and the purpose of the study: There are extensive evidences indicating that the noradrenergic system of the basolateral nucleus of the amygdala (BLA is involved in memory processes. The present study investigated the role of the BLA adrenergic receptors (ARs in hippocampus dependent spatial memory in place avoidance task in male rat. Material and Methods: Long Evans rats (n=150 were trained to avoid footshock in a 60° segment while foraging for scattered food on a circular (80-cm diameter arena. The rats were injected bilaterally in the BLA specific ARS (Adrenergic receptors agonist norepinephrine (NE, 0.5 and 1 µg/µl and specific β-ARs antagonist propranolol (PRO, 0.5 and 1 µg/µl before acquisition, after training or before retrieval of the place avoidance task. Control rats received vehicle at the same volume. The learning in a single 30-min session was assessed 24h later by a 30-min extinction trial in which the time to first entrance and the number of entrances to the shocked area measured the avoidance memory. Results: Acquisition and consolidation were enhanced and impaired significantly by NE and PRO when the drugs were injected 10 min before or immediately after training, respectively. In contrast, neither NE nor PRO influenced animal performances when injected before retention testing. Conclusion: Findings of this study indicates that adrenergic system of the BLA plays an important role in regulation of memory storage and show further evidences for the opinion that the BLA plays an important role in integrating hormonal and neurotransmitter influences on memory storage.

  15. Hyperoxia-induced developmental plasticity of the hypoxic ventilatory response in neonatal rats: contributions of glutamate-dependent and PDGF-dependent mechanisms.

    Science.gov (United States)

    Bavis, Ryan W; DeAngelis, Kathryn J; Horowitz, Terry C; Reedich, Lisa M; March, Ryan J

    2014-01-15

    Rats reared in hyperoxia exhibit a sustained (vs. biphasic) hypoxic ventilatory response (HVR) at an earlier age than untreated, Control rats. Given the similarity between the sustained HVR obtained after chronic exposure to developmental hyperoxia and the mature HVR, it was hypothesized that hyperoxia-induced plasticity and normal maturation share common mechanisms such as enhanced glutamate and nitric oxide signaling and diminished platelet-derived growth factor (PDGF) signaling. Rats reared in 21% O2 (Control) or 60% O2 (Hyperoxia) from birth until 4-5 days of age were studied after intraperitoneal injection of drugs targeting these pathways. Hyperoxia rats receiving saline showed a sustained HVR to 12% O2, but blockade of NMDA glutamate receptors (MK-801) restored the biphasic HVR typical of newborn rats. Blockade of PDGF-β receptors (imatinib) had no effect on the pattern of the HVR in Hyperoxia rats, although it attenuated ventilatory depression during the late phase of the HVR in Control rats. Neither nitric oxide synthase inhibitor used in this study (nNOS inhibitor I and l-NAME) altered the pattern of the HVR in Control or Hyperoxia rats. Drug-induced changes in the biphasic HVR were not correlated with changes in metabolic rate. Collectively, these results suggest that developmental hyperoxia hastens the transition from a biphasic to sustained HVR by upregulating glutamate-dependent mechanisms and downregulating PDGF-dependent mechanisms, similar to the changes underlying normal postnatal maturation of the biphasic HVR. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. Spontaneous appetence for wheel-running: a model of dependency on physical activity in rat.

    Science.gov (United States)

    Ferreira, Anthony; Lamarque, Stéphanie; Boyer, Patrice; Perez-Diaz, Fernando; Jouvent, Roland; Cohen-Salmon, Charles

    2006-12-01

    According to human observations of a syndrome of physical activity dependence and its consequences, we tried to examine if running activity in a free activity paradigm, where rats had a free access to activity wheel, may present a valuable animal model for physical activity dependence and most generally to behavioral dependence. The pertinence of reactivity to novelty, a well-known pharmacological dependence predictor was also tested. Given the close linkage observed in human between physical activity and drugs use and abuse, the influence of free activity in activity wheels on reactivity to amphetamine injection and reactivity to novelty were also assessed. It appeared that (1) free access to wheel may be used as a valuable model for physical activity addiction, (2) two populations differing in activity amount also differed in dependence to wheel-running. (3) Reactivity to novelty did not appeared as a predictive factor for physical activity dependence (4) activity modified novelty reactivity and (5) subjects who exhibited a high appetence to wheel-running, presented a strong reactivity to amphetamine. These results propose a model of dependency on physical activity without any pharmacological intervention, and demonstrate the existence of individual differences in the development of this addiction. In addition, these data highlight the development of a likely vulnerability to pharmacological addiction after intense and sustained physical activity, as also described in man. This model could therefore prove pertinent for studying behavioral dependencies and the underlying neurobiological mechanisms. These results may influence the way psychiatrists view behavioral dependencies and phenomena such as doping in sport or addiction to sport itself.

  17. Vehicle-Dependent Disposition Kinetics of Fluoranthene in Fisher-344 Rats

    Directory of Open Access Journals (Sweden)

    Aramandla Ramesh

    2008-03-01

    Full Text Available The objective of this study was to evaluate how the vehicles of choice affect the pharmacokinetics of orally administered Fluoranthene [FLA] in rats. Fluoranthene is a member of the family of polycyclic aromatic hydrocarbon chemicals. Fluoranthene exposure to humans may occur as a result of cigarette smoking, consumption of contaminated food and water, heating woods in stoves and boilers, industrial sources such as coal gasification, carbon and graphite electrode manufacturing. Adult male Fisher-344 rats were given single oral doses of 25 and 50 μg/kg FLA in tricaprylin, peanut oil, cod liver oil, tween 80/isotonic saline (1:5 and 2% Alkamuls-EL620 through gavage. After administration, the rats were housed individually in metabolic cages and sacrificed at 2, 4, 6, 8, 10 and 12 hours post FLA exposure. Blood, lung, liver, small intestine, adipose tissue samples, urine, and feces were collected at each time point. Samples were subjected to a liquid-liquid extraction using methanol, chloroform, and water. The extracts were analyzed by a reverse-phase HPLC, equipped with a fluorescence detector. The results revealed a dose-dependent increase in FLA concentrations in plasma and tissues for all the vehicles used. Plasma and tissue FLA concentrations were greater for peanut oil; cod liver oil, and tricaprylin vehicles compared to Alkamuls (p peanut oil > tricaprylin > alkamuls > tween 80/isotonic saline (1:5]. These findings suggest that uptake and elimination of FLA is accelerated when administered through oil-based vehicles. The low uptake of FLA from alkamuls and tween 80/isotonic saline may have been a result of the poor solubility of the chemical. In summary, our findings reiterate that absorption characteristics of FLA were governed by the dose as well as the dosing vehicle. The vehicle-dependent bioavailability of FLA suggests a need for the judicious selection of vehicles in evaluating oral toxicity studies for risk assessment purposes.

  18. Autoradiographic investigation of age-dependent proliferation kinetics in the mucosa of rat small intestine

    International Nuclear Information System (INIS)

    Kranz, D.; Laue, R.; Fuhrmann, I.

    1980-01-01

    Aging of cells depends on mitotic activity which is particularly evident in multicellular organisms. The cell kinetics of the mucosa of the small intestine in a total of 244 Wistar rats aged 6 days, 6 weeks, 6, 12, 23 and 28 months, resp., were studied histoautoradiographically. It could be demonstrated that the regeneration rate of cells per hour in the crypts of the small intestine and the migration velocity of the enterocytes differ in young and old individuals, and that the intermitotic cells have age-dependent properties as well. In addition, it could be proved that intermitotic cells have a non growth fraction, too, which, at an advanced age, decreases only slightly although significantly in terms of statistics. For the easily vulnerable crypt epithelium it is a reserve capacity and ban be included in the proliferating pool if necessary. (author)

  19. Time-dependent changes in rat lymphocyte activity in response to isolation

    International Nuclear Information System (INIS)

    Jessop, J.J.; Bayer, B.M.

    1986-01-01

    The authors have found that isolation of rats, previously adapted to group-housing conditions, resulted in time-dependent changes in mitogenic and cytolytic responses of lymphocytes. A depression (40-60%) of the uptake of 3 H-thymidine by splenic and blood lymphocytes stimulated with either phytohemagglutinin (PHA) or lipopolysaccharide (LPS) was observed during the first 48 hours after transfer of the animals to individual cages. Within 4 days the mitogenic response increased and was comparable to that of animals which had been continuously group-housed. The response continued to increase and by 10 days was enhanced by 2 to 4 fold and remained elevated for at least 8 weeks. Similar changes in activity were observed with both splenic and blood lymphocytes, however, thymic lymphocytes taken from isolated animals demonstrated no change in reactivity to PHA. As with mitogenic responses, the cytolytic activity of splenic lymphocytes was also depressed during the initial days of isolation and as isolation continued, the activity returned to normal and was significantly enhanced (80%) within 5 weeks. These data show that changes in lymphocyte activity are dependent on the duration of exposure to isolated housing conditions and may be a part of the acute, adaptive and chronic phases of the response of rats to the stress of isolation

  20. Perinatal methadone exposure produces physical dependence and altered behavioral development in the rat.

    Science.gov (United States)

    Kunko, P M; Smith, J A; Wallace, M J; Maher, J R; Saady, J J; Robinson, S E

    1996-06-01

    Pregnant rats were implanted with osmotic minipumps containing either methadone hydrochloride (9 mg/kg/day) or sterile water. Their offspring were cross-fostered so that the following prenatal/postnatal exposure groups were obtained: water/water, methadone/water, water/methadone and methadone/methadone. Methadone slightly reduced litter size, particularly the number of male offspring, and reduced litter birth weight. The induction or maintenance of physical dependence in the postnatal methadone exposure groups was confirmed by an experiment in which PD19 pups were challenged with naloxone (1 mg/kg, s.c.). Methadone concentrations were assayed in pup brain on postnatal days 4, 10 and 22. Postnatal exposure to methadone via maternal milk produced measurable levels of methadone which decreased with age. Neuromuscular and physical development were assessed. Exposure to methadone accelerated acquisition of the righting reflex, but tended to delay the acquisition of the negative geotaxic response. Postnatal exposure to methadone was associated with decreased somatic growth as measured through postnatal day 21. The older pups (postnatal day 21) exposed to methadone exhibited variations in activity levels: pups exposed to methadone both prenatally and postnatally exhibited the least amount of spontaneous locomotor activity and pups exposed only postnatally exhibited the most activity. Therefore, it is possible to induce and/or maintain physical dependence via lactation in rat pups fostered to methadone-treated dams. Perinatal exposure to methadone by this route produces several subtle disruptions of pup development in the absence of gross maternal or fetal toxicity.

  1. [Effect of Corydalis yanhusuo and L-THP on Gastrointestinal Dopamine System in Morphine-Dependent Rats].

    Science.gov (United States)

    Xu, Jing-yu; Bai, Wei-feng; Qiu, Cheng-kai; Tu, Ping; Yu, Shou-yang; Luo, Su-yuan

    2015-12-01

    To investigate the protective mechanism of Corydalis yanhuso and L-THP in morphine-dependent gastrointestinal injury rats. 180 male rats were randomly divided into nine groups, 20 rats for each group: saline group (N), model group (M), NS treatment group and three different dosage of Corydalis yanhusuo and L-THP groups (low dose group,middle dose group and high dose group). The rat CPP (conditioned place preference) model was established by injecting the rats with an increasing dosage of morphine, all groups received CPP training in a black compartments and white ones (drug-paired compartment) for ten days. At 48 h after the final training, the performance of CPP models were assessed to make sure all models were exported correctly. Then the treatment groups were administered with different concentration of Corydalis yanhuso (0.5, 1 and 2 g/kg) and L-THP (0.94, 1.88 and 3.76 mg/kg) for six days. All rats were immediately killed after finish the last CPP test. For each group, ten rats were killed to detect the contents of DA in the stomach and duodenum through the fluorescence spectrophotometer. The expression levels of D2 receptor( D2R) in different tissues (gastric cardia, gastric body, pylorus and duodenum) were checked by Western-blot in the other rats. In the NS treatment group, the time when rats stay in the white ones were significantly decreased compared with the Corydalis yanhusuo treated groups (1 and 2 g/kg) and L-THP treated groups (1.88 and 3.76 mg/kg) (P THP. This is one of mechanism underlying the protective effects of gastrointestinal tract in morphine-dependent rats.

  2. State-Dependent Decoding Algorithms Improve the Performance of a Bidirectional BMI in Anesthetized Rats

    Directory of Open Access Journals (Sweden)

    Vito De Feo

    2017-05-01

    Full Text Available Brain-machine interfaces (BMIs promise to improve the quality of life of patients suffering from sensory and motor disabilities by creating a direct communication channel between the brain and the external world. Yet, their performance is currently limited by the relatively small amount of information that can be decoded from neural activity recorded form the brain. We have recently proposed that such decoding performance may be improved when using state-dependent decoding algorithms that predict and discount the large component of the trial-to-trial variability of neural activity which is due to the dependence of neural responses on the network's current internal state. Here we tested this idea by using a bidirectional BMI to investigate the gain in performance arising from using a state-dependent decoding algorithm. This BMI, implemented in anesthetized rats, controlled the movement of a dynamical system using neural activity decoded from motor cortex and fed back to the brain the dynamical system's position by electrically microstimulating somatosensory cortex. We found that using state-dependent algorithms that tracked the dynamics of ongoing activity led to an increase in the amount of information extracted form neural activity by 22%, with a consequently increase in all of the indices measuring the BMI's performance in controlling the dynamical system. This suggests that state-dependent decoding algorithms may be used to enhance BMIs at moderate computational cost.

  3. State-Dependent Decoding Algorithms Improve the Performance of a Bidirectional BMI in Anesthetized Rats.

    Science.gov (United States)

    De Feo, Vito; Boi, Fabio; Safaai, Houman; Onken, Arno; Panzeri, Stefano; Vato, Alessandro

    2017-01-01

    Brain-machine interfaces (BMIs) promise to improve the quality of life of patients suffering from sensory and motor disabilities by creating a direct communication channel between the brain and the external world. Yet, their performance is currently limited by the relatively small amount of information that can be decoded from neural activity recorded form the brain. We have recently proposed that such decoding performance may be improved when using state-dependent decoding algorithms that predict and discount the large component of the trial-to-trial variability of neural activity which is due to the dependence of neural responses on the network's current internal state. Here we tested this idea by using a bidirectional BMI to investigate the gain in performance arising from using a state-dependent decoding algorithm. This BMI, implemented in anesthetized rats, controlled the movement of a dynamical system using neural activity decoded from motor cortex and fed back to the brain the dynamical system's position by electrically microstimulating somatosensory cortex. We found that using state-dependent algorithms that tracked the dynamics of ongoing activity led to an increase in the amount of information extracted form neural activity by 22%, with a consequently increase in all of the indices measuring the BMI's performance in controlling the dynamical system. This suggests that state-dependent decoding algorithms may be used to enhance BMIs at moderate computational cost.

  4. Hepatic enhancement on Gd-BOPTA-enhanced MR imaging: comparison between cirrhotic and normal livers

    International Nuclear Information System (INIS)

    Shin, Sang Soo; Jeong, Yong Yeon; Kang, Heoung Keun; Lim, Hyo Soon; Yoon, Woong; Seo, Jeong Jin; Park, Jin Gyoon

    2004-01-01

    To compare the enhancement features of hepatic parenchyma between cirrhotic and normal liver, using Gd-BOPTA-enhanced delayed MR imaging. The 60 patients (35 with cirrhotic and 25 with normal liver) included in our study underwent Gd-BOPTA-enhanced MR imaging using a 1.5T system with a phase-array multicoil. In all cases, T1-weighted in-phase and opposed-phase gradient-echo MR imaging was performed before and 60 minutes after intravenous administration of a bolus of Gd-BOPTA. All images were quantitatively analysed by comparing the signal-to-noise ratio (SNR) and signal enhancement (SE) of cirrhotic and normal liver before and after contrast enhancement, and in cirrhotic patients, SNR and SE were also compared in terms of the Child-Pugh classification. For qualitative analysis, the hepatic enhancement patterns of cirrhotic and normal liver were classified as homogeneous or heterogeneous according to the consensual findings of two radiologists. At contrast-enhanced imaging, both cirrhotic (p<0.001) and normal liver (p<0.001) showed substantially increased SNR relative to unenhanced images, and the SNR of cirrhotic liver was significantly lower than that of normal livers at both in-phase (p<0.001) and opposed-phase (p<0.001) imaging. The SE of cirrhotic liver was significantly lower than that of normal liver (in-phase:p=0.002; opposed phase:p=0.011). Both Child-Pugh class A (p<0.001) and B (p<0.001) cirrhotic liver showed a substantial increase in SNR at contrast-enhanced imaging relative to unenhanced imaging and the SNR of Child-Pugh class A was significantly higher than that of Child-Pugh class B at both in-phase (p<0.001) and opposed-phase (p=0.022) imaging. In addition, the SE of class A was significantly higher than that of class B at in-phase imaging (p=0.004). Cirrhotic liver showed heterogeneous enhancement in 20 of 35 patients (57%), whereas normal liver showed homogeneous enhancement in all patients. At Gd-BOPTA-enhanced delayed MR imaging, cirrhotic liver

  5. Insulin Radioimmunoassay for Clinical Research in Psychiatric, Pancreatic, Cirrhotic and Irradiated Patients

    Energy Technology Data Exchange (ETDEWEB)

    Czerniak, P.; Chlebowski, J.; Kulcar, S.; Boruchowski, Sabina [Department Of Radiotherapy and Isotopes and Department of Psychiatry, Tel-Aviv University Medical School (Israel); Faculty for Continuing Medical Education, Tel-Hashomer Hospital, Tel-Hashomer (Israel)

    1970-02-15

    A modified Hales-Randle method for insulin radioimmunoassay is described. An insulin response curve was established in normal cases after glucose loading. Pathological changes were then investigated in patients and animals before and after therapeutic, operative and radiological procedures. Four representative groups of this material will be illustrated. (1) Psychotic patients (acute and chronic schizophrenics, neurotics and depressives) were examined with the aim of learning about the variable effects produced by insulin shock-therapy, as well as for biochemical diagnosis purposes in psychotics. Highest insulin response curves were found in chronic schizophrenics with improvement after insulin therapy. Schizophrenics without improvement presented different curves. Lowest insulin values were found in acute schizophrenia. Depressives and anxiety neurotics showed insulin tolerance curves similar to those of non-psychotic patients. (2) Pancreatic patients. Special attention was paid to pancreatic carcinoma (insulinoma excepted). In most cases of pancreatic carcinoma a very low and flat insulin tolerance curve was found. The above findings may be of a diagnostic importance in this condition, which is clinically hardly recognized. (3) Liver cirrhotic patients. A special group of shunt operated patients was investigated. The study was performed on eight liver cirrhotics before and after porto-caval or reno-splenal shunt operation. The plasma insulin level was examined in the vena cava, renal and cubital blood. The influence of tolbutamide was analysed. The normally occurring retention of insulin by normal hepatic tissue was found to be considerably disturbed. Other interesting changes were observed. (4) The plasma insulin level in the radiologically exposed. Experimental and clinical studies were performed, with insulin doses before and after radiation. Whole body X-ray exposure (300 rads) to rats resulted in a rapid lowering of insulin or its disappearance. Recovery was

  6. Teaching Adult Rats Spinalized as Neonates to Walk Using Trunk Robotic Rehabilitation: Elements of Success, Failure, and Dependence.

    Science.gov (United States)

    Udoekwere, Ubong I; Oza, Chintan S; Giszter, Simon F

    2016-08-10

    Robot therapy promotes functional recovery after spinal cord injury (SCI) in animal and clinical studies. Trunk actions are important in adult rats spinalized as neonates (NTX rats) that walk autonomously. Quadrupedal robot rehabilitation was tested using an implanted orthosis at the pelvis. Trunk cortical reorganization follows such rehabilitation. Here, we test the functional outcomes of such training. Robot impedance control at the pelvis allowed hindlimb, trunk, and forelimb mechanical interactions. Rats gradually increased weight support. Rats showed significant improvement in hindlimb stepping ability, quadrupedal weight support, and all measures examined. Function in NTX rats both before and after training showed bimodal distributions, with "poor" and "high weight support" groupings. A total of 35% of rats initially classified as "poor" were able to increase their weight-supported step measures to a level considered "high weight support" after robot training, thus moving between weight support groups. Recovered function in these rats persisted on treadmill with the robot both actuated and nonactuated, but returned to pretraining levels if they were completely disconnected from the robot. Locomotor recovery in robot rehabilitation of NTX rats thus likely included context dependence and/or incorporation of models of robot mechanics that became essential parts of their learned strategy. Such learned dependence is likely a hurdle to autonomy to be overcome for many robot locomotor therapies. Notwithstanding these limitations, trunk-based quadrupedal robot rehabilitation helped the rats to visit mechanical states they would never have achieved alone, to learn novel coordinations, and to achieve major improvements in locomotor function. Neonatal spinal transected rats without any weight support can be taught weight support as adults by using robot rehabilitation at trunk. No adult control rats with neonatal spinal transections spontaneously achieve similar changes

  7. Dependence of the average life span, mortality and osteosarcoma occurence in rats on the radiation dose absorbed (Sr 90)

    International Nuclear Information System (INIS)

    Shvedov, V.L.; Panteleev, L.I.

    1975-01-01

    The dose dependence of mortality and osteosarcoma development frequency is studied in white rats which have received 0.00005-5.0μCi/day of strontium-90 throughout their lives. It is shown that total mortality in the dose range 0-10 krad is a more sensitive test than osteosarcoma frequency, osteosarcomatosis hardly reducing the mean life span of the irradiated rats. (author)

  8. Duration-dependence of the effect of treadmill exercise on hyperactivity in attention deficit hyperactivity disorder rats.

    Science.gov (United States)

    Ji, Eun-Sang; Kim, Chang-Ju; Park, Jun Heon; Bahn, Geon Ho

    2014-04-01

    Attention-deficit hyperactivity disorder (ADHD) is a common neurobehavioral disorder, and its symptoms are hyperactivity and deficits in learning and memory. Physical exercise increases dopamine synthesis and neuronal activity in various brain regions. In the present study, we investigate the duration-dependence of the treadmill exercise on hyperactivity in relation with dopamine expression in ADHD. Spontaneously hypertensive rats were used for the ADHD rats and Wistar-Kyoto rats were used for the control rats. The rats in the exercise groups were forced to run on a treadmill for 10 min, 30 min, and 60 min once daily for 28 consecutive days. For this experiment, open field test and immunohistochemistry for tyrosine hydroxylase were conducted. The present results revealed that ADHD rats showed hyperactivity, and tyrosine hydroxylase expression in the striatum and substantia nigra were decreased in ADHD rats. Treadmill exercise alleviated hyperactivity and also increased TH expression in ADHD rats. Treadmill exercise for 30 min per day showed most potent suppressing effect on hyperactivity, and this dose of treadmill exercise also most potently inhibited tyrosine hydroxylase expression. The present study suggests that treadmill exercise for 30 min once a day is the most effective therapeutic intervention for ADHD patients.

  9. Dose dependent transfer of 203lead to milk and tissue uptake in suckling offspring studied in rats and mice

    International Nuclear Information System (INIS)

    Palminger Hallen, I.; Oskarsson, A.

    1993-01-01

    The dose-dependent transfer of 203 Pb to milk and uptake in suckling rats and mice during a three-day nursing period was studied. On day 14 of lactation, the dams were administered a single intravenous dose of lead, labelled with 203 Pb, in four or five doses from 0.0005 to 2.0 mg Pb/kg b.wt. There was a linear relationship between Pb levels in plasma and milk of both species. The Pb milk: plasma ratios at 24 hr after administration were 119 and 89 in mice and rats, respectively. At 72 hr the Pb milk: plasma ratio had decreased to 72 in mice and 35 in rats. The tissue levels of lead in the suckling rats and mice were also linearly correlated with lead concentration in milk at 72 hr, showing that milk could be used as an indicator of lead exposure to the suckling offspring. It is concluded that lead is transported into rat and mouse milk to a very high extent and the excretion into milk is more efficient in mice than in rats. On the other hand, rat pups had higher lead levels in tissues than mice pups, which might be due to a higher bioavailability and/or a lower excretion of lead in rat pups. Thus, lead in breast milk could be used as a biological indicator of lead exposure in the mother as well as in the suckling offspring. (au) (38 refs.)

  10. Treatment-time-dependence models of early and delayed radiation injury in rat small intestine

    International Nuclear Information System (INIS)

    Denham, James W.; Hauer-Jensen, Martin; Kron, Tomas; Langberg, Carl W.

    2000-01-01

    Background: The present study modeled data from a large series of experiments originally designed to investigate the influence of time, dose, and fractionation on early and late pathologic endpoints in rat small intestine after localized irradiation. The objective was to obtain satisfactory descriptions of the regenerative response to injury together with the possible relationships between early and late endpoints. Methods: Two- and 26-week pathologic radiation injury data in groups of Sprague-Dawley rats irradiated with 27 different fractionation schedules were modeled using the incomplete repair (IR) version of the linear-quadratic model with or without various time correction models. The following time correction models were tested: (1) No time correction; (2) A simple exponential (SE) regenerative response beginning at an arbitrary time after starting treatment; and (3) A bi-exponential response with its commencement linked to accumulated cellular depletion and fraction size (the 'intelligent response model' [INTR]). Goodness of fit of the various models was assessed by correlating the predicted biological effective dose for each dose group with the observed radiation injury score. Results: (1) The incomplete repair model without time correction did not provide a satisfactory description of either the 2- or 26-week data. (2) The models using SE time correction performed better, providing modest descriptions of the data. (3) The INTR model provided reasonable descriptions of both the 2- and 26-week data, confirming a treatment time dependence of both early and late pathological endpoints. (4) The most satisfactory descriptions of the data by the INTR model were obtained when the regenerative response was assumed to cease 2 weeks after irradiation rather than at the end of irradiation. A fraction-size-dependent delay of the regenerative response was also suggested in the best fitting models. (5) Late endpoints were associated with low-fractionation sensitivity

  11. Sex- and dose-dependency in the pharmacokinetics and pharmacodynamics of (+)-methamphetamine and its metabolite (+)-amphetamine in rats

    International Nuclear Information System (INIS)

    Milesi-Halle, Alessandra; Hendrickson, Howard P.; Laurenzana, Elizabeth M.; Gentry, W. Brooks; Owens, S. Michael

    2005-01-01

    These studies investigated how (+)-methamphetamine (METH) dose and rat sex affect the pharmacological response to METH in Sprague-Dawley rats. The first set of experiments determined the pharmacokinetics of METH and its pharmacologically active metabolite (+)-amphetamine (AMP) in male and female Sprague-Dawley rats after 1.0 and 3.0 mg/kg METH doses. The results showed significant sex-dependent changes in METH pharmacokinetics, and females formed significantly lower amounts of AMP. While the area under the serum concentration-time curve in males increased proportionately with the METH dose, the females showed a disproportional increase. The sex differences in systemic clearance, renal clearance, volume of distribution, and percentage of unchanged METH eliminated in the urine suggested dose-dependent pharmacokinetics in female rats. The second set of studies sought to determine the behavioral implications of these pharmacokinetic differences by quantifying locomotor activity in male and female rats after saline, 1.0, and 3.0 mg/kg METH. The results showed sex- and dose-dependent differences in METH-induced locomotion, including profound differences in the temporal profile of effects at higher dose. These findings show that the pharmacokinetic and metabolic profile of METH (slower METH clearance and lower AMP metabolite formation) plays a significant role in the differential pharmacological response to METH in male and female rats

  12. Hepatorenal Syndrome with Cirrhotic Cardiomyopathy: Case Report and Literature Review

    Directory of Open Access Journals (Sweden)

    Luis Mocarzel

    2015-01-01

    Full Text Available The hepatorenal syndrome (HRS is defined as a potentially reversible kidney failure in patients with cirrhosis and ascites. An association of HRS and cirrhotic cardiomyopathy has been reported recently, but there are no result studies about the use of positive inotropes as part of the acute phase treatment. We report the case of a patient diagnosed with HRS, with high levels of NT pro-BNP, but with normal ejection fraction of the left ventricle, which showed abnormalities in systolic function through speckle tracking in echocardiography, reversible after the infusion of dobutamine. The patient showed clinical and laboratory improvement of his renal function after the infusion of dobutamine. Clinical studies are needed on HRS therapeutic approach taking into account the myocardial dysfunction as a major contributing factor to renal dysfunction.

  13. Magnetic resonance imaging of the cirrhotic liver: Anupdate

    Institute of Scientific and Technical Information of China (English)

    Agnes Watanabe; Miguel Ramalho; Mamdoh AlObaidy; Hye Jin Kim; Fernanda G Velloni; Richard C Semelka

    2015-01-01

    Noninvasive imaging has become the standard forhepatocellular carcinoma (HCC) diagnosis in cirrhoticlivers. In this review paper, we go over the basics ofMR imaging in cirrhotic livers and describe the imagingappearance of a spectrum of hepatic nodules markingthe progression from regenerative nodules to low- andhigh-grade dysplastic nodules, and ultimately to HCCs.We detail and illustrate the typical imaging appearancesof different types of HCC including focal, multifocal,massive, diffuse/infiltrative, and intra-hepaticmetastases; with emphasis on the diagnostic value ofMR in imaging these lesions. We also shed some lighton liver imaging reporting and data system, and therole of different magnetic resonance imaging (MRI)contrast agents and future MRI techniques includingthe use of advanced MR pulse sequences and utilizationof hepatocyte-specific MRI contrast agents, and howthey might contribute to improving the diagnosticperformance of MRI in early stage HCC diagnosis.

  14. Hepatocellular Carcinoma Surveillance Among Cirrhotic Patients With Commercial Health Insurance.

    Science.gov (United States)

    Goldberg, David S; Valderrama, Adriana; Kamalakar, Rajesh; Sansgiry, Sujit S; Babajanyan, Svetlana; Lewis, James D

    2016-03-01

    To evaluate hepatocellular carcinoma (HCC) surveillance rates among commercially insured patients, and evaluate factors associated with compliance with surveillance recommendations. Most HCC occurs in patients with cirrhosis. American Association for the Study of Liver Diseases and European Association for the Study of the Liver guidelines each recommend biannual HCC surveillance for cirrhotic patients to diagnose HCC at an early, curable stage. However, compliance with these guidelines in commercially insured patients is unknown. We used the Truven Health Analytics databases from 2006 to 2010, using January 1, 2006 as the anchor date for evaluating outcomes. The primary outcome was continuous surveillance measure, defined as the proportion of time "up-to-date" with surveillance (PTUDS), with the 6-month interval immediately following each ultrasound categorized as "up-to-date." During a median follow-up of 22.9 (interquartile range, 16.3 to 33.9) months among 8916 cirrhotic patients, the mean PTUDS was 0.34 (SD, 0.29), and the median was 0.31 (interquartile range, 0.03 to 0.52). These values increased only modestly with inclusion of serum alpha-fetoprotein testing, contrast-enhanced abdominal computed tomographic scans or magnetic resonance imagings, and/or extension of up-to-date time to 12 months. Being diagnosed by a nongastroenterology provider and increasing age were significantly associated with decreased HCC surveillance (Psurveillance (Psurveillance rates remained low. HCC surveillance rates in commercially insured at-risk patients remain poor despite formalized guidelines, highlighting the need to develop interventions to improve surveillance rates.

  15. Sex dependence of the components and structure of urinary calculi induced by biphenyl administration in rats.

    Science.gov (United States)

    Ohnishi, M; Yajima, H; Yamamoto, S; Matsushima, T; Ishii, T

    2000-08-01

    To obtain definitive information about the mechanisms of urinary calculus formation and the structural characteristics of the calculi induced by biphenyl administration in rats, with a focus on the sex dependency, the constituents of the urinary calculi were analyzed by HPLC, inductively coupled plasma spectroscopy (ICP), micro Fourier transform infrared spectroscopy (mFT-IR), and ion chromatography (IC), and structural analyses were carried out by microscopy, mFT-IR, and the electron probe microanalyzer (EPMA) method. We attempted to account for the appreciably higher incidence of calculi in males than in females. mFT-IR analysis revealed that the biphenyl-induced urinary calculi in male rats are composed mainly of potassium 4-hydroxybiphenyl-o-sulfate (4-HBPOSK), whereas the calculi in female rats are composed mainly of 4-hydroxybiphenyl (4-HBP) and KHSO(4) produced by the hydrolysis of 4-HBPOSK. Observations of photomicrographs and the results of mFT-IR analysis indicated that the calculi in males have a multilayer structure consisting of alternating layers of 4-HBPOSK and calcium phosphate, whereas the calculi in females have no multilayer structure, but open holes in which needle-shaped crystals are present in some places. In view of the results of these analyses, including the EPMA analysis, it appears that calculus formation in males may involve a series of successive and irreversible reactions, whereas calculus formation in females may result from a series of reversible reactions, including the hydrolysis of 4-HBPOSK. It was inferred that the series of irreversible reactions involved in calculus formation in males is relatively more stable than that in the case of females, and thus, a sex difference in the reaction features may be responsible for the observed difference in the incidence of calculus formation.

  16. PPARalpha-dependent modulation of hepatic CYP1A by clofibric acid in rats.

    Science.gov (United States)

    Shaban, Zein; El-Shazly, Samir; Ishizuka, Mayumi; Kimura, Kazuhiro; Kazusaka, Akio; Fujita, Shoichi

    2004-09-01

    Fibrates, hypolipidemic drugs, have been reported to suppress the metabolic activities of cytochrome P450 1A1 and 1A2 in rats but the mechanism has not been elucidated. In the present study we tested the hypothesis that the inhibitory effect of fibrates on arylhydrocarbon receptor (AhR) function may be due to their stimulatory effects on PPARalpha. Sudan III (S.III) treatment induced CYP 1A1 and CYP 1A2 protein expression, mRNA and their metabolic activities, methoxyresorufin-O-demethylase (MROD) and ethoxyresorufin-O-deethylase (EROD), in Wistar rats higher than those in the control. Co-treatment of rats with S.III and clofibric acid (CA) caused a 40-50% decrease in the induced levels of CYP1A1 and CYP1A2 protein, mRNA expression and their metabolic activities and reduced AhR protein expression. When we treated HepG2 cells with S.III and/or CA, no suppressive effect on S.III-induced CYP1A1 protein expression due to CA was found. HepG2 cells were transiently transfected with increasing concentrations of PPARalpha mammalian expression vector and exposed to the same treatment. CA co-treatment with S.III decreased AhR protein and S.III-induced CYP1A1 protein expression with increasing dose of PPARalpha transfected into HepG2 cells. Our results demonstrate that the suppressive effect of fibrates on CYP1A is PPARalpha-dependent and suggest that PPARalpha has an inhibitory effect on AhR function.

  17. The carotid body of the spontaneous insulin-dependent diabetic rat

    Directory of Open Access Journals (Sweden)

    Clarke J.A.

    1999-01-01

    Full Text Available The carotid bodies from adult spontaneous insulin-dependent diabetic rats (strain BB/S were perfusion-fixed at normal arterial blood pressure with 3% phosphate-buffered glutaraldehyde and compared with the organs from control rats (strain BB/Sc prepared in the same way. Serial 5-µm sections were cut, stained, and using an interactive image analysis system, were analysed to determine the volumes of the carotid body and its vascular and extravascular compartments. There was no evidence of systemic arterial disease in the carotid stem arteries in either group of animals, and the microvasculature of the organs appeared normal by light microscopy. The volume of the carotid body was unchanged 3 months after the onset of diabetes but was increased at 6 months. The total vascular volume of the organ was unchanged, but the volume of the small vessels (5-12 µm was increased. In the control group the small vessels comprised 5% of the total volume of the carotid body, or about 44% of the vascular compartment. The percentage of small vessels increased at 3 months in the diabetic group, but had returned to normal at 6 months. The extravascular volume followed the same pattern as the total carotid body volume and so did not change appreciably when expressed as a percentage of the total volume of the organ. The increase in size of the carotid body in diabetic rats is due, therefore, to an augmented extravascular volume. In one diabetic specimen the carotid sinus nerve showed signs of diabetic neuropathy, axonal swelling and intramyelinic oedema. The clinical implications of these results are discussed.

  18. Natural history of patients with non cirrhotic portal hypertension: Comparison with patients with compensated cirrhosis.

    Science.gov (United States)

    Gioia, Stefania; Nardelli, Silvia; Pasquale, Chiara; Pentassuglio, Ilaria; Nicoletti, Valeria; Aprile, Francesca; Merli, Manuela; Riggio, Oliviero

    2018-01-31

    The knowledge of natural history of patients with portal hypertension (PH) not due to cirrhosis is less well known than that of cirrhotic patients. To describe the clinical presentation and the outcomes of 89 patients with non-cirrhotic PH (25 with non-cirrhotic portal hypertension, INCPH, and 64 with chronic portal vein thrombosis, PVT) in comparison with 77 patients with Child A cirrhosis. The patients were submitted to a standardized clinical, laboratory, ultrasonographic and endoscopic follow-up. Variceal progression, incidence of variceal bleeding, portal vein thrombosis, ascites and survival were recorded. At presentation, the prevalence of varices, variceal bleeding and ascites was similar in the 3 groups. During follow-up, the rate of progression to varices at risk of bleeding (p portal hypertension in these patients and cannot be simply derived by the observation of cirrhotic patients. Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  19. Association Between Proton Pump Inhibitor Use and Spontaneous Bacterial Peritonitis in Cirrhotic Patients with Ascites

    Directory of Open Access Journals (Sweden)

    Mélissa Ratelle

    2014-01-01

    Full Text Available BACKGROUND: There are data suggesting a link between proton pump inhibitor (PPI use and the development of spontaneous bacterial peritonitis (SBP in cirrhotic patients with ascites; however, these data are controversial.

  20. Vitamin D-dependent rat renal calcium-binding protein: development of a radioimmunoassay, tissue distribution, and immunologic identification

    International Nuclear Information System (INIS)

    Sonnenberg, J.; Pansini, A.R.; Christakos, S.

    1984-01-01

    A sensitive double antibody RIA has been developed for the 28,000 mol wt rat renal vitamin D-dependent calcium-binding protein. Using this assay, concentrations of calcium-binding protein (CaBP) as low as 30 ng can be measured. The assay is precise (intraassay variability, 5.0%) and reproductible (interassay variability, 8.2%). Measurements of renal CaBP by RIA showed a good correlation with measurements of CaBP by the chelex resin assay and by polyacrylamide gel analysis by densitometric tracing using a purified CaBP marker. The concentration of CaBP in the vitamin D-replete rat kidney is 7.3 +/- 1.0 (mean +/- SEM) micrograms/mg protein. In vitamin D-deficient rats the level of renal CaBP is 2.6 +/- 0.3 micrograms/mg protein. Tissue distribution of immunoreactive rat renal CaBP showed the highest concentration of CaBP in the rat cerebellum (38.3 +/- 5.1 micrograms/mg protein). Lower concentrations of immunoreactive CaBP were detected in several other rat tissues. No immunoreactive CaBP was detected in rat or human serum. In necropsy human kidney and cerebellum, high levels of immunoreactive CaBP were also detected (1.5 +/- 0.1 and 27.3 +/- 2.1 micrograms/mg protein, respectively). When extracts of rat kidney and brain and human cerebellum and kidney were assayed at several dilutions, immunodisplacement curves parallel to that of pure renal CaBP were observed, indicating immunochemical similarity. Fractionation of extracts of rat cerebellum, human kidney, and human cerebellum on Sephadex G-100 revealed immunoreactivity and calcium-binding activity in the 28,000 mol wt region similar to rat kidney

  1. Cyclooxygenase-2-dependent bronchoconstriction in perfused rat lungs exposed to endotoxin.

    Science.gov (United States)

    Uhlig, S; Nüsing, R; von Bethmann, A; Featherstone, R L; Klein, T; Brasch, F; Müller, K M; Ullrich, V; Wendel, A

    1996-05-01

    Lipopolysaccharides (LPS), widely used to study the mechanisms of gram-negative sepsis, increase airway resistance by constriction of terminal bronchioles. The role of the cyclooxygenase (COX) isoenzymes and their prostanoid metabolites in this process was studied. Pulmonary resistance, the release of thromboxane (TX) and the expression of COX-2 mRNA were measured in isolated blood-free perfused rat lungs exposed to LPS. LPS induced the release of TX and caused increased airway resistance after about 30 min. Both TX formation and LPS-induced bronchoconstriction were prevented by treatment with the unspecific COX inhibitor acetyl salicylic acid, the specific COX-2 inhibitor CGP-28238, dexamethasone, actinomycin D, or cycloheximide. LPS-induced bronchoconstriction was also inhibited by the TX receptor antagonist BM-13177. The TX-mimetic compound, U-46619, increased airway resistance predominantly by constricting terminal bronchioles. COX-2-specific mRNA in lung tissue was elevated after LPS exposure, and this increase was attenuated by addition of dexamethasone or of actinomycin D. In contrast to LPS, platelet-activating factor (PAF) induced immediate TX release and bronchoconstriction that was prevented by acetyl salicylic acid, but not by CGP-28238. LPS elicits the following biochemical and functional changes in rat lungs: (i) induction of COX-2; (ii) formation of prostaglandins and TX; (iii) activation of the TX receptor on airway smooth muscle cells; (iv) constriction of terminal bronchioles; and (v) increased airway resistance. In contrast to LPS, the PAF-induced TX release is likely to depend on COX-1.

  2. Liver Proteome in Diabetes Type 1 Rat Model: Insulin-Dependent and -Independent Changes.

    Science.gov (United States)

    Braga, Camila Pereira; Boone, Cory H T; Grove, Ryan A; Adamcova, Dana; Fernandes, Ana Angélica Henrique; Adamec, Jiri; de Magalhães Padilha, Pedro

    2016-12-01

    Diabetes mellitus type 1 (DM1) is a major public health problem that continues to burden the healthcare systems worldwide, costing exponentially more as the epidemic grows. Innovative strategies and omics system diagnostics for earlier diagnosis or prognostication of DM1 are essential to prevent secondary complications and alleviate the associated economic burden. In a preclinical study design that involved streptozotocin (STZ)-induced DM1, insulin-treated STZ-induced DM1, and control rats, we characterized the insulin-dependent and -independent changes in protein profiles in liver samples. Digested proteins were subjected to LC-MS E for proteomic data. Progenesis QI data processing and analysis of variance were utilized for statistical analyses. We found 305 proteins with significantly altered abundance among the control, DM1, and insulin-treated DM1 groups (p < 0.05). These differentially regulated proteins were related to enzymes that function in key metabolic pathways and stress responses. For example, gluconeogenesis appeared to return to control levels in the DM1 group after insulin treatment, with the restoration of gluconeogenesis regulatory enzyme, FBP1. Insulin administration to DM1 rats also restored the blood glucose levels and enzymes of general stress and antioxidant response systems. These observations are crucial for insights on DM1 pathophysiology and new molecular targets for future clinical biomarkers, drug discovery, and development. Additionally, we underscore that proteomics offers much potential in preclinical biomarker discovery for diabetes as well as common complex diseases such as cancer, dementia, and infectious disorders.

  3. Hydrocortisone selectively inhibits IgE-dependent arachidonic acid release from rat peritoneal mast cells

    International Nuclear Information System (INIS)

    Heiman, A.S.; Crews, F.T.

    1984-01-01

    Purified rat mst cells were used to study the effects of antiinflammatory steroids on the release of [1-14C]-arachidonic acid ([1-14C]AA) and metabolites. Mast cell were incubated overnight with glucocorticoids, [1-14C]AA incorporated into cellular phospholipids and the release of [1-14C]AA, and metabolites determined using a variety of secretagogues. Release of [1-14C]AA and metabolites by concanavalin A, the antigen ovalbumin and anti-immunoglobulin E antibody was markedly reduced by glucocorticoid treatment. Neither the total incorporation of [1-14C]AA nor the distribution into phospholipids was altered by hydrocortisone pretreatment. Glucocorticoid pretreatment did not alter [1-14C]AA release stimulated by somatostatin, compound 48/80, or the calcium ionophore, A23187. These data indicate that antiinflammatory steroids selectively inhibit immunoglobulin dependent release of arachidonic acid from rat mast cells. These findings question the role of lipomodulin and macrocortin as general phospholipase inhibitors and suggest that they may be restricted to immunoglobulin stimuli

  4. Pregnancy-dependent initiation in tumorigenesis of Wistar rat mammary glands by 60Co-irradiation

    International Nuclear Information System (INIS)

    Inano, Hiroshi; Suzuki, Keiko; Ishii-Ohba, Hiroko; Ikeda, Kiyomi; Wakabayashi, Katsumi

    1991-01-01

    Pregnant Wistar rats received whole body irradiation with 260 cGy γ-rays at days 7, 14 and 20 of pregnancy and then were treated with diethylstilbestrol (DES) for 1 year. The highest incidence (92.9%) for tumorigenesis of mammary glands was observed in the rats irradiated in late pregnancy. Histological examination showed that tumors were classified as fibroadenoma and adenocarcinoma. To determine the reasons for specific induction of mammary tumors by irradiation in late pregnancy, hormone concentrations in serum and estrogen receptors in mammary glands during pregnancy were measured. Concentrations of estradiol, progesterone, 11-deoxycorticosterone and placental lactogen at day 20 were higher than at days 7 and/or 14, but no difference was observed in the concentrations of prolactin and thyroid-stimulating hormone during pregnancy. The estrogen receptor in mammary glands at day 20 was indicated to have the highest affinity and the highest binding capacity during pregnancy. Normal mammary glands at day 20 were suggested to have more abundant epithelial cells in the mammary lobes than those at days 7 and 14. The data suggest that the critical requirements for the initiation of tumorigenesis by γ-rays are dependent upon the differentiated state of mammary glands exposed to various hormones, and that the concentration and persistence of the synthetic estrogen (DES) are necessary for the promotion of tumorigenesis of the irradiated mammary glands. (Author)

  5. Glucose-Dependent Insulinotropic Polypeptide Mitigates 6-OHDA-Induced Behavioral Impairments in Parkinsonian Rats

    Directory of Open Access Journals (Sweden)

    Yu-Wen Yu

    2018-04-01

    Full Text Available In the present study, the effectiveness of glucose-dependent insulinotropic polypeptide (GIP was evaluated by behavioral tests in 6-hydroxydopamine (6-OHDA hemi-parkinsonian (PD rats. Pharmacokinetic measurements of GIP were carried out at the same dose studied behaviorally, as well as at a lower dose used previously. GIP was delivered by subcutaneous administration (s.c. using implanted ALZET micro-osmotic pumps. After two days of pre-treatment, male Sprague Dawley rats received a single unilateral injection of 6-OHDA into the medial forebrain bundle (MFB. The neuroprotective effects of GIP were evaluated by apomorphine-induced contralateral rotations, as well as by locomotor and anxiety-like behaviors in open-field tests. Concentrations of human active and total GIP were measured in plasma during a five-day treatment period by ELISA and were found to be within a clinically translatable range. GIP pretreatment reduced behavioral abnormalities induced by the unilateral nigrostriatal dopamine (DA lesion produced by 6-OHDA, and thus may be a novel target for PD therapeutic development.

  6. Glucose-Dependent Insulinotropic Polypeptide Mitigates 6-OHDA-Induced Behavioral Impairments in Parkinsonian Rats

    Science.gov (United States)

    Yu, Yu-Wen; Hsueh, Shih-Chang; Lai, Jing-Huei; Chen, Yen-Hua; Kang, Shuo-Jhen; Hsieh, Tsung-Hsun; Hoffer, Barry J.; Li, Yazhou; Greig, Nigel H.; Chiang, Yung-Hsiao

    2018-01-01

    In the present study, the effectiveness of glucose-dependent insulinotropic polypeptide (GIP) was evaluated by behavioral tests in 6-hydroxydopamine (6-OHDA) hemi-parkinsonian (PD) rats. Pharmacokinetic measurements of GIP were carried out at the same dose studied behaviorally, as well as at a lower dose used previously. GIP was delivered by subcutaneous administration (s.c.) using implanted ALZET micro-osmotic pumps. After two days of pre-treatment, male Sprague Dawley rats received a single unilateral injection of 6-OHDA into the medial forebrain bundle (MFB). The neuroprotective effects of GIP were evaluated by apomorphine-induced contralateral rotations, as well as by locomotor and anxiety-like behaviors in open-field tests. Concentrations of human active and total GIP were measured in plasma during a five-day treatment period by ELISA and were found to be within a clinically translatable range. GIP pretreatment reduced behavioral abnormalities induced by the unilateral nigrostriatal dopamine (DA) lesion produced by 6-OHDA, and thus may be a novel target for PD therapeutic development. PMID:29641447

  7. Chemoprevention of hormone-dependent prostate cancer in the Wistar-Unilever rat.

    Science.gov (United States)

    McCormick, D L; Rao, K V

    1999-01-01

    The high incidence and long latent period of prostate cancer make it an ideal target for chemoprevention. We have evaluated a series of agents for chemopreventive efficacy using a model in which hormone-dependent prostate cancers are induced in the Wistar-Unilever (WU) rat by sequential treatment with antiandrogen (cyproterone acetate), androgen (testosterone propionate), and direct-acting chemical carcinogen (N-methyl-N-nitrosourea), followed by chronic androgen stimulation (testosterone). This regimen reproducibly induces prostate cancers in high incidence, with no gross toxicity and a low incidence of neoplasia in the seminal vesicle and other non-target tissues. Dehydroepiandrosterone (DHEA) and 9-cis-retinoic acid (9-cis-RA) are the most active agents identified to date. DHEA inhibits prostate cancer induction both when chronic administration is begun prior to carcinogen exposure, and when administration is delayed until preneoplastic prostate lesions are present. 9-cis-RA is the most potent inhibitor of prostate carcinogenesis identified; a study to determine the efficacy of delayed administration of 9-cis-RA is in progress. Liarozole fumarate confers modest protection against prostate carcinogenesis, while N-(4-hydroxyphenyl)retinamide (fenretinide), alpha-difluoromethylornithine, oltipraz, DL-alpha-tocopherol acetate (vitamin E), and L-selenomethionine are inactive. Chemoprevention efficacy evaluations in the WU rat will support the identification of agents that merit study for prostate cancer chemoprevention in humans.

  8. Different dose-dependent effects of ebselen in sciatic nerve ischemia-reperfusion injury in rats.

    Science.gov (United States)

    Ozyigit, Filiz; Kucuk, Aysegul; Akcer, Sezer; Tosun, Murat; Kocak, Fatma Emel; Kocak, Cengiz; Kocak, Ahmet; Metineren, Hasan; Genc, Osman

    2015-08-26

    Ebselen is an organoselenium compound which has strong antioxidant and anti-inflammatory effects. We investigated the neuroprotective role of ebselen pretreatment in rats with experimental sciatic nerve ischemia-reperfusion (I/R) injury. Adult male Sprague Dawley rats were divided into four groups (N = 7 in each group). Before sciatic nerve I/R was induced, ebselen was injected intraperitoneally at doses of 15 and 30 mg/kg. After a 2 h ischemia and a 3 h reperfusion period, sciatic nerve tissues were excised. Tissue levels of malondialdehyde (MDA) and nitric oxide (NO), and activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) were measured. Sciatic nerve tissues were also examined histopathologically. The 15 mg/kg dose of ebselen reduced sciatic nerve damage and apoptosis (pebselen. Conversely, the 30 mg/kg dose of ebselen increased sciatic nerve damage, apoptosis, iNOS positive cells (pebselen may cause different effects depending on the dose employed. Ebselen may be protective against sciatic nerve I/R injury via antioxidant and antiapoptotic activities at a 15 mg/kg dose, conversely higher doses may cause detrimental effects.

  9. Pulmonary hypertension associated with non-cirrhotic portal hypertension in systemic lupus erythematosus.

    OpenAIRE

    Woolf, D.; Voigt, M. D.; Jaskiewicz, K.; Kalla, A. A.

    1994-01-01

    A case of non-cirrhotic portal hypertension in a patient with systemic lupus erythematosus, the first of our knowledge, is described. Severe pulmonary hypertension was associated with the portal hypertension and with markers of active auto-immunity. Pulmonary hypertension has not previously been associated with non-cirrhotic portal hypertension. The coexistence of vasculopathy of the portal and pulmonary vascular beds in this patient with active autoimmunity supports the postulate that portal...

  10. Predictive model of portal venous system thrombosis in cirrhotic portal hypertensive patients after splenectomy

    OpenAIRE

    He, Shasha; He, Fangping

    2015-01-01

    Objective: This study is to investigate the risk factors of portal venous system thrombosis (PVT) in patients with cirrhotic portal hypertension after splenectomy and to establish a Logistic regression prediction model. Methods: A total of 119 patients with cirrhotic portal hypertension were enrolled. Their clinical data was retrospectively analyzed. They were divided into PVT group (n = 18) and non-PVT group (n = 101). One-way analysis and multivariate Logistic regression analysis were perfo...

  11. Effect of scopolamine on central DAT and D2 receptor in morphine dependent rats

    International Nuclear Information System (INIS)

    Lin Yansong; Wang Shizhen; Ding Shiyu; Chen Zhenping; Zhou Xiang; Fang Ping; Wang Bocheng

    2004-01-01

    Objective: To investigate the effect of scopolamine (Sco) on central dopamine transporter (DAT) and D 2 receptor in morphine (Mor) dependent rats. Methods: Chronic Mor exposure was induced by repeated Mor (20 mg·kg -1 ·d -1 , i.p.) treatment for 8 d. Conditioned place preference test was used to evaluate the drug seeking behavior. Biodistribution of the imaging agents 125 I-2β-carbomethoxy-3β-(4-iodophenyl) tropane (β-CIT) and 125 I-3-iodo-2-hydroxy-6-methoxy-N-[(1-ethyl-2-pyrrolidinyl)methyl] benzamide (IBZM) were used to evaluate the central DAT and D 2 receptor during chronic Mor exposure. Results: For the Mor plus pretreating with Sco (Mor+Sco) rats, the time for the rats entering C2 from C1 was (1.72 ± 0.69) min in the first day, with little difference from the control and Mor group (P>0.05), and (1.12 ± 0.33) min for the 8th day, still longer than that of the Mor group (t=5.171, P 125 I-β- CIT %ID/g in striatum (ST) and nucleus accumbens (NAC) for Mor + Sco group were 3.307 ± 0.189 and 1.577 ± 0.401 respectively, higher than those of the control group (2.431 ± 0.104, 1.441 ± 0.043, t was 4.151 and 5.416 respectively, P 125 I-IBZM %ID/g in ST, NAC, hippocampus (HIP) and frontal cortex (FC) for Mor + Sco group were 0.589 ± 0.081, 0.683 ± 0.046, 0.175 ± 0.039 and 0.257 ± 0.034 lower than that of the control rats (0.735 ± 0.096, 0.709 ± 0.098, 0.281 ± 0.038, 0.289 ± 0.020, t was 7.841, 6.170, 5.446 and 4.337 respectively, P 2 receptor induced by Mor to some extent

  12. Transjugular portal vein recanalization with creation of intrahepatic portosystemic shunt (PVR-TIPS) in patients with chronic non-cirrhotic, non-malignant portal vein thrombosis.

    Science.gov (United States)

    Klinger, Christoph; Riecken, Bettina; Schmidt, Arthur; De Gottardi, Andrea; Meier, Benjamin; Bosch, Jaime; Caca, Karel

    2018-03-01

    To determine safety and efficacy of transjugular portal vein recanalization with creation of intrahepatic portosystemic shunt (PVR-TIPS) in patients with chronic non-cirrhotic, non-malignant portal vein thrombosis (PVT). This retrospective study includes 17 consecutive patients with chronic non-cirrhotic PVT (cavernous transformation n = 15). PVR-TIPS was indicated because of variceal bleeding (n = 13), refractory ascites (n = 2), portal biliopathy with recurrent cholangitis (n = 1), or abdominal pain (n = 1). Treatment consisted of a combination of transjugular balloon angioplasty, mechanical thrombectomy, and-depending on extent of residual thrombosis-transjugular intrahepatic portosystemic shunt and additional stenting of the portal venous system. Recanalization was successful in 76.5 % of patients despite cavernous transformation in 88.2 %. Both 1- and 2-year secondary PV and TIPS patency rates were 69.5 %. Procedure-related bleeding complications occurred in 2 patients (intraperitoneal bleeding due to capsule perforation, n = 1; liver hematoma, n = 1) and resolved spontaneously. However, 1 patient died due to subsequent nosocomial pneumonia. During follow-up, 3 patients with TIPS occlusion and PVT recurrence experienced portal hypertensive complications. PVR-TIPS is safe and effective in selected patients with chronic non-cirrhotic PVT. Due to technical complexity and possible complications, it should be performed only in specialized centers with high experience in TIPS procedures. © Georg Thieme Verlag KG Stuttgart · New York.

  13. Antibiotic treatment affects intestinal permeability and gut microbial composition in Wistar rats dependent on antibiotic class

    DEFF Research Database (Denmark)

    Tulstrup, Monica Vera-Lise; Christensen, Ellen Gerd; Carvalho, Vera

    2015-01-01

    Antibiotics are frequently administered orally to treat bacterial infections not necessarily related to the gastrointestinal system. This has adverse effects on the commensal gut microbial community, by disrupting the intricate balance between specific bacterial groups within this ecosystem...... potentially leading to dysbiosis. We hypothesized that modulation of community composition and function induced by antibiotics affects intestinal integrity depending on the antibiotic administered. To address this a total of 60 Wistar rats (n=12 per group) were dosed by oral gavage with either amoxicillin...... (AMX), cefataxime (CTX), vancomycin (VAN), metronidazole (MTZ), or water (CON) daily for 10-11 days. Bacterial composition, alpha diversity and cecum short chain fatty acid levels were significantly affected by AMX, CTX and VAN, and varied among antibiotic treatments. A general decrease in diversity...

  14. Reduced motivation in the BACHD rat model of Huntington disease is dependent on the choice of food deprivation strategy.

    Science.gov (United States)

    Jansson, Erik Karl Håkan; Clemens, Laura Emily; Riess, Olaf; Nguyen, Huu Phuc

    2014-01-01

    Huntington disease (HD) is an inherited neurodegenerative disease characterized by motor, cognitive, psychiatric and metabolic symptoms. Animal models of HD show phenotypes that can be divided into similar categories, with the metabolic phenotype of certain models being characterized by obesity. Although interesting in terms of modeling metabolic symptoms of HD, the obesity phenotype can be problematic as it might confound the results of certain behavioral tests. This concerns the assessment of cognitive function in particular, as tests for such phenotypes are often based on food depriving the animals and having them perform tasks for food rewards. The BACHD rat is a recently established animal model of HD, and in order to ensure that behavioral characterization of these rats is done in a reliable way, a basic understanding of their physiology is needed. Here, we show that BACHD rats are obese and suffer from discrete developmental deficits. When assessing the motivation to lever push for a food reward, BACHD rats were found to be less motivated than wild type rats, although this phenotype was dependent on the food deprivation strategy. Specifically, the phenotype was present when rats of both genotypes were deprived to 85% of their respective free-feeding body weight, but not when deprivation levels were adjusted in order to match the rats' apparent hunger levels. The study emphasizes the importance of considering metabolic abnormalities as a confounding factor when performing behavioral characterization of HD animal models.

  15. Hypoglycemic Effect of Aquatic Extract of Stevia in Pancreas of Diabetic Rats: PPARγ-dependent Regulation or Antioxidant Potential

    Science.gov (United States)

    Assaei, Raheleh; Mokarram, Pooneh; Dastghaib, Sanaz; Darbandi, Sara; Darbandi, Mahsa; Zal, Fatemeh; Akmali, Masoumeh; Ranjbar Omrani, Gholam Hossein

    2016-01-01

    Background: Traditional medicines with anti-diabetic effects are considered suitable supplements to treat diabetes. Among medicinal herbs, Stevia Rebaudiana Bertoni is famous for its sweet taste and beneficial effect in regulation of glucose. However, little is known about the exact mechanism of stevia in pancreatic tissue. Therefore, this study investigated the possible effects of stevia on pancreas in managing hyperglycemia seen in streptozotocin-induced Sprague-Dawley rats. Methods: Sprague-Dawley rats were divided into four groups including normoglycemic, diabetic and two more diabetic groups in which, one was treated with aquatic extract of stevia (400 mg/kg) and the other with pioglitazone (10 mg/kg) for the period of 28 days. After completion of the experimental duration, rats were dissected; blood samples and pancreas were further used for detecting biochemical and histopathological changes. FBS, TG, cholestrol, HDL, LDL, ALT and AST levels were measured in sera. Moreover, MDA (malondialdehyde) level, catalase activity, levels of insulin and PPARγ mRNA expression were also measured in pancreatic tissue. Results: Aquatic extract of stevia significantly reduced the FBS, triglycerides, MDA, ALT, AST levels and normalized catalase activity in treated rats compared with diabetic rats (pstevia surprisingly, increased PPARγ and insulin mRNA levels in treated rats (pstevia compensated for the histopathological damage in diabetic rats. Conclusion: It is concluded that stevia acts on pancreatic tissue to elevate the insulin level and exerts beneficial anti-hyperglycemic effects through the PPARγ-dependent mechanism and stevia’s antioxidant properties. PMID:27141265

  16. Reduced motivation in the BACHD rat model of Huntington disease is dependent on the choice of food deprivation strategy.

    Directory of Open Access Journals (Sweden)

    Erik Karl Håkan Jansson

    Full Text Available Huntington disease (HD is an inherited neurodegenerative disease characterized by motor, cognitive, psychiatric and metabolic symptoms. Animal models of HD show phenotypes that can be divided into similar categories, with the metabolic phenotype of certain models being characterized by obesity. Although interesting in terms of modeling metabolic symptoms of HD, the obesity phenotype can be problematic as it might confound the results of certain behavioral tests. This concerns the assessment of cognitive function in particular, as tests for such phenotypes are often based on food depriving the animals and having them perform tasks for food rewards. The BACHD rat is a recently established animal model of HD, and in order to ensure that behavioral characterization of these rats is done in a reliable way, a basic understanding of their physiology is needed. Here, we show that BACHD rats are obese and suffer from discrete developmental deficits. When assessing the motivation to lever push for a food reward, BACHD rats were found to be less motivated than wild type rats, although this phenotype was dependent on the food deprivation strategy. Specifically, the phenotype was present when rats of both genotypes were deprived to 85% of their respective free-feeding body weight, but not when deprivation levels were adjusted in order to match the rats' apparent hunger levels. The study emphasizes the importance of considering metabolic abnormalities as a confounding factor when performing behavioral characterization of HD animal models.

  17. Short-term outcome of total clipless laparoscopic cholecystectomy for complicated gallbladder stones in cirrhotic patients.

    Science.gov (United States)

    Kassem, Mohamed I; Hassouna, Ehab M

    2018-03-01

    Cirrhotic patients have been known to be more affected with gallstones than their non-cirrhotic counterparts; since laparoscopy was introduced, it has been generally approved as the standard approach for cholecystectomies with the exception of end-stage cirrhosis. The purpose of this study was to evaluate the safety and efficacy of clipless laparoscopic cholecystectomy using the harmonic scalpel in complicated cholelithiasis in cirrhotic patients. This prospective study was conducted on 62 cirrhotic patients presenting to the Gastrointestinal Surgery Unit in Alexandria Main University Hospital with complicated gallstones between March 2013 and March 2016. Both intraoperative time and blood loss were calculated in addition to rates of conversion to open cholecystectomy, morbidity and mortality. Most of our cases were females with a ratio of 1.7:1, with a mean age of 45.21 years, ranging from 25 to 65 years. The most common cause of cirrhotic liver was hepatitis C in 45.1% of patients. Among the 62 patients included in the study, 56 patients (90.3%) were presenting with acute cholecystitis and six patients were operated at the onset of acute biliary pancreatitis. The mean operative time was 72.9 min with mean blood loss 45.45 mL. The study concluded safety of total clipless laparoscopic cholecystectomy using a harmonic scalpel in Child A and B type cirrhotic patients, who presented with complicated gallstones. © 2017 Royal Australasian College of Surgeons.

  18. The long-term outcomes of cirrhotic patients with pleural effusion.

    Science.gov (United States)

    Hung, Tsung-Hsing; Tseng, Chih-Wei; Tsai, Chih-Chun; Tsai, Chen-Chi; Tseng, Kuo-Chih; Hsieh, Yu-Hsi

    2018-01-01

    A pleural effusion is an abnormal collection of fluid in the pleural space and may cause related morbidity or mortality in cirrhotic patients. Currently, there are insufficient data to support the long-term prognosis for cirrhotic patients with pleural effusion. In this study, we investigated the short- and long-term effects of pleural effusion on mortality in cirrhotic patients and evaluated the benefit of liver transplantation in these patients. The National Health Insurance Database, derived from the Taiwan National Health Insurance Program, was used to identify 3,487 cirrhotic patients with pleural effusion requiring drainage between January 1, 2007 and December 31, 2010. The proportional hazards Cox regression model was used to control for possible confounding factors. The 30-day, 90-day, 1-year, and 3-year mortalities were 20.1%, 40.2%, 59.1%, and 75.9%, respectively, in the cirrhotic patients with pleural effusion. After Cox proportional hazard regression analysis adjusted by patient gender, age, complications of cirrhosis and comorbid disorders, old age, esophageal variceal bleeding, hepatocellular carcinoma, hepatic encephalopathy, pneumonia, renal function impairment, and without liver transplantation conferred higher risks for 3-year mortality in the cirrhotic patients with pleura effusion. Liver transplantation is the most important factor to determine the 3-year mortalities (HR: 0.17, 95% CI 0.11- 0.26, P pleural effusion predicts poor long-term outcomes. Liver transplantation could dramatically improve the survival and should be suggested as soon as possible.

  19. Occult HCV Infection (OCI) Diagnosis in Cirrhotic and Non-cirrhotic Naïve Patients by Intra-PBMC Nested Viral RNA PCR.

    Science.gov (United States)

    Abd Alla, Mohamed Darwish Ahmed; Elibiary, Saleh Ahmed; Wu, George Y; El-Awady, Mostafa Kamel

    2017-12-28

    Background and Aims: Occult HCV infections (OCIs) include IgG antibody seronegative cryptogenic (COCIs), as well as seropositive secondary naïve (SNOCIs) and experienced (SEOCIs) cases. We used peripheral-blood-mononuclear-cell (PBMC)-PCR to evaluate COCIs and SNOCIs prevalence, serum HCV spontaneous disappearance (SCSD) in naïve cirrhotics and non-cirrhotics, intra-PBMC HCV-RNA strands in relation to cirrhosis density in naïve non-viremia cases, and HCV-RNA seroconversion after 1 year of solitary naïve intra-PBMC infection. Methods: The anti-HCV IgG antibody-positive naïve-patients ( n = 785) were classified into viremic ( n = 673) and non-viremic [ n = 112, including non-cirrhotics ( n = 55) and cirrhotics ( n = 57)], and 62 controls without evidence of HCV-infection. Controls and post-HCV non-viremia cases ( n = 62+112 = 174) were submitted to hepatic Fibroscan-Elastography evaluation. All subjects ( n = 847) were screened for intra-PBMC HCV-RNA sense and antisense strands by nested-PCR. Results: Naïve-OCI cases (4.84%) that were diagnosed by PBMC-PCR significantly raised the total numbers of HCV-infection to 714 ( p = 0.01). The percent positivity of SNOCIs (34.82%) was significantly higher than for asymptomatic-COCIs (3.125%, p = 0.0001). Comparing PBMC-PCR with single-step-reverse-transcription (SRT)-PCR for identification of SCSD in naïve IgG antibody-positive non-viremia patients ( n = 112) revealed a decline in SCSD prevalence by PBMC-PCR (from 14.27% to 9.3%), regardless of presence of hepatic cirrhosis ( p = 0.03). SCSD was found to be higher by PBMC-PCR in non-cirrhotics compared to cirrhotics ( p = 0.0001), with an insignificant difference when using SRT-PCR ( p = 0.45). Intra-PBMC HCV-RNA infection was significantly more frequent in cirrhotics compared to both non-cirrhotics and controls ( p < 0.0005). An increased hepatic fibrosis density was recognized in intra-PBMC HCV-RNA infection with sense ( p = 0.0001) or antisense strand ( p = 0

  20. Attenuation of Morphine-Induced Tolerance and Dependence by Pretreatment with Cerebrolysin in Male rats.

    Science.gov (United States)

    Ghavimi, Hamed; Darvishi, Sara; Ghanbarzadeh, Saeed

    2018-01-01

    Dependence and tolerance to morphine are major problems which limit its chronic clinical application. This study was aimed to investigate the attenuation effect of Cerebrolysin, a mixture of potent growth factors (BDNF, GDNF, NGF, CNTF etc,), on the development of Morphine-induced dependence and tolerance. Male Wistar rats were selected randomly and divided into different groups (n=8) including: a control group, groups received additive doses of morphine (5-25 mg/kg, ip, at an interval of 12 h until tolerance completion), and groups pretreated with Cerebrolysin (40, 80 and 160 mg/kg, ip, before morphine administration). Development of tolerance was assessed by tail-flick test and the attenuation effect of Cerebrolysin on morphine-induced dependence was evaluated after injection of naloxone (4 mg/kg, ip, 12 h after the morning dose of morphine). Seven distinct withdrawal signs including: jumping, rearing, genital grooming, abdominal writhing, wet dog shake and teeth grinding were recorded for 45 min and total withdrawal score (TWS) was calculated. Results showed that administration of Cerebrolysin could prolonged development (10 and 14 days in administration of 80 mg/kg and 160 mg/kg Cerebrolysin) and completion (4, 10 and 14 days in administration of 40, 80 and 160 mg/kg Cerebrolysin, respectively) of tolerance. Results also indicated that administration of Cerebrolysin (40, 80 and 160 mg/kg) could significantly decreased the TWS value (62±2, 77±4 and 85±6%, respectively). In conclusion, it was found that pretreatment with Cerebrolysin could attenuated morphine-induced tolerance and dependence. © Georg Thieme Verlag KG Stuttgart · New York.

  1. Dose-dependent metabolic disposition of hydroxytyrosol and formation of mercapturates in rats.

    Science.gov (United States)

    Kotronoulas, Aristotelis; Pizarro, Nieves; Serra, Aida; Robledo, Patricia; Joglar, Jesús; Rubió, Laura; Hernaéz, Alvaro; Tormos, Carmen; Motilva, Ma José; Fitó, Montserrat; Covas, Maria-Isabel; Solà, Rosa; Farré, Magí; Saez, Guillermo; de la Torre, Rafael

    2013-11-01

    Hydroxytyrosol (HT), one of the major polyphenols present in olive oil, is known to possess a high antioxidant capacity. The aim of the present study was to investigate dose dependent (0, 1, 10 and 100 mg/kg) alterations in the metabolism of HT in rats since it has been reported that metabolites may contribute to biological effects. Special attention was paid to the activation of the semiquinone-quinone oxidative cycle and the formation of adducts with potential deleterious effects. Thus, we developed a novel analytical methodology to monitor the in vivo formation of the HT mercapturate, N-acetyl-5-S-cysteinyl-hydroxytyrosol in urine samples. Biomarkers of hepatic and renal toxicity were evaluated within the dose range tested. Following HT administration, dose-dependent effects were observed for the recovery of all the metabolites studied. At the lowest dose of 1 mg/kg, the glucuronidation pathway was the most relevant (25-30%), with lower recoveries for sulfation (14%), while at the highest dose of 100 mg/kg, sulfation was the most prevalent (75%). In addition, we report for the first time the formation of the mercapturate conjugate of HT in a dose-dependent manner. The biochemical data did not reveal significant toxic effects of HT at any of the doses studied. An increase in the GSH/GSSG ratio at the highest dose was observed indicating that the products of HT autoxidation are counteracted by glutathione, resulting in their detoxification. These results indicate that the metabolic disposition of HT is highly dependent on the dose ingested. Copyright © 2013. Published by Elsevier Ltd.

  2. Early age-dependent impairments of context-dependent extinction learning, object recognition, and object-place learning occur in rats.

    Science.gov (United States)

    Wiescholleck, Valentina; Emma André, Marion Agnès; Manahan-Vaughan, Denise

    2014-03-01

    The hippocampus is vulnerable to age-dependent memory decline. Multiple forms of memory depend on adequate hippocampal function. Extinction learning comprises active inhibition of no longer relevant learned information concurrent with suppression of a previously learned reaction. It is highly dependent on context, and evidence exists that it requires hippocampal activation. In this study, we addressed whether context-based extinction as well as hippocampus-dependent tasks, such as object recognition and object-place recognition, are equally affected by moderate aging. Young (7-8 week old) and older (7-8 month old) Wistar rats were used. For the extinction study, animals learned that a particular floor context indicated that they should turn into one specific arm (e.g., left) to receive a food reward. On the day after reaching the learning criterion of 80% correct choices, the floor context was changed, no reward was given and animals were expected to extinguish the learned response. Both, young and older rats managed this first extinction trial in the new context with older rats showing a faster extinction performance. One day later, animals were returned to the T-maze with the original floor context and renewal effects were assessed. In this case, only young but not older rats showed the expected renewal effect (lower extinction ratio as compared to the day before). To assess general memory abilities, animals were tested in the standard object recognition and object-place memory tasks. Evaluations were made at 5 min, 1 h and 7 day intervals. Object recognition memory was poor at short-term and intermediate time-points in older but not young rats. Object-place memory performance was unaffected at 5 min, but impaired at 1 h in older but not young rats. Both groups were impaired at 7 days. These findings support that not only aspects of general memory, but also context-dependent extinction learning, are affected by moderate aging. This may reflect less flexibility in

  3. Effect of Pentylenetetrazol on Morphine State-Dependent Memory in Rat

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    Marziyeh Tavassoli

    2017-09-01

    Full Text Available Abstract Background: Learning and memory are among the higher functions of the brain. State-dependent memory (STM is a type of memory in which the recall of a learned behavior is happend only in the same sensory and physiologic condition in which the behavior is encoded. The STM is seen with some drugs, e.g. the morphine. The pentylenetetrazol (PTZ is a durg which is used for the induction of seizure in experimental models. Some studies have been revealed different effects of the PTZ on brain higher function (learning, memory …. The aim of present study was to explore the effect of PTZ on morphine-induced STM. Materials and Methods: In this study, male adult Wistar rats (190-220 g were used. Animals in 3 groups (n=8 during 3 sessions (learning/memory, STM and interaction were studied. During 48 hour (training and test the learning and memory of animals were studied in inhibitory avoidance apparatus. The step-through latency in the test day was used as a criterion for memory. Post-training injection of saline or morphine (2.5, 5 and 7.5 mg/kg-ip in different groups was carried out. In addition, the pre-test injection of morphine at the same doses was made to study the STM. Moreover, the interaction of pre-test single-dose PTZ (60 mg/kg-ip on STM was studied. The locomotion of the animals was measured using the open field. Results: The post-training injection of morphine (2.5, 5 and 7.5 mg/kg-ip impaired the inhibitory memory of rats compared to control group (p<0.001. The post-training and pre-test injections of the same dose of morphine (7.5 mg/kg-ip reversed the impaired memory compared to morphine (2.5 and 5 mg/kg-ip, (p<0.001. The pre-test PTZ (60 mg/kg-ip maintained the morphine (7.5 mg/kg-ip STM (p<0.001. Conclusion: The present study revealed that the post-training ip injection of different doses of morphine results in the impairment of inhibitory avoidance memory in rat. In addition, the pre-test injection of the same doses of morphine

  4. Boldine enhances bile production in rats via osmotic and Farnesoid X receptor dependent mechanisms

    International Nuclear Information System (INIS)

    Cermanova, Jolana; Kadova, Zuzana; Zagorova, Marie; Hroch, Milos; Tomsik, Pavel; Nachtigal, Petr; Kudlackova, Zdenka; Pavek, Petr; Dubecka, Michaela; Ceckova, Martina; Staud, Frantisek; Laho, Tomas; Micuda, Stanislav

    2015-01-01

    Boldine, the major alkaloid from the Chilean Boldo tree, is used in traditional medicine to support bile production, but evidence to support this function is controversial. We analyzed the choleretic potential of boldine, including its molecular background. The acute- and long-term effects of boldine were evaluated in rats either during intravenous infusion or after 28-day oral treatment. Infusion of boldine instantly increased the bile flow 1.4-fold in healthy rats as well as in animals with Mrp2 deficiency or ethinylestradiol induced cholestasis. This effect was not associated with a corresponding increase in bile acid or glutathione biliary excretion, indicating that the effect is not related to stimulation of either bile acid dependent or independent mechanisms of bile formation and points to the osmotic activity of boldine itself. We subsequently analyzed bile production under conditions of changing biliary excretion of boldine after bolus intravenous administration and found strong correlations between both parameters. HPLC analysis showed that bile concentrations of boldine above 10 μM were required for induction of choleresis. Importantly, long-term pretreatment, when the bile collection study was performed 24-h after the last administration of boldine, also accelerated bile formation despite undetectable levels of the compound in bile. The effect paralleled upregulation of the Bsep transporter and increased biliary clearance of its substrates, bile acids. We consequently confirmed the ability of boldine to stimulate the Bsep transcriptional regulator, FXR receptor. In conclusion, our study clarified the mechanisms and circumstances surrounding the choleretic activity of boldine. - Highlights: • Boldine may increase bile production by direct as well as indirect mechanisms. • Biliary concentrations of boldine above 10 μM directly stimulate bile production. • Long-term oral boldine administration increases bile acid (BA) biliary secretion. • Boldine

  5. Aging-dependent changes in rat heart mitochondrial glutaredoxins—Implications for redox regulation

    Directory of Open Access Journals (Sweden)

    Xing-Huang Gao

    2013-01-01

    Full Text Available Clinical and animal studies have documented that hearts of the elderly are more susceptible to ischemia/reperfusion damage compared to young adults. Recently we found that aging-dependent increase in susceptibility of cardiomyocytes to apoptosis was attributable to decrease in cytosolic glutaredoxin 1 (Grx1 and concomitant decrease in NF-κB-mediated expression of anti-apoptotic proteins. Besides primary localization in the cytosol, Grx1 also exists in the mitochondrial intermembrane space (IMS. In contrast, Grx2 is confined to the mitochondrial matrix. Here we report that Grx1 is decreased by 50–60% in the IMS, but Grx2 is increased by 1.4–2.6 fold in the matrix of heart mitochondria from elderly rats. Determination of in situ activities of the Grx isozymes from both subsarcolemmal (SSM and interfibrillar (IFM mitochondria revealed that Grx1 was fully active in the IMS. However, Grx2 was mostly in an inactive form in the matrix, consistent with reversible sequestration of the active-site cysteines of two Grx2 molecules in complex with an iron–sulfur cluster. Our quantitative evaluations of the active/inactive ratio for Grx2 suggest that levels of dimeric Grx2 complex with iron–sulfur clusters are increased in SSM and IFM in the hearts of elderly rats. We found that the inactive Grx2 can be fully reactivated by sodium dithionite or exogenous superoxide production mediated by xanthine oxidase. However, treatment with rotenone, which generates intramitochondrial superoxide through inhibition of mitochondrial respiratory chain Complex I, did not lead to Grx2 activation. These findings suggest that insufficient ROS accumulates in the vicinity of dimeric Grx2 to activate it in situ.

  6. A time-dependent degeneration manner of condyle in rat CFA-induced inflamed TMJ.

    Science.gov (United States)

    Xu, Liqin; Guo, Huilin; Li, Cheng; Xu, Jie; Fang, Wei; Long, Xing

    2016-01-01

    Temporomandibular joint (TMJ) inflammation is a potential risk factor of osteoarthritis (OA) but the detailed degenerative changes in the inflamed TMJ remain unclear. In this study, we evaluated the changes of condylar cartilage and subchondral bone in rat inflamed TMJ induced by Freund's complete adjuvant (CFA). Articular cavity was injected with CFA and the TMJ samples were collected 1, 2, 3, and 4-week post-injection. Hematoxylin & Eosin (H&E) staining, toluidine blue (TB) staining, Safranin O (S.O) staining, Masson trichrome staining and micro-CT were used to assess TMJ degeneration during inflammation. Osteoclast and osteoblast activities were analyzed by tartrate-resistant acid phosphatase (TRAP) staining and osteocalcin (OCN) immunohistochemistry staining respectively. The expression of receptor activator of NF-kB ligand (RANKL) and osteoprotegerin (OPG) in condylar cartilage and subchondral bone was also evaluated through immunohistochemistry and RANKL/OPG ratio was evaluated. Reduced cartilage thickness, decreased number of chondrocytes, and down-regulated proteoglycan expression were observed in the condylar cartilage in the inflamed TMJ. Enhanced osteoclast activity, and expanded bone marrow cavity were reached the peak in the 2-week after CFA-injection. Meanwhile the RANKL/OPG ratio in the cartilage and subchondral bone also increased in the 2-week CFA-injection. Immature, unmineralized new bones with irregular trabecular bone structure, atypical condylar shape, up-regulated OCN expression, and decreased bone mineral density (BMD) were found in the inflamed TMJ. The time-dependent degeneration manner of TMJ cartilage and subchondral bone was found in CFA-induced arthritis rat model. The degeneration in the TMJ with inflammation might be a risk factor and should be concerned.

  7. Different dose-dependent effects of ebselen in sciatic nerve ischemia-reperfusion injury in rats

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    Filiz Ozyigit

    2015-08-01

    Full Text Available Ebselen is an organoselenium compound which has strong antioxidant and anti-inflammatory effects. We investigated the neuroprotective role of ebselen pretreatment in rats with experimental sciatic nerve ischemia-reperfusion (I/R injury. Adult male Sprague Dawley rats were divided into four groups (N = 7 in each group. Before sciatic nerve I/R was induced, ebselen was injected intraperitoneally at doses of 15 and 30 mg/kg. After a 2 h ischemia and a 3 h reperfusion period, sciatic nerve tissues were excised. Tissue levels of malondialdehyde (MDA and nitric oxide (NO, and activities of superoxide dismutase (SOD, glutathione peroxidase (GPx, and catalase (CAT were measured. Sciatic nerve tissues were also examined histopathologically. The 15 mg/kg dose of ebselen reduced sciatic nerve damage and apoptosis (P < 0.01, levels of MDA, NO, and inducible nitric oxide synthase (iNOS positive cells (P < 0.01, P < 0.05, respectively, and increased SOD, GPx, and CAT activities (P < 0.001, P < 0.01, P < 0.05, respectively compared with the I/R group that did not receive ebselen. Conversely, the 30 mg/kg dose of ebselen increased sciatic nerve damage, apoptosis, iNOS positive cells (P < 0.01, P < 0.05, P < 0.001 and MDA and NO levels (P < 0.05, P < 0.01 and decreased SOD, GPx, and CAT activities (P < 0.05 compared with the sham group. The results of this study suggest that ebselen may cause different effects depending on the dose employed. Ebselen may be protective against sciatic nerve I/R injury via antioxidant and antiapoptotic activities at a 15 mg/kg dose, conversely higher doses may cause detrimental effects.

  8. Boldine enhances bile production in rats via osmotic and farnesoid X receptor dependent mechanisms.

    Science.gov (United States)

    Cermanova, Jolana; Kadova, Zuzana; Zagorova, Marie; Hroch, Milos; Tomsik, Pavel; Nachtigal, Petr; Kudlackova, Zdenka; Pavek, Petr; Dubecka, Michaela; Ceckova, Martina; Staud, Frantisek; Laho, Tomas; Micuda, Stanislav

    2015-05-15

    Boldine, the major alkaloid from the Chilean Boldo tree, is used in traditional medicine to support bile production, but evidence to support this function is controversial. We analyzed the choleretic potential of boldine, including its molecular background. The acute- and long-term effects of boldine were evaluated in rats either during intravenous infusion or after 28-day oral treatment. Infusion of boldine instantly increased the bile flow 1.4-fold in healthy rats as well as in animals with Mrp2 deficiency or ethinylestradiol induced cholestasis. This effect was not associated with a corresponding increase in bile acid or glutathione biliary excretion, indicating that the effect is not related to stimulation of either bile acid dependent or independent mechanisms of bile formation and points to the osmotic activity of boldine itself. We subsequently analyzed bile production under conditions of changing biliary excretion of boldine after bolus intravenous administration and found strong correlations between both parameters. HPLC analysis showed that bile concentrations of boldine above 10 μM were required for induction of choleresis. Importantly, long-term pretreatment, when the bile collection study was performed 24-h after the last administration of boldine, also accelerated bile formation despite undetectable levels of the compound in bile. The effect paralleled upregulation of the Bsep transporter and increased biliary clearance of its substrates, bile acids. We consequently confirmed the ability of boldine to stimulate the Bsep transcriptional regulator, FXR receptor. In conclusion, our study clarified the mechanisms and circumstances surrounding the choleretic activity of boldine. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Boldine enhances bile production in rats via osmotic and Farnesoid X receptor dependent mechanisms

    Energy Technology Data Exchange (ETDEWEB)

    Cermanova, Jolana [Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove (Czech Republic); Kadova, Zuzana [Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove (Czech Republic); Deparment of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove (Czech Republic); Zagorova, Marie [Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove (Czech Republic); Hroch, Milos [Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove (Czech Republic); Department of Medical Biochemistry, Charles University in Prague, Faculty of Medicine in Hradec Kralove (Czech Republic); Tomsik, Pavel [Department of Medical Biochemistry, Charles University in Prague, Faculty of Medicine in Hradec Kralove (Czech Republic); Nachtigal, Petr; Kudlackova, Zdenka [Department of Biological and Medical Sciences, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove (Czech Republic); Pavek, Petr; Dubecka, Michaela; Ceckova, Martina; Staud, Frantisek [Deparment of Pharmacology and Toxicology, Charles University in Prague, Faculty of Pharmacy in Hradec Kralove (Czech Republic); Laho, Tomas [Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove (Czech Republic); Micuda, Stanislav, E-mail: micuda@lfhk.cuni.cz [Department of Pharmacology, Charles University in Prague, Faculty of Medicine in Hradec Kralove (Czech Republic)

    2015-05-15

    Boldine, the major alkaloid from the Chilean Boldo tree, is used in traditional medicine to support bile production, but evidence to support this function is controversial. We analyzed the choleretic potential of boldine, including its molecular background. The acute- and long-term effects of boldine were evaluated in rats either during intravenous infusion or after 28-day oral treatment. Infusion of boldine instantly increased the bile flow 1.4-fold in healthy rats as well as in animals with Mrp2 deficiency or ethinylestradiol induced cholestasis. This effect was not associated with a corresponding increase in bile acid or glutathione biliary excretion, indicating that the effect is not related to stimulation of either bile acid dependent or independent mechanisms of bile formation and points to the osmotic activity of boldine itself. We subsequently analyzed bile production under conditions of changing biliary excretion of boldine after bolus intravenous administration and found strong correlations between both parameters. HPLC analysis showed that bile concentrations of boldine above 10 μM were required for induction of choleresis. Importantly, long-term pretreatment, when the bile collection study was performed 24-h after the last administration of boldine, also accelerated bile formation despite undetectable levels of the compound in bile. The effect paralleled upregulation of the Bsep transporter and increased biliary clearance of its substrates, bile acids. We consequently confirmed the ability of boldine to stimulate the Bsep transcriptional regulator, FXR receptor. In conclusion, our study clarified the mechanisms and circumstances surrounding the choleretic activity of boldine. - Highlights: • Boldine may increase bile production by direct as well as indirect mechanisms. • Biliary concentrations of boldine above 10 μM directly stimulate bile production. • Long-term oral boldine administration increases bile acid (BA) biliary secretion. • Boldine

  10. Estrogen- and Satiety State-Dependent Metabolic Lateralization in the Hypothalamus of Female Rats.

    Directory of Open Access Journals (Sweden)

    Istvan Toth

    Full Text Available Hypothalamus is the highest center and the main crossroad of numerous homeostatic regulatory pathways including reproduction and energy metabolism. Previous reports indicate that some of these functions may be driven by the synchronized but distinct functioning of the left and right hypothalamic sides. However, the nature of interplay between the hemispheres with regard to distinct hypothalamic functions is still unclear. Here we investigated the metabolic asymmetry between the left and right hypothalamic sides of ovariectomized female rats by measuring mitochondrial respiration rates, a parameter that reflects the intensity of cell and tissue metabolism. Ovariectomized (saline injected and ovariectomized+estrogen injected animals were fed ad libitum or fasted to determine 1 the contribution of estrogen to metabolic asymmetry of hypothalamus; and 2 whether the hypothalamic asymmetry is modulated by the satiety state. Results show that estrogen-priming significantly increased both the proportion of animals with detected hypothalamic lateralization and the degree of metabolic difference between the hypothalamic sides causing a right-sided dominance during state 3 mitochondrial respiration (St3 in ad libitum fed animals. After 24 hours of fasting, lateralization in St3 values was clearly maintained; however, instead of the observed right-sided dominance that was detected in ad libitum fed animals here appeared in form of either right- or left-sidedness. In conclusion, our results revealed estrogen- and satiety state-dependent metabolic differences between the two hypothalamic hemispheres in female rats showing that the hypothalamic hemispheres drive the reproductive and satiety state related functions in an asymmetric manner.

  11. Acute predator stress impairs the consolidation and retrieval of hippocampus-dependent memory in male and female rats.

    Science.gov (United States)

    Park, Collin R; Zoladz, Phillip R; Conrad, Cheryl D; Fleshner, Monika; Diamond, David M

    2008-04-01

    We have studied the effects of an acute predator stress experience on spatial learning and memory in adult male and female Sprague-Dawley rats. All rats were trained to learn the location of a hidden escape platform in the radial-arm water maze (RAWM), a hippocampus-dependent spatial memory task. In the control (non-stress) condition, female rats were superior to the males in the accuracy and consistency of their spatial memory performance tested over multiple days of training. In the stress condition, rats were exposed to the cat for 30 min immediately before or after learning, or before the 24-h memory test. Predator stress dramatically increased corticosterone levels in males and females, with females exhibiting greater baseline and stress-evoked responses than males. Despite these sex differences in the overall magnitudes of corticosterone levels, there were significant sex-independent correlations involving basal and stress-evoked corticosterone levels, and memory performance. Most importantly, predator stress impaired short-term memory, as well as processes involved in memory consolidation and retrieval, in male and female rats. Overall, we have found that an intense, ethologically relevant stressor produced a largely equivalent impairment of memory in male and female rats, and sex-independent corticosterone-memory correlations. These findings may provide insight into commonalities in how traumatic stress affects the brain and memory in men and women.

  12. Length dependence of force generation exhibit similarities between rat cardiac myocytes and skeletal muscle fibres.

    Science.gov (United States)

    Hanft, Laurin M; McDonald, Kerry S

    2010-08-01

    According to the Frank-Starling relationship, increased ventricular volume increases cardiac output, which helps match cardiac output to peripheral circulatory demand. The cellular basis for this relationship is in large part the myofilament length-tension relationship. Length-tension relationships in maximally calcium activated preparations are relatively shallow and similar between cardiac myocytes and skeletal muscle fibres. During twitch activations length-tension relationships become steeper in both cardiac and skeletal muscle; however, it remains unclear whether length dependence of tension differs between striated muscle cell types during submaximal activations. The purpose of this study was to compare sarcomere length-tension relationships and the sarcomere length dependence of force development between rat skinned left ventricular cardiac myocytes and fast-twitch and slow-twitch skeletal muscle fibres. Muscle cell preparations were calcium activated to yield 50% maximal force, after which isometric force and rate constants (k(tr)) of force development were measured over a range of sarcomere lengths. Myofilament length-tension relationships were considerably steeper in fast-twitch fibres compared to slow-twitch fibres. Interestingly, cardiac myocyte preparations exhibited two populations of length-tension relationships, one steeper than fast-twitch fibres and the other similar to slow-twitch fibres. Moreover, myocytes with shallow length-tension relationships were converted to steeper length-tension relationships by protein kinase A (PKA)-induced myofilament phosphorylation. Sarcomere length-k(tr) relationships were distinct between all three cell types and exhibited patterns markedly different from Ca(2+) activation-dependent k(tr) relationships. Overall, these findings indicate cardiac myocytes exhibit varied length-tension relationships and sarcomere length appears a dominant modulator of force development rates. Importantly, cardiac myocyte length

  13. Depolarization-stimulated 42K+ efflux in rat aorta is calcium- and cellular volume-dependent

    International Nuclear Information System (INIS)

    Magliola, L.; Jones, A.W.

    1987-01-01

    The purpose of this study was to investigate the factors controlling membrane permeability to potassium of smooth muscle cells from rat aorta stimulated by depolarization. The increase 42 K+ efflux (change in the rate constant) induced by depolarization (application of high concentrations of potassium chloride) was inhibited significantly by the calcium antagonists diltiazem and nisoldipine. Parallel inhibitory effects on contraction were observed. Diltiazem also inhibited potassium-stimulated 36 Cl- efflux. The addition of 25-150 mM KCl to normal physiologic solution stimulated 42 K+ efflux in a concentration-dependent manner. Diltiazem suppressed potassium-stimulated 42 K+ efflux approximately 90% at 25 mM KCl and approximately 40% at 150 mM KCl. The ability of nisoldipine to inhibit 42 K+ efflux also diminished as the potassium chloride concentration was elevated. The component of efflux that was resistant to calcium antagonists probably resulted from a decrease in the electrochemical gradient for potassium. Cellular water did not change during potassium addition. Substitution of 80 and 150 mM KCl for sodium chloride produced cellular swelling and enhanced potassium-stimulated 42 K+ efflux compared with potassium chloride addition. The addition of sucrose to prevent cellular swelling reduced efflux response to potassium substitution toward that of potassium addition. A hypoosmolar physiologic solution produced an increase in the 42 K+ efflux and a contracture that were both prevented by the addition of sucrose. We concluded that the depolarization-mediated 42 K+ efflux has three components: one is calcium dependent; a second is dependent on cellular volume; and a third is resistant to inhibition by calcium antagonists

  14. Motor vehicle accidents: How should cirrhotic patients be managed?

    Institute of Scientific and Technical Information of China (English)

    Takumi Kawaguchi; Eitaro Taniguchi; Michio Sata

    2012-01-01

    Motor vehicle accidents (MVAs) are serious social issues worldwide and driver illness is an important cause of MVAs.Minimal hepatic encephalopathy (MHE) is a complex cognitive dysfunction with attention deficit,which frequently occurs in cirrhotic patients independent of severity of liver disease.Although MHE is known as a risk factor for MVAs,the impact of diagnosis and treatment of MHE on MVA-related societal costs is largely unknown.Recently,Bajaj et al demonstrated valuable findings that the diagnosis of MHE by rapid screening using the inhibitory control test (ICT),and subsequent treatment with lactulose could substantially reduce the societal costs by preventing MVAs,Besides the ICT and lactulose,there are various diagnostic tools and therapeutic strategies for MHE.In this commentary,we discussed a current issue of diagnostic tools for MHE,including neuropsychological tests.We also discussed the advantages of the other therapeutic strategies for MHE,such as intake of a regular breakfast and coffee,and supplementation with zinc and branched chain amino acids,on the MVA-related societal costs.

  15. Severe back pain a cirrhotic patient : a diagnostic challenge

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    Ioana Stănescu

    2018-05-01

    Full Text Available Spondylodiscitis is an infection of the intervertebral disc space, involves the vertebrae, causing vertebral osteomyelitis and spread to adjacent epidural space, causing dural, radicular or spinal cord compression. Appears mainly in adult and immunocompromised patients, mainly by haematogenous inoculation from systemic infections with bacteriemia. Patients with hepatic cirrhosis have frequent bacteriemias, produced by increased gut permeability, immune dysfunction and frequent need for invasive procedures. Despite high frequency of blood stream infections, discitis and vestebral osteomyelitis are rarely reported. We present the case of a 53 years old woman, diagnosed with class B Child Pugh cirrhosis, which presents with intense back pain and cauda equina syndrome, without clinical signs of infection. Diagnosis was confirmed by spinal MRI, but very soon after treatment onset, the patient suffered a septic shock with haemodynamic instability, which leads to patient’s death. This case illustrates how an unusual complication of cirrhosis – bacteriemia - could precipitate the unfavorable evolution of the patient by producing a remote septic complication. Persistent back pain in a cirrhotic patient should also raise the hypothesis of an infectious cause, in which early management is essential. Early diagnosis in essential for successful treatment, and good prognosis after long-term antibiotic treatment can be achieved in the majority of patients.

  16. Inhibitors of glutamate dehydrogenase block sodium-dependent glutamate uptake in rat brain membranes

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    Brendan S Whitelaw

    2013-09-01

    Full Text Available We recently found evidence for anatomic and physical linkages between the astroglial Na+-dependent glutamate transporters (GLT-1/EAAT2 and GLAST/EAAT1 and mitochondria. In these same studies, we found that the glutamate dehydrogenase (GDH inhibitor, epigallocatechin-monogallate (EGCG, inhibits both glutamate oxidation and Na+-dependent glutamate uptake in astrocytes. In the present study, we extend this finding by exploring the effects of EGCG on Na+-dependent L-[3H]-glutamate (Glu uptake in crude membranes (P2 prepared from rat brain cortex. In this preparation, uptake is almost exclusively mediated by GLT-1. EGCG inhibited L-[3H]-Glu uptake in cortical membranes with an IC50 value of 230 µM. We also studied the effects of two additional inhibitors of GDH, hexachlorophene (HCP and bithionol (BTH. Both of these compounds also caused concentration-dependent inhibition of glutamate uptake in cortical membranes. Pre-incubating with HCP for up to 15 min had no greater effect than that observed with no pre-incubation, showing that the effects occur rapidly. HCP decreased the Vmax for glutamate uptake without changing the Km, consistent with a non-competitive mechanism of action. EGCG, HCP, and BTH also inhibited Na+-dependent transport of D-[3H]-aspartate (Asp, a non-metabolizable substrate, and [3H]-γ-aminobutyric acid (GABA. In contrast to the forebrain, glutamate uptake in crude cerebellar membranes (P2 is likely mediated by GLAST (EAAT1. Therefore, the effects of these compounds were examined in cerebellar membranes. In this region, none of these compounds had any effect on uptake of either L-[3H]-Glu or D-[3H]-Asp, but they all inhibited [3H]-GABA uptake. Together these studies suggest that GDH is preferentially required for glutamate uptake in forebrain as compared to cerebellum, and GDH may be required for GABA uptake as well. They also provide further evidence for a functional linkage between glutamate transport and mitochondria.

  17. Gou-teng (from Uncaria rhynchophylla Miquel)-induced endothelium-dependent and -independent relaxations in the isolated rat aorta.

    Science.gov (United States)

    Kuramochi, T; Chu, J; Suga, T

    1994-01-01

    Gou-teng is a drug used for treatment of hypertension in Chinese medicine. Its antihypertensive action has been previously confirmed in the spontaneously hypertensive rat (SHR). Here, its vasorelaxing effect and the mechanisms of actions were studied in vitro. Gou-teng extract (GTE) relaxed the norepinephrine (NE)-precontracted aortic ring preparations isolated from Wistar Kyoto rats (WKY) with and without intact endothelium; the latter was significantly less sensitive than the former. The GTE-induced endothelium-dependent relaxation was significantly inhibited by NG-monomethyl-L-arginine (NMMA) in a dose-dependent manner while indomethacin did not affect the relaxation. Atropine inhibited the acetylcholine (ACh)-induced endothelium-dependent relaxation but did not the GTE-induced one. Furthermore, once GTE was applied, the following NE-induced contraction was significantly reduced even after repeated washout. NMMA effectively reduced and rather reversed this residual effect of GTE. From these results, it is concluded that GTE relaxes the NE-precontracted rat aorta through endothelium-dependent and, to lesser extent, -independent mechanisms. The endothelium-dependent component would be mediated by EDRF/NO pathway in which the muscarinic cholinoceptors were not involved. Thus, GTE appears to be a potent and long-lasting vasodilator mainly through EDRF/NO release.

  18. Differential distribution of age and HBV serological markers in liver cirrhosis and non-cirrhotic patients with primary liver cancer

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    XU Xiuhua

    2013-03-01

    Full Text Available ObjectiveTo compare the age distributions and presence of hepatitis B virus (HBV serological markers between primary hepatic cancer (PHC patients with and without liver cirrhosis. MethodsA total of 547 PHC cases were analyzed retrospectively. After dividing into two groups according to liver cirrhosis status, the between-group differences in age and HBV serological markers, such as hepatitis B e antigen (HBeAg status, were statistically compared using the Chi-squared test. ResultsThe number of cirrhotic and non-cirrhotic PHC patients was 265 and 282, respectively. HBV infection was present in 221 cirrhotic PHC patients and 256 non-cirrhotic PHC patients (834% vs. 90.8%. There was a substantial bias in the proportion of males to females in the cirrhotic PHC patients (7.83∶1. The number of PHC patients <60 years old was similar between the cirrhotic and non-cirrhotic groups, but the non-cirrhotic group had significantly more patients >60 years old (P<0.005. In cirrhotic PHC patients, the HBV infection rate was highest in the <40 years old age group (96.7% and the HBeAg serological conversion rate was highest in the 40-60 years old age group (89.5%. In non-cirrhotic PHC patients, the 40-60 years old age group showed the highest HBV infection rate (90.3% but the lowest HBeAg serological conversion rate (80.0%. ConclusionPHC with liver cirrhosis mainly occurred in males, with the HBV infection rate being higher in individuals <60 years old. Non-cirrhotic PHC patients were more often >60 years old. Many of the HBV-infected PHC patients with cirrhosis had high HBeAg serological conversion rate.

  19. An Age-Dependent Physiologically-Based Pharmacokinetic/Pharmacodynamic Model for the Organophosphorus Insecticide Chlorpyrifos in the Preweanling Rat

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    Timchalk, Chuck; Kousba, Ahmed A.; Poet, Torka S.

    2007-08-01

    Juvenile rats are more susceptible than adults to the acute toxicity of organophosphorus insecticides like chlorpyrifos (CPF). Age- and dose-dependent differences in metabolism may be responsible. Of importance is CYP450 activation and detoxification of CPF to chlorpyrifos-oxon (CPF-oxon) and trichloropyridinol (TCP), as well as B-esterase (cholinesterase; ChE) and A-esterase (PON-1) detoxification of CPF-oxon to TCP. In the current study, a modified physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) model incorporating age-dependent changes in CYP450, PON-1, and tissue ChE levels for rats was developed. In this model, age was used as a dependent function to estimate body weight which was then used to allometrically scale both metabolism and tissue ChE levels. Model simulations suggest that preweanling rats are particularly sensitive to CPF toxicity, with levels of CPF-oxon in blood and brain disproportionately increasing, relative to the response in adult rats. This age-dependent non-linear increase in CPF-oxon concentration may potentially result from the depletion of non-target B-esterases, and a lower PON-1 metabolic capacity in younger animals. These results indicate that the PBPK/PD model behaves consistently with the general understanding of CPF toxicity, pharmacokinetics and tissue ChE inhibition in neonatal and adult rats. Hence, this model represents an important starting point for developing a computational model to assess the neurotoxic potential of environmentally relevant organophosphate exposures in infants and children.

  20. Treadmill exercise attenuates the severity of physical dependence, anxiety, depressive-like behavior and voluntary morphine consumption in morphine withdrawn rats receiving methadone maintenance treatment.

    Science.gov (United States)

    Alizadeh, Maryam; Zahedi-Khorasani, Mahdi; Miladi-Gorji, Hossein

    2018-05-30

    This study was designed to examine whether treadmill exercise would attenuate the severity of physical dependence, methadone-induced anxiety, depression and voluntary morphine consumption in morphine withdrawn rats receiving methadone maintenance treatment (MMT). The rats were chronically treated with bi-daily doses (10 mg/kg, at 12 h intervals) of morphine for 14 days. The exercising rats receiving MMT were forced to run on a motorized treadmill for 30 days during morphine withdrawal. Then, rats were tested for the severity of morphine dependence, the elevated plus-maze (EPM), sucrose preference test (SPT) and voluntary morphine consumption using a two-bottle choice (TBC) paradigm. The results showed that naloxone- precipitated opioid withdrawal signs were decreased in exercising morphine-dependent rats receiving MMT than sedentary rats. Also, the exercising morphine-dependent rats receiving MMT exhibited an increased time on open arms, preference for sucrose and a lower morphine preference ratio than sedentary rats. We conclude that treadmill exercise decreased the severity of physical dependence, anxiety/depressive-like behaviors and also the voluntary morphine consumption in morphine withdrawn rats receiving MMT. Thus, exercise may benefit in the treatment of addicts during MMT. Copyright © 2018. Published by Elsevier B.V.

  1. Comparison of qtc duration on electrocardiogram between patients of liver cirrhosis and non cirrhotic controls

    International Nuclear Information System (INIS)

    Umair, M.; Nadeem, K.; Azam, M.N.; Mansoor, J.; Khan, H.

    2012-01-01

    Objective: To compare the QTc duration on electrocardiogram (ECG) of patients of cirrhosis (hep B and C origin) with non cirrhotic controls. Study Design: Case control study. Place and duration of study: The study was carried out at the Department of Medicine, Military Hospital, Rawalpindi, from 8th Feb 2009 to 8th Aug 2009. Material and Method: After meeting the exclusion and inclusion criteria, 80 cirrhotic patients were enrolled in group-I and equal number of non cirrhotic controls were enrolled in group-II. Three 12 lead ECG recording were taken for each patient, 5 minutes apart, and QTc value was calculated for each ECG and then mean of the three was used for the analysis. A QTc value more than 0.44 seconds was taken as prolonged. Results: The mean QTc interval on electrocardiogram in group-I i.e. cirrhotic was 0.4603 seconds (SD+-0.1312) and mean QTc interval on electrocardiogram in group-II i.e. noncirrhotic was 0.407 seconds (SD+-0.029). These findings were statistically significant (p value < 0.001). Conclusion: Cirrhotic patients have prolonged QTc interval as compared to noncirrhotic controls. (author)

  2. Disrupted topological organization of brain structural network associated with prior overt hepatic encephalopathy in cirrhotic patients

    International Nuclear Information System (INIS)

    Chen, Hua-Jun; Shi, Hai-Bin; Jiang, Long-Feng; Li, Lan; Chen, Rong

    2018-01-01

    To investigate structural brain connectome alterations in cirrhotic patients with prior overt hepatic encephalopathy (OHE). Seventeen cirrhotic patients with prior OHE (prior-OHE), 18 cirrhotic patients without prior OHE (non-prior-OHE) and 18 healthy controls (HC) underwent diffusion tensor imaging. Neurocognitive functioning was assessed with Psychometric Hepatic Encephalopathy Score (PHES). Using a probabilistic fibre tracking approach, we depicted the whole-brain structural network as a connectivity matrix of 90 regions (derived from the Automated Anatomic Labeling atlas). Graph theory-based analyses were performed to analyse topological properties of the brain network. The analysis of variance showed significant group effects on several topological properties, including network strength, global efficiency and local efficiency. A progressive decrease trend for these metrics was found from non-prior-OHE to prior-OHE, compared with HC. Among the three groups, the regions with altered nodal efficiency were mainly distributed in the frontal and occipital cortices, paralimbic system and subcortical regions. The topological metrics, such as network strength and global efficiency, were correlated with PHES among cirrhotic patients. The cirrhotic patients developed structural brain connectome alterations; this is aggravated by prior OHE episode. Disrupted topological organization of the brain structural network may account for cognitive impairments related to prior OHE. (orig.)

  3. EXHALED AND PLASMA NITRITE: a comparative study among healthy, cirrhotic and liver transplant patients

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    Viviane S AUGUSTO

    2014-03-01

    Full Text Available Context There is a relative lack of studies about exhaled nitrite (NO2- concentrations in cirrhotic and transplanted patients. Objective Verify possible differences and correlations between the levels of NO2-, measured in plasma and exhaled breath condensate collected from patients with cirrhosis and liver transplant. Method Sixty adult male patients, aged between 27 and 67 years, were subdivided into three groups: a control group comprised of 15 healthy volunteers, a cirrhosis group composed of 15 volunteers, and a transplant group comprised of 30 volunteers. The NO2- concentrations were measured by chemiluminescence. Results 1 The analysis of plasma NO2- held among the three groups showed no statistical significance. 2 The comparison between cirrhotic and control groups, control and transplanted and cirrhotic and transplanted was not statistically significant. 3 The measurements performed on of NO2- exhaled breath condensate among the three groups showed no statistical difference. 4 When comparing the control group samples and cirrhotic, control and transplanted and cirrhotic and transplanted, there was no significant changes in the concentrations of NO2-. Conclusion No correlations were found between plasma and exhaled NO2-, suggesting that the exhaled NO2- is more reflective of local respiratory NO release than the systemic circulation.

  4. Characteristic risk factors in cirrhotic patients for posthepatectomy complications: comparison with noncirrhotic patients.

    Science.gov (United States)

    Itoh, Shinji; Uchiyama, Hideaki; Kawanaka, Hirofumi; Higashi, Takahiro; Egashira, Akinori; Eguchi, Daihiko; Okuyama, Toshiro; Tateishi, Masahiro; Korenaga, Daisuke; Takenaka, Kenji

    2014-02-01

    There seemed to be characteristic risk factors in cirrhotic patients for posthepatectomy complications because these patients have less hepatic reserve as compared with noncirrhotic patients. The aim of the current study was to identify these characteristic risk factors in cirrhotic patients. We performed 419 primary hepatectomies for hepatocellular carcinoma. The patients were divided into the cirrhotic group (n = 198) and the noncirrhotic group (n = 221), and the risk factors for posthepatectomy complications were compared between the groups. Thirty-six cirrhotic patients (18.2%) experienced Clavien's Grade III or more complications. Tumor size, intraoperative blood loss, duration of operation, major hepatectomy (two or more segments), and necessity of blood transfusion were found to be significant risk factors in univariate analyses. Multivariate analysis revealed that major hepatectomy and intraoperative blood loss were independent risk factors for posthepatectomy complications in patients with cirrhosis. On the other hand, the duration of operation was only an independent risk factor for posthepatectomy complication in noncirrhotic patients. Cirrhotic patients should avoid a major hepatectomy and undergo a limited resection preserving as much liver tissue as possible and meticulous surgical procedures to lessen intraoperative blood loss are mandatory to prevent major posthepatectomy complications.

  5. Disrupted topological organization of brain structural network associated with prior overt hepatic encephalopathy in cirrhotic patients

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Hua-Jun [Fujian Medical University Union Hospital, Department of Radiology, Fuzhou (China); The First Affiliated Hospital of Nanjing Medical University, Department of Radiology, Nanjing (China); Shi, Hai-Bin [The First Affiliated Hospital of Nanjing Medical University, Department of Radiology, Nanjing (China); Jiang, Long-Feng [The First Affiliated Hospital of Nanjing Medical University, Department of Infectious Diseases, Nanjing (China); Li, Lan [Fujian Medical University Union Hospital, Department of Radiology, Fuzhou (China); Chen, Rong [University of Maryland School of Medicine, Department of Diagnostic Radiology and Nuclear Medicine, Baltimore, MD (United States); Beijing Institute of Technology, Advanced Innovation Center for Intelligent Robots and Systems, Beijing (China)

    2018-01-15

    To investigate structural brain connectome alterations in cirrhotic patients with prior overt hepatic encephalopathy (OHE). Seventeen cirrhotic patients with prior OHE (prior-OHE), 18 cirrhotic patients without prior OHE (non-prior-OHE) and 18 healthy controls (HC) underwent diffusion tensor imaging. Neurocognitive functioning was assessed with Psychometric Hepatic Encephalopathy Score (PHES). Using a probabilistic fibre tracking approach, we depicted the whole-brain structural network as a connectivity matrix of 90 regions (derived from the Automated Anatomic Labeling atlas). Graph theory-based analyses were performed to analyse topological properties of the brain network. The analysis of variance showed significant group effects on several topological properties, including network strength, global efficiency and local efficiency. A progressive decrease trend for these metrics was found from non-prior-OHE to prior-OHE, compared with HC. Among the three groups, the regions with altered nodal efficiency were mainly distributed in the frontal and occipital cortices, paralimbic system and subcortical regions. The topological metrics, such as network strength and global efficiency, were correlated with PHES among cirrhotic patients. The cirrhotic patients developed structural brain connectome alterations; this is aggravated by prior OHE episode. Disrupted topological organization of the brain structural network may account for cognitive impairments related to prior OHE. (orig.)

  6. Identifying changes in the synaptic proteome of cirrhotic alcoholic superior frontal gyrus.

    Science.gov (United States)

    Etheridge, N; Mayfield, R D; Harris, R A; Dodd, P R

    2011-03-01

    Hepatic complications are a common side-effect of alcoholism. Without the detoxification capabilities of the liver, alcohol misuse induces changes in gene and protein expression throughout the body. A global proteomics approach was used to identify these protein changes in the brain. We utilised human autopsy tissue from the superior frontal gyrus (SFG) of six cirrhotic alcoholics, six alcoholics without comorbid disease, and six non-alcoholic non-cirrhotic controls. Synaptic proteins were isolated and used in two-dimensional differential in-gel electrophoresis coupled with mass spectrometry. Many expression differences were confined to one or other alcoholic sub-group. Cirrhotic alcoholics showed 99 differences in protein expression levels from controls, of which half also differed from non-comorbid alcoholics. This may reflect differences in disease severity between the sub-groups of alcoholics, or differences in patterns of harmful drinking. Alternatively, the protein profiles may result from differences between cirrhotic and non-comorbid alcoholics in subjects' responses to alcohol misuse. Ten proteins were identified in at least two spots on the 2D gel; they were involved in basal energy metabolism, synaptic vesicle recycling, and chaperoning. These post-translationally modified isoforms were differentially regulated in cirrhotic alcoholics, indicating a level of epigenetic control not previously observed in this disorder.

  7. Mortality Following Catheter Drainage Versus Thoracentesis in Cirrhotic Patients with Pleural Effusion.

    Science.gov (United States)

    Hung, Tsung-Hsing; Tseng, Chih-Wei; Tsai, Chen-Chi; Hsieh, Yu-Hsi; Tseng, Kuo-Chih; Tsai, Chih-Chun

    2017-04-01

    Pleural effusion is an abnormal collection of body fluids that may cause related morbidity or mortality in cirrhotic patients. There are insufficient data to determine the optimal method of drainage, for symptomatic relief in cirrhotic patients with pleural effusion. In this study, we compare the mortality outcomes of catheter drainage versus thoracentesis in cirrhotic patients. The National Health Insurance Database, derived from the Taiwan National Health Insurance Program, was used to identify cirrhotic patients with pleural effusion requiring drainage between January 1, 2007, and December 31, 2010. In all, 2556 cirrhotic patients with pleural effusion were selected for the study and divided into the two groups (n = 1278/group) after propensity score matching. The mean age was 61.0 ± 14.3 years, and 68.9% (1761/2556) were men. The overall 30-day mortality was 21.0% (538/2556) and was higher in patients treated with catheter drainage than those treated with thoracentesis (23.5 vs. 18.6%, respectively, P pleural effusion requiring drainage, catheter drainage is associated with higher mortality compared to thoracentesis.

  8. Interactive toxicity of chlorpyrifos and parathion in neonatal rats: Role of esterases in exposure sequence-dependent toxicity

    International Nuclear Information System (INIS)

    Kacham, R.; Karanth, S.; Baireddy, P.; Liu, J.; Pope, C.

    2006-01-01

    We previously reported that sequence of exposure to chlorpyrifos and parathion in adult rats can markedly influence toxic outcome. In the present study, we evaluated the interactive toxicity of chlorpyrifos (8 mg/kg, po) and parathion (0.5 mg/kg, po) in neonatal (7 days old) rats. Rats were exposed to the insecticides either concurrently or sequentially (separated by 4 h) and sacrificed at 4, 8, and 24 h after the first exposure for biochemical measurements (cholinesterase activity in brain, plasma, and diaphragm and carboxylesterase activity in plasma and liver). The concurrently-exposed group showed more cumulative lethality (15/24) than either of the sequential dosing groups. With sequential dosing, rats treated initially with chlorpyrifos prior to parathion (C/P) exhibited higher lethality (7/23) compared to those treated with parathion before chlorpyrifos (P/C; 1/24). At 8 h after initial dosing, brain cholinesterase inhibition was significantly greater in the C/P group (59%) compared to the P/C group (28%). Diaphragm and plasma cholinesterase activity also followed a relatively similar pattern of inhibition. Carboxylesterase inhibition in plasma and liver was relatively similar among the treatment groups across time-points. Similar sequence-dependent differences in brain cholinesterase inhibition were also noted with lower binary exposures to chlorpyrifos (2 mg/kg) and parathion (0.35 mg/kg). In vitro and ex vivo studies compared relative oxon detoxification of carboxylesterases (calcium-insensitive) and A-esterases (calcium-sensitive) in liver homogenates from untreated and insecticide pretreated rats. Using tissues from untreated rats, carboxylesterases detoxified both chlorpyrifos oxon and paraoxon, while A-esterases only detoxified chlorpyrifos oxon. With parathion pretreatment, A-esterases still detoxified chlorpyrifos oxon while liver from chlorpyrifos pretreated rats had little apparent effect on paraoxon. We conclude that while neonatal rats are less

  9. Sex-dependent effects of restraint on nociception and pituitary-adrenal hormones in the rat.

    Science.gov (United States)

    Aloisi, A M; Steenbergen, H L; van de Poll, N E; Farabollini, F

    1994-05-01

    The sex-dependent effects of acute restraint (RT) on nociceptive and pituitary-adrenal responses were investigated in the rat. In a first experiment, the effect of 30 min RT on pain sensitivity was evaluated through repeated use of the tail withdrawal test during and after treatment. RT induced an increase in the nociceptive threshold, i.e., analgesia, in males and females, but the duration and time-course of this effect varied between sexes. The latencies returned to approximately control values in females in the second half of RT, but in males they remained higher for the whole period of RT and immediately afterwards. Twenty-four hours later, males displayed longer latencies than controls in response to simple reexposure to the environment. In a second experiment, ACTH and corticosterone plasma levels were measured immediately after 15 or 30 min of RT. ACTH and corticosterone were higher in restrained animals than in controls after both periods of treatment, and in both sexes; however, females showed higher basal and stress corticosterone levels than males. The role played by corticosteroids in the nociceptive responses of the two sexes is discussed.

  10. Effects of chronic mild stress on the development of drug dependence in rats.

    Science.gov (United States)

    Papp, Mariusz; Gruca, Piotr; Lason-Tyburkiewicz, Magdalena; Litwa, Ewa; Willner, Paul

    2014-09-01

    There is high comorbidity between depression and addiction. Features of addiction relevant to depression have been studied extensively, but less is known about features of depression relevant to addiction. Here, we have studied the effects of chronic mild stress (CMS), a valid animal model of depression, on measures of physical and psychological dependence resulting from subchronic treatment of rats with three drugs of abuse that act through disparate neurobiological mechanisms: morphine, nicotine and diazepam. In animals not treated subchronically with drugs of abuse, CMS increased the withdrawal-like effects of the opiate antagonist naloxone, but not those of the nicotinic antagonist mecamylamine or the benzodiazepine antagonist flumazenil. In animals treated subchronically with drugs of abuse, CMS exacerbated, precipitated and conditioned withdrawal effects associated with all three antagonists. CMS also potentiated withdrawal-induced and cue-induced place aversions associated with all three antagonists. All of the effects of CMS were reversed by chronic treatment with the specific serotonin reuptake inhibitor citalopram. These results suggest that treatment of comorbid depression, although not a primary treatment for addiction, may facilitate other treatments for addiction, by decreasing the severity of withdrawal symptoms and the likelihood of relapse.

  11. Vasopressin-induced constriction of the isolated rat occipital artery is segment dependent.

    Science.gov (United States)

    Chelko, Stephen P; Schmiedt, Chad W; Lewis, Tristan H; Lewis, Stephen J; Robertson, Tom P

    2013-01-01

    Circulating factors delivered to the nodose ganglion (NG) by the occipital artery (OA) have been shown to affect vagal afferent activity, and thus the contractile state of the OA may influence blood flow to the NG. OA were isolated and bisected into proximal and distal segments relative to the external carotid artery. Bisection highlighted stark differences between maximal contractile responses and OA sensitivity. Specifically, maximum responses to vasopressin and the V1 receptor agonist were significantly higher in distal than proximal segments. Distal segments were significantly more sensitive to 5-hydroxytryptamine (5-HT) and the 5-HT2 receptor agonist than proximal segments. Angiotensin II (AT)2, V2 and 5-HT(1B/1D) receptor agonists did not elicit vascular responses. Additionally, AT1 receptor agonists elicited mild, yet not significantly different maximal responses between segments. The results of this study are consistent with contractile properties of rat OA being mediated via AT1, V1 and 5-HT2 receptors and dependent upon the OA segment. Furthermore, vasopressin-induced constriction of the OA, regardless of a bolus dose or a first and second concentration-response curve, retained this unique segmental difference. We hypothesize that these segmental differences may be important in the regulation of blood flow through the OA in health and disease. © 2013 S. Karger AG, Basel.

  12. Vasopressin-induced constriction of the isolated rat occipital artery is segment-dependent

    Science.gov (United States)

    Chelko, Stephen P.; Schmiedt, Chad W.; Lewis, Tristan H.; Lewis, Stephen J.; Robertson, Tom P.

    2014-01-01

    Background Circulating factors delivered to the nodose ganglion (NG) by the occipital artery (OA) have shown to affect vagal afferent activity, and thus the contractile state of the OA may influence blood flow to the NG. Methods OA were isolated and bisected into proximal and distal segments, relative to the external carotid artery. Results Bisection, highlighted stark differences between maximal contractile responses and OA sensitivity. Specifically, maximum responses to vasopressin and the V1 receptor agonist, were significantly higher in distal than proximal segments. Distal segments were significantly more sensitive to 5-HT and the 5-HT2 receptor agonist than proximal segments. AT2, V2 and 5-HT1B/1D receptor agonists did not elicit vascular responses. Additionally, AT1 receptor agonists elicited mild, yet not significantly different maximal responses between segments. Conclusion The results of this study are consistent with contractile properties of rat OA being mediated via AT1, V1 and 5-HT2 receptors, and are dependent upon the OA segment. Furthermore, vasopressin-induced constriction of the OA, regardless of a bolus dose or a first and second concentration response curve retained this unique segmental difference and therefore we hypothesize this may be a pathophysiological response in the regulation of blood flow through the OA. PMID:24192548

  13. Stimulus-dependent modulation of spontaneous low-frequency oscillations in the rat visual cortex.

    Science.gov (United States)

    Huang, Liangming; Liu, Yadong; Gui, Jianjun; Li, Ming; Hu, Dewen

    2014-08-06

    Research on spontaneous low-frequency oscillations is important to reveal underlying regulatory mechanisms in the brain. The mechanism for the stimulus modulation of low-frequency oscillations is not known. Here, we used the intrinsic optical imaging technique to examine stimulus-modulated low-frequency oscillation signals in the rat visual cortex. The stimulation was presented monocularly as a flashing light with different frequencies and intensities. The phases of low-frequency oscillations in different regions tended to be synchronized and the rhythms typically accelerated within a 30-s period after stimulation. These phenomena were confined to visual stimuli with specific flashing frequencies (12.5-17.5 Hz) and intensities (5-10 mA). The acceleration and synchronization induced by the flashing frequency were more marked than those induced by the intensity. These results show that spontaneous low-frequency oscillations can be modulated by parameter-dependent flashing lights and indicate the potential utility of the visual stimulus paradigm in exploring the origin and function of low-frequency oscillations.

  14. Electrophysiological characterization of texture information slip-resistance dependent in the rat vibrissal nerve

    Directory of Open Access Journals (Sweden)

    Albarracín Ana L

    2011-04-01

    Full Text Available Abstract Background Studies in tactile discrimination agree that rats are able to learn a rough-smooth discrimination task by actively touching (whisking objects with their vibrissae. In particular, we focus on recent evidence of how neurons at different levels of the sensory pathway carry information about tactile stimuli. Here, we analyzed the multifiber afferent discharge of one vibrissal nerve during active whisking. Vibrissae movements were induced by electrical stimulation of motor branches of the facial nerve. We used sandpapers of different grain size as roughness discrimination surfaces and we also consider the change of vibrissal slip-resistance as a way to improve tactile information acquisition. The amplitude of afferent activity was analyzed according to its Root Mean Square value (RMS. The comparisons among experimental situation were quantified by using the information theory. Results We found that the change of the vibrissal slip-resistance is a way to improve the roughness discrimination of surfaces. As roughness increased, the RMS values also increased in almost all cases. In addition, we observed a better discrimination performance in the retraction phase (maximum amount of information. Conclusions The evidence of amplitude changes due to roughness surfaces and slip-resistance levels allows to speculate that texture information is slip-resistance dependent at peripheral level.

  15. Calcium release-dependent inactivation precedes formation of the tubular system in developing rat cardiac myocytes.

    Science.gov (United States)

    Macková, Katarina; Zahradníková, Alexandra; Hoťka, Matej; Hoffmannová, Barbora; Zahradník, Ivan; Zahradníková, Alexandra

    2017-12-01

    Developing cardiac myocytes undergo substantial structural and functional changes transforming the mechanism of excitation-contraction coupling from the embryonic form, based on calcium influx through sarcolemmal DHPR calcium channels, to the adult form, relying on local calcium release through RYR calcium channels of sarcoplasmic reticulum stimulated by calcium influx. We characterized day-by-day the postnatal development of the structure of sarcolemma, using techniques of confocal fluorescence microscopy, and the development of the calcium current, measured by the whole-cell patch-clamp in isolated rat ventricular myocytes. We characterized the appearance and expansion of the t-tubule system and compared it with the appearance and progress of the calcium current inactivation induced by the release of calcium ions from sarcoplasmic reticulum as structural and functional measures of direct DHPR-RYR interaction. The release-dependent inactivation of calcium current preceded the development of the t-tubular system by several days, indicating formation of the first DHPR-RYR couplons at the surface sarcolemma and their later spreading close to contractile myofibrils with the growing t-tubules. Large variability of both of the measured parameters among individual myocytes indicates uneven maturation of myocytes within the growing myocardium.

  16. Stoichiometry of H+ ejection during respiration-dependent accumulation of Ca2+ by rat liver mitochondria.

    Science.gov (United States)

    Brand, M D; Chen, C H; Lehninger, A L

    1976-02-25

    We have investigated the energy-dependent uptake of Ca2+ by rat liver mitochondria with succinate as respiratory substrate with rotenone added to block NAD-linked electron transport. In the presence of 3-hydroxybutyric or other permeant monocarboxylic acids Ca2+ was taken up to extents approaching those seen in the presence of phosphate. The quantitative relationship between cation and anion uptake was determined from the slope of a plot of 3-hydroxybutyrate uptake against Ca2+ uptake, a method which allowed determination of the stoichiometry without requiring ambiguous corrections for early nonenergized or nonstoichiometric binding events. This procedure showed that 2 molecules of 3-hydroxtbutyrate were accumulated with each Ca2+ ion. Under these conditions close to 2 Ca2+ ions and 4 molecules of 3-hydroxybutyrate were accumulated per pair of electrons per energy-conserving site of the respiratory chain. Since 3-hydroxybutyrate must be protonated to pass the membrane as the undissociated free acid, it is concluded that 4 protons were ejected (and subsequently reabsorbed) per pair of electrons per energy-conserving site, in contrast to the value 2.0 postulated by the chemiosmotic hypothesis.

  17. Recent memory for socially transmitted food preferences in rats does not depend on the hippocampus.

    Science.gov (United States)

    Thapa, Rajat; Sparks, Fraser T; Hanif, Wahab; Gulbrandsen, Tine; Sutherland, Robert J

    2014-10-01

    The standard model of systems consolidation holds that the hippocampus (HPC) is involved only in the initial storage and retrieval of a memory. With time hippocampal-neocortical interactions slowly strengthen the neocortical memory, ultimately enabling retrieval of the memory without the HPC. Key support for this idea comes from experiments measuring memory recall in the socially-transmitted food preference (STFP) task in rats. HPC damage within a day or two of STFP learning can abolish recall, but similar damage five or more days after learning has no effect. We hypothesize that disruption of cellular consolidation outside the HPC could contribute to the amnesia with recent memories, perhaps playing a more important role than the loss of HPC. This view predicts that intraHPC infusion of Tetrodotoxin (TTX), which can block conduction of action potentials from the lesion sites, will block the retrograde amnesia in the STFP task. Here we confirm the previously reported retrograde amnesia with neurotoxic HPC damage within the first day after learning, but show that co-administration of TTX with the neurotoxin blocks the retrograde amnesia despite very extensive HPC damage. These results indicate that HPC damage disrupts cellular consolidation of the recent memory elsewhere; STFP memory may not ever depend on the HPC. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. Comparison of vitamin D deficiency and magnitude of severity of vitamin D deficiency in cirrhotic and non-cirrhotic patients with chronic hepatitis C in a tertiary care hospital Rawalpindi, Pakistan

    International Nuclear Information System (INIS)

    Hamid, S.; Faheem, M.; Ambreen, S.; Tirmizi, A.; Umar, M.

    2017-01-01

    Objective: To determine Vitamin D deficiency in both cirrhotic and non-cirrhotic patients with chronic hepatitis C (CHC). Methodology: We conducted a cross-sectional study at Centre for Liver and Digestive Diseases (CLD), Holy Family Hospital, Rawalpindi, Pakistan from August 2015 to February 2016 and included 120 Patients with CHC with or without cirrhosis. Two groups were formed and vitamin D levels were measured and level of severity was assessed. Results: Out of 120 patients, 94(78.3%) patients had Vitamin D deficiency. 63(100%) cirrhotic patients and 31 54.4%) non cirrhotic patients had Vitamin D deficiency. In cirrhotic patients, 26(41.3%) had mild and 36(58.7%) had moderate Vitamin D deficiency while in non-cirrhotic patients 25(43.9%) had mild and 6(10.5%) had moderate deficiency. No patient with severe Vitamin D deficiency was observed. Conclusion: Most of the patients infected with CHC suffer from vitamin D deficiency. This was observed more in cirrhotic patients than non-cirrhotic patients. Moreover, positive correlation was observed among vitamin D deficiency and stage of fibrosis. (author)

  19. Effects of BDNF receptor antagonist on the severity of physical and psychological dependence, morphine-induced locomotor sensitization and the ventral tegmental area-nucleus accumbens BDNF levels in morphine- dependent and withdrawn rats.

    Science.gov (United States)

    Khalil-Khalili, Masoumeh; Rashidy-Pour, Ali; Bandegi, Ahmad Reza; Yousefi, Behpoor; Jorjani, Hassan; Miladi-Gorji, Hossein

    2018-03-06

    This study examined the effects of systemic administration of the TrkB receptor antagonist (ANA-12) on the severity of physical and psychological dependence and morphine-induced locomotor sensitization, the ventral tegmental area (VTA)-nucleus accumbens (NAc) BDNF levels in morphine-dependent and withdrawn rats. Rats were injected with bi-daily doses (10 mg/kg, at 12 h intervals) of morphine for 10 days. Then, rats were tested for naloxone-precipitated morphine withdrawal signs, the anxiety (the elevated plus maze-EPM) after the last morphine injection and injection of ANA12 (ip). Also, morphine-induced locomotor sensitization was evaluated after morphine challenge followed by an injection of ANA-12 in morphine-withdrawn rats. The VTA-NAc BDNF levels were assessed in morphine-dependent and withdrawn rats. The overall Gellert-Holtzman score was significantly higher in morphine-dependent rats receiving ANA-12 than in those receiving saline. Also, the percentage of time spent in the open arms in control and morphine-dependent rats receiving ANA-12 were higher compared to the Cont/Sal and D/Sal rats, respectively. There was no significant difference in the locomotor activity and the VTA-NAc BDNF levels between D/Sal/morphine and D/ANA-12/morphine groups after morphine withdrawal. We conclude that the systemic administration of ANA-12 exacerbates the severity of physical dependence on morphine and partially attenuates the anxiety-like behavior in morphine-dependent rats. However, ANA-12 did not affect morphine-induced locomotor sensitization and the VTA-NAc BDNF levels in morphine-dependent and withdrawn rats. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Oxygen dependency of epidermal growth factor receptor binding and DNA synthesis of rat hepatocytes

    International Nuclear Information System (INIS)

    Hirose, Tetsuro; Terajima, Hiroaki; Yamauchi, Akira

    1997-01-01

    Background/Aims: Changes in oxygen availability modulate replicative responses in several cell types, but the effects on hepatocyte replication remain unclear. We have studied the effects of transient nonlethal hypoxia on epidermal growth factor receptor binding and epidermal growth factor-induced DNA synthesis of rat hepatocytes. Methods: Lactate dehydrogenase activity in culture supernatant, intracellular adenosine triphosphate content, 125 I-epidermal growth factor specific binding, epidermal growth factor receptor protein expression, and 3 H-thymidine incorporation were compared between hepatocytes cultured in hypoxia and normoxia. Results: Hypoxia up to 3 h caused no significant increase in lactate dehydrogenase activity in the culture supernatant, while intracellular adenosine triphosphate content decreased time-dependently and was restored to normoxic levels by reoxygenation (nonlethal hypoxia). Concomitantly, 125 I-epidermal growth factor specific binding to hepatocytes decreased time-dependently (to 54.1% of normoxia) and was restored to control levels by reoxygenation, although 125 I-insulin specific binding was not affected. The decrease in 125 I-epidermal growth factor specific binding was explained by the decrease in the number or available epidermal growth factor receptors (21.37±3.08 to 12.16±1.42 fmol/10 5 cells), while the dissociation constant of the receptor was not affected. The change in the number of available receptors was not considered to be due to receptor degradation-resynthesis, since immuno-detection of the epidermal growth factor receptor revealed that the receptor protein expression did not change during hypoxia and reoxygenation, and since neither actinomycin D nor cycloheximide affected the recovery of 125 I-epidermal growth factor binding by reoxygenation. Inhibition of epidermal growth factor-induced DNA synthesis after hypoxia (to 75.4% of normoxia by 3 h hypoxia) paralleled the decrease in 125 I-epidermal growth factor binding

  1. Temperature dependence and GABA modulation of [3H]triazolam binding in the rat brain

    International Nuclear Information System (INIS)

    Earle, M.E.; Concas, A.; Wamsley, J.K.; Yamamura, H.I.

    1987-01-01

    The hypnotic triazolam (TZ), a triazolobenzodiazepine displays a short physiological half life and has been used for the treatment of insomnia related to anxiety states. The authors major objectives were the direct measurement of the temperature dependence and the gamma-aminobutyric acid (GABA) effect of [ 3 H]TZ binding in the rat brain. Saturation studies showed a shift to lower affinity with increasing temperatures (K/sub d/ = 0.27 +/- 08 nM at 0 0 C; K/sub d/ = 1.96 +/- 0.85 nM at 37 0 C) while the B/sub max/ values remained unchanged (1220 +/- 176 fmoles/mg protein at 0 0 C and 1160 +/- 383 fmoles/mg protein at 37 0 C). Saturation studies of [ 3 H]TZ binding in the presence or absence of GABA (100μM) showed a GABA-shift. At 0 0 C the K/sub d/ values were (K/sub d/ = 0.24 +/- 0.03 nM/-GABA; K/sub d/ = 0.16 +/- 0.04/+GABA) and at 37 0 C the K/sub d/ values were (K/sub d/ = 1.84 +/- 0.44 nM/-GABA; K/sub d/ = 0.95 +/- 0.29 nM/+GABA). In contrast to reported literature, the authors findings show that TZ interacts with benzodiazepine receptors with a temperature dependence and GABA-shift consistent with predicted behavior for benzodiazepine agonists. 20 references, 3 tables

  2. Leptin-dependent neurotoxicity via induction of apoptosis in adult rat neural stem cells

    Directory of Open Access Journals (Sweden)

    Stéphanie eSEGURA

    2015-09-01

    Full Text Available Adipocyte-derived hormone leptin has been recently implicated in the control of neuronal plasticity. To explore whether modulation of adult neurogenesis may contribute to leptin control of neuronal plasticity, we used the neurosphere assay of neural stem cells derived from the adult rat subventricular zone (SVZ. Endogenous expression of specific leptin receptor (ObRb transcripts, as revealed by RT-PCR, is associated with activation of both ERK and STAT-3 pathways via phosphorylation of the critical ERK/STAT-3 amino acid residues upon addition of leptin to neurospheres. Furthermore, leptin triggered withdrawal of neural stem cells from the cell cycle as monitored by Ki67 labelling. This effect was blocked by pharmacological inhibition of ERK activation thus demonstrating that ERK mediates leptin effects on neural stem cell expansion. Leptin-dependent withdrawal of neural stem cells from the cell cycle was associated with increased apoptosis, as detected by TUNEL, which was preceded by cyclin D1 induction. Cyclin D1 was indeed extensively colocalized with TUNEL-positive apoptotic cells. Cyclin-D1 silencing by specific shRNA prevented leptin-induced decrease of the cell number per neurosphere thus pointing to the causal relationship between leptin actions on apoptosis and cyclin D1 induction. Leptin target cells in SVZ neurospheres were identified by double TUNEL/phenotypic marker immunocytofluorescence as differentiating neurons mostly. The inhibition of neural stem cell expansion via ERK/cyclin D1-triggered apoptosis defines novel biological action of leptin which may be involved in adiposity-dependent neurotoxicity.

  3. Feeding blueberry diets to young rats dose-dependently inhibits bone resorption through suppression of RANKL in stromal cells.

    Directory of Open Access Journals (Sweden)

    Jian Zhang

    Full Text Available Previous studies have demonstrated that weanling rats fed AIN-93G semi-purified diets supplemented with 10% whole blueberry (BB powder for two weeks beginning on postnatal day 21 (PND21 significantly increased bone formation at PND35. However, the minimal level of dietary BB needed to produce these effects is, as yet, unknown. The current study examined the effects of three different levels of BB diet supplementation (1, 3, and 5% for 35 days beginning on PND25 on bone quality, and osteoclastic bone resorption in female rats. Peripheral quantitative CT scan (pQCT of tibia, demonstrated that bone mineral density (BMD and content (BMC were dose-dependently increased in BB-fed rats compared to controls (P<0.05. Significantly increased bone mass after feeding 5% BB extracts was also observed in a TEN (total enteral nutrition rat model in which daily caloric and food intake was precisely controlled. Expression of RANKL (receptor activator of nuclear factor-κB ligand a protein essential for osteoclast formation was dose-dependently decreased in the femur of BB animals. In addition, expression of PPARγ (peroxisome proliferator-activated receptor γ which regulates bone marrow adipogenesis was suppressed in BB diet rats compared to non-BB diet controls. Finally, a set of in vitro cell cultures revealed that the inhibitory effect of BB diet rat serum on RANKL expression was more profound in mesenchymal stromal cells compared to its effect on mature osteoblasts, pre-adipocytes and osteocytes. These results suggest that inhibition of bone resorption may contribute to increased bone mass during early development after BB consumption.

  4. Early-life exposure to fibroblast growth factor-2 facilitates context-dependent long-term memory in developing rats.

    Science.gov (United States)

    Graham, Bronwyn M; Richardson, Rick

    2010-06-01

    Fibroblast growth factor-2 (FGF2) is a potent neurotrophic factor that is involved in brain development and the formation of long-term memory. It has recently been shown that acute FGF2, administered at the time of learning, enhances long-term memory for contextual fear conditioning as well as extinction of conditioned fear in developing rats. As other research has shown that administering FGF2 on the first day of life leads to long-term morphological changes in the hippocampus, in the present study we investigated whether early life exposure to FGF2 affects contextual fear conditioning, and renewal following extinction, later in life. Experiment 1 demonstrated that a single injection of FGF2 on Postnatal Day (PND) 1 did not lead to any detectable changes in contextual fear conditioning in PND 16 or PND 23 rats. Experiments 2 and 3 demonstrated that 5 days of injections of FGF2 (from PND 1-5) facilitated contextual fear conditioning in PND 16 and PND 23 rats. Experiment 4 demonstrated that the observed facilitation of memory was not due to FGF2 increasing rats' sensitivity to foot shock. Experiment 5 showed that early life exposure to FGF2 did not affect learning about a discrete conditioned stimulus, but did allow PND 16 rats to use contextual information in more complex ways, leading to context-dependent extinction of conditioned fear. These results further implicate FGF2 as a critical signal involved in the development of learning and memory.

  5. TNF-α- Mediated-p38-Dependent Signaling Pathway Contributes to Myocyte Apoptosis in Rats Subjected to Surgical Trauma

    Directory of Open Access Journals (Sweden)

    Huaxing Wu

    2015-03-01

    Full Text Available Background: The accumulation of cytokines in the plasma after trauma can induce myocyte apoptosis. We aimed to identify which cytokine(s present in the plasma responsible for myocyte apoptosis, and delineated the signal transduction mechanism in rats subjected to surgical trauma. Methods: Rats were randomized into two groups: control and trauma groups, which was divided into five subgroups: posttraumatic 0, 3, 6, 12, and 24 h subgroups. Cardiomyocytes isolated from traumatized rats were incubated with one of the factors for 12 h (normal plasma; Cytomix; TNF-α; IL-1β; IFN-γ; trauma plasma; anti-TNF-α antibody; SB203580. Myocyte apoptosis, cytokine levels, and MAPKs activation, as the primary experimental outcomes, were measured by TUNEL, flow cytometry, ELISA and Western blot, respectively. Results: Myocyte apoptosis was induced by surgical trauma during the early stage after trauma. Accompanying this change, plasma TNF-α, IL-1β, and IFN-γ levels were elevated in traumatized rats. Incubation of traumatized cardiomyocytes with cytomix or TNF-α alone induced myocyte apoptosis, and increased the activation of p38 and ERK1/2. Myocyte apoptosis and p38 activation were elevated in traumatized cardiomyocytes with trauma plasma, and these increases were partly abolished by anti-TNF-α antibody or SB203580. Conclusion: Our study demonstrated that there exists the TNF-α-mediated-p38-dependent signaling pathway that contributed to posttraumatic myocyte apoptosis of rats undergoing surgical trauma.

  6. Androgen-dependent and independent process of bone formation in the distal segment of Os penis in the rat.

    Science.gov (United States)

    Murakami, R; Izumi, K; Yamaoka, I

    1995-11-01

    The distal segment of the os penis of the rat develops as a fibrocartilage which is replaced with non-lamellar bone by endochondral ossification after puberty. Development of the fibrocartilage and its calcification have been shown to be induced by androgens, but androgen-dependency of the endochondral ossification has not been studied in detail. In the present study, immature male rats of various ages were castrated and the ossification of the fibrocartilage of os penis was examined. In rats castrated at 6 weeks, when the fibrocartilage was scarcely calcified, ossification did not occur even at 24 weeks. When the castrated rats were treated with testosterone, ossification started before 12 weeks of age. In rats castrated at 8 weeks, when the fibrocartilage was heavily calcified, endochondral ossification was observed in some of the animals (5/7) at 24 weeks of age. The results of this study indicate that once the fibrocartilage is calcified, the endochondral ossification can take place without androgen, although the androgen can promote the process of ossification.

  7. Sex-dependent effects of high-fat-diet feeding on rat pancreas oxidative stress.

    Science.gov (United States)

    Gómez-Pérez, Yolanda; Gianotti, Magdalena; Lladó, Isabel; Proenza, Ana M

    2011-07-01

    The objective of the study was to investigate whether sex differences in oxidative stress-associated insulin resistance previously reported in rats could be attributed to a possible sex dimorphism in pancreas redox status. Fifteen-month-old male and female Wistar rats were fed a control diet or a high-fat diet for 14 weeks. Serum glucose, lipids, and hormone levels were measured. Insulin immunohistochemistry and morphometric analysis of islets were performed. Pancreas triglyceride content, oxidative damage, and antioxidant enzymatic activities were determined. Lipoprotein lipase, hormone-sensitive lipase, and uncoupling protein 2 (UCP2) levels were also measured. Male rats showed a more marked insulin resistance profile than females. In control female rats, pancreas Mn-superoxide dismutase activity and UCP2 levels were higher, and oxidative damage was lower compared with males. High-fat-diet feeding decreased pancreas triglyceride content in female rats and UCP2 levels in male rats. High-fat-diet female rats showed larger islets than both their control and sex counterparts. These results confirm the existence of a sex dimorphism in pancreas oxidative status in both control and high-fat-diet feeding situations, with female rats showing higher protection against oxidative stress, thus maintaining pancreatic function and contributing to a lower risk of insulin resistance.

  8. Voxel Scale Complex Networks of Functional Connectivity in the Rat Brain: Neurochemical State Dependence of Global and Local Topological Properties

    Directory of Open Access Journals (Sweden)

    Adam J. Schwarz

    2012-01-01

    Full Text Available Network analysis of functional imaging data reveals emergent features of the brain as a function of its topological properties. However, the brain is not a homogeneous network, and the dependence of functional connectivity parameters on neuroanatomical substrate and parcellation scale is a key issue. Moreover, the extent to which these topological properties depend on underlying neurochemical changes remains unclear. In the present study, we investigated both global statistical properties and the local, voxel-scale distribution of connectivity parameters of the rat brain. Different neurotransmitter systems were stimulated by pharmacological challenge (d-amphetamine, fluoxetine, and nicotine to discriminate between stimulus-specific functional connectivity and more general features of the rat brain architecture. Although global connectivity parameters were similar, mapping of local connectivity parameters at high spatial resolution revealed strong neuroanatomical dependence of functional connectivity in the rat brain, with clear differentiation between the neocortex and older brain regions. Localized foci of high functional connectivity independent of drug challenge were found in the sensorimotor cortices, consistent with the high neuronal connectivity in these regions. Conversely, the topological properties and node roles in subcortical regions varied with neurochemical state and were dependent on the specific dynamics of the different functional processes elicited.

  9. Electrophysiological characterization of activation state-dependent Ca(v)2 channel antagonist TROX-1 in spinal nerve injured rats.

    Science.gov (United States)

    Patel, R; Rutten, K; Valdor, M; Schiene, K; Wigge, S; Schunk, S; Damann, N; Christoph, T; Dickenson, A H

    2015-06-25

    Prialt, a synthetic version of Ca(v)2.2 antagonist ω-conotoxin MVIIA derived from Conus magus, is the first clinically approved voltage-gated calcium channel blocker for refractory chronic pain. However, due to the narrow therapeutic window and considerable side effects associated with systemic dosing, Prialt is only administered intrathecally. N-triazole oxindole (TROX-1) is a novel use-dependent and activation state-selective small-molecule inhibitor of Ca(v)2.1, 2.2 and 2.3 calcium channels designed to overcome the limitations of Prialt. We have examined the neurophysiological and behavioral effects of blocking calcium channels with TROX-1. In vitro, TROX-1, in contrast to state-independent antagonist Prialt, preferentially inhibits Ca(v)2.2 currents in rat dorsal root ganglia (DRG) neurons under depolarized conditions. In vivo electrophysiology was performed to record from deep dorsal horn lamina V/VI wide dynamic range neurons in non-sentient spinal nerve-ligated (SNL) and sham-operated rats. In SNL rats, spinal neurons exhibited reduced responses to innocuous and noxious punctate mechanical stimulation of the receptive field following subcutaneous administration of TROX-1, an effect that was absent in sham-operated animals. No effect was observed on neuronal responses evoked by dynamic brushing, heat or cold stimulation in SNL or sham rats. The wind-up response of spinal neurons following repeated electrical stimulation of the receptive field was also unaffected. Spinally applied TROX-1 dose dependently inhibited mechanically evoked neuronal responses in SNL but not sham-operated rats, consistent with behavioral observations. This study confirms the pathological state-dependent actions of TROX-1 through a likely spinal mechanism and reveals a modality selective change in calcium channel function following nerve injury. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  10. Elements in normal and cirrhotic human liver. Potassium, iron, copper, zinc and bromine measured by X-ray fluorescence spectrometry

    DEFF Research Database (Denmark)

    Laursen, J.; Milman, N.; Leth, Peter Mygind

    1990-01-01

    Various elements (K, Fe, Cu, Zn, Br) were measured by X-ray flourescence spectrometry in cellular and connective tissue fractions of normal and cirrhotic liver samples obtained at autopsy. Normal livers: 32 subjects (16 males, 16 females) median age 69 years. Cirrhotic livers: 14 subjects (13 mal...

  11. Leucine metabolism in cirrhotic patients with hepatic encephalopathy

    International Nuclear Information System (INIS)

    McGhee, A.S.

    1985-01-01

    The purpose of this study was to determine whether increased oxidation of or protein synthesis requiring leucine occurs in cirrhotic patients. Five control subjects and four subjects with cirrhosis were equilibrated on a baseline diet (0.6 g protein per kg ideal body weight [IBW]) with sufficient nonprotein calories to preclude negative nitrogen balance. An additional four patients were equilibrated on the same type of diet with a higher protein level (0.75 g per kg IBW). Control subjects and the patients were then studied during continuous infusion of L-[ 15 N, 1- 13 C] leucine in the fasted state and, in the fed state, with a Propac diet which had the same distribution of energy nutrients as the baseline diets. Plasma levels of L-[ 15 N, 1- 13 C], L-[1- 13 C] and L-[ 15 N] leucine were measured during isotopic steady state by gas chromatography-mass spectrometry and fractional excretion of 13 CO 2 in breath samples were analyzed by isotopic ratio mass spectrometry. During the fasted and fed states leucine metabolism was measured to quantitate rates of nitrogen flux (Q/sub N/), carbon flux (Q/sub c/) and oxidation to carbon dioxide and water (C). From these measured values, proteins breakdown (B), protein synthesis (S), deamination (X 0 ) and reamination (X/sub N/) were calculated. The results showed that protein synthesis and leucine metabolism were identical in controls and patients when both were fed a diet with 0.6 g protein/kg IBW and maintenance level of nonprotein calories. The data also showed that leucine metabolism can be quantitatively and reproducibly measured in subjects with cirrhosis

  12. Low-dose sevoflurane promotes hippocampal neurogenesis and facilitates the development of dentate gyrus-dependent learning in neonatal rats.

    Science.gov (United States)

    Chen, Chong; Shen, Feng-Yan; Zhao, Xuan; Zhou, Tao; Xu, Dao-Jie; Wang, Zhi-Ru; Wang, Ying-Wei

    2015-01-01

    Huge body of evidences demonstrated that volatile anesthetics affect the hippocampal neurogenesis and neurocognitive functions, and most of them showed impairment at anesthetic dose. Here, we investigated the effect of low dose (1.8%) sevoflurane on hippocampal neurogenesis and dentate gyrus-dependent learning. Neonatal rats at postnatal day 4 to 6 (P4-6) were treated with 1.8% sevoflurane for 6 hours. Neurogenesis was quantified by bromodeoxyuridine labeling and electrophysiology recording. Four and seven weeks after treatment, the Morris water maze and contextual-fear discrimination learning tests were performed to determine the influence on spatial learning and pattern separation. A 6-hour treatment with 1.8% sevoflurane promoted hippocampal neurogenesis and increased the survival of newborn cells and the proportion of immature granular cells in the dentate gyrus of neonatal rats. Sevoflurane-treated rats performed better during the training days of the Morris water maze test and in contextual-fear discrimination learning test. These results suggest that a subanesthetic dose of sevoflurane promotes hippocampal neurogenesis in neonatal rats and facilitates their performance in dentate gyrus-dependent learning tasks. © The Author(s) 2015.

  13. Low-Dose Sevoflurane Promotes Hippocampal Neurogenesis and Facilitates the Development of Dentate Gyrus-Dependent Learning in Neonatal Rats

    Directory of Open Access Journals (Sweden)

    Chong Chen

    2015-04-01

    Full Text Available Huge body of evidences demonstrated that volatile anesthetics affect the hippocampal neurogenesis and neurocognitive functions, and most of them showed impairment at anesthetic dose. Here, we investigated the effect of low dose (1.8% sevoflurane on hippocampal neurogenesis and dentate gyrus-dependent learning. Neonatal rats at postnatal day 4 to 6 (P4–6 were treated with 1.8% sevoflurane for 6 hours. Neurogenesis was quantified by bromodeoxyuridine labeling and electrophysiology recording. Four and seven weeks after treatment, the Morris water maze and contextual-fear discrimination learning tests were performed to determine the influence on spatial learning and pattern separation. A 6-hour treatment with 1.8% sevoflurane promoted hippocampal neurogenesis and increased the survival of newborn cells and the proportion of immature granular cells in the dentate gyrus of neonatal rats. Sevoflurane-treated rats performed better during the training days of the Morris water maze test and in contextual-fear discrimination learning test. These results suggest that a subanesthetic dose of sevoflurane promotes hippocampal neurogenesis in neonatal rats and facilitates their performance in dentate gyrus-dependent learning tasks.

  14. Effect of agmatine on the development of morphine dependence in rats: potential role of cAMP system

    Science.gov (United States)

    Aricioglu, Feyza; Means, Andrea; Regunathan, Soundar

    2010-01-01

    Agmatine is an endogenous amine derived from arginine that potentiates morphine analgesia and blocks symptoms of naloxone-precipitated morphine withdrawal in rats. In this study, we sought to determine whether treatment with agmatine during the development of morphine dependence inhibits the withdrawal symptoms and that the effect is mediated by cAMP system. Exposure of rats to morphine for 7 days resulted in marked naloxone-induced withdrawal symptoms and agmatine treatment along with morphine significantly decreasing the withdrawal symptoms. The levels of cAMP were markedly increased in morphine-treated rat brain slices when incubated with naloxone and this increase was significantly reduced in rats treated with morphine and agmatine. The induction of tyrosine hydroxylase after morphine exposure was also reduced in locus coeruleus when agmatine was administered along with morphine. We conclude that agmatine reduces the development of dependence to morphine and that this effect is probably mediated by the inhibition of cAMP signaling pathway during chronic morphine exposure. PMID:15541421

  15. Time-Dependent Expression Profiles of microRNAs and mRNAs in Rat Milk Whey

    Science.gov (United States)

    Izumi, Hirohisa; Kosaka, Nobuyoshi; Shimizu, Takashi; Sekine, Kazunori; Ochiya, Takahiro; Takase, Mitsunori

    2014-01-01

    Functional RNAs, such as microRNA (miRNA) and mRNA, are present in milk, but their roles are unknown. To clarify the roles of milk RNAs, further studies using experimental animals such as rats are needed. However, it is unclear whether rat milk also contains functional RNAs and what their time dependent expression profiles are. Thus, we prepared total RNA from whey isolated from rat milk collected on days 2, 9, and 16 postpartum and analyzed using microarrays and quantitative PCR. The concentration of RNA in colostrum whey (day 2) was markedly higher than that in mature milk whey (days 9 and 16). Microarray analysis detected 161 miRNAs and 10,948 mRNA transcripts. Most of the miRNAs and mRNA transcripts were common to all tested milks. Finally, we selected some immune- and development-related miRNAs and mRNAs, and analysed them by quantitative PCR (in equal sample volumes) to determine their time-dependent changes in expression in detail. Some were significantly more highly expressed in colostrum whey than in mature milk whey, but some were expressed equally. And mRNA expression levels of some cytokines and hormones did not reflect the protein levels. It is still unknown whether RNAs in milk play biological roles in neonates. However, our data will help guide future in vivo studies using experimental animals such as rats. PMID:24533154

  16. The Eag domain regulates the voltage-dependent inactivation of rat Eag1 K+ channels.

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    Ting-Feng Lin

    Full Text Available Eag (Kv10 and Erg (Kv11 belong to two distinct subfamilies of the ether-à-go-go K+ channel family (KCNH. While Erg channels are characterized by an inward-rectifying current-voltage relationship that results from a C-type inactivation, mammalian Eag channels display little or no voltage-dependent inactivation. Although the amino (N-terminal region such as the eag domain is not required for the C-type inactivation of Erg channels, an N-terminal deletion in mouse Eag1 has been shown to produce a voltage-dependent inactivation. To further discern the role of the eag domain in the inactivation of Eag1 channels, we generated N-terminal chimeras between rat Eag (rEag1 and human Erg (hERG1 channels that involved swapping the eag domain alone or the complete cytoplasmic N-terminal region. Functional analyses indicated that introduction of the homologous hERG1 eag domain led to both a fast phase and a slow phase of channel inactivation in the rEag1 chimeras. By contrast, the inactivation features were retained in the reverse hERG1 chimeras. Furthermore, an eag domain-lacking rEag1 deletion mutant also showed the fast phase of inactivation that was notably attenuated upon co-expression with the rEag1 eag domain fragment, but not with the hERG1 eag domain fragment. Additionally, we have identified a point mutation in the S4-S5 linker region of rEag1 that resulted in a similar inactivation phenotype. Biophysical analyses of these mutant constructs suggested that the inactivation gating of rEag1 was distinctly different from that of hERG1. Overall, our findings are consistent with the notion that the eag domain plays a critical role in regulating the inactivation gating of rEag1. We propose that the eag domain may destabilize or mask an inherent voltage-dependent inactivation of rEag1 K+ channels.

  17. Chronic intracerebroventricular morphine and lactation in rats: dependence and tolerance in relation to oxytocin neurones.

    Science.gov (United States)

    Rayner, V C; Robinson, I C; Russell, J A

    1988-02-01

    1. Acutely, opioids inhibit oxytocin secretion. To study the responses of oxytocin neurones during chronic opioid exposure, forty-five lactating rats were infused continuously from a subcutaneous osmotically driven mini-pump via a lateral cerebral ventricle with morphine sulphate solution from day 2 post-partum for 5-7 days; the infusion rate was increased 2- or 2.5-fold each 40 h from 10 micrograms/h initially up to 50 micrograms/h; controls were infused with vehicle (1 microliter/h, twenty-eight rats) or were untreated (eight rats). 2. Maternal behaviour was disrupted in 27% of the morphine-treated rats; in rats that remained maternal morphine did not affect body weight or water intake but increased rectal temperature by 0.82 +/- 0.14 degrees C (mean +/- S.E.M.) across the first 4 days. 3. Weight gain of the litters of maternal morphine-treated rats was reduced by 32% during 7 days, predominantly in the first day of treatment when milk transfer was also reduced. Observation of pup behaviour during suckling showed decreased frequency of milk ejections on only the second day of morphine treatment. Plasma concentration of prolactin after 6 days was similar in maternal morphine-treated and control rats, but reduced by 90% in non-maternal morphine-treated rats, indicating normal control of prolactin secretion by suckling in morphine-treated rats. 4. Oxytocin and vasopressin contents, measured by radioimmunoassay, in the supraoptic and paraventricular nuclei and in the neurohypophysis were similar between fourteen maternal morphine-treated, twelve vehicle-treated and eight untreated lactating rats; thus exposure to morphine did not involve increased production and storage of oxytocin. 5. Distribution of [3H]morphine infused intracerebroventricularly into six virgin female rats for 6 days was measured by scintillation counting of tissue extracts. Morphine concentration in the hypothalamus and neurohypophysis was 2.7 and 12.8 micrograms/g, respectively, and in blood

  18. Clinical utility of breath ammonia for evaluation of ammonia physiology in healthy and cirrhotic adults

    Science.gov (United States)

    Spacek, Lisa A; Mudalel, Matthew; Tittel, Frank; Risby, Terence H; Solga, Steven F

    2016-01-01

    Blood ammonia is routinely used in clinical settings to assess systemic ammonia in hepatic encephalopathy and urea cycle disorders. Despite its drawbacks, blood measurement is often used as a comparator in breath studies because it is a standard clinical test. We sought to evaluate sources of measurement error and potential clinical utility of breath ammonia compared to blood ammonia. We measured breath ammonia in real time by quartz enhanced photoacoustic spectrometry and blood ammonia in 10 healthy and 10 cirrhotic participants. Each participant contributed 5 breath samples and blood for ammonia measurement within 1 h. We calculated the coefficient of variation (CV) for 5 breath ammonia values, reported medians of healthy and cirrhotic participants, and used scatterplots to display breath and blood ammonia. For healthy participants, mean age was 22 years (±4), 70% were men, and body mass index (BMI) was 27 (±5). For cirrhotic participants, mean age was 61 years (±8), 60% were men, and BMI was 31 (±7). Median blood ammonia for healthy participants was within normal range, 10 μmol L−1 (interquartile range (IQR), 3–18) versus 46 μmol L−1 (IQR, 23–66) for cirrhotic participants. Median breath ammonia was 379 pmol mL−1 CO2 (IQR, 265–765) for healthy versus 350 pmol mL−1 CO2 (IQR, 180–1013) for cirrhotic participants. CV was 17 ± 6%. There remains an important unmet need in the evaluation of systemic ammonia, and breath measurement continues to demonstrate promise to fulfill this need. Given the many differences between breath and blood ammonia measurement, we examined biological explanations for our findings in healthy and cirrhotic participants. We conclude that based upon these preliminary data breath may offer clinically important information this is not provided by blood ammonia. PMID:26658550

  19. The thalamus in cirrhotic patients with and without hepatic encephalopathy: A volumetric MRI study

    International Nuclear Information System (INIS)

    Tao, Ran; Zhang, Jiuquan; You, Zhonglan; Wei, Luqing; Fan, Yi; Cui, Jinguo; Wang, Jian

    2013-01-01

    Background and aims: The thalamus is a major relay and filter station in the central neural system. Some previous studies have suggested that the thalamus maybe implicated in the pathogenesis of hepatic encephalopathy. The aim of our study was to investigate changing thalamic volumes in cirrhotic patients with and without hepatic encephalopathy. Methods: Neuropsychological tests and structural MR scanning were performed on 24 cirrhotic patients, 23 cirrhotic patients with minimal hepatic encephalopathy, 24 cirrhotic patients during their first episode of overt hepatic encephalopathy, and 33 healthy controls. Voxel-based morphometry analysis was performed to detect gray matter morphological changes. The thalamus and whole brain volume were extrapolated. A receiver operating characteristic curve analysis of thalamic volumes was used to discriminate patients with minimal hepatic encephalopathy from those with hepatic cirrhosis. Results: Thalamic volume increased in a stepwise manner in patients with progressively worse stages of hepatic encephalopathy compared to healthy subjects. Additionally, a comparison of gray matter morphometry between patients with Child–Pugh grades A, B, or C and controls revealed a progression in thalamic volumes in parallel with the degree of liver failure. Moreover, thalamic volume was significantly correlated with the number connection test A time and digit-symbol test score in cirrhotic patients with minimal hepatic encephalopathy (r = 0.659, P = 0.001; r = −0.577, P = 0.004; respectively). The area under the receiver operating characteristic curve was 0.827 (P = 0.001). Conclusions: A significantly increased thalamic volume may be provide an objective imaging measure for predicting seizures due to minimal hepatic encephalopathy in cirrhotic patients

  20. The thalamus in cirrhotic patients with and without hepatic encephalopathy: A volumetric MRI study

    Energy Technology Data Exchange (ETDEWEB)

    Tao, Ran, E-mail: taoran1648@yahoo.cn [Department of Radiology, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China); Department of Radiology, Bethune International Peace Hospital of People' s Liberty Army, Shijiazhuang 050082, Hebei Province (China); Zhang, Jiuquan, E-mail: jiuquanzhang@yahoo.com [Department of Radiology, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China); You, Zhonglan, E-mail: you_zhonglan@163.com [Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China); Wei, Luqing, E-mail: weiluqing@foxmail.com [Department of Radiology, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China); Fan, Yi, E-mail: fanyi1978@yahoo.cn [Department of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China); Cui, Jinguo, E-mail: cuijinguo2005@163.com [Department of Radiology, Bethune International Peace Hospital of People' s Liberty Army, Shijiazhuang 050082, Hebei Province (China); Wang, Jian, E-mail: wangjian_811@yahoo.com [Department of Radiology, Southwest Hospital, Third Military Medical University, Chongqing 400038 (China)

    2013-11-01

    Background and aims: The thalamus is a major relay and filter station in the central neural system. Some previous studies have suggested that the thalamus maybe implicated in the pathogenesis of hepatic encephalopathy. The aim of our study was to investigate changing thalamic volumes in cirrhotic patients with and without hepatic encephalopathy. Methods: Neuropsychological tests and structural MR scanning were performed on 24 cirrhotic patients, 23 cirrhotic patients with minimal hepatic encephalopathy, 24 cirrhotic patients during their first episode of overt hepatic encephalopathy, and 33 healthy controls. Voxel-based morphometry analysis was performed to detect gray matter morphological changes. The thalamus and whole brain volume were extrapolated. A receiver operating characteristic curve analysis of thalamic volumes was used to discriminate patients with minimal hepatic encephalopathy from those with hepatic cirrhosis. Results: Thalamic volume increased in a stepwise manner in patients with progressively worse stages of hepatic encephalopathy compared to healthy subjects. Additionally, a comparison of gray matter morphometry between patients with Child–Pugh grades A, B, or C and controls revealed a progression in thalamic volumes in parallel with the degree of liver failure. Moreover, thalamic volume was significantly correlated with the number connection test A time and digit-symbol test score in cirrhotic patients with minimal hepatic encephalopathy (r = 0.659, P = 0.001; r = −0.577, P = 0.004; respectively). The area under the receiver operating characteristic curve was 0.827 (P = 0.001). Conclusions: A significantly increased thalamic volume may be provide an objective imaging measure for predicting seizures due to minimal hepatic encephalopathy in cirrhotic patients.

  1. The long-term outcomes of cirrhotic patients with pleural effusion

    Science.gov (United States)

    Hung, Tsung-Hsing; Tseng, Chih-Wei; Tsai, Chih-Chun; Tsai, Chen-Chi; Tseng, Kuo-Chih; Hsieh, Yu-Hsi

    2018-01-01

    Background/Aim: A pleural effusion is an abnormal collection of fluid in the pleural space and may cause related morbidity or mortality in cirrhotic patients. Currently, there are insufficient data to support the long-term prognosis for cirrhotic patients with pleural effusion. In this study, we investigated the short- and long-term effects of pleural effusion on mortality in cirrhotic patients and evaluated the benefit of liver transplantation in these patients. Patients and Methods: The National Health Insurance Database, derived from the Taiwan National Health Insurance Program, was used to identify 3,487 cirrhotic patients with pleural effusion requiring drainage between January 1, 2007 and December 31, 2010. The proportional hazards Cox regression model was used to control for possible confounding factors. Results: The 30-day, 90-day, 1-year, and 3-year mortalities were 20.1%, 40.2%, 59.1%, and 75.9%, respectively, in the cirrhotic patients with pleural effusion. After Cox proportional hazard regression analysis adjusted by patient gender, age, complications of cirrhosis and comorbid disorders, old age, esophageal variceal bleeding, hepatocellular carcinoma, hepatic encephalopathy, pneumonia, renal function impairment, and without liver transplantation conferred higher risks for 3-year mortality in the cirrhotic patients with pleura effusion. Liver transplantation is the most important factor to determine the 3-year mortalities (HR: 0.17, 95% CI 0.11- 0.26, P effusion predicts poor long-term outcomes. Liver transplantation could dramatically improve the survival and should be suggested as soon as possible. PMID:29451184

  2. Attenuation of Morphine Physical Dependence and Blood Levels of Cortisol by Central and Systemic Administration of Ramelteon in Rat

    Directory of Open Access Journals (Sweden)

    Majid Motaghinejad

    2015-05-01

    Full Text Available Background: Chronic administration of morphine cause physical dependence but the exact mechanism of this phenomenon remains unclear. The aim of this study is the assessment of systemic and intracerebroventricular (icv administration of ramelteon (a melatonin receptor agonist on morphine physical dependence. Methods: 88 adult male rats were divided into 2 major groups, namely “systematic” and “central” administration of ramelteon. In the first category, systemic administration of ramelteon at various dosages (10, 20, and 40 mg/kg was assessed on dependent animals and withdrawal signs were compared with positive (received morphine and saline as systemic administration, negative control (saline and group under treatment by ramelteon (40 mg/kg groups. In the second category, central administration of ramelteon at various dosages (25, 50, or 100 μg, was assessed on dependent animals and withdrawal signs were compared with the positive control (received morphine and saline as icv and negative control (saline groups, and the group under treatment by ramelteon (50 μg/5 μl/rat. On the test day, all animals received naloxone (3 mg/kg and were observed for withdrawal signs. Total withdrawal score (TWS was also determined. Finally, to evaluate the stress level of dependent rats, blood cortisols were measured. Results: Central administration of ramelteon in all doses and systemic administration in high doses attenuate withdrawal syndrome in comparison with the dependent positive control group (P<0.05. Both central and systemic administrations of ramelteon can attenuate the blood cortisol level in comparison with the dependent positive control group (P<0.05. Conclusion: In conclusion, we found that central administration of ramelteon attenuated morphine withdrawal symptoms and cortisol level as a stress marker.

  3. Hepatocellular carcinoma arising from hepatocellular adenoma in a hepatitis B virus-associated cirrhotic liver

    International Nuclear Information System (INIS)

    Seo, J.M.; Lee, S.J.; Kim, S.H.; Park, C.K.; Ha, S.Y.

    2012-01-01

    Hepatocellular adenoma (HCA) is a rare, benign proliferation of hepatocytes that occurs mostly in a normal liver and in extreme rare cases, occurs in a cirrhotic liver. Hepatocellular carcinomas (HCC) arising within HCA through malignant transformation is rare. The specific incidence and mechanism of malignant transformation has not been established, but the long term use of oral contraceptives is considered a causative agent. We report a case of HCC arising from HCA detected in a hepatitis B-related cirrhotic liver with serial radiologic images.

  4. Hepatocellular carcinoma arising from hepatocellular adenoma in a hepatitis B virus-associated cirrhotic liver

    Energy Technology Data Exchange (ETDEWEB)

    Seo, J.M. [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Lee, S.J., E-mail: lucia@skku.edu [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Kim, S.H. [Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of); Park, C.K.; Ha, S.Y. [Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (Korea, Republic of)

    2012-04-15

    Hepatocellular adenoma (HCA) is a rare, benign proliferation of hepatocytes that occurs mostly in a normal liver and in extreme rare cases, occurs in a cirrhotic liver. Hepatocellular carcinomas (HCC) arising within HCA through malignant transformation is rare. The specific incidence and mechanism of malignant transformation has not been established, but the long term use of oral contraceptives is considered a causative agent. We report a case of HCC arising from HCA detected in a hepatitis B-related cirrhotic liver with serial radiologic images.

  5. Prosocial Choice in Rats Depends on Food-Seeking Behavior Displayed by Recipients.

    Science.gov (United States)

    Márquez, Cristina; Rennie, Scott M; Costa, Diana F; Moita, Marta A

    2015-06-29

    Animals often are prosocial, displaying behaviors that result in a benefit to one another [1-15] even in the absence of self-benefit [16-21] (but see [22-25]). Several factors have been proposed to modulate these behaviors, namely familiarity [6, 13, 18, 20] or display of seeking behavior [16, 21]. Rats have been recently shown to be prosocial under distress [17, 18] (but see [26-29]); however, what drives prosociality in these animals remains unclear. To address this issue, we developed a two-choice task in which prosocial behavior did not yield a benefit or a cost to the focal rat. We used a double T-maze in which only the focal rat controlled access to the food-baited arms of its own and the recipient rat's maze. In this task, the focal rat could choose between one side of the maze, which yielded food only to itself (selfish choice), and the opposite side, which yielded food to itself and the recipient rat (prosocial choice). Rats showed a high proportion of prosocial choices. By manipulating reward delivery to the recipient and its ability to display a preference for the baited arm, we found that the display of food-seeking behavior leading to reward was necessary to drive prosocial choices. In addition, we found that there was more social investigation between rats in selfish trials than in prosocial trials, which may have influenced the focals' choices. This study shows that rats provide access to food to others in the absence of added direct self-benefit, bringing new insights into the factors that drive prosociality. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Pertussis toxin-sensitive alpha-adrenergic modulation of voltage - dependent calcium channels in spontaneously hypertensive rats (SHR)

    Czech Academy of Sciences Publication Activity Database

    Zicha, Josef; Pintérová, Mária; Dobešová, Zdenka; Líšková, Silvia; Kuneš, Jaroslav

    2006-01-01

    Roč. 24, č. S6 (2006), s. 34-34 ISSN 0263-6352. [Scientific Meeting of the International Society of Hypertension /21./. 15.10.2006-19.10.2006, Fukuoka] R&D Projects: GA MZd(CZ) NR7786 Institutional research plan: CEZ:AV0Z50110509 Keywords : pertussis toxin * alpha adrenergic vasoconstriction * voltage-dependent calcium channels * SHR rat Subject RIV: FA - Cardiovascular Diseases incl. Cardiotharic Surgery

  7. Gallic acid attenuates calcium calmodulin-dependent kinase II-induced apoptosis in spontaneously hypertensive rats.

    Science.gov (United States)

    Jin, Li; Piao, Zhe Hao; Liu, Chun Ping; Sun, Simei; Liu, Bin; Kim, Gwi Ran; Choi, Sin Young; Ryu, Yuhee; Kee, Hae Jin; Jeong, Myung Ho

    2018-03-01

    Hypertension causes cardiac hypertrophy and leads to heart failure. Apoptotic cells are common in hypertensive hearts. Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is associated with apoptosis. We recently demonstrated that gallic acid reduces nitric oxide synthase inhibition-induced hypertension. Gallic acid is a trihydroxybenzoic acid and has been shown to have beneficial effects, such as anti-cancer, anti-calcification and anti-oxidant activity. The purpose of this study was to determine whether gallic acid regulates cardiac hypertrophy and apoptosis in essential hypertension. Gallic acid significantly lowered systolic and diastolic blood pressure in spontaneously hypertensive rats (SHRs). Wheat germ agglutinin (WGA) and H&E staining revealed that gallic acid reduced cardiac enlargement in SHRs. Gallic acid treatment decreased cardiac hypertrophy marker genes, including atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), in SHRs. The four isoforms, α, β, δ and γ, of CaMKII were increased in SHRs and were significantly reduced by gallic acid administration. Gallic acid reduced cleaved caspase-3 protein as well as bax, p53 and p300 mRNA levels in SHRs. CaMKII δ overexpression induced bax and p53 expression, which was attenuated by gallic acid treatment in H9c2 cells. Gallic acid treatment reduced DNA fragmentation and the TUNEL positive cells induced by angiotensin II. Taken together, gallic acid could be a novel therapeutic for the treatment of hypertension through suppression of CaMKII δ-induced apoptosis. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  8. Corticosteroid effects on ventilator-induced diaphragm dysfunction in anesthetized rats depend on the dose administered

    Directory of Open Access Journals (Sweden)

    Decramer Marc

    2010-12-01

    Full Text Available Abstract Background High dose of corticosteroids has been previously shown to protect against controlled mechanical ventilation (CMV-induced diaphragmatic dysfunction while inhibiting calpain activation. Because literature suggests that the calpain inhibiting effect of corticosteroid depends on the dose administered, we determined whether lower doses of corticosteroids would also provide protection of the diaphragm during CMV. This may be important for patients undergoing mechanical ventilation and receiving corticosteroids. Methods Rats were assigned to controls or to 24 hours of CMV while being treated at the start of mechanical ventilation with a single intramuscular administration of either saline, or 5 mg/kg (low MP or 30 mg/kg (high MP of methylprednisolone. Results Diaphragmatic force was decreased after CMV and this was exacerbated in the low MP group while high MP rescued this diaphragmatic dysfunction. Atrophy was more severe in the low MP group than after CMV while no atrophy was observed in the high MP group. A significant and similar increase in calpain activity was observed in both the low MP and CMV groups whereas the high dose prevented calpain activation. Expression of calpastatin, the endogenous inhibitor of calpain, was decreased in the CMV and low MP groups but its level was preserved to controls in the high MP group. Caspase-3 activity increased in all CMV groups but to a lesser extent in the low and high MP groups. The 20S proteasome activity was increased in CMV only. Conclusions Administration of 30 mg/kg methylprednisolone during CMV protected against CMV-induced diaphragm dysfunction while 5 mg/kg was more deleterious. The protective effect is due mainly to an inhibition of the calpain system through preservation of calpastatin levels and to a lesser extent to a caspase-3 inhibition.

  9. Layer-dependent role of collagen recruitment during loading of the rat bladder wall.

    Science.gov (United States)

    Cheng, Fangzhou; Birder, Lori A; Kullmann, F Aura; Hornsby, Jack; Watton, Paul N; Watkins, Simon; Thompson, Mark; Robertson, Anne M

    2018-04-01

    In this work, we re-evaluated long-standing conjectures as to the source of the exceptionally large compliance of the bladder wall. Whereas these conjectures were based on indirect measures of loading mechanisms, in this work we take advantage of advances in bioimaging to directly assess collagen fibers and wall architecture during biaxial loading. A custom biaxial mechanical testing system compatible with multiphoton microscopy was used to directly measure the layer-dependent collagen fiber recruitment in bladder tissue from 9 male Fischer rats (4 adult and 5 aged). As for other soft tissues, the bladder loading curve was exponential in shape and could be divided into toe, transition and high stress regimes. The relationship between collagen recruitment and loading curves was evaluated in the context of the inner (lamina propria) and outer (detrusor smooth muscle) layers. The large extensibility of the bladder was found to be possible due to folds in the wall (rugae) that provide a mechanism for low resistance flattening without any discernible recruitment of collagen fibers throughout the toe regime. For more extensible bladders, as the loading extended into the transition regime, a gradual coordinated recruitment of collagen fibers between the lamina propria layer and detrusor smooth muscle layer was found. A second important finding was that wall extensibility could be lost by premature recruitment of collagen in the outer wall that cut short the toe region. This change was correlated with age. This work provides, for the first time, a mechanistic understanding of the role of collagen recruitment in determining bladder extensibility and capacitance.

  10. Antibiotic Treatment Affects Intestinal Permeability and Gut Microbial Composition in Wistar Rats Dependent on Antibiotic Class.

    Directory of Open Access Journals (Sweden)

    Monica Vera-Lise Tulstrup

    Full Text Available Antibiotics are frequently administered orally to treat bacterial infections not necessarily related to the gastrointestinal system. This has adverse effects on the commensal gut microbial community, as it disrupts the intricate balance between specific bacterial groups within this ecosystem, potentially leading to dysbiosis. We hypothesized that modulation of community composition and function induced by antibiotics affects intestinal integrity depending on the antibiotic administered. To address this a total of 60 Wistar rats (housed in pairs with 6 cages per group were dosed by oral gavage with either amoxicillin (AMX, cefotaxime (CTX, vancomycin (VAN, metronidazole (MTZ, or water (CON daily for 10-11 days. Bacterial composition, alpha diversity and caecum short chain fatty acid levels were significantly affected by AMX, CTX and VAN, and varied among antibiotic treatments. A general decrease in diversity and an increase in the relative abundance of Proteobacteria was observed for all three antibiotics. Additionally, the relative abundance of Bifidobacteriaceae was increased in the CTX group and both Lactobacillaceae and Verrucomicrobiaceae were increased in the VAN group compared to the CON group. No changes in microbiota composition or function were observed following MTZ treatment. Intestinal permeability to 4 kDa FITC-dextran decreased after CTX and VAN treatment and increased following MTZ treatment. Plasma haptoglobin levels were increased by both AMX and CTX but no changes in expression of host tight junction genes were found in any treatment group. A strong correlation between the level of caecal succinate, the relative abundance of Clostridiaceae 1 family in the caecum, and the level of acute phase protein haptoglobin in blood plasma was observed. In conclusion, antibiotic-induced changes in microbiota may be linked to alterations in intestinal permeability, although the specific interactions remain to be elucidated as changes in

  11. Duodenal activation of cAMP-dependent protein kinase induces vagal afferent firing and lowers glucose production in rats.

    Science.gov (United States)

    Rasmussen, Brittany A; Breen, Danna M; Luo, Ping; Cheung, Grace W C; Yang, Clair S; Sun, Biying; Kokorovic, Andrea; Rong, Weifang; Lam, Tony K T

    2012-04-01

    The duodenum senses nutrients to maintain energy and glucose homeostasis, but little is known about the signaling and neuronal mechanisms involved. We tested whether duodenal activation of adenosine 3',5'-cyclic monophosphate (cAMP)-dependent protein kinase A (PKA) is sufficient and necessary for cholecystokinin (CCK) signaling to trigger vagal afferent firing and regulate glucose production. In rats, we selectively activated duodenal PKA and evaluated changes in glucose kinetics during the pancreatic (basal insulin) pancreatic clamps and vagal afferent firing. The requirement of duodenal PKA signaling in glucose regulation was evaluated by inhibiting duodenal activation of PKA in the presence of infusion of the intraduodenal PKA agonist (Sp-cAMPS) or CCK1 receptor agonist (CCK-8). We also assessed the involvement of a neuronal network and the metabolic impact of duodenal PKA activation in rats placed on high-fat diets. Intraduodenal infusion of Sp-cAMPS activated duodenal PKA and lowered glucose production, in association with increased vagal afferent firing in control rats. The metabolic and neuronal effects of duodenal Sp-cAMPS were negated by coinfusion with either the PKA inhibitor H89 or Rp-CAMPS. The metabolic effect was also negated by coinfusion with tetracaine, molecular and pharmacologic inhibition of NR1-containing N-methyl-d-aspartate (NMDA) receptors within the dorsal vagal complex, or hepatic vagotomy in rats. Inhibition of duodenal PKA blocked the ability of duodenal CCK-8 to reduce glucose production in control rats, whereas duodenal Sp-cAMPS bypassed duodenal CCK resistance and activated duodenal PKA and lowered glucose production in rats on high-fat diets. We identified a neural glucoregulatory function of duodenal PKA signaling. Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.

  12. Activity of cAMP-dependent protein kinases and cAMP-binding proteins of rat kidney cytosol during dehydration

    International Nuclear Information System (INIS)

    Zelenina, M.N.; Solenov, E.I.; Ivanova, L.N.

    1985-01-01

    The activity of cAMP-dependent protein kinases, the binding of cAMP, and the spectrum of cAMP-binding proteins in the cytosol of the renal papilla was studied in intact rats and in rats after 24 h on a water-deprived diet. It was found that the activation of protein kinases by 10 -6 M cAMP is significantly higher in the experimental animals than in the intact animals. In chromatography on DEAE-cellulose, the positions of the peaks of specific reception of cAMP corresponded to the peaks of the regulatory subunits of cAMP-dependent protein kinases of types I and II. In this case, in intact animals more than 80% of the binding activity was detected in peaks II, whereas in rats subjected to water deprivation, more than 60% of the binding was observed in peak I. The general regulatory activity of the cytosol was unchanged in the experimental animals in comparison with intact animals. It is suggested that during dehydration there is an induction of the synthesis of the regulatory subunit of type I cAMP-dependent protein kinase in the renal papilla

  13. Peripubertal Caffeine Exposure Impairs Longitudinal Bone Growth in Immature Male Rats in a Dose- and Time-Dependent Manner.

    Science.gov (United States)

    Choi, Yun-Young; Choi, Yuri; Kim, Jisook; Choi, Hyeonhae; Shin, Jiwon; Roh, Jaesook

    2016-01-01

    This study investigated the dose- and time-dependent effects of caffeine consumption throughout puberty in peripubertal rats. A total of 85 male SD rats were randomly divided into four groups: control and caffeine-fed groups with 20, 60, or 120 mg/kg/day through oral gavage for 10, 20, 30, or 40 days. Caffeine decreased body weight gain and food consumption in a dose- and time-dependent manner, accompanied by a reduction in muscle and body fat. In addition, it caused a shortening and lightening of leg bones and spinal column. The total height of the growth plate decreased sharply at 40 days in the controls, but not in the caffeine-fed groups, and the height of hypertrophic zone in the caffeine-fed groups was lower than in the control. Caffeine increased the height of the secondary spongiosa, whereas parameters related to bone formation, such as bone area ratio, thickness and number of trabeculae, and bone perimeter, were significantly reduced. Furthermore, serum levels of IGF-1, estradiol, and testosterone were also reduced by the dose of caffeine exposure. Our results demonstrate that caffeine consumption can dose- and time-dependently inhibit longitudinal bone growth in immature male rats, possibly by blocking the physiologic changes in body composition and hormones relevant to bone growth.

  14. Prediction and evaluation of route dependent dosimetry of BPA in rats at different life stages using a physiologically based pharmacokinetic model

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Xiaoxia, E-mail: Xiaoxia.Yang@fda.hhs.gov; Doerge, Daniel R.; Fisher, Jeffrey W.

    2013-07-01

    Bisphenol A (BPA) has received considerable attention throughout the last decade due to its widespread use in consumer products. For the first time a physiologically based pharmacokinetic (PBPK) model was developed in neonatal and adult rats to quantitatively evaluate age-dependent pharmacokinetics of BPA and its phase II metabolites. The PBPK model was calibrated in adult rats using studies on BPA metabolism and excretion in the liver and gastrointestinal tract, and pharmacokinetic data with BPA in adult rats. For immature rats the hepatic and gastrointestinal metabolism of BPA was inferred from studies on the maturation of phase II enzymes coupled with serum time course data in pups. The calibrated model predicted the measured serum concentrations of BPA and BPA conjugates after administration of 100 μg/kg of d6-BPA in adult rats (oral gavage and intravenous administration) and postnatal days 3, 10, and 21 pups (oral gavage). The observed age-dependent BPA serum concentrations were partially attributed to the immature metabolic capacity of pups. A comparison of the dosimetry of BPA across immature rats and monkeys suggests that dose adjustments would be necessary to extrapolate toxicity studies from neonatal rats to infant humans. - Highlights: • A PBPK model predicts the kinetics of bisphenol A (BPA) in young and adult rats. • BPA metabolism within enterocytes is required for fitting of oral BPA kinetic data. • BPA dosimetry in young rats is different than adult rats and young monkeys.

  15. Prediction and evaluation of route dependent dosimetry of BPA in rats at different life stages using a physiologically based pharmacokinetic model

    International Nuclear Information System (INIS)

    Yang, Xiaoxia; Doerge, Daniel R.; Fisher, Jeffrey W.

    2013-01-01

    Bisphenol A (BPA) has received considerable attention throughout the last decade due to its widespread use in consumer products. For the first time a physiologically based pharmacokinetic (PBPK) model was developed in neonatal and adult rats to quantitatively evaluate age-dependent pharmacokinetics of BPA and its phase II metabolites. The PBPK model was calibrated in adult rats using studies on BPA metabolism and excretion in the liver and gastrointestinal tract, and pharmacokinetic data with BPA in adult rats. For immature rats the hepatic and gastrointestinal metabolism of BPA was inferred from studies on the maturation of phase II enzymes coupled with serum time course data in pups. The calibrated model predicted the measured serum concentrations of BPA and BPA conjugates after administration of 100 μg/kg of d6-BPA in adult rats (oral gavage and intravenous administration) and postnatal days 3, 10, and 21 pups (oral gavage). The observed age-dependent BPA serum concentrations were partially attributed to the immature metabolic capacity of pups. A comparison of the dosimetry of BPA across immature rats and monkeys suggests that dose adjustments would be necessary to extrapolate toxicity studies from neonatal rats to infant humans. - Highlights: • A PBPK model predicts the kinetics of bisphenol A (BPA) in young and adult rats. • BPA metabolism within enterocytes is required for fitting of oral BPA kinetic data. • BPA dosimetry in young rats is different than adult rats and young monkeys

  16. Glutamate co-transmission from developing medial nucleus of the trapezoid body - Lateral superior olive synapses is cochlear dependent in kanamycin-treated rats

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jae Ho [Institute of Tissue Regeneration Engineering (ITREN), Dankook University, San 29, Anseo-dong, Cheonan-si, Chungnam 330-714 (Korea, Republic of); Pradhan, Jonu [Department of Nanobio Medical Science, Dankook University, San 29, Anseo-dong, Cheonan-si, Chungnam 330-714 (Korea, Republic of); Maskey, Dhiraj; Park, Ki Sup [Department of Anatomy, College of Medicine, Dankook University, San 29, Anseo-dong, Cheonan-si, Chungnam 330-714 (Korea, Republic of); Hong, Sung Hwa [Department of Otorhinolaryngology-Head and Neck Surgery, Samsung Medical Center, Sungkyunkwan University, School of Medicine, 50, Irwon-dong, Gangnam-gu, Seoul 135-710 (Korea, Republic of); Suh, Myung-Whan [Department of Otorhinolaryngology-Head and Neck Surgery, College of Medicine, Dankook University, San 29, Anseo-dong, Cheonan-si, Chungnam 330-714 (Korea, Republic of); Kim, Myeung Ju, E-mail: mjukim99@dankook.ac.kr [Department of Anatomy, College of Medicine, Dankook University, San 29, Anseo-dong, Cheonan-si, Chungnam 330-714 (Korea, Republic of); Ahn, Seung Cheol, E-mail: ansil67@hanmail.net [Department of Physiology, College of Medicine, Dankook University, San 29, Anseo-dong, Cheonan-si, Chungnam 330-714 (Korea, Republic of)

    2011-02-11

    Research highlights: {yields} Glutamate co-transmission is enhanced in kanamycin-treated rats. {yields} VGLUT3 expression is increased in kanamycin-treated rats. {yields} GlyR expression is decreased in kanamycin-treated rats. {yields} GlyR, VGLUT3 expression patterns are asymmetric in unilaterally cochlear ablated rat. -- Abstract: Cochlear dependency of glutamate co-transmission at the medial nucleus of the trapezoid body (MNTB) - the lateral superior olive (LSO) synapses was investigated using developing rats treated with high dose kanamycin. Rats were treated with kanamycin from postnatal day (P) 3 to P8. A scanning electron microscopic study on P9 demonstrated partial cochlear hair cell damage. A whole cell voltage clamp experiment demonstrated the increased glutamatergic portion of postsynaptic currents (PSCs) elicited by MNTB stimulation in P9-P11 kanamycin-treated rats. The enhanced VGLUT3 immunoreactivities (IRs) in kanamycin-treated rats and asymmetric VGLUT3 IRs in the LSO of unilaterally cochlear ablated rats supported the electrophysiologic data. Taken together, it is concluded that glutamate co-transmission is cochlear-dependent and enhanced glutamate co-transmission in kanamycin-treated rats is induced by partial cochlear damage.

  17. Opposite Effect of Opuntia ficus-indica L. Juice Depending on Fruit Maturity Stage on Gastrointestinal Physiological Parameters in Rat.

    Science.gov (United States)

    Rtibi, Kais; Selmi, Slimen; Grami, Dhekra; Amri, Mohamed; Sebai, Hichem; Marzouki, Lamjed

    2018-06-01

    The phytochemical composition and the effect of the green and ripe Opuntia ficus-indica juice on some gastrointestinal (GI) physiological parameters such as stomach emptying and small-intestinal motility and permeability were determined in rats administered multiple concentrations of the prickly pear juice (5, 10, and 20 mL kg -1 , b.w., p.o.). Other separate groups of rats were received, respectively; sodium chloride (0.9%, b.w., p.o.), clonidine (α- 2 -adrenergic agonist, 1 mg kg -1 , b.w., i.p.), yohimbine (α- 2 -adrenergic antagonist, 2 mg kg -1 , b.w., i.p.), and loperamide (5 mg kg -1 , b.w., p.o.). In vivo reverse effect of juice on GI physiological parameters was investigated using a charcoal meal test, phenol-red colorimetric method, loperamide-induced acute constipation, and castor oil-caused small-bowel hypersecretion. However, the opposite in vitro influence of juice on intestinal permeability homeostasis was assessed by the Ussing chamber system. Mature prickly pear juice administration stimulated significantly and dose dependently the GI transit (GIT; 8-26%) and gastric emptying (0.9-11%) in a rat model. Conversely, the immature prickly pear juice reduced gastric emptying (7-23%), GIT (10-28%), and diarrhea (59-88%). Moreover, the standard drugs have produced their antagonistic effects on GI physiological functions. The permeability of the isolated perfused rat small-intestine has a paradoxical response flowing prickly pear juices administration at diverse doses and maturity grade. Most importantly, the quantitative phytochemical analyses of both juices showed a different composition depending on the degree of maturity. In conclusion, the prickly pear juice at two distinct phases of maturity has different phytochemical characteristics and opposite effects on GI physiological actions in rat.

  18. Differential Changes in Expression of Stress- and Metabolic-Related Neuropeptides in the Rat Hypothalamus during Morphine Dependence and Withdrawal.

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    Bernadett Pintér-Kübler

    Full Text Available Chronic morphine treatment and naloxone precipitated morphine withdrawal activates stress-related brain circuit and results in significant changes in food intake, body weight gain and energy metabolism. The present study aimed to reveal hypothalamic mechanisms underlying these effects. Adult male rats were made dependent on morphine by subcutaneous implantation of constant release drug pellets. Pair feeding revealed significantly smaller weight loss of morphine treated rats compared to placebo implanted animals whose food consumption was limited to that eaten by morphine implanted pairs. These results suggest reduced energy expenditure of morphine-treated animals. Chronic morphine exposure or pair feeding did not significantly affect hypothalamic expression of selected stress- and metabolic related neuropeptides - corticotropin-releasing hormone (CRH, urocortin 2 (UCN2 and proopiomelanocortin (POMC compared to placebo implanted and pair fed animals. Naloxone precipitated morphine withdrawal resulted in a dramatic weight loss starting as early as 15-30 min after naloxone injection and increased adrenocorticotrophic hormone, prolactin and corticosterone plasma levels in morphine dependent rats. Using real-time quantitative PCR to monitor the time course of relative expression of neuropeptide mRNAs in the hypothalamus we found elevated CRH and UCN2 mRNA and dramatically reduced POMC expression. Neuropeptide Y (NPY and arginine vasopressin (AVP mRNA levels were transiently increased during opiate withdrawal. These data highlight that morphine withdrawal differentially affects expression of stress- and metabolic-related neuropeptides in the rat hypothalamus, while relative mRNA levels of these neuropeptides remain unchanged either in rats chronically treated with morphine or in their pair-fed controls.

  19. The delay in the development of experimental colitis from isomaltosyloligosaccharides in rats is dependent on the degree of polymerization.

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    Hitoshi Iwaya

    Full Text Available Isomaltosyloligosaccharides (IMO and dextran (Dex are hardly digestible in the small intestine and thus influence the luminal environment and affect the maintenance of health. There is wide variation in the degree of polymerization (DP in Dex and IMO (short-sized IMO, S-IMO; long-sized IMO, L-IMO, and the physiological influence of these compounds may be dependent on their DP.Five-week-old male Wistar rats were given a semi-purified diet with or without 30 g/kg diet of the S-IMO (DP = 3.3, L-IMO (DP = 8.4, or Dex (DP = 1230 for two weeks. Dextran sulfate sodium (DSS was administered to the rats for one week to induce experimental colitis. We evaluated the clinical symptoms during the DSS treatment period by scoring the body weight loss, stool consistency, and rectal bleeding. The development of colitis induced by DSS was delayed in the rats fed S-IMO and Dex diets. The DSS treatment promoted an accumulation of neutrophils in the colonic mucosa in the rats fed the control, S-IMO, and L-IMO diets, as assessed by a measurement of myeloperoxidase (MPO activity. In contrast, no increase in MPO activity was observed in the Dex-diet-fed rats even with DSS treatment. Immune cell populations in peripheral blood were also modified by the DP of ingested saccharides. Dietary S-IMO increased the concentration of n-butyric acid in the cecal contents and the levels of glucagon-like peptide-2 in the colonic mucosa.Our study provided evidence that the physiological effects of α-glucosaccharides on colitis depend on their DP, linkage type, and digestibility.

  20. Differential effect of amylin on endothelial-dependent vasodilation in mesenteric arteries from control and insulin resistant rats.

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    Mariam El Assar

    Full Text Available Insulin resistance (IR is frequently associated with endothelial dysfunction and has been proposed to play a major role in cardiovascular disease (CVD. On the other hand, amylin has long been related to IR. However the role of amylin in the vascular dysfunction associated to IR is not well addressed. Therefore, the aim of the study was to assess the effect of acute treatment with amylin on endothelium-dependent vasodilation of isolated mesenteric arteries from control (CR and insulin resistant (IRR rats and to evaluate the possible mechanisms involved. Five week-old male Wistar rats received 20% D-fructose dissolved in drinking water for 8 weeks and were compared with age-matched CR. Plasmatic levels of glucose, insulin and amylin were measured. Mesenteric microvessels were dissected and mounted in wire myographs to evaluate endothelium-dependent vasodilation to acetylcholine. IRR displayed a significant increase in plasmatic levels of glucose, insulin and amylin and reduced endothelium-dependent relaxation when compared to CR. Acute treatment of mesenteric arteries with r-amylin (40 pM deteriorated endothelium-dependent responses in CR. Amylin-induced reduction of endothelial responses was unaffected by the H2O2 scavenger, catalase, but was prevented by the extracellular superoxide scavenger, superoxide dismutase (SOD or the NADPH oxidase inhibitor (VAS2870. By opposite, amylin failed to further inhibit the impaired relaxation in mesenteric arteries of IRR. SOD, or VAS2870, but not catalase, ameliorated the impairment of endothelium-dependent relaxation in IRR. At concentrations present in insulin resistance conditions, amylin impairs endothelium-dependent vasodilation in mircrovessels from rats with preserved vascular function and low levels of endogenous amylin. In IRR with established endothelial dysfunction and elevated levels of amylin, additional exposure to this peptide has no effect on endothelial vasodilation. Increased superoxide

  1. Nitric oxide-dependent vasodilation and Ca2+ signalling induced by erythrodiol in rat aorta

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    Fidèle Ntchapda

    2015-06-01

    Full Text Available Objective: To evaluate the pharmacological property of erythrodiol, a natural triterpenoid contained in propolis, as vasodilatory agent, and to determine its mechanism of action. Methods: Rats aortic rings were isolated and suspended in organ baths, and the effects of erythrodiol were studied by means of isometric tension recording experiments. Nitric oxide (NO was detected by ozone-induced chemiluminescence. The technique used to evaluate changes in intracellular Ca2+ concentration in intact endothelium was opened aortic ring and loaded with 16 µmol Fura-2/AM for 60 min at room temperature, washed and fixed by small pins with the luminal face up. In situ, ECs were visualized by an upright epifluorescence Axiolab microscope (Carl Zeiss, Oberkochen, Germany equipped with a Zeiss×63 Achroplan objective (water immersion, 2.0 mm working distance, 0.9 numerical apertures. ECs were excited alternately at 340 and 380 nm, and the emitted light was detected at 510 nm. Results: In aortic rings with intact endothelium pre-contracted with norepinephrine (10-4 mol/L, the addition of erythrodiol (10-8-10-4 mol/L induced vasorelaxation in a concentration-dependent manner; in endothelium-denuded rings, the relaxant response induced by erythrodiol was almost completely abolished suggesting that vasorelaxation was endothelium-dependent. They had almost no relaxant effect on depolarised or endothelium-denuded aortic segments. The relaxation was significantly attenuated by pre-treatment with the NO synthase inhibitor Nvnitro-L-arginine-methylester. Erythrodiol (10-4 mol/L was able to significantly increase NOx levels. This effect was completely abolished after removal of the vascular endothelium. Erythrodiol (100 µmol/L caused a slow, long-lasting increase in intracellular Ca2+ concentration. These results further supported the hypothesis that erythrodiol can induce activation of the NO/soluble guanylate cyclase/cyclic guanosine monophosphate pathway, as

  2. Acute tryptophan depletion dose dependently impairs object memory in serotonin transporter knockout rats

    NARCIS (Netherlands)

    Olivier, J D A; Jans, L A W; Korte-Bouws, G A H; Korte, S M; Deen, P M T; Cools, A R; Ellenbroek, B A; Blokland, A

    2008-01-01

    RATIONALE: Acute tryptophan depletion (ATD) transiently lowers central serotonin levels and can induce depressive mood states and cognitive defects. Previous studies have shown that ATD impairs object recognition in rats. OBJECTIVES: As individual differences exist in central serotonin

  3. ATP-dependent transport of statins by human and rat MRP2/Mrp2

    Energy Technology Data Exchange (ETDEWEB)

    Ellis, Lucy C.J., E-mail: Luc_ellis@yahoo.co.uk [Section of Translational Medicine, Division of Applied Biology, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD (United Kingdom); Hawksworth, Gabrielle M. [Section of Translational Medicine, Division of Applied Biology, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD (United Kingdom); Weaver, Richard J. [Biologie Servier, Drug Safety Research Centre, 905 Route de Saran, 45520 Gidy (France)

    2013-06-01

    Multidrug resistance associated protein-2, MRP2 (human), Mrp2 (rat) are an efflux transporter, responsible for the transport of numerous endogenous and xenobiotic compounds including taurocholate, methotrexate and carboxydichlorofluorescein (CDF). The present study aims to characterise transport of statins by human and rat MRP2/Mrp2 using membrane and vesicle preparations. All statins tested (simvastatin, pravastatin, pitavastatin, fluvastatin, atorvastatin, lovastatin and rosuvastatin) stimulated vanadate-sensitive ATPase activity in membranes expressing human or rat MRP2/Mrp2, suggesting that all statins are substrates of human and rat MRP2/Mrp2. The substrate affinity (Km) of all statins for MRP2/Mrp2 was comparable and no correlation between lipophilicity (logD{sub 7.0}) and Km was seen. All statins also inhibited uptake of the fluorescent Mrp2 substrate, CDF (1 μM) into vesicles expressing human or rat MRP2/Mrp2 with similar IC{sub 50} values. Fitting of the inhibitory data to the hill slope equation, gave hill coefficients (h) of greater than one, suggesting that transport involved more than one binding site for inhibitors of MPR2 and Mrp2. We conclude that statins were transported by both human and rat MRP2/Mrp2 with similar affinity. Statins were also shown to compete with other substrates for transport by MRP2/Mrp2 and that this transport involved more than one binding site on the Mrp2/MRP2 protein. - Highlights: • We characterised MRP2 (human)/Mrp2 (rat)-mediated transport of statins. • We show statins were transported by human and rat MRP2/Mrp2. • Statins competed with a known substrate for transport by MRP2/Mrp2. • Competition involved more than one binding site on the MRP2/Mrp2 protein.

  4. ATP-dependent transport of statins by human and rat MRP2/Mrp2

    International Nuclear Information System (INIS)

    Ellis, Lucy C.J.; Hawksworth, Gabrielle M.; Weaver, Richard J.

    2013-01-01

    Multidrug resistance associated protein-2, MRP2 (human), Mrp2 (rat) are an efflux transporter, responsible for the transport of numerous endogenous and xenobiotic compounds including taurocholate, methotrexate and carboxydichlorofluorescein (CDF). The present study aims to characterise transport of statins by human and rat MRP2/Mrp2 using membrane and vesicle preparations. All statins tested (simvastatin, pravastatin, pitavastatin, fluvastatin, atorvastatin, lovastatin and rosuvastatin) stimulated vanadate-sensitive ATPase activity in membranes expressing human or rat MRP2/Mrp2, suggesting that all statins are substrates of human and rat MRP2/Mrp2. The substrate affinity (Km) of all statins for MRP2/Mrp2 was comparable and no correlation between lipophilicity (logD 7.0 ) and Km was seen. All statins also inhibited uptake of the fluorescent Mrp2 substrate, CDF (1 μM) into vesicles expressing human or rat MRP2/Mrp2 with similar IC 50 values. Fitting of the inhibitory data to the hill slope equation, gave hill coefficients (h) of greater than one, suggesting that transport involved more than one binding site for inhibitors of MPR2 and Mrp2. We conclude that statins were transported by both human and rat MRP2/Mrp2 with similar affinity. Statins were also shown to compete with other substrates for transport by MRP2/Mrp2 and that this transport involved more than one binding site on the Mrp2/MRP2 protein. - Highlights: • We characterised MRP2 (human)/Mrp2 (rat)-mediated transport of statins. • We show statins were transported by human and rat MRP2/Mrp2. • Statins competed with a known substrate for transport by MRP2/Mrp2. • Competition involved more than one binding site on the MRP2/Mrp2 protein

  5. Age-dependent changes of presynaptic neuromodulation via A1-adenosine receptors in rat hippocampal slices.

    Science.gov (United States)

    Sperlágh, B; Zsilla, G; Baranyi, M; Kékes-Szabó, A; Vizi, E S

    1997-10-01

    The presynaptic neuromodulation of stimulation-evoked release of [3H]-acetylcholine by endogenous adenosine, via A1-adenosine receptors, was studied in superfused hippocampal slices taken from 4-, 12- and 24-month-old rats. 8-Cyclopentyl-1,3-dimethylxanthine (0.25 microM), a selective A1-receptor antagonist, increased significantly the electrical field stimulation-induced release of [3H]-acetylcholine in slices prepared from 4- and 12-month-old rats, showing a tonic inhibitory action of endogenous adenosine via stimulation of presynaptic A1-adenosine receptors. In contrast, 8-cyclopentyl-1,3-dimethylxanthine had no effect in 24-month-old rats. 2-Chloroadenosine (10 microM), an adenosine receptor agonist decreased the release of [3H]-acetylcholine in slices taken from 4- and 12-month-old rats, and no significant change was observed in slices taken from 24-month-old rats. In order to show whether the number/or affinity of the A1-receptors was affected in aged rats, [3H]-8-cyclopentyl-1,3-dimethylxanthine binding was studied in hippocampal membranes prepared from rats of different ages. Whereas the Bmax value was significantly lower in 2-year-old rats than in younger counterparts, the dissociation constant (Kd) was not affected by aging, indicating that the density rather than the affinity of adenosine receptors was altered. Endogenous adenosine levels present in the extracellular space were also measured in the superfusate by high performance liquid chromatography (HPLC) coupled with ultraviolet detection, and an age-related increase in the adenosine level was found. In summary, our results indicate that during aging the level of adenosine in the extracellular fluid is increased in the hippocampus. There is a downregulation and reduced responsiveness of presynaptic adenosine A1-receptors, and it seems likely that these changes are due to the enhanced adenosine level in the extracellular space.

  6. Ethanol concentration-dependent alterations in gene expression during acute binge drinking in the HIV-1 transgenic rat.

    Science.gov (United States)

    Sarkar, Sraboni; Chang, Sulie L

    2013-07-01

    Binge drinking of high ethanol (EtOH) concentration beverages is common among young adults and can be a risk factor for exposure to sexually transmitted diseases, including HIV-1. We used a novel noninfectious HIV-1 transgenic (HIV-1Tg) rat model that mimics HIV-1 patients in terms of altered immune responses and deficits in cognitive learning and memory to investigate EtOH concentration-dependent effects on 48 alcohol-modulated genes during binge EtOH administration. HIV-1Tg and control F344 rats were administered water, 8% EtOH, or 52% EtOH by gavage (i.g.) for 3 days (2.0 g/kg/d). Two hours after final treatment, blood, liver, and spleen were collected from each animal. Serum blood EtOH concentration (BEC) was measured, and gene expression in the liver and spleen was determined using a specifically designed PCR array. The BEC was significantly higher in the 52% EtOH-treated HIV-1Tg rats compared with the 8% EtOH group; however, the BEC was higher in the 8% EtOH-treated control rats compared with the 52% EtOH group. There was no change in expression of the EtOH metabolism-related genes, Adh1, Adh4, and Cyp2e1, in either the 8 or 52% EtOH-treated HIV-1Tg rats, whereas expression of those genes was significantly higher in the liver of the 52% EtOH control rats, but not in the 8% EtOH group. In the HIV-1Tg rats, expression of the GABAA , metabotropic glutamate, and dopamine neurotransmitter receptor genes was significantly increased in the spleen of the 52% EtOH group, but not in the 8% EtOH group, whereas no change was observed in those genes in either of the control groups. Our data indicate that, in the presence of HIV-1 infection, EtOH concentration-dependent binge drinking can have significantly different molecular effects. Copyright © 2013 by the Research Society on Alcoholism.

  7. Excipient-mediated alteration in drug bioavailability in the rat depends on the sex of the animal.

    Science.gov (United States)

    Mai, Yang; Afonso-Pereira, Francisco; Murdan, Sudaxshina; Basit, Abdul W

    2017-09-30

    The pharmaceutical excipient, polyethylene glycol 400 (PEG 400), unexpectedly alters the bioavailability of the BCS class III drug ranitidine in a sex-dependent manner. As ranitidine is a substrate for the efflux transporter P-glycoprotein (P-gp), we hypothesized that the sex-related influence could be due to interactions between PEG 400 and P-gp. In this study, we tested this hypothesis by: i) measuring the influence of PEG 400 on the oral bioavailability of another P-gp substrate (ampicillin) and of a non-P-gp substrate (metformin); and ii) measuring the effect of PEG 400 on drug bioavailability in the presence of a P-gp inhibitor (cyclosporine A) in male and female rats. We found that PEG 400 significantly increased (pbioavailability of ampicillin (the P-gp substrate) in male rats, but not in female ones. In contrast, PEG 400 had no influence on the bioavailability of the non-P-gp substrate, metformin in male or female rats. Inhibition of P-gp by oral pre-treatment with cyclosporine A increased the bioavailability of the P-gp substrates (ampicillin and ranitidine) in males and females (pbioavailability of metformin in either male or female rats. These results prove the hypothesis that the sex-specific effect of PEG 400 on the bioavailability of certain drugs is due to the interaction of PEG 400 with the efflux transporter P-gp. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Salt-induced epithelial-to-mesenchymal transition in Dahl salt-sensitive rats is dependent on elevated blood pressure

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Y.; Mu, J.J.; Liu, F.Q.; Ren, K.Y.; Xiao, H.Y. [Xi' an Jiaotong University, Medical College, First Affiliated Hospital, Cardiovascular Department, Xi' an, China, Cardiovascular Department, First Affiliated Hospital, Medical College, Xi' an Jiaotong University, Xi' an (China); Ministry of Education, Key Laboratory of Environment and Genes Related to Diseases, Xi' an, China, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi' an (China); Yang, Z. [Xi' an Jiaotong University, Medical College, First Affiliated Hospital, Department of Pathology, Xi' an, China, Department of Pathology, First Affiliated Hospital, Medical College, Xi' an Jiaotong University, Xi' an (China); Yuan, Z.Y. [Xi' an Jiaotong University, Medical College, First Affiliated Hospital, Cardiovascular Department, Xi' an, China, Cardiovascular Department, First Affiliated Hospital, Medical College, Xi' an Jiaotong University, Xi' an (China); Ministry of Education, Key Laboratory of Environment and Genes Related to Diseases, Xi' an, China, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi' an (China)

    2014-03-03

    Dietary salt intake has been linked to hypertension and cardiovascular disease. Accumulating evidence has indicated that salt-sensitive individuals on high salt intake are more likely to develop renal fibrosis. Epithelial-to-mesenchymal transition (EMT) participates in the development and progression of renal fibrosis in humans and animals. The objective of this study was to investigate the impact of a high-salt diet on EMT in Dahl salt-sensitive (SS) rats. Twenty-four male SS and consomic SS-13{sup BN} rats were randomized to a normal diet or a high-salt diet. After 4 weeks, systolic blood pressure (SBP) and albuminuria were analyzed, and renal fibrosis was histopathologically evaluated. Tubular EMT was evaluated using immunohistochemistry and real-time PCR with E-cadherin and alpha smooth muscle actin (α-SMA). After 4 weeks, SBP and albuminuria were significantly increased in the SS high-salt group compared with the normal diet group. Dietary salt intake induced renal fibrosis and tubular EMT as identified by reduced expression of E-cadherin and enhanced expression of α-SMA in SS rats. Both blood pressure and renal interstitial fibrosis were negatively correlated with E-cadherin but positively correlated with α-SMA. Salt intake induced tubular EMT and renal injury in SS rats, and this relationship might depend on the increase in blood pressure.

  9. Repeated exposure to methamphetamine induces sex-dependent hypersensitivity to ischemic injury in the adult rat heart.

    Directory of Open Access Journals (Sweden)

    Boyd R Rorabaugh

    Full Text Available We previously reported that adult female, but not male rats that were prenatally exposed to methamphetamine exhibit myocardial hypersensitivity to ischemic injury. However, it is unknown whether hypersensitivity to ischemic injury develops when rats are exposed to methamphetamine during adulthood. The goal of this study was to determine whether methamphetamine exposure during adulthood sensitizes the heart to ischemic injury.Adult male and female rats received daily injections of methamphetamine (5 mg/kg or saline for 10 days. Their hearts were isolated on day 11 and subjected to a 20 min ischemic insult on a Langendorff isolated heart apparatus. Cardiac contractile function was measured by an intraventricular balloon, and infarct size was measured by triphenyltetrazolium chloride staining.Hearts from methamphetamine-treated females exhibited significantly larger infarcts and suppressed postischemic recovery of contractile function compared to hearts from saline-treated females. In contrast, methamphetamine had no effect on infarct size or contractile recovery in male hearts. Subsequent experiments demonstrated that hypersensitivity to ischemic injury persisted in female hearts following a 1 month period of abstinence from methamphetamine. Myocardial protein kinase C-ε expression, Akt phosphorylation, and ERK phosphorylation were unaffected by adult exposure to methamphetamine.Exposure of adult rats to methamphetamine sex-dependently increases the extent of myocardial injury following an ischemic insult. These data suggest that women who have a heart attack might be at risk of more extensive myocardial injury if they have a recent history of methamphetamine abuse.

  10. Repeated exposure to methamphetamine induces sex-dependent hypersensitivity to ischemic injury in the adult rat heart

    Science.gov (United States)

    Seeley, Sarah L.; Stoops, Thorne S.; D’Souza, Manoranjan S.

    2017-01-01

    Background We previously reported that adult female, but not male rats that were prenatally exposed to methamphetamine exhibit myocardial hypersensitivity to ischemic injury. However, it is unknown whether hypersensitivity to ischemic injury develops when rats are exposed to methamphetamine during adulthood. The goal of this study was to determine whether methamphetamine exposure during adulthood sensitizes the heart to ischemic injury. Methods Adult male and female rats received daily injections of methamphetamine (5 mg/kg) or saline for 10 days. Their hearts were isolated on day 11 and subjected to a 20 min ischemic insult on a Langendorff isolated heart apparatus. Cardiac contractile function was measured by an intraventricular balloon, and infarct size was measured by triphenyltetrazolium chloride staining. Results Hearts from methamphetamine-treated females exhibited significantly larger infarcts and suppressed postischemic recovery of contractile function compared to hearts from saline-treated females. In contrast, methamphetamine had no effect on infarct size or contractile recovery in male hearts. Subsequent experiments demonstrated that hypersensitivity to ischemic injury persisted in female hearts following a 1 month period of abstinence from methamphetamine. Myocardial protein kinase C-ε expression, Akt phosphorylation, and ERK phosphorylation were unaffected by adult exposure to methamphetamine. Conclusions Exposure of adult rats to methamphetamine sex-dependently increases the extent of myocardial injury following an ischemic insult. These data suggest that women who have a heart attack might be at risk of more extensive myocardial injury if they have a recent history of methamphetamine abuse. PMID:28575091

  11. Salt-induced epithelial-to-mesenchymal transition in Dahl salt-sensitive rats is dependent on elevated blood pressure

    International Nuclear Information System (INIS)

    Wang, Y.; Mu, J.J.; Liu, F.Q.; Ren, K.Y.; Xiao, H.Y.; Yang, Z.; Yuan, Z.Y.

    2014-01-01

    Dietary salt intake has been linked to hypertension and cardiovascular disease. Accumulating evidence has indicated that salt-sensitive individuals on high salt intake are more likely to develop renal fibrosis. Epithelial-to-mesenchymal transition (EMT) participates in the development and progression of renal fibrosis in humans and animals. The objective of this study was to investigate the impact of a high-salt diet on EMT in Dahl salt-sensitive (SS) rats. Twenty-four male SS and consomic SS-13 BN rats were randomized to a normal diet or a high-salt diet. After 4 weeks, systolic blood pressure (SBP) and albuminuria were analyzed, and renal fibrosis was histopathologically evaluated. Tubular EMT was evaluated using immunohistochemistry and real-time PCR with E-cadherin and alpha smooth muscle actin (α-SMA). After 4 weeks, SBP and albuminuria were significantly increased in the SS high-salt group compared with the normal diet group. Dietary salt intake induced renal fibrosis and tubular EMT as identified by reduced expression of E-cadherin and enhanced expression of α-SMA in SS rats. Both blood pressure and renal interstitial fibrosis were negatively correlated with E-cadherin but positively correlated with α-SMA. Salt intake induced tubular EMT and renal injury in SS rats, and this relationship might depend on the increase in blood pressure

  12. Evaluation of renal resistive index in cirrhotic patients for predicting the hepatirenal syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Baek, Seung Yon; Kim, Hyae young; Yi, Sun Young [Ewha WoMans Univ. Mokdong Hospital, Seoul (Korea, Republic of)

    1996-04-01

    To evaluate the usefulness of renal resistive index(RI) in patients with liver cirrhosis as an indicator for predicting hepatorenal syndrome. Renal RIs of thirty cirrhotic patients were analyzed using the gray-scale and Doppler ultrasonograms. As a control group, eight normal subjects were included. Renal RIs were measured at three sites of interlobar or arcuate arteries of both kidneys. The patients were divided into three groups (A, B, or C) according to the Child-Turcotte-Pugh classification and their serum BUN and creatinine levels were compared. We determined whether RIs of normal controls differed from those of cirrhotic patients or whether RIs of cirrhotic patients correlated with the Child-Turcotte-Pugh classification or BUN and creatinine levels. Mean RIs(0.63 {+-}0.33) of normal subjects were statistically different from those(0.67 {+-} 0.05) of cirrhotic patients(P=0.009). RIs of group A(n=6), B(n=9) and C(n=15) were 0.65 {+-} 0.03, 0.65 {+-} 0.04 and 0.70 {+-} 0.04, respectively. The ANOVA test revealed statistically significant differences between the three groups(F ratio=4.472, P=0.021). RIs did not correlate with BUN or creatinine levels. RI could be used as an index for predicting hepatorenal syndrome before the renal function becomes impaired.

  13. Evaluation of renal resistive index in cirrhotic patients for predicting the hepatirenal syndrome

    International Nuclear Information System (INIS)

    Baek, Seung Yon; Kim, Hyae young; Yi, Sun Young

    1996-01-01

    To evaluate the usefulness of renal resistive index(RI) in patients with liver cirrhosis as an indicator for predicting hepatorenal syndrome. Renal RIs of thirty cirrhotic patients were analyzed using the gray-scale and Doppler ultrasonograms. As a control group, eight normal subjects were included. Renal RIs were measured at three sites of interlobar or arcuate arteries of both kidneys. The patients were divided into three groups (A, B, or C) according to the Child-Turcotte-Pugh classification and their serum BUN and creatinine levels were compared. We determined whether RIs of normal controls differed from those of cirrhotic patients or whether RIs of cirrhotic patients correlated with the Child-Turcotte-Pugh classification or BUN and creatinine levels. Mean RIs(0.63 ±0.33) of normal subjects were statistically different from those(0.67 ± 0.05) of cirrhotic patients(P=0.009). RIs of group A(n=6), B(n=9) and C(n=15) were 0.65 ± 0.03, 0.65 ± 0.04 and 0.70 ± 0.04, respectively. The ANOVA test revealed statistically significant differences between the three groups(F ratio=4.472, P=0.021). RIs did not correlate with BUN or creatinine levels. RI could be used as an index for predicting hepatorenal syndrome before the renal function becomes impaired

  14. A low muscle mass increases mortality in compensated cirrhotic patients with sepsis.

    Science.gov (United States)

    Lucidi, Cristina; Lattanzi, Barbara; Di Gregorio, Vincenza; Incicco, Simone; D'Ambrosio, Daria; Venditti, Mario; Riggio, Oliviero; Merli, Manuela

    2018-05-01

    Severe infections and muscle wasting are both associated to poor outcome in cirrhosis. A possible synergic effect of these two entities in cirrhotic patients has not been previously investigated. We aimed at analysing if a low muscle mass may deteriorate the outcome of cirrhotic patients with sepsis. Consecutive cirrhotic patients hospitalized for sepsis were enrolled in the study. Patients were classified for the severity of liver impairment (Child-Pugh class) and for the presence of "low muscle mass" (mid-arm muscle circumferencelow muscle mass. In patients with and without low muscle mass, severity of liver disease and characteristics of infections were similar. Mortality tended to be higher in patients with low muscle mass (47% vs 26%, P = .06). A multivariate analysis selected low muscle mass (P low muscle mass compared with those without (50% vs 16%; P = .01). The mortality rate and the incidence of complications in malnourished patients classified in Child-Pugh A-B were similar to those Child-Pugh C. Low muscle mass worsen prognosis in cirrhotic patients with severe infections. This is particularly evident in patients with Child A-B cirrhosis in whom the coexistence of low muscle mass and sepsis caused a negative impact on mortality similar to that observable in all Child C patients with sepsis. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  15. Non-variceal upper gastrointestinal bleeding in cirrhotic patients in Nile Delta.

    Science.gov (United States)

    Gabr, Mamdouh Ahmed; Tawfik, Mohamed Abd El-Raouf; El-Sawy, Abd Allah Ahmed

    2016-01-01

    Acute upper gastrointestinal bleeding (AUGIB) in cirrhotic patients occurs mainly from esophageal and gastric varices; however, quite a large number of cirrhotic patients bleed from other sources as well. The aim of the present work is to determine the prevalence of non-variceal UGIB as well as its different causes among the cirrhotic portal hypertensive patients in Nile Delta. Emergency upper gastrointestinal (UGI) endoscopy for AUGIB was done in 650 patients. Out of these patients, 550 (84.6%) patients who were proved to have cirrhosis were the subject of the present study. From all cirrhotic portal hypertensive patients, 415 (75.5%) bled from variceal sources (esophageal and gastric) while 135 (24.5%) of them bled from non-variceal sources. Among variceal sources of bleeding, esophageal varices were much more common than gastric varices. Peptic ulcer was the most common non-variceal source of bleeding. Non-variceal bleeding in cirrhosis was not frequent, and sources included peptic ulcer, portal hypertensive gastropathy, and erosive disease of the stomach and duodenum.

  16. Aging-Dependent Changes in the Radiation Response of the Adult Rat Brain

    International Nuclear Information System (INIS)

    Schindler, Matthew K.; Forbes, M. Elizabeth; Robbins, Mike E.; Riddle, David R.

    2008-01-01

    Purpose: To assess the impact of aging on the radiation response in the adult rat brain. Methods and Materials: Male rats 8, 18, or 28 months of age received a single 10-Gy dose of whole-brain irradiation (WBI). The hippocampal dentate gyrus was analyzed 1 and 10 weeks later for sensitive neurobiologic markers associated with radiation-induced damage: changes in density of proliferating cells, immature neurons, total microglia, and activated microglia. Results: A significant decrease in basal levels of proliferating cells and immature neurons and increased microglial activation occurred with normal aging. The WBI induced a transient increase in proliferation that was greater in older animals. This proliferation response did not increase the number of immature neurons, which decreased after WBI in young rats, but not in old rats. Total microglial numbers decreased after WBI at all ages, but microglial activation increased markedly, particularly in older animals. Conclusions: Age is an important factor to consider when investigating the radiation response of the brain. In contrast to young adults, older rats show no sustained decrease in number of immature neurons after WBI, but have a greater inflammatory response. The latter may have an enhanced role in the development of radiation-induced cognitive dysfunction in older individuals

  17. Sex-dependent effects of fluoxetine and triiodothyronine in the forced swim test in rats.

    Science.gov (United States)

    Lifschytz, Tzuri; Shalom, Galit; Lerer, Bernard; Newman, Michael E

    2006-02-01

    The effects of triiodothyronine (T3) and fluoxetine, administered separately and combined, on behavior of male and female rats in the forced swim test, a procedure for screening antidepressant-like activity, were determined. There were no consistent effects of low doses of fluoxetine (5 mg/kg) or T3 (20 microg/kg), administered daily for 2 weeks. Fluoxetine administered daily at 10 mg/kg for 7 days reduced immobility and increased active behaviors in male rats, but had no effects in female rats. The effects of fluoxetine in male rats were not potentiated by T3. In female rats, T3 at 100 microg/kg given daily for 7 days decreased immobility and increased swimming when these were measured 72 h after the last injection, but not when measurements were performed at an earlier time point. These results provide some support from an animal model for the efficacy of T3 as antidepressant therapy in female patients, but do not provide support for the augmentation and acceleration effects seen clinically when T3 is used in conjunction with established antidepressants such as fluoxetine.

  18. Effect of prolonged incubation with copper on endothelium-dependent relaxation in rat isolated aorta

    Science.gov (United States)

    Chiarugi, Alberto; Pitari, Giovanni Mario; Costa, Rosa; Ferrante, Margherita; Villari, Loredana; Amico-Roxas, Matilde; Godfraind, Théophile; Bianchi, Alfredo; Salomone, Salvatore

    2002-01-01

    We investigated the effects of prolonged exposure to copper (Cu2+) on vascular functioning of isolated rat aorta. Aortic rings were exposed to CuSO4 (3–24 h) in Dulbecco's modified Eagle medium with or without 10% foetal bovine serum (FBS) and then challenged with vasoconstrictors or vasodilators in the absence of Cu2+. Exposure to 2 μM Cu2+ in the absence of FBS did not modify the response to phenylephrine (PE) or acetylcholine (ACh) in aortic rings incubated for 24 h. Identical exposure in the presence of FBS increased the contractile response to 1 μM PE by 30% (P<0.05) and impaired the relaxant response to 3 μM ACh or 1 μM A23187 (ACh, from 65.7±7.1 to 6.2±1.1%, n=8; A23187, from 74.6±8.2 to 12.0±0.8%, n=6; P<0.01 for both). Cu2+ exposure did not affect the relaxant response to NO-donors. Impairment of vasorelaxation appeared 3 h after incubation with 2 μM Cu2+ and required 12 h to attain a steady state. Vasorelaxation to ACh was partially restored by 1 mM tiron (intracellular scavenger of superoxide ions; maximum relaxation 34.2±6.4%, n=10, P<0.01 vs Cu2+ alone), whereas catalase, superoxide dismutase or cycloheximide were ineffective. Twenty-four hour-exposure to 2 μM Cu2+ did not affect endothelium integrity or eNOS expression, and increased the Cu content in arterial rings from 6.8±1.1 to 18.9±2.9 ng mg−1 wet weight, n=8; P<0.01. Our results show that, in the presence of FBS, prolonged exposure to submicromolar concentrations of Cu2+ impaired endothelium-dependent vasorelaxation in aortic rings, probably through an intracellular generation of superoxide ions. PMID:12163352

  19. Cardiac systolic function in cirrhotic patients’ candidate of liver trans-plantation compared with control group

    Directory of Open Access Journals (Sweden)

    Roya Sattarzadeh-Badkoubeh

    2017-02-01

    Full Text Available Background: We assessed different systolic cardiac indices to describe left and right ventricular dysfunction in cirrhotic patients before liver transplantation. Methods: In this case-control study, eighty-one consecutive individuals with the confirmed hepatic cirrhosis and candidate for liver transplantation in the Imam Khomeini Hospital between March 2008 and March 2010 were selected. Thirty-two age and gender cross-matched healthy volunteers were also selected as the control group. A detailed two-dimensional and Doppler echocardiography was obtained in all patients and controls performed by the same operator on the day of admission. Results: Dimensions of both left and right atriums as well as left ventricular end-diastolic volume and basal right ventricular dimension in the cirrhotic group were significantly higher than control group. Left ventricular end-systolic dimensions as well as aortic annulus diameter were not different between the two study groups. Left ventricular outflow tract velocity time integral, isovolumic pre-ejection time, isovolumic relaxation time, stroke volume, left ventricular ejection fraction, IVCT+IVRT+ET, systolic velocity of tricuspid annulus, systolic velocity of basal segment of RV free wall, systolic velocity of basal segment of septal wall, peak strain of septal margin (base, peak strain of septal margin (midpoint, peak strain of lateral margin (midpoint, strain rate of septal margin (base, strain rate of septal margin (midpoint, strain rate of lateral margin (base, strain rate of lateral margin (midpoint, Tei index (left and right ventricles, systolic time interval and tricuspid annular plane systolic excursion were higher in cirrhotic group, significantly, (P< 0.05. Left ventricular ejection time and systolic velocity of mid segment of lateral wall were lower in cirrhotic group, significantly, (P< 0.05. Conclusion: In this study, the effects of liver on heart were volume overload, hyperdynamic state and

  20. Assessment of tumor vascularization with functional computed tomography perfusion imaging in patients with cirrhotic liver disease.

    Science.gov (United States)

    Li, Jin-Ping; Zhao, De-Li; Jiang, Hui-Jie; Huang, Ya-Hua; Li, Da-Qing; Wan, Yong; Liu, Xin-Ding; Wang, Jin-E

    2011-02-01

    Hepatocellular carcinoma (HCC) is a common malignant tumor in China, and early diagnosis is critical for patient outcome. In patients with HCC, it is mostly based on liver cirrhosis, developing from benign regenerative nodules and dysplastic nodules to HCC lesions, and a better understanding of its vascular supply and the hemodynamic changes may lead to early tumor detection. Angiogenesis is essential for the growth of primary and metastatic tumors due to changes in vascular perfusion, blood volume and permeability. These hemodynamic and physiological properties can be measured serially using functional computed tomography perfusion (CTP) imaging and can be used to assess the growth of HCC. This study aimed to clarify the physiological characteristics of tumor angiogenesis in cirrhotic liver disease by this fast imaging method. CTP was performed in 30 volunteers without liver disease (control subjects) and 49 patients with liver disease (experimental subjects: 27 with HCC and 22 with cirrhosis). All subjects were also evaluated by physical examination, laboratory screening and Doppler ultrasonography of the liver. The diagnosis of HCC was made according to the EASL criteria. All patients underwent contrast-enhanced ultrasonography, pre- and post-contrast triple-phase CT and CTP study. A mathematical deconvolution model was applied to provide hepatic blood flow (HBF), hepatic blood volume (HBV), mean transit time (MTT), permeability of capillary vessel surface (PS), hepatic arterial index (HAI), hepatic arterial perfusion (HAP) and hepatic portal perfusion (HPP) data. The Mann-Whitney U test was used to determine differences in perfusion parameters between the background cirrhotic liver parenchyma and HCC and between the cirrhotic liver parenchyma with HCC and that without HCC. In normal liver, the HAP/HVP ratio was about 1/4. HCC had significantly higher HAP and HAI and lower HPP than background liver parenchyma adjacent to the HCC. The value of HBF at the tumor

  1. Histone demethylase retinoblastoma binding protein 2 regulates the expression of α-smooth muscle actin and vimentin in cirrhotic livers

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Q. [Department of Microbiology, Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Medicine, Shandong University, Jinan (China); Wang, L.X. [Department of Pharmacology, School of Medicine, Shandong University, Jinan (China); Zeng, J.P. [Department of Biochemistry, School of Medicine, Shandong University, Jinan (China); Liu, X.J.; Liang, X.M.; Zhou, Y.B. [Department of Microbiology, Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Medicine, Shandong University, Jinan (China)

    2013-09-06

    Liver cirrhosis is one of the most common diseases of Chinese patients. Herein, we report the high expression of a newly identified histone 3 lysine 4 demethylase, retinoblastoma binding protein 2 (RBP2), and its role in liver cirrhosis in humans. The siRNA knockdown of RBP2 expression in hepatic stellate cells (HSCs) reduced levels of α-smooth muscle actin (α-SMA) and vimentin and decreased the proliferation of HSCs; and overexpression of RBP2 increased α-SMA and vimentin levels. Treatment with transforming growth factor β (TGF-β) upregulated the expression of RBP2, α-SMA, and vimentin, and the siRNA knockdown of RBP2 expression attenuated TGF-β-mediated upregulation of α-SMA and vimentin expression and HSC proliferation. Furthermore, RBP2 was highly expressed in cirrhotic rat livers. Therefore, RBP2 may participate in the pathogenesis of liver cirrhosis by regulating the expression of α-SMA and vimentin. RBP2 may be a useful marker for the diagnosis and treatment of liver cirrhosis.

  2. Histone demethylase retinoblastoma binding protein 2 regulates the expression of α-smooth muscle actin and vimentin in cirrhotic livers

    International Nuclear Information System (INIS)

    Wang, Q.; Wang, L.X.; Zeng, J.P.; Liu, X.J.; Liang, X.M.; Zhou, Y.B.

    2013-01-01

    Liver cirrhosis is one of the most common diseases of Chinese patients. Herein, we report the high expression of a newly identified histone 3 lysine 4 demethylase, retinoblastoma binding protein 2 (RBP2), and its role in liver cirrhosis in humans. The siRNA knockdown of RBP2 expression in hepatic stellate cells (HSCs) reduced levels of α-smooth muscle actin (α-SMA) and vimentin and decreased the proliferation of HSCs; and overexpression of RBP2 increased α-SMA and vimentin levels. Treatment with transforming growth factor β (TGF-β) upregulated the expression of RBP2, α-SMA, and vimentin, and the siRNA knockdown of RBP2 expression attenuated TGF-β-mediated upregulation of α-SMA and vimentin expression and HSC proliferation. Furthermore, RBP2 was highly expressed in cirrhotic rat livers. Therefore, RBP2 may participate in the pathogenesis of liver cirrhosis by regulating the expression of α-SMA and vimentin. RBP2 may be a useful marker for the diagnosis and treatment of liver cirrhosis

  3. Oxidative stress-dependent contribution of HMGB1 to the interplay between apoptosis and autophagy in diabetic rat liver.

    Science.gov (United States)

    Petrović, Anja; Bogojević, Desanka; Korać, Aleksandra; Golić, Igor; Jovanović-Stojanov, Sofija; Martinović, Vesna; Ivanović-Matić, Svetlana; Stevanović, Jelena; Poznanović, Goran; Grigorov, Ilijana

    2017-11-01

    The progression of oxidative stress, resulting cell damage, and cell death underlies the etiology of liver damage/dysfunction as a complication of diabetes. High-mobility group box 1 (HMGB1) protein, a chromatin-binding nuclear protein and damage-associated molecular pattern molecule, is integral to oxidative stress and signaling pathways regulating cell death and cell survival. We previously found that in streptozotocin (STZ)-induced diabetic rats, reduction of oxidative stress after melatonin administration lowered necrotic cell death and increased expression of HMGB1 and hepatocellular damage. In the present study, we examined whether alleviation of diabetes-attendant oxidative stress and ensuing change in HMGB1 expression influence the dynamic equilibrium between apoptosis/autophagy and liver damage. We observed that elevated HMGB1 protein levels in diabetic rat liver accompanied increased interactions of HMGB1 with TLR4 and RAGE, and activation of the intrinsic apoptotic pathway and Beclin 1-dependent autophagy. The absence of p62 degradation in diabetic rat liver pointed to defective autophagy which was responsible for lower autophagosome/autophagolysosome formation and an increased apoptosis/autophagy ratio. Compared to diabetic rats, in melatonin-treated diabetic rats, the structure of liver cells was preserved, HMGB1/TLR4 interaction and downstream apoptotic signaling were significantly reduced, HMGB1/Beclin 1 colocalization and interactions were augmented and Beclin 1-mediated autophagy, mithophagy in particular, were increased. We concluded that in mild oxidative stress, HMGB1 is cytoprotective, whereas in intense oxidative stress, HMGB1 actions promote cell death and liver damage. Since reduced HMGB1 binds to RAGE but not to TLR4, redox modification of HMGB1 as a mechanism regulating the cross-talk between apoptosis and autophagy in diabetes is discussed.

  4. Intervention effect and dose-dependent response of tanreqing injection on airway inflammation in lipopolysaccharide-induced rats.

    Science.gov (United States)

    Dong, Shoujin; Zhong, Yunqing; Yang, Kun; Xiong, Xiaoling; Mao, Bing

    2013-08-01

    To assess the effect of Tanreqing injection on airway inflammation in rats. A rat model of airway inflammation was generated with lipopolysaccharide (LPS). Tanreqing injection was given by intratracheal instillation, and bronchoalveolar lavage fluid (BALF) from the right lung was collected. BALF total cell and neutrophil counts were then determined. In addition, BALF levels of inflammatory cytokines interleukin-13, cytokine-induced neutrophil chemoat-tractant-1, and tumor necrosis factor-alpha were measured using enzyme linked immunosorbent assay. The middle lobe of the right lung was stained with hematoxylin-eosin and histological changes examined. LPS increased airway inflammation, decreased BALF inflammatory cell count, inflammatory cytokine levels, and suppressed leukocyte influx of the lung. The LPS-induced airway inflammation peaked at 24 h, decreased beginning at 48 h, and had decreased markedly by 96 h. Tanreqing injection contains anti-inflammatory properties, and inhibits airway inflammation in a dose-dependent manner.

  5. Loss of predator aversion in female rats after Toxoplasma gondii infection is not dependent on ovarian steroids.

    Science.gov (United States)

    Abdulai-Saiku, Samira; Vyas, Ajai

    2017-10-01

    Toxoplasma gondii infection reduces aversion to cat odors in male rats. Relevant proximate mechanisms include interaction of gonadal testosterone and brain nonapeptide arginine-vasopressin. Both of these substrates are sexually dimorphic with preferential expression in males; suggesting either absence of behavioral change in females or mediation by analogous neuroendocrine substrates. Here we demonstrate that Toxoplasma gondii infection reduces aversion to cat odor in female rats. This change is not accompanied by altered steroid hormones; cannot be rescued by gonadal removal; and, does not depend on arginine-vasopressin. Thus behavioral change in males and female occur through non-analogous mechanisms that remain hitherto unknown. Copyright © 2017 Elsevier Inc. All rights reserved.

  6. Agmatine induced NO dependent rat mesenteric artery relaxation and its impairment in salt-sensitive hypertension.

    Science.gov (United States)

    Gadkari, Tushar V; Cortes, Natalie; Madrasi, Kumpal; Tsoukias, Nikolaos M; Joshi, Mahesh S

    2013-11-30

    l-Arginine and its decarboxylated product, agmatine are important mediators of NO production and vascular relaxation. However, the underlying mechanisms of their action are not understood. We have investigated the role of arginine and agmatine in resistance vessel relaxation of Sprague-Dawley (SD) and Dahl salt-sensitive hypertensive rats. Second or 3rd-order mesenteric arterioles were cannulated in an organ chamber, pressurized and equilibrated before perfusing intraluminally with agonists. The vessel diameters were measured after mounting on the stage of a microscope fitted with a video camera. The gene expression in Dahl rat vessel homogenates was ascertained by real-time PCR. l-Arginine initiated relaxations (EC50, 5.8±0.7mM; n=9) were inhibited by arginine decarboxylase (ADC) inhibitor, difluoromethylarginine (DFMA) (EC50, 18.3±1.3mM; n=5) suggesting that arginine-induced vessel relaxation was mediated by agmatine formation. Agmatine relaxed the SD rat vessels at significantly lower concentrations (EC50, 138.7±12.1μM; n=22), which was compromised by l-NAME (l-N(G)-nitroarginine methyl ester, an eNOS inhibitor), RX821002 (α-2 AR antagonist) and pertussis toxin (G-protein inhibitor). The agmatine-mediated vessel relaxation from high salt Dahl rats was abolished as compared to that from normal salt rats (EC50, 143.9±23.4μM; n=5). The α-2A AR, α-2B AR and eNOS mRNA expression was downregulated in mesenteric arterioles of high-salt treated Dahl hypertensive rats. These findings demonstrate that agmatine facilitated the relaxation via activation of α-2 adrenergic G-protein coupled receptor and NO synthesis, and this pathway is compromised in salt-sensitive hypertension. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Ethanol affects acylated and total ghrelin levels in peripheral blood of alcohol-dependent rats.

    Science.gov (United States)

    Szulc, Michal; Mikolajczak, Przemyslaw L; Geppert, Bogna; Wachowiak, Roman; Dyr, Wanda; Bobkiewicz-Kozlowska, Teresa

    2013-07-01

    There is a hypothesis that ghrelin could take part in the central effects of alcohol as well as function as a peripheral indicator of the changes which occur during long-term alcohol consumption. The aim of this study was to determine a correlation between alcohol concentration and acylated and total form of ghrelin after a single administration of alcohol (intraperitoneal, i.p.) (experiment 1) and prolonged ethanol consumption (experiment 2). The study was performed using Wistar alcohol preferring (PR) and non-preferring (NP) rats and rats from inbred line (Warsaw High Preferring, WHP; Warsaw Low Preferring, WLP). It was found that ghrelin in ethanol-naive WHP animals showed a significantly lower level when compared with the ethanol-naive WLP or Wistar rats. After acute ethanol administration in doses of 1.0; 2.0 and 4.0 g/kg, i.p., the simple (WHP) or inverse (WLP and Wistar) relationship between alcohol concentration and both form of ghrelin levels in plasma were found. Chronic alcohol intake in all groups of rats led to decrease of acylated ghrelin concentration. PR and WHP rats, after chronic alcohol drinking, had lower levels of both form of ghrelin in comparison with NP and WLP rats, respectively, and the observed differences in ghrelin levels were in inverse relationship with their alcohol intake. In conclusion, it is suggested that there is a strong relationship between alcohol administration or intake, ethanol concentration in blood and both active and total ghrelin level in the experimental animals, and that ghrelin plasma concentration can be a marker of alcohol drinking predisposition. © 2013 The Authors, Addiction Biology © 2013 Society for the Study of Addiction.

  8. Motor System Development Depends on Experience: A Microgravity Study of Rats

    Science.gov (United States)

    Walton, Kerry D.; Llinas, Rodolfo R.; Kalb, Robert; Hillman, Dean; DeFelipe, Javier; Garcia-Segura, Luis Miguel

    2003-01-01

    Animals move about their environment by sensing their surroundings and making adjustments according to need. All animals take the force of gravity into account when the brain and spinal cord undertake the planning and execution of movements. To what extent must animals learn to factor in the force of gravity when making neural calculations about movement? Are animals born knowing how to respond to gravity, or must the young nervous system learn to enter gravity into the equation? To study this issue, young rats were reared in two different gravitational environments (the one-G of Earth and the microgravity of low Earth orbit) that necessitated two different types of motor operations (movements) for optimal behavior. We inquired whether those portions of the young nervous system involved in movement, the motor system, can adapt to different gravitational levels and, if so, the cellular basis for this phenomenon. We studied two groups of rats that had been raised for 16 days in microgravity (eight or 14 days old at launch) and compared their walking and righting (ability to go from upside down to upright) and brain structure to those of control rats that developed on Earth. Flight rats were easily distinguished from the age-matched ground control rats in terms of both motor function and central nervous system structure. Mature surface righting predominated in control rats on the day of landing (R+O), while immature righting predominated in the flight rats on landing day and 30 days after landing. Some of these changes appear to be permanent. Several conclusions can be drawn from these studies: (1) Many aspects of motor behavior are preprogrammed into the young nervous system. In addition, several aspects of motor behavior are acquired as a function of the interaction of the developing organism and the rearing environment; (2) Widespread neuroanatomical differences between one-G- and microgravity-reared rats indicate that there is a structural basis for the adaptation

  9. Hepatocellular Carcinoma Surveillance Rates in Commercially Insured Patients with Non-Cirrhotic Chronic Hepatitis B

    Science.gov (United States)

    Goldberg, David S.; Valderrama, Adriana; Kamalakar, Rajesh; Sansgiry, Sujit S; Babajanyan, Svetlana; Lewis, James D.

    2015-01-01

    AASLD and EASL guidelines recommend biannual hepatocellular carcinoma (HCC) screening for non-cirrhotic patients with chronic hepatitis B infection (HBV), yet there are no data estimating surveillance rates or factors associated with surveillance. We performed a retrospective cohort study of U.S. patients using the Truven Health Analytics databases from 2006-2010, and identified patients with non-cirrhotic chronic HBV. Surveillance patterns were characterized using categorical and continuous outcomes, with the continuous measure of the proportion of time “up-to-date” with surveillance (PUTDS), with the six-month interval following each ultrasound categorized as “up-to-date.” During a median follow-up of 26.0 (IQR: 16.2-40.0) months among 4,576 non-cirrhotic patients with chronic HBV (median age: 44 years, IQR: 36-52), only 306 (6.7%) had complete surveillance (one ultrasound every 6-month interval), 2,727 (59.6%) incomplete (≥1 ultrasound), and 1,543 (33.7%) none. The mean PUTDS was 0.34 ± 0.29, and the median was 0.32 (IQR: 0.03-0.52). In multinomial logistic regression models, patients diagnosed by a non-gastroenterologist were significantly less likely to have complete surveillance (psurveillance. Patients with HIV had an absolute decrease in the PUTDS of 0.24, while patients in less populated rural areas had an absolute decrease of 0.10. HCC surveillance rates in non-cirrhotic patients with chronic HBV in the United States are poor, and lower than reported rates of HCC surveillance in cirrhotic patients. PMID:25581816

  10. Neomysin inhibits Ca2+-stimulated phosphatidylinositol hydrolysis and protects cultured rat cardiomyocytes from Ca2+-dependent cell injury

    International Nuclear Information System (INIS)

    Babson, J.R.; Dougherty, J.M.

    1991-01-01

    Exposure of cultured rat cardiomyocytes to ionomycin and extracellular Ca 2+ leads to a rapid, sustained increase in intracellular free Ca 2+ as monitored by Ca 2+ -dependent phosphorylase a activation and to a subsequent loss of cardiomyocyte viability as determined by lactate dehydrogenase (LDH) leakage. The intracellular free Ca 2+ increase coincided with a rapid hydrolysis of phosphatidylinositol that preceded cell death. Phosphatidylinositol hydrolysis was monitored by the release of radiolabeled phosphoinositides from cardiomyocytes prelabeled with [2- 3 H]-myo-inositol. Neomycin, a known inhibitor of phospholipase C, inhibited the phosphatidylinositol hydrolysis and markedly reduced the extent of cell injury. Inhibitors of other Ca 2+ -activated processes, including intracellular proteases and phospholipase A 2 , had no effect on ionomycin-mediated cell injury. These data suggest that ionomycin-induced Ca 2+ -dependent cell injury in cultured cardiomyocytes may be due in part to the stimulation of phosphatidylinositol hydrolysis, presumably catalyzed by a Ca 2+ -dependent phospholipase C

  11. Inhibitory effect of metformin on oxidation of NADH-dependent substrates in rat liver homogenate

    Czech Academy of Sciences Publication Activity Database

    Páleníčková, E.; Cahová, M.; Drahota, Zdeněk; Kazdová, L.; Kalous, M.

    2011-01-01

    Roč. 60, č. 5 (2011), s. 835-839 ISSN 0862-8408 R&D Projects: GA MZd NS10504 Institutional research plan: CEZ:AV0Z50110509 Keywords : Metformin * mitochondrial respiration * rat liver homogenate Subject RIV: FB - Endocrinology, Diabetology, Metabolism, Nutrition Impact factor: 1.555, year: 2011

  12. CYTOCHROME P450-DEPENDENT METABOLISM OF TRICHLOROETHYLENE IN THE RAT KIDNEY

    Science.gov (United States)

    The metabolism of trichloroethylene (Tri) by cytochrome P450 (P450) was studied in microsomes from liver and kidney homogenates and from isolated renal proximal tubular (PT) and distal tubular (DT) cells from male Fischer 344 rats. Chloral hydrate (CH) was the only metabolite con...

  13. Age-dependent external root resorption during tooth movement in rats

    NARCIS (Netherlands)

    Ren, Yijin; Maltha, Jaap C.; Liem, Robert S. B.; Stokroos, Ietse; Kuijpers-Jagtman, Anne Marie

    OBJECTIVE: To investigate the effect of age on root resorption and distribution along different parts of the root during prolonged light force application. MATERIAL AND METHODS: Orthodontic appliances were placed in two groups of 30 rats (one group 6 weeks old, the other 9-12 months old), with

  14. Age-dependent external root resorption during tooth movement in rats.

    NARCIS (Netherlands)

    Ren, Y.; Maltha, J.C.; Liem, R.S.; Stokroos, I.; Kuijpers-Jagtman, A.M.

    2008-01-01

    OBJECTIVE: To investigate the effect of age on root resorption and distribution along different parts of the root during prolonged light force application. MATERIAL AND METHODS: Orthodontic appliances were placed in two groups of 30 rats (one group 6 weeks old, the other 9-12 months old), with

  15. Swimming exercise attenuates psychological dependence and voluntary methamphetamine consumption in methamphet- amine withdrawn rats

    Directory of Open Access Journals (Sweden)

    Fatemeh Damghani

    2016-06-01

    Conclusion: This study showed that regular swimming exercise reduced voluntary METH consumption in animal models of craving by reducing anxiety, OCD, and depression in the METH-withdrawn rats. Thus, physical training may be ameliorating some of the withdrawal behavioral consequences of METH.

  16. Stress susceptibility as a determinant of endothelium-dependent vascular reactivity in rat mesenteric arteries.

    NARCIS (Netherlands)

    Riksen, N.P.; Ellenbroek, B.A.; Cools, A.R.; Siero, H.L.M.; Rongen, G.A.P.J.M.; Smits, B.W.; Russel, F.G.M.; Smits, P.

    2003-01-01

    In order to investigate the consequences of stress susceptibility on vascular function, the authors assessed the respective contributions of nitric oxide (NO), prostanoids, and endothelium-derived hyperpolarizing factor to the vascular tone in rats with a constitutionally determined high and low

  17. Repeated stress exposure causes strain-dependent shifts in the behavioral economics of cocaine in rats

    NARCIS (Netherlands)

    Groblewski, Peter A.; Zietz, Chad; Willuhn, Ingo; Phillips, Paul E. M.; Chavkin, Charles

    2015-01-01

    Cocaine-experienced Wistar and Wistar Kyoto (WKY) rats received four daily repeated forced swim stress sessions (R-FSS), each of which preceded 4-hour cocaine self-administration sessions. Twenty-four hours after the last swim stress, cocaine valuation was assessed during a single-session threshold

  18. Ethyl benzene-induced ototoxicity in rats : a dose-dependent mild-frequency hearing loss

    NARCIS (Netherlands)

    Cappaert, N.L.M.; Klis, S.F.L.; Baretta, A.B.; Muijser, H.; Smoorenburg, G.F.

    2000-01-01

    Rats were exposed to ethyl benzene at 0, 300, 400 and 550 ppm for 8 hours/day for 5 consecutive days. Three to six weeks after the exposure, auditory function was tested by measuring compound action potentials (CAP) in the frequency range of 1-24 kHz and 2f1-f2 distortion product otoacoustic

  19. Age dependent effects of combined irradiation on lipid peroxidation in rat blood

    International Nuclear Information System (INIS)

    Mazhul', L.M.; Volykhina, V.E.; Gatsko, G.G.

    2000-01-01

    It was studied the effects of combined action of external acute gamma-irradiation in dose 1.0 Gy and chronic internal irradiation of cesium 137 (0.8 MBq/kg) on lipid peroxidation system in rat blood. Animals of two aged groups (2 and 6 months old) was investigated. The experiments were conducted on 10, 30, 90 and 180 days after the cessation of cesium 137 injection. Internal irradiation didn't exert influence on lipid peroxidation system in blood. Antioxidant system was activated on 10 days after acute irradiation at 2-months old animals and by 180 days at 6-months ones. In the case of combined irradiation activation of the antioxidant system in blood serum of 2-months old rats in early terms (10 days) possibly supports the invariable level of lipid peroxidation products. At 6-months old rats, on the contrary, the activation of the antioxidant system was not registered, however the content of malonic dialdehyde was increased. Possibly, at 2-months old rats the combined irradiation in early terms stimulates the protective systems of the organism in higher degree than at 6-months old ones

  20. Reciprocal cooperation between unrelated rats depends on cost to donor and benefit to recipient

    Directory of Open Access Journals (Sweden)

    Schneeberger Karin

    2012-03-01

    Full Text Available Abstract Background Although evolutionary models of cooperation build on the intuition that costs of the donor and benefits to the receiver are the most general fundamental parameters, it is largely unknown how they affect the decision of animals to cooperate with an unrelated social partner. Here we test experimentally whether costs to the donor and need of the receiver decide about the amount of help provided by unrelated rats in an iterated prisoner's dilemma game. Results Fourteen unrelated Norway rats were alternately presented to a cooperative or defective partner for whom they could provide food via a mechanical apparatus. Direct costs for this task and the need of the receiver were manipulated in two separate experiments. Rats provided more food to cooperative partners than to defectors (direct reciprocity. The propensity to discriminate between helpful and non-helpful social partners was contingent on costs: An experimentally increased resistance in one Newton steps to pull food for the social partner reduced the help provided to defectors more strongly than the help returned to cooperators. Furthermore, test rats provided more help to hungry receivers that were light or in poor condition, which might suggest empathy, whereas this relationship was inverse when experimental partners were satiated. Conclusions In a prisoner's dilemma situation rats seem to take effect of own costs and potential benefits to a receiver when deciding about helping a social partner, which confirms the predictions of reciprocal cooperation. Thus, factors that had been believed to be largely confined to human social behaviour apparently influence the behaviour of other social animals as well, despite widespread scepticism. Therefore our results shed new light on the biological basis of reciprocity.

  1. Focal Stroke in the Developing Rat Motor Cortex Induces Age- and Experience-Dependent Maladaptive Plasticity of Corticospinal System.

    Science.gov (United States)

    Gennaro, Mariangela; Mattiello, Alessandro; Mazziotti, Raffaele; Antonelli, Camilla; Gherardini, Lisa; Guzzetta, Andrea; Berardi, Nicoletta; Cioni, Giovanni; Pizzorusso, Tommaso

    2017-01-01

    Motor system development is characterized by an activity-dependent competition between ipsilateral and contralateral corticospinal tracts (CST). Clinical evidence suggests that age is crucial for developmental stroke outcome, with early lesions inducing a "maladaptive" strengthening of ipsilateral projections from the healthy hemisphere and worse motor impairment. Here, we investigated in developing rats the relation between lesion timing, motor outcome and CST remodeling pattern. We induced a focal ischemia into forelimb motor cortex (fM1) at two distinct pre-weaning ages: P14 and P21. We compared long-term motor outcome with changes in axonal sprouting of contralesional CST at red nucleus and spinal cord level using anterograde tracing. We found that P14 stroke caused a more severe long-term motor impairment than at P21, and induced a strong and aberrant contralesional CST sprouting onto denervated spinal cord and red nucleus. The mistargeted sprouting of CST, and the worse motor outcome of the P14 stroke rats were reversed by an early skilled motor training, underscoring the potential of early activity-dependent plasticity in modulating lesion outcome. Thus, changes in the mechanisms controlling CST plasticity occurring during the third postnatal week are associated with age-dependent regulation of the motor outcome after stroke.

  2. Hormonal therapy with estradiol and drospirenone improves endothelium-dependent vasodilation in the coronary bed of ovariectomized spontaneously hypertensive rats

    International Nuclear Information System (INIS)

    Borgo, M.V.; Claudio, E.R.G.; Silva, F.B.; Romero, W.G.; Gouvea, S.A.; Moysés, M.R.; Santos, R.L.; Almeida, S.A.; Podratz, P.L.; Graceli, J.B.; Abreu, G.R.

    2015-01-01

    Drospirenone (DRSP) is a progestin with anti-aldosterone properties and it reduces blood pressure in hypertensive women. However, the effects of DRSP on endothelium-dependent coronary vasodilation have not been evaluated. This study investigated the effects of combined therapy with estrogen (E2) and DRSP on endothelium-dependent vasodilation of the coronary bed of ovariectomized (OVX) spontaneously hypertensive rats. Female spontaneously hypertensive rats (n=87) at 12 weeks of age were randomly divided into sham operated (Sham), OVX, OVX treated with E2 (E2), and OVX treated with E2 and DRSP (E2+DRSP) groups. Hemodynamic parameters were directly evaluated by catheter insertion into the femoral artery. Endothelium-dependent vasodilation in response to bradykinin in the coronary arterial bed was assessed using isolated hearts according to a modified Langendorff method. Coronary protein expression of endothelial nitric oxide synthase and estrogen receptor alpha (ER-α) was assessed by Western blotting. Histological slices of coronary arteries were stained with hematoxylin and eosin, and morphometric parameters were analyzed. Oxidative stress was assessed in situ by dihydroethidium fluorescence. Ovariectomy increased systolic blood pressure, which was only prevented by E2+DRSP treatment. Estrogen deficiency caused endothelial dysfunction, which was prevented by both treatments. However, the vasodilator response in the E2+DRSP group was significantly higher at the three highest concentrations compared with the OVX group. Reduced ER-α expression in OVX rats was restored by both treatments. Morphometric parameters and oxidative stress were augmented by OVX and reduced by E2 and E2+DRSP treatments. Hormonal therapy with E2 and DRSP may be an important therapeutic option in the prevention of coronary heart disease in hypertensive post-menopausal women

  3. Hormonal therapy with estradiol and drospirenone improves endothelium-dependent vasodilation in the coronary bed of ovariectomized spontaneously hypertensive rats

    Energy Technology Data Exchange (ETDEWEB)

    Borgo, M.V.; Claudio, E.R.G.; Silva, F.B.; Romero, W.G.; Gouvea, S.A.; Moysés, M.R.; Santos, R.L.; Almeida, S.A. [Departamento de Ciências Fisiológicas, Centro de Ciências da Saúde, Universidade Federal de Espírito Santo, Vitória, ES (Brazil); Podratz, P.L.; Graceli, J.B. [Departamento de Morfologia, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, ES (Brazil); Abreu, G.R. [Departamento de Ciências Fisiológicas, Centro de Ciências da Saúde, Universidade Federal de Espírito Santo, Vitória, ES (Brazil)

    2015-11-17

    Drospirenone (DRSP) is a progestin with anti-aldosterone properties and it reduces blood pressure in hypertensive women. However, the effects of DRSP on endothelium-dependent coronary vasodilation have not been evaluated. This study investigated the effects of combined therapy with estrogen (E2) and DRSP on endothelium-dependent vasodilation of the coronary bed of ovariectomized (OVX) spontaneously hypertensive rats. Female spontaneously hypertensive rats (n=87) at 12 weeks of age were randomly divided into sham operated (Sham), OVX, OVX treated with E2 (E2), and OVX treated with E2 and DRSP (E2+DRSP) groups. Hemodynamic parameters were directly evaluated by catheter insertion into the femoral artery. Endothelium-dependent vasodilation in response to bradykinin in the coronary arterial bed was assessed using isolated hearts according to a modified Langendorff method. Coronary protein expression of endothelial nitric oxide synthase and estrogen receptor alpha (ER-α) was assessed by Western blotting. Histological slices of coronary arteries were stained with hematoxylin and eosin, and morphometric parameters were analyzed. Oxidative stress was assessed in situ by dihydroethidium fluorescence. Ovariectomy increased systolic blood pressure, which was only prevented by E2+DRSP treatment. Estrogen deficiency caused endothelial dysfunction, which was prevented by both treatments. However, the vasodilator response in the E2+DRSP group was significantly higher at the three highest concentrations compared with the OVX group. Reduced ER-α expression in OVX rats was restored by both treatments. Morphometric parameters and oxidative stress were augmented by OVX and reduced by E2 and E2+DRSP treatments. Hormonal therapy with E2 and DRSP may be an important therapeutic option in the prevention of coronary heart disease in hypertensive post-menopausal women.

  4. Hormonal therapy with estradiol and drospirenone improves endothelium-dependent vasodilation in the coronary bed of ovariectomized spontaneously hypertensive rats

    Directory of Open Access Journals (Sweden)

    M.V. Borgo

    2016-01-01

    Full Text Available Drospirenone (DRSP is a progestin with anti-aldosterone properties and it reduces blood pressure in hypertensive women. However, the effects of DRSP on endothelium-dependent coronary vasodilation have not been evaluated. This study investigated the effects of combined therapy with estrogen (E2 and DRSP on endothelium-dependent vasodilation of the coronary bed of ovariectomized (OVX spontaneously hypertensive rats. Female spontaneously hypertensive rats (n=87 at 12 weeks of age were randomly divided into sham operated (Sham, OVX, OVX treated with E2 (E2, and OVX treated with E2 and DRSP (E2+DRSP groups. Hemodynamic parameters were directly evaluated by catheter insertion into the femoral artery. Endothelium-dependent vasodilation in response to bradykinin in the coronary arterial bed was assessed using isolated hearts according to a modified Langendorff method. Coronary protein expression of endothelial nitric oxide synthase and estrogen receptor alpha (ER-α was assessed by Western blotting. Histological slices of coronary arteries were stained with hematoxylin and eosin, and morphometric parameters were analyzed. Oxidative stress was assessed in situ by dihydroethidium fluorescence. Ovariectomy increased systolic blood pressure, which was only prevented by E2+DRSP treatment. Estrogen deficiency caused endothelial dysfunction, which was prevented by both treatments. However, the vasodilator response in the E2+DRSP group was significantly higher at the three highest concentrations compared with the OVX group. Reduced ER-α expression in OVX rats was restored by both treatments. Morphometric parameters and oxidative stress were augmented by OVX and reduced by E2 and E2+DRSP treatments. Hormonal therapy with E2 and DRSP may be an important therapeutic option in the prevention of coronary heart disease in hypertensive post-menopausal women.

  5. Infection of inbred rat strains with Rift Valley fever virus: development of a congenic resistant strain and observations on age-dependence of resistance.

    Science.gov (United States)

    Anderson, G W; Rosebrock, J A; Johnson, A J; Jennings, G B; Peters, C J

    1991-05-01

    A congenic rat strain (WF.LEW) was derived from the susceptible Wistar-Furth (WF) (background strain) and the resistant LEW (donor strain) inbred strains and was used to evaluate the phenotypic expression of a dominant Mendelian gene that confers resistance to fatal hepatic disease caused by the ZH501 strain of Rift Valley fever virus (RVFV). Resistance to hepatic disease developed gradually with age, with full expression at approximately 10 weeks in the WF.LEW and LEW rat strains. The ZH501 strain caused fatal hepatitis in WF rats regardless of age. However, resistance to the SA75 RVFV strain (relatively non-pathogenic for adult rats), was age- and dose-dependent in both WF and LEW rats. The resistance gene transferred to the newly derived WF.LEW congenic rat strain appears to amplify age-dependent resistance of adult rats, resulting in protection against fatal hepatic disease caused by the virulent ZH501 strain. The congenic rat strain will be a valuable asset in elucidating the mechanism of resistance to Rift Valley fever virus governed by the dominant Mendelian gene.

  6. Methylene blue improves mitochondrial respiration and decreases oxidative stress in a substrate-dependent manner in diabetic rat hearts.

    Science.gov (United States)

    Duicu, Oana M; Privistirescu, Andreea; Wolf, Adrian; Petruş, Alexandra; Dănilă, Maria D; Raţiu, Corina D; Muntean, Danina M; Sturza, Adrian

    2017-11-01

    Diabetic cardiomyopathy has been systematically associated with compromised mitochondrial energetics and increased generation of reactive oxygen species (ROS) that underlie its progression to heart failure. Methylene blue is a redox drug with reported protective effects mainly on brain mitochondria. The purpose of the present study was to characterize the effects of acute administration of methylene blue on mitochondrial respiration, H 2 O 2 production, and calcium sensitivity in rat heart mitochondria isolated from healthy and 2 months (streptozotocin-induced) diabetic rats. Mitochondrial respiratory function was assessed by high-resolution respirometry. H 2 O 2 production and calcium retention capacity were measured spectrofluorimetrically. The addition of methylene blue (0.1 μmol·L -1 ) elicited an increase in oxygen consumption of mitochondria energized with complex I and II substrates in both normal and diseased mitochondria. Interestingly, methylene blue elicited a significant increase in H 2 O 2 release in the presence of complex I substrates (glutamate and malate), but had an opposite effect in mitochondria energized with complex II substrate (succinate). No changes in the calcium retention capacity of healthy or diabetic mitochondria were found in the presence of methylene blue. In conclusion, in cardiac mitochondria isolated from diabetic and nondiabetic rat hearts, methylene blue improved respiratory function and elicited a dichotomic, substrate-dependent effect on ROS production.

  7. Age-dependent effect of high cholesterol diets on anxiety-like behavior in elevated plus maze test in rats.

    Science.gov (United States)

    Hu, Xu; Wang, Tao; Luo, Jia; Liang, Shan; Li, Wei; Wu, Xiaoli; Jin, Feng; Wang, Li

    2014-09-01

    Cholesterol is an essential component of brain and nerve cells and is essential for maintaining the function of the nervous system. Epidemiological studies showed that patients suffering from anxiety disorders have higher serum cholesterol levels. In this study, we investigated the influence of high cholesterol diet on anxiety-like behavior in elevated plus maze in animal model and explored the relationship between cholesterol and anxiety-like behavior from the aspect of central neurochemical changes. Young (3 weeks old) and adult (20 weeks old) rats were given a high cholesterol diet for 8 weeks. The anxiety-like behavior in elevated plus maze test and changes of central neurochemical implicated in anxiety were measured. In young rats, high cholesterol diet induced anxiolytic-like behavior, decreased serum corticosterone (CORT), increased hippocampal brain-derived neurotrophic factor (BDNF), increased hippocampal mineralocorticoid receptor (MR) and decreased glucocorticoid receptor (GR). In adult rats, high cholesterol diet induced anxiety-like behavior and increase of serum CORT and decrease of hippocampal BDNF comparing with their respective control group that fed the regular diet. High cholesterol diet induced age-dependent effects on anxiety-like behavior and central neurochemical changes. High cholesterol diet might affect the central nervous system (CNS) function differently, and resulting in different behavior performance of anxiety in different age period.

  8. Age-dependent effect of high cholesterol diets on anxiety-like behavior in elevated plus maze test in rats

    Science.gov (United States)

    2014-01-01

    Background Cholesterol is an essential component of brain and nerve cells and is essential for maintaining the function of the nervous system. Epidemiological studies showed that patients suffering from anxiety disorders have higher serum cholesterol levels. In this study, we investigated the influence of high cholesterol diet on anxiety-like behavior in elevated plus maze in animal model and explored the relationship between cholesterol and anxiety-like behavior from the aspect of central neurochemical changes. Methods Young (3 weeks old) and adult (20 weeks old) rats were given a high cholesterol diet for 8 weeks. The anxiety-like behavior in elevated plus maze test and changes of central neurochemical implicated in anxiety were measured. Results In young rats, high cholesterol diet induced anxiolytic-like behavior, decreased serum corticosterone (CORT), increased hippocampal brain-derived neurotrophic factor (BDNF), increased hippocampal mineralocorticoid receptor (MR) and decreased glucocorticoid receptor (GR). In adult rats, high cholesterol diet induced anxiety-like behavior and increase of serum CORT and decrease of hippocampal BDNF comparing with their respective control group that fed the regular diet. Discussion High cholesterol diet induced age-dependent effects on anxiety-like behavior and central neurochemical changes. High cholesterol diet might affect the central nervous system (CNS) function differently, and resulting in different behavior performance of anxiety in different age period. PMID:25179125

  9. iNOS-dependent increase in colonic mucus thickness in DSS-colitic rats.

    Directory of Open Access Journals (Sweden)

    Olof Schreiber

    Full Text Available AIM: To investigate colonic mucus thickness in vivo in health and during experimental inflammatory bowel disease. METHODS: Colitis was induced with 5% DSS in drinking water for 8 days prior to experiment, when the descending colonic mucosa of anesthetized rats was studied using intravital microscopy. Mucus thickness was measured with micropipettes attached to a micromanipulator. To assess the contributions of NOS and prostaglandins in the regulation of colonic mucus thickness, the non-selective NOS-inhibitor L-NNA (10 mg/kg bolus followed by 3 mg/kg/h, the selective iNOS-inhibitor L-NIL (10 mg/kg bolus followed by 3 mg/kg/h and the non-selective COX-inhibitor diclofenac (5 mg/kg were administered intravenously prior to experiment. To further investigate the role of iNOS in the regulation of colonic mucus thickness, iNOS -/- mice were used. RESULTS: Colitic rats had a thicker firmly adherent mucus layer following 8 days of DSS treatment than untreated rats (88±2 µm vs 76±1 µm. During induction of colitis, the thickness of the colonic mucus layer initially decreased but was from day 3 significantly thicker than in untreated rats. Diclofenac reduced the mucus thickness similarly in colitic and untreated rats (-16±5 µm vs -14±2 µm. While L-NNA had no effect on colonic mucus thickness in DSS or untreated controls (+3±2 µm vs +3±1 µm, L-NIL reduced the mucus thickness significantly more in colitic rats than in controls (-33±4 µm vs -10±3 µm. The importance of iNOS in regulating the colonic mucus thickness was confirmed in iNOS-/- mice, which had thinner colonic mucus than wild-type mice (35±3 µm vs 50±2 µm, respectively. Furthermore, immunohistochemistry revealed increased levels of iNOS in the colonic surface epithelium following DSS treatment. CONCLUSION: Both prostaglandins and nitric oxide regulate basal colonic mucus thickness. During onset of colitis, the thickness of the mucus layer is initially reduced followed by an i

  10. Dose-dependent effect of ghrelin on gastric emptying in rats and the related mechanism of action

    Directory of Open Access Journals (Sweden)

    Shu-Guang Cao

    2016-03-01

    Full Text Available The aim of this study was to investigate the dose-dependent effect of ghrelin on gastric emptying in rats and the related mechanism of action. Sixty Wistar rats were randomized into control and test groups, which respectively received intraperitoneal injection of normal saline and ghrelin at different doses (0.5 nmol/kg, 1.0 nmol/kg, 1.5 nmol/kg, 2.0 nmol/kg, and 2.5 nmol/kg. After 45 minutes, all rats were gavaged with semisolid paste. The gastric emptying rate was determined 30 minutes later, and the plasma cholecystokinin level was tested by radioimmunoassay. The mean gastric emptying rate in the test groups was significantly higher than in the control group (38.24 ± 7.15% and 27.18 ± 2.37%, respectively, p < 0.05. Medium and high doses of ghrelin (1.0 nmol/kg, 1.5 nmol/kg, 2.0 nmol/kg, and 2.5 nmol/kg, but not low dose (0.5 nmol/kg, accelerated the gastric emptying. In addition, the plasma cholecystokinin level in the test groups was significantly higher than in the control group (p < 0.01. The gastric emptying rate was positively correlated with the plasma cholecystokinin level (p < 0.01. Intraperitoneal injection of ghrelin at medium and high doses significantly accelerated gastric emptying in rats.

  11. Age-dependent changes in expression of alpha1-adrenergic receptors in rat myocardium

    International Nuclear Information System (INIS)

    Schaffer, W.; Williams, R.S.

    1986-01-01

    The expression of alpha 1 -adrenergic receptors within ventricular myocardium of rats ranging in age from 21 days of fetal life to 24 months after birth was measured from [ 125 I] 2-(β hydroxy phenyl) ethylaminomethyl tetralone binding isotherms. No difference was observed in binding affinity between any of the age groups studied. The number of alpha 1 -adrenergic receptors was found to be 60-120% higher in membranes from fetal or immature rats up to 25 days of age when compared with adult animals. The increased expression of alpha 1 -adrenergic receptors in the developing heart relative to that observed in adult heart is consistent with the hypothesis that alpha 1 -adrenergic receptor stimulation may modulate protein synthesis and growth in mammalian myocardium

  12. The morphological study of age-dependent effects in rat thyroids after γ-ray irradiation

    International Nuclear Information System (INIS)

    Zhang Xuefeng; Guo Lisheng; Tu Kaicheng; Xian Guoliang; Shi Feiman

    1993-01-01

    The purpose of this paper is to identify the differences in age-related harmful effects of the thyroid gland to ionizing radiation. The infant (0.5 month) and adult rats (2.5,6 and 15 months, respectively) were exposed to single γ-ray neck irradiation (0 Gy, as control, 0.5 Gy, 2 Gy, 4 Gy, 8 Gy, 16 Gy). The structure of irradiated thyroid gland under light and transmission electron microscope were observed at 6 weeks after partial irradiation. Some morphometric parameters were measured under light microscope. The results showed that the infant rat thyroids changed significantly after 0.5 Gy, but the adult thyroids expressed similar response after more than 2 Gy. Analyses of these data and information on pathology suggested that the infant thyroids were more radiosensitive than the adult ones

  13. Cortex-dependent recovery of unassisted hindlimb locomotion after complete spinal cord injury in adult rats

    Science.gov (United States)

    Manohar, Anitha; Foffani, Guglielmo; Ganzer, Patrick D; Bethea, John R; Moxon, Karen A

    2017-01-01

    After paralyzing spinal cord injury the adult nervous system has little ability to ‘heal’ spinal connections, and it is assumed to be unable to develop extra-spinal recovery strategies to bypass the lesion. We challenge this assumption, showing that completely spinalized adult rats can recover unassisted hindlimb weight support and locomotion without explicit spinal transmission of motor commands through the lesion. This is achieved with combinations of pharmacological and physical therapies that maximize cortical reorganization, inducing an expansion of trunk motor cortex and forepaw sensory cortex into the deafferented hindlimb cortex, associated with sprouting of corticospinal axons. Lesioning the reorganized cortex reverses the recovery. Adult rats can thus develop a novel cortical sensorimotor circuit that bypasses the lesion, probably through biomechanical coupling, to partly recover unassisted hindlimb locomotion after complete spinal cord injury. DOI: http://dx.doi.org/10.7554/eLife.23532.001 PMID:28661400

  14. Effects of Nicotine Administration and Stress on Sensory-Gating Depend on Rat Strain and Sex

    Science.gov (United States)

    1998-01-01

    L., & Rosecrans, J. (1993). Nicotine: An addictive drug with therapeutic potential. Medicinal Chemistry Research, 2, 509-513. Levin, E.D., Morgan...11, 863-870. Russell, M.A.H., Peto, J., & Patel, U.A. (1974). The classification of smoking by factorial structure of motives. Journal ofthe Royal...Takada, Y., Thara, H., Urano, T., & Takada, A. (1995). Changes in the central and peripheral serotonergic system in rats exposed to water-immersion

  15. Stimulus-dependent changes of extracellular glucose in the rat hippocampus determined by in vivo microdialysis.

    Science.gov (United States)

    Rex, A; Bert, B; Fink, H; Voigt, J-P

    2009-10-19

    Neuronal activity is tightly coupled with brain energy metabolism; and glucose is an important energy substrate for neurons. The present in vivo microdialysis study was aimed at investigating changes in extracellular glucose concentrations in the rat ventral hippocampus due to exposure to the elevated plus maze. Determination of basal hippocampal glucose and lactate/pyruvate ratio in male Wistar rats was conducted in the home cage using in vivo microdialysis. Rats were exposed to the elevated plus maze, a rodent model of anxiety-related behaviour, or to unspecific stress induced by white noise (95dB) as a control condition. Basal hippocampal levels of glucose, as determined by zero-net-flux, and the basal lactate/pyruvate ratio were 1.49+/-0.05mmol/l and 13.8+/-1.1, respectively. In rats without manipulation, glucose levels remained constant throughout the experiment (120min). By contrast, exposure to the elevated plus maze led to a temporary decline in hippocampal glucose (-33.2+/-4.4%) which returned to baseline level in the home cage. White noise caused only a non-significant decrease in extracellular glucose level (-9.3+/-3.5%). In all groups, the lactate/pyruvate ratio remained unchanged by the experimental procedures. Our microdialysis study demonstrates that exposure to the elevated plus maze induces a transient decrease in extracellular hippocampal glucose concentration. In contrast, an unspecific stimulus did not change hippocampal glucose. The latter suggests that only specific behavioural stimuli increase hippocampal glucose utilization in the ventral hippocampus.

  16. Cyclooxygenase-2-dependent bronchoconstriction in perfused rat lungs exposed to endotoxin.

    OpenAIRE

    Uhlig, S.; Nüsing, R.; von Bethmann, A.; Featherstone, R. L.; Klein, T.; Brasch, F.; Müller, K. M.; Ullrich, V.; Wendel, A.

    1996-01-01

    BACKGROUND: Lipopolysaccharides (LPS), widely used to study the mechanisms of gram-negative sepsis, increase airway resistance by constriction of terminal bronchioles. The role of the cyclooxygenase (COX) isoenzymes and their prostanoid metabolites in this process was studied. MATERIALS AND METHODS: Pulmonary resistance, the release of thromboxane (TX) and the expression of COX-2 mRNA were measured in isolated blood-free perfused rat lungs exposed to LPS. RESULTS: LPS induced the release of T...

  17. Vehicle-Dependent Disposition Kinetics of Fluoranthene in Fisher-344 Rats

    OpenAIRE

    Harris, Deacqunita L.; Hood, Darryl B.; Ramesh, Aramandla

    2008-01-01

    The objective of this study was to evaluate how the vehicles of choice affect the pharmacokinetics of orally administered Fluoranthene [FLA] in rats. Fluoranthene is a member of the family of polycyclic aromatic hydrocarbon chemicals. Fluoranthene exposure to humans may occur as a result of cigarette smoking, consumption of contaminated food and water, heating woods in stoves and boilers, industrial sources such as coal gasification, carbon and graphite electrode manufacturing. Adult male Fis...

  18. Neurogenesis in the olfactory bulb induced by paced mating in the female rat is opioid dependent.

    Directory of Open Access Journals (Sweden)

    Marianela Santoyo-Zedillo

    Full Text Available The possibility to control the rate of sexual stimulation that the female rat receives during a mating encounter (pacing increases the number of newborn neurons that reach the granular layer of the accessory olfactory bulb (AOB. If females mate repeatedly, the increase in the number of neurons is observed in other regions of the AOB and in the main olfactory bulb (MOB. It has also been shown that paced mating induces a reward state mediated by opioids. There is also evidence that opioids modulate neurogenesis. In the present study, we evaluated whether the opioid receptor antagonist naloxone (NX could reduce the increase in neurogenesis in the AOB induced by paced mating. Ovariectomized female rats were randomly divided in 5 different groups: 1 Control (not mated treated with saline, 2 control (not mated treated with naloxone, 3 females that mated without controlling the sexual interaction (no-pacing, 4 females injected with saline before pacing the sexual interaction and 5 females injected with NX before a paced mating session. We found, as previously described, that paced mating induced a higher number of new cells in the granular layer of the AOB. The administration of NX before paced mating, blocked the increase in the number of newborn cells and prevented these cells from differentiating into neurons. These data suggest that opioid peptides play a fundamental role in the neurogenesis induced by paced mating in female rats.

  19. Solid-state dependent dissolution and oral bioavailability of piroxicam in rats.

    Science.gov (United States)

    Lust, Andres; Laidmäe, Ivo; Palo, Mirja; Meos, Andres; Aaltonen, Jaakko; Veski, Peep; Heinämäki, Jyrki; Kogermann, Karin

    2013-01-23

    The aim of this study was to gain understanding about the effects of different solid-state forms of a poorly water-soluble piroxicam on drug dissolution and oral bioavailability in rats. Three different solid-state forms of piroxicam were studied: anhydrate I (AH), monohydrate (MH), and amorphous form in solid dispersion (SD). In addition, the effect of a new polymeric excipient Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer) on oral bioavailability of piroxicam was investigated. Significant differences in the dissolution and oral bioavailability were found between the solid-state forms of piroxicam. Amorphous piroxicam in SD showed the fastest dissolution in vitro and a solid-state transformation to MH in the dissolution medium. Despite the presence of solid-state transformation, SD exhibited the highest rate and extent of oral absorption in rats. Oral bioavailability of other two solid-state forms decreased in the order AH and MH. The use of Soluplus® was found to enhance the dissolution and oral bioavailability of piroxicam in rats. The present study shows the importance of solid-state form selection for oral bioavailability of a poorly water-soluble drug. Copyright © 2012 Elsevier B.V. All rights reserved.

  20. Temperature dependence of intracellular Ca2+ homeostasis in rat meiotic and postmeiotic spermatogenic cells.

    Science.gov (United States)

    Herrera, E; Salas, K; Lagos, N; Benos, D J; Reyes, J G

    2001-10-01

    The hypothesis that intracellular [Ca2+] is a cell parameter responsive to extreme temperatures in rat meiotic and postmeiotic spermatogenic cells was tested using intracellular fluorescent probes for Ca2+ and pH. In agreement with this hypothesis, extreme temperatures induced a rapid increase of cytosolic [Ca2+] in rat pachytene spermatocytes and round spermatids. Oscillatory changes in temperature can induce oscillations in cytosolic [Ca2+] in these cells. Intracellular [Ca2+] homeostasis in round spermatids was more sensitive to high temperatures compared with pachytene spermatocytes. The calculated activation energies for SERCA ATPase-mediated fluxes in pachytene spermatocytes and round spermatids were 62 and 75 kJ mol(-1), respectively. The activation energies for leak fluxes from intracellular Ca2+ stores were 55 and 68 kJ mol(-1) for pachytene spermatocytes and round spermatids, respectively. Together with changes in cytosolic [Ca2+], round spermatids undergo a decrease in pH(i) at high temperatures. This temperature-induced decrease in pH(i) appears to be partially responsible for the increase in cytosolic [Ca2+] of round spermatids induced by high temperatures. This characteristic of rat meiotic and postmeiotic spermatogenic cells to undergo an increment in cytosolic Ca2+ at temperatures > 33 degrees C can be related to the induction of programmed cell death by high temperatures in these cells.

  1. Effects of voluntary exercise on the viability, proliferation and BDNF levels of bone marrow stromal cells in rat pups born from morphine- dependent mothers during pregnancy.

    Science.gov (United States)

    Haydari, Sakineh; Safari, Manouchehr; Zarbakhsh, Sam; Bandegi, Ahmad Reza; Miladi-Gorji, Hossein

    2016-11-10

    This study was designed to investigate whether free access to a running wheel during pregnancy in morphine-dependent mothers would influence the viability, proliferation and BDNF levels of bone marrow stromal cells in rat pups. Pregnant rats were made dependent by chronic administration of morphine in drinking water simultaneously with free access to a running wheel. Male pups are weaned at 21days of birth and their bones marrows were aspirated from the femurs and tibias and also the bone marrow stromal cells (BMSCs) cultured. MTT assay was used to determine cell viability and proliferation rate. The level of BDNF was measured in the supernant of BMSCs culture by ELISA. The sedentary morphine-dependent mothers' pups showed a significant increase in the percentage cell viability and proliferation rate and also a significant decrease in the BDNF protein levels in BMSCs. The rat pups borne from exercising the control and morphine-dependent mothers exhibited an increase in the percentage viability, proliferation rate and BDNF levels of the BMSCs. This study showed that maternal exercise during pregnancy in morphine-dependent and non-dependent mothers, with increasing of BDNF levels increased the proliferation and viability of BMSCs in the rat pups. Also, chronic administration of morphine during pregnancy was able to increase the proliferation and viability of BMSCs in the rat pups. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  2. Effects of early life trauma are dependent on genetic predisposition: a rat study

    Directory of Open Access Journals (Sweden)

    Russell Vivienne A

    2011-05-01

    Full Text Available Abstract Background Trauma experienced early in life increases the risk of developing a number of psychological and/or behavioural disorders. It is unclear, however, how genetic predisposition to a behavioural disorder, such as attention-deficit/hyperactivity disorder (ADHD, modifies the long-term effects of early life trauma. There is substantial evidence from family and twin studies for susceptibility to ADHD being inherited, implying a strong genetic component to the disorder. In the present study we used an inbred animal model of ADHD, the spontaneously hypertensive rat (SHR, to investigate the long-term consequences of early life trauma on emotional behaviour in individuals predisposed to developing ADHD-like behaviour. Methods We applied a rodent model of early life trauma, maternal separation, to SHR and Wistar-Kyoto rats (WKY, the normotensive control strain from which SHR were originally derived. The effects of maternal separation (removal of pups from dam for 3 h/day during the first 2 weeks of life on anxiety-like behaviour (elevated-plus maze and depressive-like behaviour (forced swim test were assessed in prepubescent rats (postnatal day 28 and 31. Basal levels of plasma corticosterone were measured using radioimmunoassay. Results The effect of maternal separation on SHR and WKY differed in a number of behavioural measures. Similar to its reported effect in other rat strains, maternal separation increased the anxiety-like behaviour of WKY (decreased open arm entries but not SHR. Maternal separation increased the activity of SHR in the novel environment of the elevated plus-maze, while it decreased that of WKY. Overall, SHR showed a more active response in the elevated plus-maze and forced swim test than WKY, regardless of treatment, and were also found to have higher basal plasma corticosterone compared to WKY. Maternal separation increased basal levels of plasma corticosterone in SHR females only, possibly through adaptive

  3. Prenatal iron deficiency causes sex-dependent mitochondrial dysfunction and oxidative stress in fetal rat kidneys and liver.

    Science.gov (United States)

    Woodman, Andrew G; Mah, Richard; Keddie, Danae; Noble, Ronan M N; Panahi, Sareh; Gragasin, Ferrante S; Lemieux, Hélène; Bourque, Stephane L

    2018-06-01

    Prenatal iron deficiency alters fetal developmental trajectories, which results in persistent changes in organ function. Here, we studied the effects of prenatal iron deficiency on fetal kidney and liver mitochondrial function. Pregnant Sprague-Dawley rats were fed partially or fully iron-restricted diets to induce a state of moderate or severe iron deficiency alongside iron-replete control rats. We assessed mitochondrial function via high-resolution respirometry and reactive oxygen species generation via fluorescence microscopy on gestational d 21. Hemoglobin levels were reduced in dams in the moderate (-31%) and severe groups (-54%) compared with controls, which was accompanied by 55% reductions in fetal hemoglobin levels in both moderate and severe groups versus controls. Male iron-deficient kidneys exhibited globally reduced mitochondrial content and respiration, as well as increased cytosolic superoxide and decreased NO. Female iron-deficient kidneys exhibited complex II down-regulation and increased mitochondrial oxidative stress. Male iron-deficient livers exhibited reduced complex IV respiration and increased cytosolic superoxide, whereas female liver tissues exhibited no alteration in oxidant levels or mitochondrial function. These findings indicate that prenatal iron deficiency causes changes in mitochondrial content and function as well as oxidant status in a sex- and organ-dependent manner, which may be an important mechanism that underlies the programming of cardiovascular disease.-Woodman, A. G., Mah, R., Keddie, D., Noble, R. M. N., Panahi, S., Gragasin, F. S., Lemieux, H., Bourque, S. L. Prenatal iron deficiency causes sex-dependent mitochondrial dysfunction and oxidative stress in fetal rat kidneys and liver.

  4. Cytoskeletal protein translation and expression in the rat brain are stressor-dependent and region-specific.

    Directory of Open Access Journals (Sweden)

    Petra Sántha

    Full Text Available Stress is an integral component of life that can sometimes cause a critical overload, depending on the qualitative and quantitative natures of the stressors. The involvement of actin, the predominant component of dendritic integrity, is a plausible candidate factor in stress-induced neuronal cytoskeletal changes. The major aim of this study was to compare the effects of three different stress conditions on the transcription and translation of actin-related cytoskeletal genes in the rat brain. Male Wistar rats were exposed to one or other of the frequently used models of physical stress, i.e. electric foot shock stress (EFSS, forced swimming stress (FSS, or psychosocial stress (PSS for periods of 3, 7, 14, or 21 days. The relative mRNA and protein expressions of β-actin, cofilin and mitogen-activated protein kinase 1 (MAPK-1 were determined by qRT- PCR and western blotting from hippocampus and frontal cortex samples. Stressor-specific alterations in both β-actin and cofilin expression levels were seen after stress. These alterations were most pronounced in response to EFSS, and exhibited a U-shaped time course. FSS led to a significant β-actin mRNA expression elevation in the hippocampus and the frontal cortex after 3 and 7 days, respectively, without any subsequent change. PSS did not cause any change in β-actin or cofilin mRNA or protein expression in the examined brain regions. EFSS, FSS and PSS had no effect on the expression of MAPK-1 mRNA at any tested time point. These findings indicate a very delicate, stress type-dependent regulation of neuronal cytoskeletal components in the rat hippocampus and frontal cortex.

  5. Activity-dependent intracellular Ca2+ transients in unmyelinated nerve fibres of the isolated adult rat vagus nerve.

    Science.gov (United States)

    Wächtler, J; Mayer, C; Grafe, P

    1998-04-01

    Confocal laser scanning microscopy was used to follow changes in the free intracellular calcium concentration ([Ca2+]i) in nerve fibres and adjacent Schwann cells in isolated rat vagus nerves. [Ca2+]i was monitored by the Ca2+-sensitive fluorescent dyes Calcium Green-1 and Fura Red. Intracellular Ca2+ transients were observed during repetitive (1-50 Hz) supramaximal electrical stimulation or by bath application of ATP. Trains of action potentials were more effective at elongated, fibre-like structures of the vagus nerves, whereas ATP-induced Ca2+ transients were found predominantly in regions of Schwann cell bodies. Activity-induced Ca2+ signals were unaffected by pharmacological manipulation of intracellular Ca2+ stores, during long-lasting application of purinergic receptor agonists, or by substitution of extracellular Na+ with Li+. However, they were abolished in the presence of Ca2+-free bathing solution or after the blocking of Ca2+ channels with Cd2+. Ca2+ transients were also observed during Ca2+ action potentials. Such "Ca2+ spikes" were elicited by electrical stimulation in the presence of a combination of tetrodotoxin and K+ channel blockers. These data suggest that voltage-dependent Ca2+ channels, activated during short trains of Na+ action potentials, produce an increase in intra-axonal [Ca2+] of rat vagus nerves. We did not find evidence for activity-dependent Ca2+ transients in the Schwann cells surrounding the unmyelinated axons.

  6. Effects of quercetin on hemoglobin-dependent redox reactions: relationship to iron-overload rat liver injury.

    Science.gov (United States)

    Lu, Nai-Hao; Chen, Chao; He, Ying-Jie; Tian, Rong; Xiao, Qiang; Peng, Yi-Yuan

    2013-01-01

    Flavonoids have been widely reported to protect liver injury in iron-overload diseases, where the mechanism of this therapeutic action is dependent on their antioxidant effects, including free radical scavenging and metal-chelating. In this study, in contrast to the significant decrease in iron content, quercetin (Qu) from lower diet (0.3%, w/w) showed pro-oxidant ability on protein carbonyl formation and exhibited unobvious effect on iron-overload rat liver injury. Furthermore, the anti- and pro-oxidant activities of Qu on hemoglobin (Hb)-dependent redox reactions (i.e. the oxidative stability of Hb and its cytotoxic ferryl intermediate, Hb-induced protein oxidation) were investigated to illustrate the elevated protein oxidation in lower Qu-treated iron-overload rat. It was found that superoxide (O₂·⁻) and hydrogen peroxide (H₂O₂) were generated during the reaction between Qu and Hb. Qu, however, effectively reduced ferryl intermediate back to ferric Hb in a biphasic kinetic reaction. Moreover, Qu could significantly aggravate Hb-H₂O₂-induced protein oxidation at low concentrations and exhibit protective effects at high concentrations. Different from the classic antioxidant mechanisms of Qu, the dual effects on Hb redox reactions in vitro, therefore, may provide new insights into the physiological and pharmacological implications of Qu with iron-overload disease.

  7. Hepatic stellate cell and myofibroblast-like cell gene expression in the explanted cirrhotic livers of patients undergoing liver transplantation.

    Science.gov (United States)

    Estep, J Michael; O'Reilly, Linda; Grant, Geraldine; Piper, James; Jonsson, Johann; Afendy, Arian; Chandhoke, Vikas; Younossi, Zobair M

    2010-02-01

    Hepatic stellate cells (HSC) are involved in hepatic fibrogenesis. Cell signaling associated with an insult to the liver affects an HSC transdifferentiation to fibrogenic myofibroblast-like cells. To investigate the transcriptional expression distinguishing HSC and myofibroblast-like cells between livers with and without cirrhosis. Tissue from ten cirrhotic livers (undergoing transplant) and four non-cirrhotic livers from the National Disease Research Interchange underwent cell separation to extract HSC and myofibroblast-like cell populations. Separated cell types as well as LI-90 cells were subjected to microarray analysis. Selected microarray results were verified by quantitative real-time PCR. Differential expression of some genes, such as IL-1beta, IL-1alpha, and IL-6, was associated with both transdifferentiation and disease. Other genes, such as fatty acid 2-hydroxylase only show differential expression in association with disease. Functional analysis supported these findings, indicating some signal transduction pathways (IL-6) are involved in disease and activation, whereas retinoid X receptor signaling in HSC from cirrhotic and non-cirrhotic livers varies in scope and quality. These findings indicate distinct phenotypes for HSC from cirrhotic and non-cirrhotic livers. Furthermore, coordinated differential expression between genes involved in the same signal transduction pathways provides some insight into the mechanisms that may control the balance between fibrogenesis and fibrolysis.

  8. Strain-dependent effects of acute caffeine on anxiety-related behavior in PVG/c, Long-Evans and Wistar rats.

    Science.gov (United States)

    Hughes, Robert N; Hancock, Nicola J

    2016-01-01

    To assess the possibility that acute caffeine's behavioral action might depend on rats' strain, effects of 50mg/kg of the drug were observed on activity, anxiety-related behavior and habituation learning in male and female rats from three different strains, namely PVG/c, Long-Evans and Wistar. All subjects were tested in an open field, an elevated plus maze and a light-dark box. For the three strains combined, increased occupancy of the center of the open field and entries of the open plus-maze arms with caffeine suggested caffeine-induced anxiolysis, whereas increased grooming in the open field, decreased rearing in the plus maze and increased risk assessment in the light-dark box were consistent with anxiogenesis. Caffeine also reduced open-field rearing only for PVG/c rats, and entries into and occupation of the light side of the light-dark box only for Long-Evans rats, and increased total defecation in the three types of apparatus for all three strains combined. Overall, caffeine appeared to be mainly anxiogenic. The drug also increased open-field ambulation for PVG/c rats and walking for all rats, but decreased open-field ambulation and entries into the plus maze closed arms for Wistar rats alone. In general, Wistar rats appeared to be the least and Long-Evans the most anxious of the three strains investigated. Caffeine also decreased within-session habituation of open-field ambulation for PVG/c rats alone, thereby suggesting strain-dependent interference with non-associative learning and short-term memory. Several overall sex differences were also observed that supported female rats being more active and less anxious than males. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. Hampered long-term depression and thin spine loss in the nucleus accumbens of ethanol-dependent rats.

    Science.gov (United States)

    Spiga, Saturnino; Talani, Giuseppe; Mulas, Giovanna; Licheri, Valentina; Fois, Giulia R; Muggironi, Giulia; Masala, Nicola; Cannizzaro, Carla; Biggio, Giovanni; Sanna, Enrico; Diana, Marco

    2014-09-02

    Alcoholism involves long-term cognitive deficits, including memory impairment, resulting in substantial cost to society. Neuronal refinement and stabilization are hypothesized to confer resilience to poor decision making and addictive-like behaviors, such as excessive ethanol drinking and dependence. Accordingly, structural abnormalities are likely to contribute to synaptic dysfunctions that occur from suddenly ceasing the use of alcohol after chronic ingestion. Here we show that ethanol-dependent rats display a loss of dendritic spines in medium spiny neurons of the nucleus accumbens (Nacc) shell, accompanied by a reduction of tyrosine hydroxylase immunostaining and postsynaptic density 95-positive elements. Further analysis indicates that "long thin" but not "mushroom" spines are selectively affected. In addition, patch-clamp experiments from Nacc slices reveal that long-term depression (LTD) formation is hampered, with parallel changes in field potential recordings and reductions in NMDA-mediated synaptic currents. These changes are restricted to the withdrawal phase of ethanol dependence, suggesting their relevance in the genesis of signs and/or symptoms affecting ethanol withdrawal and thus the whole addictive cycle. Overall, these results highlight the key role of dynamic alterations in dendritic spines and their presynaptic afferents in the evolution of alcohol dependence. Furthermore, they suggest that the selective loss of long thin spines together with a reduced NMDA receptor function may affect learning. Disruption of this LTD could contribute to the rigid emotional and motivational state observed in alcohol dependence.

  10. Passive transfer of resistance and the site of immune-dependent elimination of the challenge infection in rats vaccinated with highly irradiated cercariae of Schistosoma mansoni

    International Nuclear Information System (INIS)

    Ford, M.J.; Bickle, Q.D.; Taylor, M.G.; Andrews, B.J.

    1984-01-01

    The immune-dependent elimination of a challenge infection in rats vaccinated with highly-irradiated cercariae of Schistosoma mansoni was analysed by passive transfer of serum, recovery of the challenge from the lungs and livers and by transferring lung-stage schistosomula. Recipients of serum from rats immunized with either unirradiated, 20 or 40 krad.-irradiated cercariae, were equally resistant if the serum was injected on the day of infection or 5-7 days after infection. Vaccinated rat serum transferred to mice and vaccinated rabbit serum transferred to rats conferred comparable protection when injected on day 0 or 5 days after infection of the recipients. This apparent susceptibility of the lung schistosomula to immune attack was confirmed by challenging 20 or 40 krad.-irradiated cercariae vaccinated rats with lung-stage schistosomula derived from mice or rats. All the detectable attrition of a cercarial challenge in vaccinated rats occurred between 7 and 10 days post-challenge, before the parasites reached the liver. Since there was no evidence of damage or attrition in the skin or lungs before day 7 it was concluded that immune-dependent elimination occurred rapidly following a 'window of sensitivity' coinciding with the migration of the parasites from the lungs to the liver. (author)

  11. Modified technique for preparation of venous circulation resin casts in the cirrhotic liver

    Directory of Open Access Journals (Sweden)

    JOSÉ OLÍMPIO MAIA DE VASCONCELOS FILHO

    Full Text Available ABSTRACT This study describes two major adaptations for the preparation of resin casts in human cirrhotic liver, harvested at the time of transplantation. The first is the way of fixing the catheter in the ostia of the hepatic and portal veins through a cerclage, so as to prevent displacement of the catheter and / or leakage of the resin during its injection. The second is the extension of corrosion time in the NaOH solution, averaging 6.8 days, with daily replacement the solution until complete removal of parenchymal tissue. We applied the method in 14 cirrhotic livers, with good filling and coloring of the portal and hepatic vein territories, using different colors. This allows an anatomical study of these vessels, able to complement the knowledge of the histopathology in research work, and the planning of therapeutic procedures, such as the Trans-Jugular Intrahepatic Port-Systemic Shunt (TIPS.

  12. Correlations between cerebral glucose metabolism and neuropsychological test performance in nonalcoholic cirrhotics.

    Science.gov (United States)

    Lockwood, Alan H; Weissenborn, Karin; Bokemeyer, Martin; Tietge, U; Burchert, Wolfgang

    2002-03-01

    Many cirrhotics have abnormal neuropsychological test scores. To define the anatomical-physiological basis for encephalopathy in nonalcoholic cirrhotics, we performed resting-state fluorodeoxyglucose positron emission tomographic scans and administered a neuropsychological test battery to 18 patients and 10 controls. Statistical parametric mapping correlated changes in regional glucose metabolism with performance on the individual tests and a composite battery score. In patients without overt encephalopathy, poor performance correlated with reductions in metabolism in the anterior cingulate. In all patients, poor performance on the battery was positively correlated (p glucose metabolism in bifrontal and biparietal regions of the cerebral cortex and negatively correlated with metabolism in hippocampal, lingual, and fusiform gyri and the posterior putamen. Similar patterns of abnormal metabolism were found when comparing the patients to 10 controls. Metabolic abnormalities in the anterior attention system and association cortices mediating executive and integrative function form the pathophysiological basis for mild hepatic encephalopathy.

  13. In vivo P-31 MR spectroscopic studies of liver in normal adults and cirrhotic patients

    International Nuclear Information System (INIS)

    Ban, N.; Moriyasu, F.; Tamada, T.

    1986-01-01

    The author performed in vivo P-31 MR spectroscopic studies of normal and diseased human liver using an experimental 2.0-T whole-body MR imager. Then normal adults and ten cirrhotic patients in the fasting state were studied. Spatially localized in vivo P-31 MR spectra of human liver were obtained in combination with the use of a surface coil and gradient magnetic field. Six spectral peaks were observed in both groups and were assigned, from left to right, to phosphomonoester, inorganic phosphate, phosophodiester, γ-ATP, α-ATP, and β-ATP, on the basis of the chemical shifts. There were no definite differences between the spectral patterns of normal adults and those of cirrhotic patients in the fasting state

  14. Hormone-dependence of sarin lethality in rats: Sex differences and stage of the estrous cycle

    Energy Technology Data Exchange (ETDEWEB)

    Smith, Carl D., E-mail: carl.d.smith179.mil@mail.mil; Wright, Linnzi K.M.; Garcia, Gregory E.; Lee, Robyn B.; Lumley, Lucille A.

    2015-09-15

    Chemical warfare nerve agents (CWNAs) are highly toxic compounds that cause a cascade of symptoms and death, if exposed casualties are left untreated. Numerous rodent models have investigated the toxicity and mechanisms of toxicity of CWNAs, but most are limited to male subjects. Given the profound physiological effects of circulating gonadal hormones in female rodents, it is possible that the daily cyclical fluctuations of these hormones affect females' sensitivity to the lethal effects of CWNAs, and previous reports that included female subjects did not control for the stage of the hormonal cycle. The aim of the current study was to determine the 24-hour median lethal dose (LD{sub 50}) of the CWNA sarin in male, ovariectomized (OVEX) female, and female rats during different stages of the estrous cycle (diestrus, proestrus, and estrus). Additionally, baseline activity levels of plasma acetylcholinesterase, butyrylcholinesterase, and carboxylesterase were measured to determine differences among the groups. Results indicated that females in proestrus had a significantly higher LD{sub 50} of sarin compared to OVEX and estrous females. Although some sex differences were observed in the activity levels of plasma esterases, they were not consistent and likely not large enough to significantly affect the LD{sub 50}s. These results suggest that hormonal cyclicity can influence the outcome of CWNA-related studies using female rodents, and that this variability can be minimized by controlling for the stage of the cycle. Additional research is necessary to determine the precise mechanism of the observed differences because it is unlikely to be solely explained by plasma esterase activity. - Highlights: • The LD{sub 50} of sarin was determined in female rats throughout the stages of the estrous cycle. • Females in proestrus had a significantly higher LD{sub 50} compared to estrous or ovariectomized females. • No sex differences were observed between male and female

  15. Dose-dependent effects of dihydrotestosterone in the streptozotocin-induced diabetic rat kidney

    OpenAIRE

    Xu, Qin; Prabhu, Anjali; Xu, Shujing; Manigrasso, Michaele B.; Maric, Christine

    2009-01-01

    We recently reported that castration exacerbates albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis associated with diabetic renal disease. The aim of the present study was to examine whether these effects of castration can be attenuated with dihydrotestosterone (DHT) supplementation. The study was performed in castrated male Sprague-Dawley, streptozotocin-induced diabetic rats treated with 0 mg/day DHT (DHT0), 0.75 mg/day DHT (DHT0.75), or 2.0 mg/day DHT (DHT2.0) for 14 wk. Tre...

  16. Quantitative measurements of brain iron deposition in cirrhotic patients using susceptibility mapping.

    Science.gov (United States)

    Xia, Shuang; Zheng, Gang; Shen, Wen; Liu, Saifeng; Zhang, Long Jiang; Haacke, E Mark; Lu, Guang Ming

    2015-03-01

    Susceptibility-weighted imaging (SWI) has been used to detect micro-bleeds and iron deposits in the brain. However, no reports have been published on the application of SWI in studying iron changes in the brain of cirrhotic patients. To compare the susceptibility of different brain structures in cirrhotic patients with that in healthy controls and to evaluate susceptibility as a potential biomarker and correlate the measured susceptibility and cadaveric brain iron concentration for a variety of brain structures. Forty-three cirrhotic patients (27 men, 16 women; mean age, 50 ± 9 years) and 34 age- and sex-matched healthy controls (22 men, 12 women; mean age, 47 ± 7 years) were included in this retrospective study. Susceptibility was measured in the frontal white matter, basal ganglia, midbrain, and dentate nucleus and compared with results gathered from two postmortem brain studies. Correlation between susceptibility and clinical biomarkers and neuropsychiatric tests scores was calculated. In cirrhotic patients, the susceptibility of left frontal white matter, bilateral caudate head, and right substantia nigra was higher than that in healthy controls (P brain study (r = 0.835, P = 0.01) in eight deep grey matter structures and another in five brain structures (r = 0.900, P = 0.03). The susceptibility of right caudate head (r = 0.402) and left caudate head (r = 0.408) correlated with neuropsychological test scores (both P brain regions appears to reflect neurocognitive changes. © The Foundation Acta Radiologica 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  17. Can the tyrosine kinase inhibitors trigger metabolic encephalopathy in cirrhotic patients?

    Science.gov (United States)

    Brandi, Giovanni; de Rosa, Francesco; Calzà, Laura; Girolamo, Stefania Di; Tufoni, Manuel; Ricci, Carmen Serena; Cirignotta, Fabio; Caraceni, Paolo; Biasco, Guido

    2013-03-01

    Sorafenib is the standard treatment of advanced hepatocarcinoma (HCC) in cirrhotic patients with preserved liver function. It shares many adverse effects with other tyrosine-kinase (TK) inhibitors and antiangiogenic drugs. TK inhibitors could have a direct toxicity on CNS, both by interfering with TK-related pathways and by inhibiting angiogenesis. The aim of this study was to investigate whether sorafenib administration can be associated to metabolic encephalopathy in patients with cirrhosis. We retrospectively reviewed medical records of all cirrhotic patients treated with sorafenib for HCC afferent at our Department from January 2009 to December 2011. Among 62 patients, we identified 10 patients with clinically significant cognitive impairment. Seven of these were clearly diagnosed with overt hepatic encephalopathy (HE), one with brain metastases and two with drug-related toxic-metabolic encephalopathy. These last two cases were characterized by severe cognitive impairment, mood alteration and memory deficit. Clinical exam, blood tests and brain CT excluded organic causes of encephalopathy and precipitating factors of HE. Sorafenib discontinuation was associated with complete reversal of the syndrome, which recurred on drug re-administration in one case. Our study suggests that sorafenib may be a precipitating factor of metabolic encephalopathy in cirrhotic patients with advanced HCC. This neurological syndrome appears to be not responsive to the conventional treatment for HE, but it is fully reversible by drug discontinuation. It can be speculated that the potential direct neuronal action of sorafenib may represent a trigger for the onset of metabolic encephalopathy in a subset of cirrhotic patients. © 2012 John Wiley & Sons A/S.

  18. Image quality dependence on thickness of sliced rat kidney taken by a simplest DEI construction

    Energy Technology Data Exchange (ETDEWEB)

    Li Gang [Institute of High Energy Physics, Chinese Academy of Science, Yuquan Rd. No 19, Beijing 100039 (China)]. E-mail: lig@ihep.ac.cn; Chen Zhihua [China-Japan Friendship Institute of Clinical Medical Science, Yinghua Rd., Beijing 100029 (China); Wu Ziyu [Institute of High Energy Physics, Chinese Academy of Science, Yuquan Rd. No 19, Beijing 100039 (China); Ando, M. [Photon Factory, KEK, Oho 1-1, Tsukuba, Ibaraki 305-0801 (Japan); Pan Lin [China-Japan Friendship Institute of Clinical Medical Science, Yinghua Rd., Beijing 100029 (China); Wang, J.Y. [Institute of High Energy Physics, Chinese Academy of Science, Yuquan Rd. No 19, Beijing 100039 (China); Jiang, X.M. [Institute of High Energy Physics, Chinese Academy of Science, Yuquan Rd. No 19, Beijing 100039 (China)

    2005-08-11

    The excised rat kidney slices were investigated using a simplified diffraction-enhanced imaging (DEI) configuration with only two crystals: the first one working as monochromator and the second one working as analyzer in the Bragg geometry that was developed at Beijing Synchrotron Radiation Facility (BSRF). Many fine anatomic structures of the sliced rat kidneys with thickness of 2mm and 120{mu}m can be distinguished clearly in the DEI images that were obtained at the shoulder of a rocking curve. The authors would like to emphasize that the thick and thin slices DEI provides very different images; in the thick sample only the structure with the big density gradient or that near the surface where X-ray comes out can be distinguished, while in the thin ones some fine structures, which can not be distinguished at the thick sample under the same condition, can be seen very clearly. The reason related with the counteraction of {delta}(x,y,z) gradient in the integral process along the X-ray path inside the thick sample is discussed.

  19. Time-dependent changes in cardiorespiratory functions of anesthetized rats exposed to sustained hypoxia.

    Science.gov (United States)

    Kato, Kouki; Morinaga, Ryosuke; Fushuku, Seigo; Nakamuta, Nobuaki; Yamamoto, Yoshio

    2018-07-01

    Although cardiovascular responses may be altered by respiratory changes under prolonged hypoxia, the relationship between respiratory and cardiovascular changes remains unknown. The aim of the present study is to clarify cardiorespiratory changes in anesthetized rats during and after hypoxic conditions using simultaneous recordings of cardiorespiratory variables with 20-sec recording intervals. After air breathing for 20 min (pre-exposure period), rats were subjected to 10% O 2 for 2 h (hypoxic exposure period) and then air for 30 min (recovery period). Minute ventilation (V E ), respiratory frequency, tidal volume, arterial blood pressure (BP), and heart rate (HR) were continuously monitored during the experimental period. Just after hypoxic exposure, V E , BP, and HR exhibited an overshoot, undershoot, and overshoot followed by a decrease, respectively. During the remaining hypoxic exposure period, continuous high V E and low BP were observed, whereas HR re-increased. In the recovery period, V E , BP, and HR showed an undershoot, increase, and decrease followed by an increase, respectively. These results suggest that the continuation of enhanced V E and re-increased HR, probably, due to carotid body excitation and accompanying sympathetic activation, during the late period of hypoxic exposure are protective responses to avoid worsening hypoxemia and further circulatory insufficiencies under sustained hypoxia. Copyright © 2018 Elsevier B.V. All rights reserved.

  20. Image quality dependence on thickness of sliced rat kidney taken by a simplest DEI construction

    International Nuclear Information System (INIS)

    Li Gang; Chen Zhihua; Wu Ziyu; Ando, M.; Pan Lin; Wang, J.Y.; Jiang, X.M.

    2005-01-01

    The excised rat kidney slices were investigated using a simplified diffraction-enhanced imaging (DEI) configuration with only two crystals: the first one working as monochromator and the second one working as analyzer in the Bragg geometry that was developed at Beijing Synchrotron Radiation Facility (BSRF). Many fine anatomic structures of the sliced rat kidneys with thickness of 2mm and 120μm can be distinguished clearly in the DEI images that were obtained at the shoulder of a rocking curve. The authors would like to emphasize that the thick and thin slices DEI provides very different images; in the thick sample only the structure with the big density gradient or that near the surface where X-ray comes out can be distinguished, while in the thin ones some fine structures, which can not be distinguished at the thick sample under the same condition, can be seen very clearly. The reason related with the counteraction of δ(x,y,z) gradient in the integral process along the X-ray path inside the thick sample is discussed

  1. Impairment of innate immune responses in cirrhotic patients and treatment by branched-chain amino acids

    Science.gov (United States)

    Nakamura, Ikuo

    2014-01-01

    It has been reported that host defense responses, such as phagocytic function of neutrophils and natural killer (NK) cell activity of lymphocytes, are impaired in cirrhotic patients. This review will concentrate on the impairment of innate immune responses in decompensated cirrhotic patients and the effect of the treatment by branched-chain amino acids (BCAA) on innate immune responses. We already reported that phagocytic function of neutrophils was significantly improved by 3-mo BCAA supplementation. In addition, the changes of NK activity were also significant at 3 mo of supplementation compared with before supplementation. Also, Fisher’s ratios were reported to be significantly increased at 3 mo of BCAA supplementation compared with those before oral supplementation. Therefore, administration of BCAA could reduce the risk of bacterial and viral infection in patients with decompensated cirrhosis by restoring impaired innate immune responses of the host. In addition, it was also revealed that BCAA oral supplementation could reduce the risk of development of hepatocellular carcinoma in cirrhotic patients. The mechanisms of the effects will also be discussed in this review article. PMID:24966600

  2. APTR is a prognostic marker in cirrhotic patients with portal hypertension during TIPS procedure.

    Science.gov (United States)

    Yu, Shanshan; Qi, Yanhua; Jiang, Jue; Wang, Hua; Zhou, Qi

    2018-03-01

    Portal hypertension is a major cause of mortality and morbidity in cirrhotic patients. In this study, we aimed to analyze the clinical characteristics of Alu-mediated p21 transcriptional regulator (APTR) during transjugular intrahepatic portosystemic shunt (TIPS) procedure. Portal and hepatic venous blood was drawn from 84 patients with liver cirrhosis and portal hypertension before and after TIPS treatment. Then, we detected biochemical, hemodynamic parameters and APTR expression before and after TIPS treatment. Indeed, TIPS treatment could markedly ameliorate the serum blood urea nitrogen (BUN) level and portal vein hemodynamics in cirrhotic patients. We found that portal venous levels of APTR was significantly decreased after TIPS treatment and its aberrant expression levels were positively correlated with Model for End Stage Liver Disease (MELD), portal hepatic venous pressure gradient (PHPG) in patients. Higher APTR expression in portal vein was associated with poor prognosis. APTR level in portal vein was an independent predictors of mortality. Our data indicated that APTR may serve as a novel biomarker for cirrhotic patients with portal hypertension before and after receiving TIPS. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Laparoscopic versus open cholecystectomy in cirrhotic patients: a prospective randomized study.

    Science.gov (United States)

    El-Awadi, Saleh; El-Nakeeb, Ayman; Youssef, Tamer; Fikry, Amir; Abd El-Hamed, Tito M; Ghazy, Hosam; Foda, Elyamany; Farid, Mohamed

    2009-02-01

    Improved laparoscopic experience and techniques have made laparoscopic cholecystectomy (LC) feasible options in cirrhotic patients. This study was designed to compare the risk and benefits of open cholecystectomy (OC) versus LC in compensated cirrhosis. A randomized prospective study, in the period from October 2002 till December 2006, where 110 cirrhotic patients with symptomatic gallstone were randomly divided into OC group (55 patients) and LC group (55 patients). There was no operative mortality. In LC group 4 (7.33%) patients were converted to OC. Mean surgical time was significantly longer in OC group than LC group (96.13+17.35 min versus 76.13+15.12) P<0.05, associated with significantly higher intraoperative bleeding in OC group (P<0.01), necessitating blood transfusions to 7 (12.72%) patients in OC group. The time to resume diet was 18.36+8.18 h in LC group which is significantly earlier than in OC group 47.84+14.6h P<0.005. Hospital stay was significantly longer in OC group than LC group (6+1.74 days versus 1.87+1.11 days) P<0.01 with low postoperative morbidity. LC in cirrhotics is still complicated and highly difficult which associates with significant morbidity compared with that of patients without cirrhosis. However, it offers lower morbidity, shorter operative time; early resume dieting with less need for blood transfusion and reducing hospital stay than OC.

  4. Longitudinal intrinsic brain activity changes in cirrhotic patients before and one month after liver transplantation

    International Nuclear Information System (INIS)

    Cheng, Yue; Huang, Li Xiang; Xie, Shuang

    2017-01-01

    To evaluate the spontaneous brain activity alterations in liver transplantation (LT) recipients using resting-state functional MRI. Twenty cirrhotic patients as transplant candidates and 25 healthy controls (HCs) were included in this study. All patients repeated the MRI study one month after LT. Amplitude of low-frequency fluctuation (ALFF) values were compared between cirrhotic patients (both pre- and post-LT) and HCs as well as between the pre- and post-LT groups. The relationship between ALFF changes and venous blood ammonia levels and neuropsychological tests were investigated using Pearson's correlation analysis. In the cirrhotic patients, decreased ALFF in the vision-related regions (left lingual gyrus and calcarine), sensorimotor-related regions (left postcentral gyrus and middle cingulate cortex), and the default-mode network (bilateral precuneus and left inferior parietal lobule) were restored, and the increased ALFF in the temporal and frontal lobe improved in the early period after LT. The ALFF decreases persisted in the right supplementary motor area, inferior parietal lobule, and calcarine. The ALFF changes in the right precuneus were negatively correlated with changes in number connection test-A scores (r = 0.507, p < 0.05). LT improved spontaneous brain activity and the results for associated cognition tests. However, decreased ALFF in some areas persisted, and new-onset abnormal ALFF were possible, indicating that complete cognitive function recovery may need more time

  5. [An analysis of clinical characteristic and related risk factors in 208 cirrhotic patients complicated with infections].

    Science.gov (United States)

    Zhang, G H; Wang, M; Wang, L; Wang, X M; Wang, Y; Ou, X J; Jia, J D

    2018-02-01

    Objective: To analyze the clinical features and risk factors of cirrhotic patients complicated with infections. Methods: The clinical and laboratory characteristics of cirrhotic patients complicated with infections hospitalized from April 2014 to June 2017 were retrospectively analyzed. Relevant risk factors for infection and mortality were explored. Results: The overall incidence of infections was 17.6% in 1 670 hospitalized cirrhotic patients. Among the recruited 208 patients in this study, alcoholic, viral hepatitis B or C and autoimmune liver diseases accounted for 29.8% (62/208), 26.0% (54/208), and 22.1% (46/208), respectively. The most common infection site was respiratory tract (70.2%), followed by urinary tract, intestinal and intra-abdomen. Forty-six pathogens were isolated from 32 patients, including 22 (47.8%) Gram negative bacteria, 16 (34.8%) Gram positive bacteria and 2(4.3%) mycobacterium tuberculosis, 5 (10.9%) fungi and 1 (2.2%) mycoplasma. The mortality in patients with nosocomial infections (16.7%,7/42) was higher than that in patients with community-acquired infections (6.0%,10/166, P =0.025). All 17 deaths occurred in decompensated cirrhosis. Multivariate analysis demonstrated that hepatic encephalopathy and prothrombin time were independent risk factors of mortality. Conclusions: Patients with decompensated cirrhosis are more susceptible to infections. Hepatic encephalopathy and prothrombin time are independent risk factors for death.

  6. Longitudinal intrinsic brain activity changes in cirrhotic patients before and one month after liver transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Yue; Huang, Li Xiang; Xie, Shuang [Dept. of Radiology, Tianjin First Central Hospital, Tianjin (China); and others

    2017-04-15

    To evaluate the spontaneous brain activity alterations in liver transplantation (LT) recipients using resting-state functional MRI. Twenty cirrhotic patients as transplant candidates and 25 healthy controls (HCs) were included in this study. All patients repeated the MRI study one month after LT. Amplitude of low-frequency fluctuation (ALFF) values were compared between cirrhotic patients (both pre- and post-LT) and HCs as well as between the pre- and post-LT groups. The relationship between ALFF changes and venous blood ammonia levels and neuropsychological tests were investigated using Pearson's correlation analysis. In the cirrhotic patients, decreased ALFF in the vision-related regions (left lingual gyrus and calcarine), sensorimotor-related regions (left postcentral gyrus and middle cingulate cortex), and the default-mode network (bilateral precuneus and left inferior parietal lobule) were restored, and the increased ALFF in the temporal and frontal lobe improved in the early period after LT. The ALFF decreases persisted in the right supplementary motor area, inferior parietal lobule, and calcarine. The ALFF changes in the right precuneus were negatively correlated with changes in number connection test-A scores (r = 0.507, p < 0.05). LT improved spontaneous brain activity and the results for associated cognition tests. However, decreased ALFF in some areas persisted, and new-onset abnormal ALFF were possible, indicating that complete cognitive function recovery may need more time.

  7. Hepatic encephalopathy in patients with non-cirrhotic portal hypertension: Description, prevalence and risk factors.

    Science.gov (United States)

    Nicoletti, Valeria; Gioia, Stefania; Lucatelli, Pierleone; Nardelli, Silvia; Pasquale, Chiara; Nogas Sobrinho, Stefano; Pentassuglio, Ilaria; Greco, Francesca; De Santis, Adriano; Merli, Manuela; Riggio, Oliviero

    2016-09-01

    Hepatic encephalopathy (HE) is a common complication of cirrhosis but it is less studied in patients with non-cirrhotic portal hypertension (NCPH). To describe the prevalence of cognitive impairment (overt and covert HE) in NCPH patients and to identify the risk factors for its development. 51 patients with NCPH, 35 with chronic portal vein thrombosis (PVT) and 16 with idiopathic non-cirrhotic portal hypertension (INCPH), were evaluated for the presence of previous or present overt HE (OHE). The psychometric hepatic encephalopathy score and the SCAN battery were used to detect the presence of covert HE (CHE). 34 compensated cirrhotic patients were used as control. In NCPH patients, abdominal scans were performed to detect the presence of shunts. None of the patients experienced OHE at evaluation while 5.7% of PVT and 12.5% of INCPH patients referred at least one documented episode of previous OHE, similarly to patients with cirrhosis (14.7%). Even if lower than in patients with cirrhosis (64.7%), a considerable proportion of patients with chronic PVT (34.3%) and INCPH (25%) had CHE (p=0.008). The presence of a large portal-systemic shunt was the only factor significantly correlated to cognitive impairment in NCPH patients. HE is a tangible complication of NCPH and is mainly related to the presence of portal-systemic shunts. Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  8. Low Molecular Weight Heparin in Portal Vein Thrombosis of Cirrhotic Patients: Only Therapeutic Purposes?

    Directory of Open Access Journals (Sweden)

    Raffaele Licinio

    2014-01-01

    Full Text Available Cirrhosis has always been regarded as hemorrhagic coagulopathy caused by the reduction in the hepatic synthesis of procoagulant proteins. However, with the progression of liver disease, the cirrhotic patient undergoes a high rate of thrombotic phenomena in the portal venous system. Although the progression of liver failure produces a reduction in the synthesis of anticoagulant molecules, a test able to detect the patients with hemostatic balance shifting towards hypercoagulability has not yet been elaborated. The need of treatment and/or prophylaxis of cirrhotic patients is demonstrated by the increased mortality, the risk of bleeding from esophageal varices, and the mortality of liver transplantation, when portal vein thrombosis (PVT occurs even if current guidelines do not give indications about PVT treatment in cirrhosis. In view of the general feeling that the majority of cirrhotic patients at an advanced stage may be in a procoagulant condition (suggested by the sharp increase in the prevalence of PVT, it is presumable that a prophylaxis of this population could be of benefit. The safety and the efficacy of prophylaxis and treatment with enoxaparin in patients with cirrhosis demonstrated by a single paper suggest this option only in controlled trials and, currently, there are no sufficient evidences for a recommendation in the clinical practice.

  9. The Effect of Opium Dependency of Parent (s) on Offspring's Spatial Learning & Memory in Adult Male Rats.

    Science.gov (United States)

    Saberi Moghadam, Arezoo; Sepehri, Gholamreza; Sheibani, Vahid; Haghpanah, Tahereh; Divsalar, Kouros; Hajzadeh, Mousa-Al-Reza; Afarineshkhaki, Mohammadreza

    2013-05-01

    As far as we know, there has been no report regarding the effects of opium addiction or dependency of both parents on the learning and memory process in offspring. The aim of this study was to examine the learning and memory changes of adult male offspring whose mothers, fathers and/or both parents had dependency to opium before and during pregnancy. Materials and Methods : All experiments were carried out on Wistar rats. Opium dependency was induced by daily injections of opium (10 mg/kg/SC, bid/10 d) before mating. The presence of a vaginal plug was designated as gestation day. Treatment with opium continued through breeding and gestation until parturition. Spatial memory was tested in male offspring of control, saline and prenatal opium treated groups by a training trial and the probe test in the Morris water maze. Swimming escape latency in the maze and the ability to find the platform in the training trial were recorded. The time spent in the trigger zone and number of times the rats crossed the platform during the probe phase and swimming speed were measured. The data revealed increased escape latency and a greater distance traveled to find the hidden platform in the offspring's whose mother, father and /or both parents were exposed to opium. Crossings to target quadrant at probe trials was significantly reduced in all of the prenatal opium exposed offsprings. The swimming speed showed a significant increase in father and parent's opium exposed offspring. Prenatal opium exposure of either parent may cause deficits in spatial learning, but the precise mechanism(s) remain largely unknown.

  10. The Effect of Opium Dependency of Parent (s on Offspring’s Spatial Learning & Memory in Adult Male Rats

    Directory of Open Access Journals (Sweden)

    Arezoo Saberi Moghadam

    2013-05-01

    Full Text Available Objective(s:As far as we know,there has been no report regarding the effects of opium addiction or dependency of both parents on the learning and memory process in offspring. The aim of this study was to examine the learning and memory changes of adult male offspring whose mothers, fathers and/or both parents had dependency to opium before and during pregnancy. Materials and Methods: All experiments were carried out on Wistar rats. Opium dependency was induced by daily injections of opium (10 mg/kg/SC, bid/10 d before mating. The presence of a vaginal plug was designated as gestation day. Treatment with opium continued through breeding and gestation until parturition. Spatial memory was tested in male offspring of control, saline and prenatal opium treated groups by a training trial and the probe test in the Morris water maze. Swimming escape latency in the maze and the ability to find the platform in the training trial were recorded. The time spent in the trigger zone and number of times the rats crossed the platform during the probe phase and swimming speed were measured. Results:Thedata revealed increased escape latency and a greater distance traveled to find the hidden platform in the offspring’s whose mother, father and /or both parents were exposed to opium. Crossings to target quadrant at probe trials was significantly reduced in all of the prenatal opium exposed offsprings. The swimming speed showed a significant increase in father and parent’s opium exposed offspring.  Conclusion:Prenatal opium exposure of either parent may cause deficits in spatial learning, but the precise mechanism(s remain largely unknown.

  11. Inhibition of PKC-dependent extracellular Ca2+ entry contributes to the depression of contractile activity in long-term pressure-overloaded endothelium-denuded rat aortas

    International Nuclear Information System (INIS)

    Padilla, J.; López, R.M.; López, P.; Castillo, M.C.; Querejeta, E.; Ruiz, A.; Castillo, E.F.

    2014-01-01

    We examined the contractile responsiveness of rat thoracic aortas under pressure overload after long-term suprarenal abdominal aortic coarctation (lt-Srac). Endothelium-dependent angiotensin II (ANG II) type 2 receptor (AT 2 R)-mediated depression of contractions to ANG II has been reported in short-term (1 week) pressure-overloaded rat aortas. Contractility was evaluated in the aortic rings of rats subjected to lt-Srac or sham surgery (Sham) for 8 weeks. ANG I and II levels and AT 2 R protein expression in the aortas of lt-Srac and Sham rats were also evaluated. lt-Srac attenuated the contractions of ANG II and phenylephrine in the aortas in an endothelium-independent manner. However, lt-Srac did not influence the transient contractions induced in endothelium-denuded aortic rings by ANG II, phenylephrine, or caffeine in Ca 2+ -free medium or the subsequent tonic constrictions induced by the addition of Ca 2+ in the absence of agonists. Thus, the contractions induced by Ca 2+ release from intracellular stores and Ca 2+ influx through stored-operated channels were not inhibited in the aortas of lt-Srac rats. Potassium-elicited contractions in endothelium-denuded aortic rings of lt-Srac rats remained unaltered compared with control tissues. Consequently, the contractile depression observed in aortic tissues of lt-Srac rats cannot be explained by direct inhibition of voltage-operated Ca 2+ channels. Interestingly, 12-O-tetradecanoylphorbol-13-acetate-induced contractions in endothelium-denuded aortic rings of lt-Srac rats were depressed in the presence but not in the absence of extracellular Ca 2+ . Neither levels of angiotensins nor of AT 2 R were modified in the aortas after lt-Srac. The results suggest that, in rat thoracic aortas, lt-Srac selectively inhibited protein kinase C-mediated activation of contraction that is dependent on extracellular Ca 2+ entry

  12. The Frequency-Dependent Aerobic Exercise Effects of Hypothalamic GABAergic Expression and Cardiovascular Functions in Aged Rats

    Directory of Open Access Journals (Sweden)

    Yan Li

    2017-06-01

    Full Text Available A decline in cardiovascular modulation is a feature of the normal aging process and associated with cardiovascular diseases (CVDs such as hypertension and stroke. Exercise training is known to promote cardiovascular adaptation in young animals and positive effects on motor and cognitive capabilities, as well as on brain plasticity for all ages in mice. Here, we examine the question of whether aerobic exercise interventions may impact the GABAergic neurons of the paraventricular nucleus (PVN in aged rats which have been observed to have a decline in cardiovascular integration function. In the present study, young (2 months and old (24 months male Wistar rats were divided into young control (YC, old sedentary, old low frequency exercise (20 m/min, 60 min/day, 3 days/week, 12 weeks and old high frequency exercise (20 m/min, 60 min/day, 5 days/week, 12 weeks. Exercise training indexes were obtained, including resting heart rate (HR, blood pressure (BP, plasma norepinephrine (NE, and heart weight (HW-to-body weight (BW ratios. The brain was removed and processed according to the immunofluorescence staining and western blot used to analyze the GABAergic terminal density, the proteins of GAD67, GABAA receptor and gephyrin in the PVN. There were significant changes in aged rats compared with those in the YC. Twelve weeks aerobic exercise training has volume-dependent ameliorated effects on cardiovascular parameters, autonomic nervous activities and GABAergic system functions. These data suggest that the density of GABAergic declines in the PVN is associated with imbalance in autonomic nervous activities in normal aging. Additionally, aerobic exercise can rescue aging-related an overactivity of the sympathetic nervous system and induces modifications the resting BP and HR to lower values via improving the GABAergic system in the PVN.

  13. The Frequency-Dependent Aerobic Exercise Effects of Hypothalamic GABAergic Expression and Cardiovascular Functions in Aged Rats

    Science.gov (United States)

    Li, Yan; Zhao, Ziqi; Cai, Jiajia; Gu, Boya; Lv, Yuanyuan; Zhao, Li

    2017-01-01

    A decline in cardiovascular modulation is a feature of the normal aging process and associated with cardiovascular diseases (CVDs) such as hypertension and stroke. Exercise training is known to promote cardiovascular adaptation in young animals and positive effects on motor and cognitive capabilities, as well as on brain plasticity for all ages in mice. Here, we examine the question of whether aerobic exercise interventions may impact the GABAergic neurons of the paraventricular nucleus (PVN) in aged rats which have been observed to have a decline in cardiovascular integration function. In the present study, young (2 months) and old (24 months) male Wistar rats were divided into young control (YC), old sedentary, old low frequency exercise (20 m/min, 60 min/day, 3 days/week, 12 weeks) and old high frequency exercise (20 m/min, 60 min/day, 5 days/week, 12 weeks). Exercise training indexes were obtained, including resting heart rate (HR), blood pressure (BP), plasma norepinephrine (NE), and heart weight (HW)-to-body weight (BW) ratios. The brain was removed and processed according to the immunofluorescence staining and western blot used to analyze the GABAergic terminal density, the proteins of GAD67, GABAA receptor and gephyrin in the PVN. There were significant changes in aged rats compared with those in the YC. Twelve weeks aerobic exercise training has volume-dependent ameliorated effects on cardiovascular parameters, autonomic nervous activities and GABAergic system functions. These data suggest that the density of GABAergic declines in the PVN is associated with imbalance in autonomic nervous activities in normal aging. Additionally, aerobic exercise can rescue aging-related an overactivity of the sympathetic nervous system and induces modifications the resting BP and HR to lower values via improving the GABAergic system in the PVN. PMID:28713263

  14. Molecular Binding Contributes to Concentration Dependent Acrolein Deposition in Rat Upper Airways: CFD and Molecular Dynamics Analyses

    Directory of Open Access Journals (Sweden)

    Jinxiang Xi

    2018-03-01

    Full Text Available Existing in vivo experiments show significantly decreased acrolein uptake in rats with increasing inhaled acrolein concentrations. Considering that high-polarity chemicals are prone to bond with each other, it is hypothesized that molecular binding between acrolein and water will contribute to the experimentally observed deposition decrease by decreasing the effective diffusivity. The objective of this study is to quantify the probability of molecular binding for acrolein, as well as its effects on acrolein deposition, using multiscale simulations. An image-based rat airway geometry was used to predict the transport and deposition of acrolein using the chemical species model. The low Reynolds number turbulence model was used to simulate the airflows. Molecular dynamic (MD simulations were used to study the molecular binding of acrolein in different media and at different acrolein concentrations. MD results show that significant molecular binding can happen between acrolein and water molecules in human and rat airways. With 72 acrolein embedded in 800 water molecules, about 48% of acrolein compounds contain one hydrogen bond and 10% contain two hydrogen bonds, which agreed favorably with previous MD results. The percentage of hydrogen-bonded acrolein compounds is higher at higher acrolein concentrations or in a medium with higher polarity. Computational dosimetry results show that the size increase caused by the molecular binding reduces the effective diffusivity of acrolein and lowers the chemical deposition onto the airway surfaces. This result is consistent with the experimentally observed deposition decrease at higher concentrations. However, this size increase can only explain part of the concentration-dependent variation of the acrolein uptake and acts as a concurrent mechanism with the uptake-limiting tissue ration rate. Intermolecular interactions and associated variation in diffusivity should be considered in future dosimetry modeling of

  15. Adverse effect of combination of chronic psychosocial stress and high fat diet on hippocampus-dependent memory in rats.

    Science.gov (United States)

    Alzoubi, K H; Abdul-Razzak, K K; Khabour, O F; Al-Tuweiq, G M; Alzubi, M A; Alkadhi, K A

    2009-12-01

    The combined effects of high fat diet (HFD) and chronic stress on the hippocampus-dependent spatial learning and memory were studied in rats using the radial arm water maze (RAWM). Chronic psychosocial stress and/or HFD were simultaneously administered for 3 months to young adult male Wister rats. In the RAWM, rats were subjected to 12 learning trials as well as short-term and long-term memory tests. This procedure was applied on a daily basis until the animal reaches days to criterion (DTC) in the 12th learning trial and in memory tests. DTC is the number of days that the animal takes to make zero error in two consecutive days. Groups were compared based on the number of errors per trial or test as well as on the DTC. Chronic stress, HFD and chronic stress/HFD animal groups showed impaired learning as indicated by committing significantly (Pchronic stress, HFD and chronic stress/HFD groups showed significantly impaired performance compared to control group. Additionally, the stress/HFD was the only group that showed significantly impaired performance in memory tests on the 5th training day, suggesting more severe memory impairment in that group. Furthermore, DTC value for above groups indicated that chronic stress or HFD, alone, resulted in a mild impairment of spatial memory, but the combination of chronic stress and HFD resulted in a more severe and long-lasting memory impairment. The data indicated that the combination of stress and HFD produced more deleterious effects on hippocampal cognitive function than either chronic stress or HFD alone.

  16. Molecular Binding Contributes to Concentration Dependent Acrolein Deposition in Rat Upper Airways: CFD and Molecular Dynamics Analyses.

    Science.gov (United States)

    Xi, Jinxiang; Hu, Qin; Zhao, Linlin; Si, Xiuhua April

    2018-03-27

    Existing in vivo experiments show significantly decreased acrolein uptake in rats with increasing inhaled acrolein concentrations. Considering that high-polarity chemicals are prone to bond with each other, it is hypothesized that molecular binding between acrolein and water will contribute to the experimentally observed deposition decrease by decreasing the effective diffusivity. The objective of this study is to quantify the probability of molecular binding for acrolein, as well as its effects on acrolein deposition, using multiscale simulations. An image-based rat airway geometry was used to predict the transport and deposition of acrolein using the chemical species model. The low Reynolds number turbulence model was used to simulate the airflows. Molecular dynamic (MD) simulations were used to study the molecular binding of acrolein in different media and at different acrolein concentrations. MD results show that significant molecular binding can happen between acrolein and water molecules in human and rat airways. With 72 acrolein embedded in 800 water molecules, about 48% of acrolein compounds contain one hydrogen bond and 10% contain two hydrogen bonds, which agreed favorably with previous MD results. The percentage of hydrogen-bonded acrolein compounds is higher at higher acrolein concentrations or in a medium with higher polarity. Computational dosimetry results show that the size increase caused by the molecular binding reduces the effective diffusivity of acrolein and lowers the chemical deposition onto the airway surfaces. This result is consistent with the experimentally observed deposition decrease at higher concentrations. However, this size increase can only explain part of the concentration-dependent variation of the acrolein uptake and acts as a concurrent mechanism with the uptake-limiting tissue ration rate. Intermolecular interactions and associated variation in diffusivity should be considered in future dosimetry modeling of high

  17. The changes in levels of C-P and insulin in glucose tolerance test in rats with experimental non-insulin dependent diabetes mellitus

    International Nuclear Information System (INIS)

    Liu Xinqiu; Lei Ming

    2001-01-01

    The changes in levels of C-P and insulin were investigated in the GT test in rats with non-insulin dependent diabetes mellitus. In order to establish a model of non-insulin dependent diabetes mellitus (NIDDM), the authors injected rats with small dose streptozocoi (i.v.). Two weeks after the injection, the rats developed impaired glucose tolerance (IGT). Then, they were fed with high energy diet for eight weeks to form NIDDM. The results showed that the highest peak time of C-P and insulin in NIDDM was remarkably later than that in normal subjects, the highest peak time was in two hours (P < 0.05). The data suggest that level of C-P could accurately respond to level of insulin, and this experimental non-insulin dependent diabetes mellitus model is ideal

  18. Effect of lithium on endothelium-dependent and neurogenic relaxation of rat corpus cavernosum: role of nitric oxide pathway.

    Science.gov (United States)

    Sadeghipour, Hamed; Ghasemi, Mehdi; Ebrahimi, Farzad; Dehpour, Ahmad Reza

    2007-02-01

    Some studies have reported erectile dysfunction in patients receiving lithium through a mechanism that has not yet been defined. The aim of the present study was to verify the effect of acute lithium administration on the nonadrenergic noncholinergic (NANC)- and endothelium-mediated relaxation of rat isolated corpus cavernosum. The isolated rat corporeal strips were precontracted with phenylephrine hydrochloride (7.5 microM) and electrical field stimulation (EFS) was applied at different frequencies (2, 5, 10, and 15 Hz) to obtain NANC-mediated relaxation or relaxed by adding cumulative doses of acetylcholine (10nM-1mM) to obtain endothelium-dependent relaxation in the presence or absence of lithium (0.3, 0.5, 1, and 5mM). Also, effects of combining lithium (0.3mM) with 30 nM and 0.1 nM L-NAME (an NO synthase inhibitor) on NANC- and acetylcholine-mediated relaxation was investigated, respectively. Moreover, effects of combining lithium (1mM) with 0.1mM and 10 microM L-arginine (a precursor of NO) on NANC- and endothelium-mediated relaxation was assessed, respectively. Also, the effect of lithium (1mM) on relaxation to sodium nitroprusside (SNP; 1nM-1mM), an NO donor, was investigated. The NANC-mediated relaxation was significantly (Pacetylcholine in a concentration-dependent manner. Combination of lithium (0.3mM) with 30 and 0.1 nM L-NAME, which separately had a minimum effect on NANC- and endothelium-mediated relaxation, significantly (Pacetylcholine and EFS, it improved the inhibition by lithium (1mM) of relaxant responses to acetylcholine and EFS, respectively. Also, SNP produced similar concentration-dependent relaxations from both groups. Our experiments indicated that lithium likely by interfering with NO pathway in both endothelium and nitrergic nerve can result in impairment of both the endothelium- and NANC-mediated relaxation of rat corpus cavernosum.

  19. Maternal swimming exercise during pregnancy attenuates anxiety/depressive-like behaviors and voluntary morphine consumption in the pubertal male and female rat offspring born from morphine dependent mothers.

    Science.gov (United States)

    Torabi, Masoumeh; Pooriamehr, Alireza; Bigdeli, Imanollah; Miladi-Gorji, Hossein

    2017-10-17

    This study was designed to examine whether maternal swimming exercise during pregnancy would attenuate prenatally morphine-induced anxiety, depression and voluntary consumption of morphine in the pubertal male and female rat offspring. Pregnant rats during the development of morphine dependence were allowed to swim (30-45min/d, 3days per a week) on gestational days 11-18. Then, the pubertal male and female rat offspring were tested for the elevated plus-maze (EPM), sucrose preference test (SPT) and voluntary morphine consumption using a two-bottle choice (TBC) paradigm. The results showed that male and female rat offspring born of the swimmer morphine-dependent mothers exhibited an increase in EPM open arm time and entries, higher levels of sucrose preference than their sedentary control mothers. Voluntary consumption of morphine was less in the male and female rat offspring born of the swimmer morphine-dependent mothers as compared with their sedentary control mothers during three periods of the intake of drug. Thus, swimming exercise in pregnant morphine dependent mothers decreased anxiety, depressive-like behavior and also the voluntary morphine consumption in the pubertal male and female offspring, which may prevent prenatally morphine-induced behavioral sensitization in offspring. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Mu-opioid receptor inhibition decreases voluntary wheel running in a dopamine-dependent manner in rats bred for high voluntary running.

    Science.gov (United States)

    Ruegsegger, Gregory N; Brown, Jacob D; Kovarik, M Cathleen; Miller, Dennis K; Booth, Frank W

    2016-12-17

    The mesolimbic dopamine and opioid systems are postulated to influence the central control of physical activity motivation. We utilized selectively bred rats for high (HVR) or low (LVR) voluntary running behavior to examine (1) inherent differences in mu-opioid receptor (Oprm1) expression and function in the nucleus accumbens (NAc), (2) if dopamine-related mRNAs, wheel-running, and food intake are differently influenced by intraperitoneal (i.p.) naltrexone injection in HVR and LVR rats, and (3) if dopamine is required for naltrexone-induced changes in running and feeding behavior in HVR rats. Oprm1 mRNA and protein expression were greater in the NAc of HVR rats, and application of the Oprm1 agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) to dissociated NAc neurons produced greater depolarizing responses in neurons from HVR versus LVR rats. Naltrexone injection dose-dependently decreased wheel running and food intake in HVR, but not LVR, rats. Naltrexone (20mg/kg) decreased tyrosine hydroxylase mRNA in the ventral tegmental area and Fos and Drd5 mRNA in NAc shell of HVR, but not LVR, rats. Additionally, lesion of dopaminergic neurons in the NAc with 6-hydroxydopamine (6-OHDA) ablated the decrease in running, but not food intake, in HVR rats following i.p. naltrexone administration. Collectively, these data suggest the higher levels of running observed in HVR rats, compared to LVR rats, are mediated, in part, by increased mesolimbic opioidergic signaling that requires downstream dopaminergic activity to influence voluntary running, but not food intake. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  1. Sex-dependent behavior, neuropeptide profile and antidepressant response in rat model of depression

    DEFF Research Database (Denmark)

    Sanchez, Connie; El Khoury, Aram; Hassan, Moustapha

    2018-01-01

    A plethora of animal models of depression is described in the literature, aiming at mimicking different aspects of depression. Understanding the link between depression and stress has been and remains a major focus area for development of animal models, but lines of research with a more mechanistic...... focus targeting deficiencies in neurotransmitter systems or dysfunctional neuronal circuitries and neuroinflammation are also pursued vigorously. The main objectives of the present study were systematically to evaluate strain and sex characteristics of a genetic animal model, the Flinders Sensitive Line...... (FSL)/ Flinders Resistant Line (FRL), by applying behavioral, molecular and pharmacological measures relevant to depression, and compare it with the outbred Sprague Dawley rat. In addition, we aimed at comparing across strains and sex the expression of NPY, CRF, CGRP in brain regions critically...

  2. Intermittent hypoxia alters dose dependent caffeine effects on renal prostanoids and receptors in neonatal rats.

    Science.gov (United States)

    Beharry, Kay D; Cai, Charles L; Soontarapornchai, Kultida; Ahmad, Taimur; Valencia, Gloria B; Aranda, Jacob V

    2018-01-01

    Caffeine, one of the most commonly prescribed drugs in preterm neonates, is given in standard or suprapharmacologic doses. Although known as a diuretic, its effects in the neonatal kidneys are not well studied. We tested the hypothesis that neonatal intermittent hypoxia (IH) and high caffeine doses (HCD) alter renal regulators of vasomotor tone and water balance. Newborn rats were randomized to room air, hyperoxia, or IH and treated with standard or high caffeine doses; or placebo saline. Renal prostanoids; histopathology; and cyclooxygenase (COX), prostanoid receptor, and aquaporin (AQP) immunoreactivity were determined. HCD in IH caused severe pathological changes in the glomeruli and proximal tubules, consistent with acute kidney injury. This was associated with reductions in anthropometric growth, PGI 2, and IP, DP, and AQP-4 immunoreactivity, well as a robust increase in COX-2, suggesting that the use of HCD should be avoided in preterm infants who experience frequent IH episodes. Published by Elsevier Inc.

  3. Nature cures nature: Hypericum perforatum attenuates physical withdrawal signs in opium dependent rats.

    Science.gov (United States)

    Khan, Munasib; Subhan, Fazal; Khan, Arif-Ullah; Abbas, Muzaffar; Ali, Gowhar; Rauf, Khalid; Gilani, Anwarul Hassan

    2014-05-01

    Hypericum perforatum Linn. (Hypericaceae) (St. John's wort) attenuates opium withdrawal signs. To explore the therapeutic potential of Hypericum perforatum in the management of opium-induced withdrawal syndrome. The effect of the Hypericum perforatum hydro-ethanol extract was investigated for potential to reverse naloxone (0.25 mg/kg)-induced opium withdrawal physical signs. Rats received opium extract (80-650 mg/kg) twice daily for 8 days along with Hypericum perforatum (20 mg/kg, orally) twice daily in chronic treatment and the same single dose 1 h before induction of withdrawal syndrome in the acute treated group. Hypericum perforatum reduced stereotype jumps and wet dog shake number in the chronic treatment compared to the saline control group (F(2, 24) = 3.968, p opium withdrawal syndrome possibly through direct or indirect interaction with opioid receptors. Further study is needed to clarify its mechanism.

  4. Time- and sequence-dependent responses to cisplatin and radiation in the rat kidney

    International Nuclear Information System (INIS)

    Rongen, Eric van; Kuijpers, W.C.; Baten-Wittwer, Andrea

    1991-01-01

    The influence of time interval and sequence between administration of cisplatin and a radiation dose was studied in the rat kidney. Changes in glomerular function were only detected after 30 weeks following the higher drug dose (6.0 mg/kg). X-rays alone caused measurable alterations in both glomerular and tubular function after 16 weeks. In the combined treatment the influence of time and sequence was significant. If cisplatin was given at 7 to 1 days before X-rays the effect of time was minimal. Administration of cisplatin 12 h to 15 min before irradiation resulted in an increase of radiation damage with decreasing time interval. Total damage sharply decreased when both modalities were given at the same time, and decreased further with increasing time between irradiation and drug administration. (author)

  5. Age dependent accumulation of N-acyl-ethanolamine phospholipids in ischemic rat brain

    DEFF Research Database (Denmark)

    Moesgaard, B.; Petersen, G.; Hansen, Harald S.

    2000-01-01

    N-acyl-ethanolamine phospholipids (NAPE) can be formed as a stress response during neuronal injury, and they are precursors for N-acyl- ethanolamines (NAE), some of which are endocannabinoids. The levels of NAPE accumulated during post-decapitative ischemia (6 h at 37°C) were studied in rat brains...... of various age (1, 6, 12, 19, 30, and ~70 days) by the use of P NMR spectroscopy of lipid extracts. This ability to accumulate NAPE was compared with the activity of N-acyltransferase and of NAPE-hydrolyzing phospholipase D (NAPE-PLD) in brain microsomes. These two enzymes are involved in the formation...... brains NAPE accumulation could not be detected (detection limit 0.09 %)]; and 2) this age pattern of accumulation can be explained by a combination of the decreased activity of N- acyltransferase and the increased activity of NAPE-PLD during development. These results point out that it would...

  6. Arecoline-induced growth arrest and p21WAF1 expression are dependent on p53 in rat hepatocytes

    International Nuclear Information System (INIS)

    Chou, W.-W.; Guh, J.-Y.; Tsai, J.-F.; Hwang, C.-C.; Chen, H.-C.; Huang, J.-S.; Yang, Y.-L.; Hung, W.-C.; Chuang, L.-Y.

    2008-01-01

    Betel-quid use is associated with the risk of liver cirrhosis and hepatocellular carcinoma and arecoline, the major alkaloid of betel-quid, is hepatotoxic in mice. Therefore, we studied the cytotoxic and genotoxic effects of arecoline in normal rat hepatocytes (Clone-9 cells). Arecoline dose-dependently (0.1-1 mM) decreased cell cycle-dependent proliferation while inducing DNA damage at 24 h. Moreover, arecoline (1 mM)-induced apoptosis and necrosis at 24 h. Arecoline dose-dependently (0.1-0.5 mM) increased transforming growth factor-β (TGF-β) mRNA, gene transcription and bioactivity and neutralizing TGF-β antibody attenuated arecoline (0.5 mM)-inhibited cell proliferation at 24 h. Arecoline (0.5 mM) also increased p21 WAF1 protein expression and p21 WAF1 gene transcription. Moreover, arecoline (0.5 mM) time-dependently (8-24 h) increased p53 serine 15 phosphorylation. Pifithrin-α (p53 inhibitor) and the loss of the two p53-binding elements in the p21 WAF1 gene promoter attenuated arecoline-induced p21 WAF1 gene transcription at 24 h. Pifithrin-α also attenuated arecoline (0.5 mM)-inhibited cell proliferation at 24 h. We concluded that arecoline induces cytotoxicity, DNA damage, G 0 /G 1 cell cycle arrest, TGF-β1, p21 WAF1 and activates p53 in Clone-9 cells. Moreover, arecoline-induced p21 WAF1 is dependent on p53 while arecoline-inhibited growth is dependent on both TGF-β and p53

  7. [Extracellular fluid, plasma and interstitial volume in cirrhotic patients without clinical edema or ascites].

    Science.gov (United States)

    Noguera Viñas, E C; Hames, W; Mothe, G; Barrionuevo, M P

    1989-01-01

    Extracellular fluid volume (E.C.F.) and plasma volume (P.V.), were measured with sodium sulfate labeled with 35I and 131I human serum albumin, respectively, by the dilution technique in control subjects and in cirrhotic patients without clinical ascites or edema, renal or hepatic failure, gastrointestinal bleeding or diuretics. Results are expressed as mean +/- DS in both ml/m2 and ml/kg. In normal subjects E.C.F. (n = 8) was 7,533 +/- 817 ml/m2 (201.3 +/- 182 ml/kg), P.V. (n = 11) 1,767 +/- 337 ml/m2 (47.2 +/- 9.3 ml/kg), and interstitial fluid (I.S.F.) (n = 7) 5,758 +/- 851 ml/m2 (Table 2). In cirrhotic patients E.C.F. (n = 11) was 10,318 +/- 2,980 ml/m2 (261.7 +/- 76.8 ml/kg), P.V. (n = 12) 2,649 +/- 558 ml/m2 (67.7 +/- 15.6 ml/kg) and I.S.F. (n = 11) 7,866 +/- 2,987 ml/m2 (Table 3). Cirrhotic patients compared with normal subjects have hypervolemia due to a significant E.C.F. and P.V. expansion (p less than 0.02 and less than 0.001 respectively) (Fig. 1). Reasons for E.C.F. and P.V. abnormalities in cirrhotic patients may reflect urinary sodium retention related to portal hipertension which stimulates aldosterone release or enhanced renal tubular sensitivity to the hormone. However, it is also possible that these patients, in the presence of hypoalbuminemia (Table 1), have no clinical edema or ascites due to increased glomerular filtration, suppressed release of vasopressin, increased natriuretic factor, and urinary prostaglandin excretion, in response to the intravascular expansion, all of which increased solute and water delivery to the distal nephron and improved renal water excretion. We conclude that in our clinical experience cirrhotic patients without ascites or edema have hypervolemia because of a disturbance in E.C.F.

  8. Heme oxygenase-1 dependant pathway contributes to protection by tetramethylpyrazine against chronic hypoxic injury on medulla oblongata in rats.

    Science.gov (United States)

    Ding, Yan; Hou, Xuefei; Chen, Li; Zhou, Hua; Gong, Yanju; Dai, Liqun; Zheng, Yu

    2016-02-15

    Tetramethylpyrazine (TMP), one of the active ingredients of the Chinese herb Lingusticum Wallichii (Chuan Xiong) has been proved to protect the medulla oblongata from chronic hypoxia injury. However, the underlying mechanism remains unclear. The purpose of this study was to determine whether the protective effects of TMP are associated with the heme oxygenase-1 (HO-1) dependant pathway in adult rats. The morphological changes of neurons in the hypoglossal nucleus (12N), the nucleus ambiguus (Amb), the nucleus tractus solitarius (NTS), and the pre-Bötzinger complex (pre-BötC) were investigated by Nissl staining; the malondialdehyde (MDA) content and superoxide dismutase (SOD) activity were measured to evaluate the anti-oxidant effect; some apoptosis parameters, Bax mRNA and Bcl-2 mRNA, were tested; and the double immunochemistry staining of active caspase-3/NeuN was performed. Meanwhile, the HO-1 protein expression and heme oxygenase (HO) activity were examined. Tin-protoporphyrin (SnPP), a potent inhibitor of HO, was used to further confirm the effect of HO-1. We found that TMP ameliorated the neuron loss in 12N, Amb and NTS, the decrease in SOD activity and the increase in MDA content, the decrease in Bcl-2 mRNA of medulla oblongata (Pmedulla oblongata in the rats. Copyright © 2015 Elsevier B.V. All rights reserved.

  9. p,p′-DDE Induces Apoptosis of Rat Sertoli Cells via a FasL-Dependent Pathway

    Directory of Open Access Journals (Sweden)

    Yuqin Shi

    2009-01-01

    Full Text Available One,1-dichloro-2,2 bis(p-chlorophenyl ethylene (p,p′-DDE, the major metabolite of 2,2-bis(4-Chlorophenyl-1,1,1-trichloroethane (DDT, is a known persistent organic pollutant and male reproductive toxicant. It has antiandrogenic effect. However, the mechanism by which p,p′-DDE exposure causes male reproductive toxicity remains unknown. In the present study, rat Sertoli cells were used to investigate the molecular mechanism involved in p,p′-DDE-induced toxicity in male reproductive system. The results indicated that p,p′-DDE exposure at over 30 μM showed the induction of apoptotic cell death. p,p′-DDE could induce increases in FasL mRNA and protein, which could be blocked by an antioxidant agent, N-acetyl-l-cysteine (NAC. In addition, caspase-3 and -8 were activated by p,p′-DDE treatment in these cells. The activation of NF-κB was enhanced with the increase of p,p′-DDE dose. Taken together, these results suggested that exposure to p,p′-DDE might induce apoptosis of rat Sertoli cells through a FasL-dependent pathway.

  10. Endothelium-Dependent Vasorelaxant Effect of Butanolic Fraction from Caryocar brasiliense Camb. Leaves in Rat Thoracic Aorta

    Directory of Open Access Journals (Sweden)

    Lais Moraes de Oliveira

    2012-01-01

    Full Text Available Caryocar brasiliense Camb. “pequi” is a native plant from the Cerrado region of Brazil that contains bioactive components reported to be antioxidant agents. Previous work has demonstrated that dietary supplementation with pequi decreased the arterial pressure of volunteer athletes. We found that the crude hydroalcoholic extract (CHE of C. brasiliense leaves relaxed, in a concentration-dependent manner, rat aortic rings precontracted with phenylephrine, and that the butanolic fraction (BF produced an effect similar to that of the CHE. Aortic relaxation induced by BF was abolished by endothelium removal, by incubation of the nitric oxide synthase inhibitor L-NAME, or the soluble guanylatecyclase inhibitor ODQ. However, incubation with atropine and pyrilamine had no effect on the BF-induced vasorelaxation. Moreover, this effect was not inhibited by indomethacin and tetraethylammonium. The concentration-response curve to calcium in denuded-endothelium rings was not modified after incubation with BF, and the vasorelaxation by BF in endothelium-intact rings precontracted with KCl was abolished after incubation with L-NAME. In addition, administration of BF in anesthetized rats resulted in a reversible hypotension. The results reveal that C. brasiliense possesses both in vivo and in vitro activities and that the vascular effect of BF involves stimulation of the nitric oxide/cyclic GMP pathway.

  11. Dose-dependent utilisation of casein-linked lysinoalanine, N(epsilon)-fructoselysine and N(epsilon)-carboxymethyllysine in rats.

    Science.gov (United States)

    Somoza, Veronika; Wenzel, Elisabeth; Weiss, Carola; Clawin-Rädecker, Ingrid; Grübel, Nadine; Erbersdobler, Helmut F

    2006-09-01

    During the heat treatment of protein-containing foods, the amino acid lysine is most prone to undergo chemical reactions in the course of amino acid cross-linking or Maillard reactions. Among the reaction products formed, lysinoalanine (LAL), N(epsilon)-fructoselysine (FL) and N(epsilon)-carboxymethyllysine (CML) are those which serve as sensitive markers for the heat treatment applied. From a nutritional perspective, these compounds are ingested with the diet in considerable amounts but information about their metabolic transit and putative in vivo effects is scarce. In the present study, casein-linked LAL, FL and CML were administered to rats in two different doses for 10 days. Quantitation of LAL, FL and CML in plasma, tissue and faeces samples revealed that the kidneys are the predominant sites of accumulation and excretion. The maximum percent of dietary LAL, FL and CML excreted in the urine was 5.6, 5.2 and 29%, whereas the respective recoveries in the kidneys were 0.02, 26 and 1.4%. The plasma and tissue analyses revealed that the endogenous load of either compound is increased by its dietary intake. But the dose-dependent utilisation of dietary protein-linked LAL, FL and CML in rats has been demonstrated for the first time to vary substantially from each other.

  12. The novel dehydroepiandrosterone (DHEA) derivative BNN27 counteracts delay-dependent and scopolamine-induced recognition memory deficits in rats.

    Science.gov (United States)

    Pitsikas, Nikolaos; Gravanis, Achille

    2017-04-01

    Experimental evidence indicates that the neurosteroids dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS) are involved in cognition. BNN27 is a novel 17C spiroepoxy-DHEA derivative, which devoid of steroidogenic activity. The neuroprotective effects of BNN27 have been recently reported. The present study was designed to investigate the effects of BNN27 on recognition memory in rats. For this purpose, the novel object task (NOT), a procedure assessing non-spatial recognition memory and the novel location task (NLT), a procedure evaluating spatial recognition memory were used. Intraperitoneal (i.p.) administration of BNN27 (3 and 10mg/kg) antagonized delay-dependent deficits in the NOT in the normal rat, suggesting that this DHEA derivative affected acquisition, storage and retrieval of information. In addition, BNN27 (3 and 10mg/kg, i.p.) counteracted the scopolamine [0.2mg/kg, subcutaneously (s.c.)]-induced non-spatial and spatial recognition memory deficits. These findings suggest that BNN27 may modulate different aspects of recognition memory, potentially interacting with the cholinergic system, relevant to cognition. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. He-Ne laser irradiation affects proliferation of cultured rat Schwann cells in a dose-dependent manner

    International Nuclear Information System (INIS)

    Breugel, H.H.F.I. van; Bar, P.R.

    1993-01-01

    Schwann cell proliferation is considered an essential part of Wallerian degeneration after nerve damage. Laminin, an important component of the extracellular matrix and produced by Schwann cells, provides a preferred substrate for outgrowing axons. To study whether low energy (He-Ne) laser irradiation may exert a positive effect on nerve regeneration through an effect on Schwann cells, its effect was evaluated in vitro. Schwann cells were isolated from sciatic nerves of 4-5-day old Wistar rats and cultures on 96-multiwell plates. The cells were irradiated by a He-Ne laser beam. At three consecutive days, starting either at day 5 or day 8, cells were irradiated each day for 0.5, 1, 2, 5 or 10 min. Both cell number and laminin production were determined for each irradiation condition within one experiment. Schwann cells that were irradiated from day 8 on were hardly affected by laser irradiation. However, the proliferation of cells that were irradiated starting on day 5 was significantly increased after 1, 2 and 5 min of daily irradiation, compared to non-irradiated control cultures. The lamin production per cell of these Schwann cells was not significantly altered. From these results we conclude that He-Ne laser irradiation can modulate proliferation of rat Schwann cells in vitro in a dose-dependent manner. (Author)

  14. Time-Dependent Structural Alteration of Rituximab Analyzed by LC/TOF-MS after a Systemic Administration to Rats.

    Directory of Open Access Journals (Sweden)

    Yuki Otani

    Full Text Available Therapeutic monoclonal antibodies (mAbs have heterogeneities in their structures. Multiple studies have reported that the variety of post-translational modifications could affect the pharmacokinetic profiles or pharmacological potencies of therapeutic mAbs. Taking into the account that the structural modification of mAbs would affect the efficacy, it is worth investigating the structural alteration of therapeutic mAbs in the blood and the relationship between their structures and pharmacological effects. Herein, we have developed the method to isolate rituximab from plasma in which endogenous IgGs interfere the detection of rituximab, and successfully developed the analytical method with a liquid chromatograph time-of-flight mass spectrometer to detect the structure of rituximab in plasma with errors less than 30 parts per millions. Eight types of carbohydrate chains in rituximab were detected by this method. Interestingly, time-dependent changes in carbohydrate chains such as AAF (G2F and GnGn (G0 were observed in rats, although the amino acids were stable. Additionally, these structural changes were observed via incubation in plasma as in the rat experiment, suggesting that a certain type of enzyme in plasma caused the alterations of the carbohydrate chains. The present analytical methods could clarify the actual pharmacokinetics of therapeutic mAbs, and help to evaluate the interindividual variations in pharmacokinetics and efficacy.

  15. [Effects of qishenyiqi gutta pills on calcium/calmodulin dependent protein kinase II in rats with renal hypertension].

    Science.gov (United States)

    Zhang, Xiao-ying; Wei, Wan-lin; Shu, Chang-cheng; Zhang, Ling; Tian, Guo-xiang

    2013-02-05

    To explore the effects of qishenyiqi gutta pills on myocardial hypertrophy of left ventricle and calcium/calmodulin dependent protein kinase II (CAMK II) in rats with renal hypertension and elucidate its intervention mechanism for myocardial hypertrophy. A total of 50 Wistar rats were randomly divided into 5 groups of sham-operation, control, high-dose qishenyiqi gutta pills, low-dose qishenyiqi gutta pills and valsartan (n = 10 each). The rat model of myocardial hypertrophy with renal hypertension was established by the 2-kidney 1-clip (2K1C) method. The experimental animals were divided into control, high-dose, low-dose and valsartan groups. At Week 5 postoperation, valsartan group received an oral dose of valsartan (30 mg×kg(-1)×d(-1)), high-dose and low-dose groups took qishenyiqi gutta pills (250 and 125 mg×kg(-1)×d(-1)) while sham-operation and control groups had the same dose of normal saline solution. Tail arterial pressure was detected weekly and continued for 8 weeks. At the end of Week 12, the animals were sacrificed to harvest myocardial tissue of left ventricle for detecting left ventricular mass index (LVMI). The collagen volume fraction (CVF) of myocardium was examined by Van Gieson staining, the activities of superoxide dismutase (SOD) and reactive oxygen species (ROS) were detected by enzyme-linked immunosorbent assay (ELISA) and the expression of CAMK II was detected by immunohistochemistry and Western blot. (1) Blood pressures were significantly higher in high-dose, low-dose and control groups than those in sham-operation and valsartan groups ((167.66 ± 11.48), (166.72 ± 13.51), (174.34 ± 14.52) vs (119.57 ± 6.30), (131.80 ± 12.49) mm Hg, P pills may retard myocardial hypertrophy of left ventricle in rats with renal hypertension. And the mechanism is probably be correlated with its antioxidant activity and inhibited expression of myocardial CAMK II.

  16. Co-administration of morphine and gabapentin leads to dose dependent synergistic effects in a rat model of postoperative pain

    DEFF Research Database (Denmark)

    Papathanasiou, Theodoros; Juul, Rasmus Vestergaard; Heegaard, Anne-Marie

    2016-01-01

    dose combinations and investigate whether co-administration leads to synergistic effects in a preclinical model of postoperative pain. The pharmacodynamic effects of morphine (1, 3 and 7 mg/kg), gabapentin (10, 30 and 100 mg/kg) or their combination (9 combinations in total) were evaluated in the rat...... plantar incision model using an electronic von Frey device. The percentage of maximum possible effect (%MPE) and the area under the response curve (AUC) were used for evaluation of the antihyperalgesic effects of the drugs. Identification of synergistic interactions was based on Loewe additivity response...... surface analyses. The combination of morphine and gabapentin resulted in synergistic antihyperalgesic effects in a preclinical model of postoperative pain. The synergistic interactions were found to be dose dependent and the increase in observed response compared to the theoretical additive response...

  17. Stage-specific and age-dependent profiles of zinc, copper, manganese, and selenium in rat seminiferous tubules

    International Nuclear Information System (INIS)

    Homma-Takeda, S.; Nishimura, Y.; Watanabe, Y.; Imaseki, H.; Yukawa, M.

    2004-01-01

    Stage-specific and age-dependent profiles of zinc, copper, manganese, and selenium in testis were examined in Wistar rats by both inductively coupled argon plasma-mass spectrometry (ICP-MS) with a microdissection technique and in situ elemental imaging of micro-PIXE analysis. The young adult animals (10 weeks old) contained higher levels of zinc and manganese in the seminiferous tubules at stages VII-VIII than stages XI through VI and IX-X and the levels were higher than those of the immature and old animals. Copper and selenium levels at stages VII-VIII of the young adult animals were also higher than those of the immature and old animals. In stages VII and VIII, zinc was higher in the central area of the seminiferous epithelium, where spermatozoa were localized, demonstrating a cell-specific property. (author)

  18. Dopamine D1 receptor-dependent regulation of extracellular citrulline level in the rat nucleus accumbens during conditioned fear response.

    Science.gov (United States)

    Saulskaya, Natalia B; Fofonova, Nellia V; Sudorghina, Polina V; Saveliev, Sergey A

    2008-08-01

    Nucleus accumbens (N.Acc) contains a subclass of nitric oxide (NO)-generating interneurons that are presumably regulated by the dopamine input. Receptor mechanisms underlying dopamine-NO interaction in the N.Acc are poorly understood. In the current study, we used in vivo microdialysis combined with high-performance liquid chromatography to examine participation of dopamine D1 receptors in regulation of extracellular levels of citrulline (an NO co-product) in the medial N.Acc of Sprague-Dawley rats during both pharmacological challenge and a conditioned fear response. The intraaccumbal infusion of the D1 receptor agonist SKF-38393 (100-500 microM) increased dose-dependently the local dialysate citrulline levels. The SKF-38393-induced increase in extracellular citrulline was prevented by intraaccumbal infusions of 500 microM 7-nitroindazole, a neuronal NO synthase inhibitor. In behavioral microdialysis experiment, the accumbal levels of extracellular citrulline markedly increased in rats given a mild footshock paired with tone. The presentation of the tone previously paired with footshock (the conditioned fear response) produced a "conditioned" rise of extracellular citrulline levels in the N.Acc which was attenuated by intraaccumbal infusion of 100 microM SCH-23390, a dopamine D1 receptor antagonist, and prevented by intraaccumbal infusion of 500 microM 7-nitroindazole. The results suggest that in the N.Acc, the dopamine D1 receptors might regulate the neuronal NO synthase activity; this dopamine-dependent mechanism seems to participate in activation of the neuronal NO synthase and probably NO formation in this brain area during the conditioned fear response.

  19. The Effect of Nitric Oxide Synthetase Inhibitor (L-NAME on Prevention of Morphine Dependence in Rats

    Directory of Open Access Journals (Sweden)

    A. Rafati

    2004-10-01

    Full Text Available Prevention of dependency to morphine or delaying to it and decreasing of tendency to morphine craving and also decreasing in morphine induced hyperalgesia(tolerance were the aims of this study. Nitric oxide is one of the neurotransmitters, which involves in the Dopamine reuptake in striatum. Dopamine is one of the most important neurotransmitters in reward system in central nervous system and it has a critical role in morphine addiction and dependency, tendency and tolerance to it, so in this study we survied the role of L- NAME as a nitric oxide synthetase (NOS inhibitor on the prevention of morphine addiction in rats. In this study we evaluated behavioral changes such as morphine craving by self - administration as a criterion for tendency, dependency by observation of withdrawal syndrom signs (e.g Jumping, wet dog shaking and also responses to nociceptive condenced bim of light by using tail flick analgesia metric device in sham (consuming tap water, control (consuming increasing doses of morphine sulfate solution from 0.1mg/ml up to 0.4mg/ml and test (treated with 45 mg/kg of L- NAME 30 minutes before consuming of morphine sulfate solution per day groups. The results showed that pretreatment with L- NAME in test group lead to a significant decline in tendency to morphine craving, withdrawal signs and also a significant reversal of morphine induced hyperalgesia. We concluded that L- NAME is a potent agent in the prevention of morphine addiction.

  20. NO involvement in the inhibition of ghrelin on voltage-dependent potassium currents in rat hippocampal cells.

    Science.gov (United States)

    Lu, Yong; Dang, Shaokang; Wang, Xu; Zhang, Junli; Zhang, Lin; Su, Qian; Zhang, Huiping; Lin, Tianwei; Zhang, Xiaoxiao; Zhang, Yurong; Sun, Hongli; Zhu, Zhongliang; Li, Hui

    2018-01-01

    Ghrelin is a peptide hormone that plays an important role in promoting appetite, regulating distribution and rate of use of energy, cognition, and mood disorders, but the relevant neural mechanisms of these function are still not clear. In this study, we examined the effect of ghrelin on voltage-dependent potassium (K + ) currents in hippocampal cells of 1-3 days SD rats by whole-cell patch-clamp technique, and discussed whether NO was involved in this process. The results showed that ghrelin significantly inhibited the voltage-dependent K + currents in hippocampal cells, and the inhibitory effect was more significant when l-arginine was co-administered. In contrast, N-nitro- l-arginine methyl ester increased the ghrelin inhibited K + currents and attenuated the inhibitory effect of ghrelin. While d-arginine (D-AA) showed no significant impact on the ghrelin-induced decrease in K + current. These results show that ghrelin may play a physiological role by inhibiting hippocampal voltage dependent K + currents, and the NO pathway may be involved in this process. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Contribution to the penetration of radionuclides across the skin. Age dependence of promethium through rat skin in vitro

    International Nuclear Information System (INIS)

    Kassai, Z.; Koprda, V.; Harangozo, M.; Bendova, P.; Bauerova, K.

    2001-01-01

    In this paper: - the time dependence of permeation of 147 Pm 3+ from aqueous solution through animal skin model was studied; - the age dependence of promethium through the skin was proved; - the optimum biological model of human skin was selected, and - the relative importance of the main diffusion pathways for 147 Pm 3+ the diffusion across the intact skin and the diffusion through the hair channels was assessed. Concluding it can be said, that: -it was proved, that the 5-day-old rats (5DR) represents the optimum animal model to the human skin; - in the case of 8DR to 11DR the dominant route of 147 Pm 3+ penetration is along the follicles; - the permeation resistance of the skin depends on the thickness and mechanical properties of the skin. Comparing amounts of penetrated ions of promethium through the skin without hairs (3DR to 6DR) and through the skin with hairs, it was showed that the additional diffusion along hair's follicles pronounced with animal skin can be important also in case of human skin where hair density is many times lower than in used animal models. (authors)

  2. Time- and concentration-dependent genomic responses of the rat airway to inhaled nickel subsulfide

    Energy Technology Data Exchange (ETDEWEB)

    Efremenko, A.Y., E-mail: aefremenko@thehamner.org [The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC 27709 (United States); Campbell, J.L.; Dodd, D.E. [The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC 27709 (United States); Oller, A.R. [NiPERA, Inc., 2525 Meridian Parkway, Suite 240, Durham, NC 27713 (United States); Clewell, H.J. [The Hamner Institutes for Health Sciences, 6 Davis Drive, Research Triangle Park, NC 27709 (United States)

    2014-09-15

    Objective: To provide insights into the mode of action for Ni{sub 3}S{sub 2} lung carcinogenicity by examining gene expression changes in target cells after inhalation exposure. Methods: Gene expression changes were determined in micro-dissected lung broncho-alveolar cells from Fischer 344 rats following inhalation of Ni{sub 3}S{sub 2} at 0.0, 0.04, 0.08, 0.15, and 0.60 mg/m{sup 3} (0.03, 0.06, 0.11, and 0.44 mg Ni/m{sup 3}) for one and four weeks (6 h/day, 5 days/week). Results: Broncho-alveolar lavage fluid evaluation and lung histopathology provided evidence of inflammation only at the two highest concentrations, which were similar to those tested in the 2-year bioassay. The number of statistically significant up- and down-regulated genes decreased markedly from one to four weeks of exposure, suggesting adaptation. Cell signal pathway enrichment at both time-points primarily reflected responses to toxicity, including inflammatory and proliferative signaling. While proliferative signaling was up-regulated at both time points, some inflammatory signaling reversed from down-regulation at 1 week to up-regulation at 4 weeks. Conclusions: These results support a mode of action for Ni{sub 3}S{sub 2} carcinogenicity driven by chronic toxicity, inflammation and proliferation, leading to mis-replication, rather than by direct genotoxicity. Benchmark dose (BMD) analysis identified the lowest pathway transcriptional BMD exposure concentration as 0.026 mg Ni/m{sup 3}, for apoptosis/survival signaling. When conducted on the basis of lung Ni concentration the lowest pathway BMD was 0.64 μg Ni/g lung, for immune/inflammatory signaling. Implications: These highly conservative BMDs could be used to derive a point of departure in a nonlinear risk assessment for Ni{sub 3}S{sub 2} toxicity and carcinogenicity. - Highlights: • The mode of action for lung carcinogenicity of inhaled Ni{sub 3}S{sub 2} was investigated in rats. • Gene expression changes were determined in micro

  3. Time- and concentration-dependent genomic responses of the rat airway to inhaled nickel subsulfide

    International Nuclear Information System (INIS)

    Efremenko, A.Y.; Campbell, J.L.; Dodd, D.E.; Oller, A.R.; Clewell, H.J.

    2014-01-01

    Objective: To provide insights into the mode of action for Ni 3 S 2 lung carcinogenicity by examining gene expression changes in target cells after inhalation exposure. Methods: Gene expression changes were determined in micro-dissected lung broncho-alveolar cells from Fischer 344 rats following inhalation of Ni 3 S 2 at 0.0, 0.04, 0.08, 0.15, and 0.60 mg/m 3 (0.03, 0.06, 0.11, and 0.44 mg Ni/m 3 ) for one and four weeks (6 h/day, 5 days/week). Results: Broncho-alveolar lavage fluid evaluation and lung histopathology provided evidence of inflammation only at the two highest concentrations, which were similar to those tested in the 2-year bioassay. The number of statistically significant up- and down-regulated genes decreased markedly from one to four weeks of exposure, suggesting adaptation. Cell signal pathway enrichment at both time-points primarily reflected responses to toxicity, including inflammatory and proliferative signaling. While proliferative signaling was up-regulated at both time points, some inflammatory signaling reversed from down-regulation at 1 week to up-regulation at 4 weeks. Conclusions: These results support a mode of action for Ni 3 S 2 carcinogenicity driven by chronic toxicity, inflammation and proliferation, leading to mis-replication, rather than by direct genotoxicity. Benchmark dose (BMD) analysis identified the lowest pathway transcriptional BMD exposure concentration as 0.026 mg Ni/m 3 , for apoptosis/survival signaling. When conducted on the basis of lung Ni concentration the lowest pathway BMD was 0.64 μg Ni/g lung, for immune/inflammatory signaling. Implications: These highly conservative BMDs could be used to derive a point of departure in a nonlinear risk assessment for Ni 3 S 2 toxicity and carcinogenicity. - Highlights: • The mode of action for lung carcinogenicity of inhaled Ni 3 S 2 was investigated in rats. • Gene expression changes were determined in micro-dissected lung tissue at 1–4 weeks. • A non-genotoxic mode

  4. Detection of Ca2+-dependent acid phosphatase activity identifies neuronal integrity in damaged rat central nervous system after application of bacterial melanin

    Directory of Open Access Journals (Sweden)

    Tigran R Petrosyan

    2016-01-01

    Full Text Available The study aims to confirm the neuroregenerative effects of bacterial melanin (BM on central nervous system injury using a special staining method based on the detection of Ca2+-dependent acid phosphatase activity. Twenty-four rats were randomly assigned to undergo either unilateral destruction of sensorimotor cortex (group I; n = 12 or unilateral rubrospinal tract transection at the cervical level (C3–4 (group II; n = 12. In each group, six rats were randomly selected after surgery to undergo intramuscular injection of BM solution (BM subgroup and the remaining six rats were intramuscularly injected with saline (saline subgroup. Neurological testing confirmed that BM accelerated the recovery of motor function in rats from both BM and saline subgroups. Two months after surgery, Ca2+-dependent acid phosphatase activity detection in combination with Chilingarian's calcium adenoside triphosphate method revealed that BM stimulated the sprouting of fibers and dilated the capillaries in the brain and spinal cord. These results suggest that BM can promote the recovery of motor function of rats with central nervous system injury; and detection of Ca2+-dependent acid phosphatase activity is a fast and easy method used to study the regeneration-promoting effects of BM on the injured central nervous system.

  5. Fluoride absorption from the rat urinary bladder: a pH-dependent event

    International Nuclear Information System (INIS)

    Whitford, G.M.; Pashley, D.H.; Reynolds, K.E.

    1977-01-01

    Urinary bladder absorption of stable and radiofluoride was studied as a function of pH in anesthetized rats to further evaluate the influence of pH gradients on fluoride transport. Buffered pH values and stable fluoride concentrations ranged from 1.85 to 7.90 and from 0.012 to 8.81 mM, respectively. [ 14 C]inulin served as a marker for solute concentration changes due to water migration or dilution. The results indicate that bladder fluoride absorption is inversely related to pH over the 1.85 to 5.50 range. Mean, 15-min radiofluoride absorption values of 70 percent at pH 1.85, 37 percent at pH 3.95, and 5 percent at pH 5.50 were observed. These fractional absorption values were not significantly influenced by carrier fluoride concentration, the buffers used, or the presence of urine. Above pH 5.50, pH-independent absorption occurs to a slight extent. The results are consistent with a first-order absorptive process which occurs by the nonionic diffusion of hydrogen fluoride

  6. Sex-dependent differences in phenobarbitane-induced oestradiol-2-hydroxylase activity in rat liver

    Energy Technology Data Exchange (ETDEWEB)

    Theron, C.N.; Neethling, A.C.; Taljaard, J.J.F. (Stellenbosch Univ. (South Africa). Dept. of Chemical Pathology)

    1981-08-15

    Oestradiol-2-hydroxylase (E/sub 2/-OH) activity was measured in liver and brain microsomes of 6-8-week-old Wistar rats. Phenobarbitone (75 mg/kg daily for 3 days) significantly increased enzyme activity in the liver of males and females, but there were striking differences between the two sexes. In males the enzyme activity was increased by 37% over control values and in females by 200%. The total microsomol cytochrome P-450 content was increased by 75% in males and by 82% in females. The apparent Michaelis constant (K(m)) of E/sub 2/-OH for 17..beta..-oestradiol in untreated males (9,8 ..mu..M) and females (9,2 ..mu..M) did not differ significantly. Phenobarbitone treatment, however, tended to reduce the apparent K(m) in males (8,2 ..mu..M) and to increase it in females (18,7 ..mu..M). E/sub 2/-OH activity was also detected in brain tissue of both sexes, but it was 50-200-fold lower than in the liver and was not increased by phenobarbitone.

  7. Sex-dependent differences in phenobarbitane-induced oestradiol-2-hydroxylase activity in rat liver

    International Nuclear Information System (INIS)

    Theron, C.N.; Neethling, A.C.; Taljaard, J.J.F.

    1981-01-01

    Oestradiol-2-hydroxylase (E 2 -OH) activity was measured in liver and brain microsomes of 6-8-week-old Wistar rats. Phenobarbitone (75 mg/kg daily for 3 days) significantly increased enzyme activity in the liver of males and females, but there were striking differences between the two sexes. In males the enzyme activity was increased by 37% over control values and in females by 200%. The total microsomol cytochrome P-450 content was increased by 75% in males and by 82% in females. The apparent Michaelis constant (K(m)) of E 2 -OH for 17β-oestradiol in untreated males (9,8 μM) and females (9,2 μM) did not differ significantly. Phenobarbitone treatment, however, tended to reduce the apparent K(m) in males (8,2 μM) and to increase it in females (18,7 μM). E 2 -OH activity was also detected in brain tissue of both sexes, but it was 50-200-fold lower than in the liver and was not increased by phenobarbitone

  8. Extracellular Calcium-Dependent Modulation of Endothelium Relaxation in Rat Mesenteric Small Artery

    DEFF Research Database (Denmark)

    Hangaard, Lise; Jessen, Peter B; Kamaev, Dmitrii

    2015-01-01

    The nature of NO- and COX-independent endothelial hyperpolarization (EDH) is not fully understood but activation of small- and intermittent-conductance Ca(2+)-activated K(+) channels (SKCa and IKCa) is important. Previous studies have suggested that the significance of IKCa depends on [Ca(2+)]out...

  9. Rats

    Directory of Open Access Journals (Sweden)

    Alexey Kondrashov

    2012-01-01

    Full Text Available We aimed to perform a chemical analysis of both Alibernet red wine and an alcohol-free Alibernet red wine extract (AWE and to investigate the effects of AWE on nitric oxide and reactive oxygen species production as well as blood pressure development in normotensive Wistar Kyoto (WKY and spontaneously hypertensive rats (SHRs. Total antioxidant capacity together with total phenolic and selected mineral content was measured in wine and AWE. Young 6-week-old male WKY and SHR were treated with AWE (24,2 mg/kg/day for 3 weeks. Total NOS and SOD activities, eNOS and SOD1 protein expressions, and superoxide production were determined in the tissues. Both antioxidant capacity and phenolic content were significantly higher in AWE compared to wine. The AWE increased NOS activity in the left ventricle, aorta, and kidney of SHR, while it did not change NOS activity in WKY rats. Similarly, increased SOD activity in the plasma and left ventricle was observed in SHR only. There were no changes in eNOS and SOD1 expressions. In conclusion, phenolics and minerals included in AWE may contribute directly to increased NOS and SOD activities of SHR. Nevertheless, 3 weeks of AWE treatment failed to affect blood pressure of SHR.

  10. Single photon emission computed tomography and statistical parametric mapping analysis in cirrhotic patients with and without minimal hepatic encephalopathy

    International Nuclear Information System (INIS)

    Nakagawa, Yuri; Matsumura, Kaname; Iwasa, Motoh; Kaito, Masahiko; Adachi, Yukihiko; Takeda, Kan

    2004-01-01

    The early diagnosis and treatment of cognitive impairment in cirrhotic patients is needed to improve the patients' daily living. In this study, alterations of regional cerebral blood flow (rCBF) were evaluated in cirrhotic patients using statistical parametric mapping (SPM). The relationships between rCBF and neuropsychological test, severity of disease and biochemical data were also assessed. 99m Tc-ethyl cysteinate dimer single photon emission computed tomography was performed in 20 patients with non-alcoholic liver cirrhosis without overt hepatic encephalopathy (HE) and in 20 age-matched healthy subjects. Neuropsychological tests were performed in 16 patients; of these 7 had minimal HE. Regional CBF images were also analyzed in these groups using SPM. On SPM analysis, cirrhotic patients showed regions of significant hypoperfusion in the superior and middle frontal gyri, and inferior parietal lobules compared with the control group. These areas included parts of the premotor and parietal associated areas of the cortex. Among the cirrhotic patients, those with minimal HE had regions of significant hypoperfusion in the cingulate gyri bilaterally as compared with those without minimal HE. Abnormal function in the above regions may account for the relatively selective neuropsychological deficits in the cognitive status of patients with cirrhosis. These findings may be important in the identification and management of cirrhotic patients with minimal HE. (author)

  11. Estrogen-dependent efficacy of limb ischemic preconditioning in female rats.

    Science.gov (United States)

    Pócs, Levente; Janovszky, Ágnes; Garab, Dénes; Terhes, Gabriella; Ocsovszki, Imre; Kaszaki, József; Boros, Mihály; Piffkó, József; Szabó, Andrea

    2018-01-01

    Our aim was to examine the effects of ischemic preconditioning (IPC) on the local periosteal and systemic inflammatory consequences of hindlimb ischemia-reperfusion (IR) in Sprague-Dawley rats with chronic estrogen deficiency (13 weeks after ovariectomy, OVX) in the presence and absence of chronic 17beta-estradiol supplementation (E2, 20 µg kg -1 , 5 days/week for 5 weeks); sham-operated (non-OVX) animals served as controls. As assessed by intravital fluorescence microscopy, rolling and the firm adhesion of polymorphonuclear neutrophil leukocytes (PMNs) gave similar results in the Sham + IR and OVX + IR groups in the tibial periosteal microcirculation during the 3-h reperfusion period after a 60-min tourniquet ischemia. Postischemic increases in periosteal PMN adhesion and PMN-derived adhesion molecule CD11b expressions, however, were significantly reduced by IPC (two cycles of 10'/10') in Sham animals, but not in OVX animals; neither plasma free radical levels (as measured by chemiluminescence), nor TNF-alpha release was affected by IPC. E2 supplementation in OVX animals restored the IPC-related microcirculatory integrity and PMN-derived CD11b levels, and TNF-alpha and free radical levels were reduced by IPC only with E2. An enhanced estrogen receptor beta expression could also be demonstrated after E2 in the periosteum. Overall, the beneficial periosteal microcirculatory effects of limb IPC are lost in chronic estrogen deficiency, but they can be restored by E2 supplementation. This suggests that the presence of endogenous estrogen is a necessary facilitating factor of the anti-inflammatory protection provided by limb IPC in females. The IPC-independent effects of E2 on inflammatory reactions should also be taken into account in this model. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:97-105, 2018. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

  12. State-dependent changes in auditory sensory gating in different cortical areas in rats.

    Directory of Open Access Journals (Sweden)

    Renli Qi

    Full Text Available Sensory gating is a process in which the brain's response to a repetitive stimulus is attenuated; it is thought to contribute to information processing by enabling organisms to filter extraneous sensory inputs from the environment. To date, sensory gating has typically been used to determine whether brain function is impaired, such as in individuals with schizophrenia or addiction. In healthy subjects, sensory gating is sensitive to a subject's behavioral state, such as acute stress and attention. The cortical response to sensory stimulation significantly decreases during sleep; however, information processing continues throughout sleep, and an auditory evoked potential (AEP can be elicited by sound. It is not known whether sensory gating changes during sleep. Sleep is a non-uniform process in the whole brain with regional differences in neural activities. Thus, another question arises concerning whether sensory gating changes are uniform in different brain areas from waking to sleep. To address these questions, we used the sound stimuli of a Conditioning-testing paradigm to examine sensory gating during waking, rapid eye movement (REM sleep and Non-REM (NREM sleep in different cortical areas in rats. We demonstrated the following: 1. Auditory sensory gating was affected by vigilant states in the frontal and parietal areas but not in the occipital areas. 2. Auditory sensory gating decreased in NREM sleep but not REM sleep from waking in the frontal and parietal areas. 3. The decreased sensory gating in the frontal and parietal areas during NREM sleep was the result of a significant increase in the test sound amplitude.

  13. Age-dependent changes of the antioxidant system in rat livers are accompanied by altered MAPK activation and a decline in motor signaling

    Science.gov (United States)

    Yang, Wei; Burkhardt, Britta; Fischer, Luise; Beirow, Maja; Bork, Nadja; Wönne, Eva C.; Wagner, Cornelia; Husen, Bettina; Zeilinger, Katrin; Liu, Liegang; Nussler, Andreas K.

    2015-01-01

    Aging is characterized by a progressive decrease of cellular functions, because cells gradually lose their capacity to respond to injury. Increased oxidative stress is considered to be one of the major contributors to age-related changes in all organs including the liver. Our study has focused on elucidating whether important antioxidative enzymes, the mTOR pathway, and MAPKs exhibit age-dependent changes in the liver of rats during aging. We found an age-dependent increase of GSH in the cytosol and mitochondria. The aged liver showed an increased SOD enzyme activity, while the CAT enzyme activity decreased. HO-1 and NOS-2 gene expression was lower in adult rats, but up-regulated in aged rats. Western blot analysis revealed that SOD1, SOD2, GPx, GR, γ-GCL, and GSS were age-dependent up-regulated, while CAT remained constant. We also demonstrated that the phosphorylation of Akt, JNK, p38, and TSC2Ser1254 decreased while ERK1/2 and TSC2Thr1462 increased age-dependently. Furthermore, our data show that the mTOR pathway seems to be activated in livers of aged rats, and hence stimulating cell proliferation/regeneration, as confirmed by an age-dependent increase of PCNA and p-eIF4ESer209 protein expression. Our data may help to explain the fact that liver cells only proliferate in cases of necessity, like injury and damage. In summary, we have demonstrated that, age-dependent changes of the antioxidant system and stress-related signaling pathways occur in the livers of rats, which may help to better understand organ aging. PMID:27004051

  14. Volume-Dependent Expression of In-Field and Out-of-Field Effects in the Proton-Irradiated Rat Lung

    NARCIS (Netherlands)

    Coppes, Robert P.; Muijs, Christina T.; Faber, Hette; Gross, Sascha; Schippers, Jacobus M.; Brandenburg, Sytze; Langendijk, Johannes A.; van Luijk, Peter

    2011-01-01

    Purpose: To investigate whether occurance of early radiation effects in lung tissue depends on local close only. Methods and Materials: Twenty-five percent. 50%, 66%, 88%, or 100% of the rat lung was irradiated using single fractions of 150-MeV protons. For all volumes, in-field and out-of-field

  15. EXPOSURE TO DIETHYL HEXYL PHTHALATE (DEHP) DELAYS PUBERTY AND REDUCES ANDROGEN-DEPENDENT TISSUE WEIGHTS IN LONG EVANS HOODED AND SPRAGUE DAWLEY MALE RATS

    Science.gov (United States)

    DEHP is a plasticizer that alters sexual differentiation in the male rat by reducing fetal Leydig cell testosterone synthesis and insl3 mRNA levels. When exposure includes the pubertal stage of life, DEHP and other phthalates delay puberty and reduce androgen-dependent tissue wei...

  16. Epidermal growth factor receptor-induced activato protein 1 activity controls density-dependent growht inhibition in normal rat kidney fibroblasts.

    NARCIS (Netherlands)

    Hornberg, J.J.; Dekker, H.; Peters, P.H.J.; Langerak, P.; Westerhoff, H.V.; Lankelma, J.; Zoelen, E.J.J.

    2006-01-01

    Density-dependent growth inhibition secures tissue homeostasis. Dysfunction of the mechanisms, which regulate this type of growth control is a major cause of neoplasia. In confluent normal rat kidney (NRK) fibroblasts, epidermal growth factor (EGF) receptor levels decline, ultimately rendering these

  17. EXPRESSION OF CALCIUM-BINDING PROTEINS IN THE NEUROTROPHIN-3-DEPENDENT SUBPOPULATION OF RAT EMBRYONIC DORSAL-ROOT GANGLION-CELLS IN CULTURE

    NARCIS (Netherlands)

    COPRAY, JCVM; MANTINGHOTTER, IJ; BROUWER, N

    1994-01-01

    In this study we have examined the calcium-binding protein expression in rat embryonic (E16) dorsal root ganglia (DRG) neurons in vitro in the presence of neurotrophin-3 (NT-3). A comparison was made with the expression of calcium-binding proteins in DRG subpopulations that depended in vitro on

  18. Local application of SCH 39166 reversibly and dose-dependently decreases acetylcholine release in the rat striatum.

    Science.gov (United States)

    Acquas, E; Di Chiara, G

    1999-11-03

    The effect of local application by reverse dialysis of the dopamine D(1) receptor antagonist (-)-trans-6,7,7a,8,9, 13b-exahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo-[d]-nap hto-[2, 1b]-azepine hydrochloride (SCH 39166) on acetylcholine release was studied in awake, freely moving rats implanted with concentric microdialysis probes in the dorsal striatum. In these experiments, the reversible acetylcholine esterase inhibitor, neostigmine, was added to the perfusion solution at two different concentrations, 0.01 and 0.1 microM. SCH 39166 (1, 5 and 10 microM), in the presence of 0.01 microM neostigmine, reversibly decreased striatal acetylcholine release (1 microM SCH 39166 by 8+/-4%; 5 microM SCH 39166 by 24+/-5%; 10 microM SCH 39166 by 27+/-7%, from basal). Similarly, SCH 39166, applied in the presence of a higher neostigmine concentration (0.1 microM), decreased striatal acetylcholine release by 14+/-4% at 1 microM, by 28+/-8% at 5 microM and by 30+/-5% at 10 microM, in a dose-dependent and time-dependent manner. These results are consistent with the existence of a facilitatory tone of dopamine on striatal acetylcholine transmission mediated by dopamine D(1) receptors located on striatal cholinergic interneurons.

  19. The role of GABA in NMDA-dependent long term depression (LTD) of rat medial vestibular nuclei.

    Science.gov (United States)

    Grassi, S; Della Torre, G; Capocchi, G; Zampolini, M; Pettorossi, V E

    1995-11-20

    The role of GABA in NMDA-dependent long term depression (LTD) in the medial vestibular nuclei (MVN) was studied on rat brainstem slices. High frequency stimulation (HFS) of the primary vestibular afferents induces a long lasting reduction of the polysynaptic (N2) component of the field potentials recorded in the dorsal portion of the MVN. The induction but not the maintenance of this depression was abolished by AP5, a specific blocking agent for glutamate NMDA receptors. The involvement of GABA in mediating the depression was checked by applying the GABAA and GABAB receptor antagonists, bicuculline and saclofen, before and after HFS. Under bicuculline and saclofen perfusion, HFS provoked a slight potentiation of the N2 wave, while the N2 depression clearly emerged after drug wash-out. This indicates that GABA is not involved in inducing the long term effect, but it is necessary for its expression. Similarly, the LTD reversed and a slight potentiation appeared when both drugs were administered after its induction. Most of these effects were due to the bicuculline, suggesting that GABAA receptors contribute to LTD more than GABAB do. According to our results, it is unlikely that the long lasting vestibular depression is the result of a homosynaptic LTD. On the contrary, our findings suggest that the depression is due to an enhancement of the GABA inhibitory effect, caused by an HFS dependent increase in gabaergic interneuron activity, which resets vestibular neuron excitability at a lower level.

  20. Sex-dependent impact of early-life stress and adult immobilization in the attribution of incentive salience in rats.

    Science.gov (United States)

    Fuentes, Silvia; Carrasco, Javier; Hatto, Abigail; Navarro, Juan; Armario, Antonio; Monsonet, Manel; Ortiz, Jordi; Nadal, Roser

    2018-01-01

    Early life stress (ELS) induces long-term effects in later functioning and interacts with further exposure to other stressors in adulthood to shape our responsiveness to reward-related cues. The attribution of incentive salience to food-related cues may be modulated by previous and current exposures to stressors in a sex-dependent manner. We hypothesized from human data that exposure to a traumatic (severe) adult stressor will decrease the attribution of incentive salience to reward-associated cues, especially in females, because these effects are modulated by previous ELS. To study these factors in Long-Evans rats, we used as an ELS model of restriction of nesting material and concurrently evaluated maternal care. In adulthood, the offspring of both sexes were exposed to acute immobilization (IMO), and several days after, a Pavlovian conditioning procedure was used to assess the incentive salience of food-related cues. Some rats developed more attraction to the cue predictive of reward (sign-tracking) and others were attracted to the location of the reward itself, the food-magazine (goal-tracking). Several dopaminergic markers were evaluated by in situ hybridization. The results showed that ELS increased maternal care and decreased body weight gain (only in females). Regarding incentive salience, in absolute control animals, females presented slightly greater sign-tracking behavior than males. Non-ELS male rats exposed to IMO showed a bias towards goal-tracking, whereas in females, IMO produced a bias towards sign-tracking. Animals of both sexes not exposed to IMO displayed an intermediate phenotype. ELS in IMO-treated females was able to reduce sign-tracking and decrease tyrosine hydroxylase expression in the ventral tegmental area and dopamine D1 receptor expression in the accumbens shell. Although the predicted greater decrease in females in sign-tracking after IMO exposure was not corroborated by the data, the results highlight the idea that sex is an

  1. Sex-dependent impact of early-life stress and adult immobilization in the attribution of incentive salience in rats.

    Directory of Open Access Journals (Sweden)

    Silvia Fuentes

    Full Text Available Early life stress (ELS induces long-term effects in later functioning and interacts with further exposure to other stressors in adulthood to shape our responsiveness to reward-related cues. The attribution of incentive salience to food-related cues may be modulated by previous and current exposures to stressors in a sex-dependent manner. We hypothesized from human data that exposure to a traumatic (severe adult stressor will decrease the attribution of incentive salience to reward-associated cues, especially in females, because these effects are modulated by previous ELS. To study these factors in Long-Evans rats, we used as an ELS model of restriction of nesting material and concurrently evaluated maternal care. In adulthood, the offspring of both sexes were exposed to acute immobilization (IMO, and several days after, a Pavlovian conditioning procedure was used to assess the incentive salience of food-related cues. Some rats developed more attraction to the cue predictive of reward (sign-tracking and others were attracted to the location of the reward itself, the food-magazine (goal-tracking. Several dopaminergic markers were evaluated by in situ hybridization. The results showed that ELS increased maternal care and decreased body weight gain (only in females. Regarding incentive salience, in absolute control animals, females presented slightly greater sign-tracking behavior than males. Non-ELS male rats exposed to IMO showed a bias towards goal-tracking, whereas in females, IMO produced a bias towards sign-tracking. Animals of both sexes not exposed to IMO displayed an intermediate phenotype. ELS in IMO-treated females was able to reduce sign-tracking and decrease tyrosine hydroxylase expression in the ventral tegmental area and dopamine D1 receptor expression in the accumbens shell. Although the predicted greater decrease in females in sign-tracking after IMO exposure was not corroborated by the data, the results highlight the idea that sex

  2. Increased synaptophysin is involved in inflammation-induced heat hyperalgesia mediated by cyclin-dependent kinase 5 in rats.

    Directory of Open Access Journals (Sweden)

    Hong-Hai Zhang

    Full Text Available Mechanisms associated with cyclin-dependent kinase 5 (Cdk5-mediated heat hyperalgesia induced by inflammation remain undefined. This study was designed to examine whether Cdk5 mediates heat hyperalgesia resulting from peripheral injection of complete Freund's adjuvant (CFA in the spinal dorsal horns of rats by interacting with synaptophysin, a well known membrane protein mediating the endocytosis-exocytosis cycle of synaptic vesicles as a molecular marker associated with presynaptic vesicle membranes. The role of Cdk5 in mediating synaptophysin was examined through the combined use of behavioral approaches, imaging studies, and immunoprecipitation following CFA-induced inflammatory pain. Results showed that Cdk5 colocalized with both synaptophysin and soluble N-ethylmaleimide-sensitive factor (NSF attachment protein receptors (SNAREs consisting of VAMP-2, SNAP-25, and syntaxin 1A in spinal dorsal horn of rats. Increased synaptophysin expression of spinal cord horn neurons post intraplantar injection of CFA coincided with increased duration of heat hyperalgesia lasting from 6 h to 3 d. Intrathecal administration of roscovitine, a Cdk5 specific inhibitor, significantly depressed synaptophysin expression during peak heat hyperalgesia and heat hyperalgesia induced by peripheral injection of CFA. Data presented in this report indicated that calpain activity was transiently upregulated 6 h post CFA-treatment despite previous reports suggesting that calpain was capable of cleaving p35 into p25. Results from previous studies obtained by other laboratories demonstrated that significant changes in p35 expression levels within spinal cord horn neurons were not observed in the CFA-treated inflammatory pain model although significant upregulation of Cdk5 kinase was observed between 2 h to 7 d. Therefore, generation of p25 occurred in a calpain-independent fashion in a CFA-treated inflammatory pain model. Our results demonstrated that increased synaptophysin

  3. Aging-induced dysregulation of dicer1-dependent microRNA expression impairs angiogenic capacity of rat cerebromicrovascular endothelial cells.

    Science.gov (United States)

    Ungvari, Zoltan; Tucsek, Zsuzsanna; Sosnowska, Danuta; Toth, Peter; Gautam, Tripti; Podlutsky, Andrej; Csiszar, Agnes; Losonczy, Gyorgy; Valcarcel-Ares, M Noa; Sonntag, William E; Csiszar, Anna

    2013-08-01

    Age-related impairment of angiogenesis is likely to play a central role in cerebromicrovascular rarefaction and development of vascular cognitive impairment, but the underlying mechanisms remain elusive. To test the hypothesis that dysregulation of Dicer1 (ribonuclease III, a key enzyme of the microRNA [miRNA] machinery) impairs endothelial angiogenic capacity in aging, primary cerebromicrovascular endothelial cells (CMVECs) were isolated from young (3 months old) and aged (24 months old) Fischer 344 × Brown Norway rats. We found an age-related downregulation of Dicer1 expression both in CMVECs and in small cerebral vessels isolated from aged rats. In aged CMVECs, Dicer1 expression was increased by treatment with polyethylene glycol-catalase. Compared with young cells, aged CMVECs exhibited altered miRNA expression profile, which was associated with impaired proliferation, adhesion to vitronectin, collagen and fibronectin, cellular migration (measured by a wound-healing assay using electric cell-substrate impedance sensing technology), and impaired ability to form capillary-like structures. Overexpression of Dicer1 in aged CMVECs partially restored miRNA expression profile and significantly improved angiogenic processes. In young CMVECs, downregulation of Dicer1 (siRNA) resulted in altered miRNA expression profile associated with impaired proliferation, adhesion, migration, and tube formation, mimicking the aging phenotype. Collectively, we found that Dicer1 is essential for normal endothelial angiogenic processes, suggesting that age-related dysregulation of Dicer1-dependent miRNA expression may be a potential mechanism underlying impaired angiogenesis and cerebromicrovascular rarefaction in aging.

  4. P38/TRHr-Dependent Regulation of TPO in Thyroid Cells Contributes to the Hypothyroidism of Triclosan-Treated Rats

    Directory of Open Access Journals (Sweden)

    Pei Zhang

    2018-02-01

    Full Text Available Background/Aims: Triclosan, as an antimicrobial agent and a potential endocrine disruptor, has been used extensively in diverse products, resulting in widespread human exposure. In recent years, studies suggest that triclosan could disturb thyroid functions and decline thyroid hormones (THs. Methods: To verify our hypothesis that the MAPK pathway may function significantly in triclosan-induced hypothyroidism, Sprague-Dawley rats were gavaged with triclosan for 31 consecutive days; Nthy-ori 3-1 cells were treated with triclosan in the presence/absence of NAC, inhibitors (SB203580 and SB202474, or TRHr siRNA. Tissues and/or cells were analyzed by several techniques including transmission electron microscopy, confocal laser scanning microscopy, gene silencing, western blot, and real-time PCR. Results: Triclosan led to histopathologic changes in the thyroid and decreases in triiodothyronine (T3 and thyroxine (T4. Triclosan stimulated ROS production and oxidative stress occurrence, thereby activating the p38 pathway in vivo and in vitro. Thyrotropin releasing hormone receptor (TRHr was induced when the p38 pathway was activated, and was suppressed when that pathway was inhibited. Moreover, thyroid peroxidase (TPO was restrained and modulated by the p38/TRHr pathway after triclosan treatment. Furthermore, deiodinase 3 (D3 and hepatic enzymes (Ugt2b1, CYP1a1, CYP1a2, CYP2b1, CYP3a1, and Sult1e1 were also induced by triclosan. Conclusion: Taken together, p38/TRHr-dependent regulation of TPO in thyroid cells contributes to the hypothyroidism of triclosan-treated rats.

  5. Glucose-Dependent Insulinotropic Polypeptide Ameliorates Mild Traumatic Brain Injury-Induced Cognitive and Sensorimotor Deficits and Neuroinflammation in Rats

    Science.gov (United States)

    Yu, Yu-Wen; Hsieh, Tsung-Hsun; Chen, Kai-Yun; Wu, John Chung-Che; Hoffer, Barry J.; Greig, Nigel H.; Li, Yazhou; Lai, Jing-Huei; Chang, Cheng-Fu; Lin, Jia-Wei; Chen, Yu-Hsin

    2016-01-01

    Abstract Mild traumatic brain injury (mTBI) is a major public health issue, representing 75–90% of all cases of TBI. In clinical settings, mTBI, which is defined as a Glascow Coma Scale (GCS) score of 13–15, can lead to various physical, cognitive, emotional, and psychological-related symptoms. To date, there are no pharmaceutical-based therapies to manage the development of the pathological deficits associated with mTBI. In this study, the neurotrophic and neuroprotective properties of glucose-dependent insulinotropic polypeptide (GIP), an incretin similar to glucagon-like peptide-1 (GLP-1), was investigated after its steady-state subcutaneous administration, focusing on behavior after mTBI in an in vivo animal model. The mTBI rat model was generated by a mild controlled cortical impact (mCCI) and used to evaluate the therapeutic potential of GIP. We used the Morris water maze and novel object recognition tests, which are tasks for spatial and recognition memory, respectively, to identify the putative therapeutic effects of GIP on cognitive function. Further, beam walking and the adhesive removal tests were used to evaluate locomotor activity and somatosensory functions in rats with and without GIP administration after mCCI lesion. Lastly, we used immunohistochemical (IHC) staining and Western blot analyses to evaluate the inflammatory markers, glial fibrillary acidic protein (GFAP), amyloid-β precursor protein (APP), and bone marrow tyrosine kinase gene in chromosome X (BMX) in animals with mTBI. GIP was well tolerated and ameliorated mTBI-induced memory impairments, poor balance, and sensorimotor deficits after initiation in the post-injury period. In addition, GIP mitigated mTBI-induced neuroinflammatory changes on GFAP, APP, and BMX protein levels. These findings suggest GIP has significant benefits in managing mTBI-related symptoms and represents a novel strategy for mTBI treatment. PMID:26972789

  6. Time-Dependent Changes in T1 during Fracture Healing in Juvenile Rats: A Quantitative MR Approach.

    Directory of Open Access Journals (Sweden)

    Katharina Baron

    Full Text Available Quantitative magnetic resonance imaging (qMRI offers several advantages in imaging and determination of soft tissue alterations when compared to qualitative imaging techniques. Although applications in brain and muscle tissues are well studied, its suitability to quantify relaxation times of intact and injured bone tissue, especially in children, is widely unknown. The objective observation of a fracture including its age determination can become of legal interest in cases of child abuse or maltreatment. Therefore, the aim of this study is the determination of time dependent changes in intact and corresponding injured bones in immature rats via qMRI, to provide the basis for an objective and radiation-free approach for fracture dating. Thirty-five MR scans of 7 Sprague-Dawley rats (male, 4 weeks old, 100 ± 5 g were acquired on a 3T MRI scanner (TimTrio, Siemens AG, Erlangen, Germany after the surgical infliction of an epiphyseal fracture in the tibia. The images were taken at days 1, 3, 7, 14, 28, 42 and 82 post-surgery. A proton density-weighted and a T1-weighted 3D FLASH sequence were acquired to calculate the longitudinal relaxation time T1 of the fractured region and the surrounding tissues. The calculation of T1 in intact and injured bone resulted in a quantitative observation of bone development in intact juvenile tibiae as well as the bone healing process in the injured tibiae. In both areas, T1 decreased over time. To evaluate the differences in T1 behaviour between the intact and injured bone, the relative T1 values (bone-fracture were calculated, showing clear detectable alterations of T1 after fracture occurrence. These results indicate that qMRI has a high potential not only for clinically relevant applications to detect growth defects or developmental alterations in juvenile bones, but also for forensically relevant applications such as the dating of fractures in cases of child abuse or maltreatment.

  7. Premature hippocampus-dependent memory decline in middle-aged females of a genetic rat model of depression.

    Science.gov (United States)

    Lim, Patrick H; Wert, Stephanie L; Tunc-Ozcan, Elif; Marr, Robert; Ferreira, Adriana; Redei, Eva E

    2018-02-25

    Aging and major depressive disorder are risk factors for dementia, including Alzheimer's Disease (AD), but the mechanism(s) linking depression and dementia are not known. Both AD and depression show greater prevalence in women. We began to investigate this connection using females of the genetic model of depression, the inbred Wistar Kyoto More Immobile (WMI) rat. These rats consistently display depression-like behavior compared to the genetically close control, the Wistar Kyoto Less Immobile (WLI) strain. Hippocampus-dependent contextual fear memory did not differ between young WLI and WMI females, but, by middle-age, female WMIs showed memory deficits compared to same age WLIs. This deficit, measured as duration of freezing in the fear provoking-context was not related to activity differences between the strains prior to fear conditioning. Hippocampal expression of AD-related genes, such as amyloid precursor protein, amyloid beta 42, beta secretase, synucleins, total and dephosphorylated tau, and synaptophysin, did not differ between WLIs and WMIs in either age group. However, hippocampal transcript levels of catalase (Cat) and hippocampal and frontal cortex expression of insulin-like growth factor 2 (Igf2) and Igf2 receptor (Igf2r) paralleled fear memory differences between middle-aged WLIs and WMIs. This data suggests that chronic depression-like behavior that is present in this genetic model is a risk factor for early spatial memory decline in females. The molecular mechanisms of this early memory decline likely involve the interaction of aging processes with the genetic components responsible for the depression-like behavior in this model. Copyright © 2018 Elsevier B.V. All rights reserved.

  8. Nutritional status-dependent endocannabinoid signalling regulates the integration of rat visceral information.

    Science.gov (United States)

    Khlaifia, Abdessattar; Matias, Isabelle; Cota, Daniela; Tell, Fabien

    2017-06-01

    Vagal sensory inputs transmit information from the viscera to brainstem neurones located in the nucleus tractus solitarii to set physiological parameters. These excitatory synapses exhibit a CB1 endocannabinoid-induced long-term depression (LTD) triggered by vagal fibre stimulation. We investigated the impact of nutritional status on long-term changes in this long-term synaptic plasticity. Food deprivation prevents LTD induction by disrupting CB1 receptor signalling. Short-term refeeding restores the capacity of vagal synapses to express LTD. Ghrelin and cholecystokinin, respectively released during fasting and refeeding, play a key role in the control of LTD via the activation of energy sensing pathways such as AMPK and the mTOR and ERK pathways. Communication form the viscera to the brain is essential to set physiological homoeostatic parameters but also to drive more complex behaviours such as mood, memory and emotional states. Here we investigated the impact of the nutritional status on long-term changes in excitatory synaptic transmission in the nucleus tractus solitarii, a neural hub integrating visceral signals. These excitatory synapses exhibit a CB1 endocannabinoid (eCB)-induced long-term depression (LTD) triggered by vagal fibre stimulation. Since eCB signalling is known to be an important component of homoeostatic regulation of the body and is regulated during various stressful conditions, we tested the hypothesis that food deprivation alters eCB signalling in central visceral afferent fibres. Food deprivation prevents eCB-LTD induction due to the absence of eCB signalling. This loss was reversed by blockade of ghrelin receptors. Activation of the cellular fuel sensor AMP-activated protein kinase or inhibition of the mechanistic target of rapamycin pathway abolished eCB-LTD in free-fed rats. Signals associated with energy surfeit, such as short-term refeeding, restore eCB-LTD induction, which in turn requires activation of cholecystokinin receptors and

  9. Activation of a remote (1-year old) emotional memory interferes with the retrieval of a newly formed hippocampus-dependent memory in rats.

    Science.gov (United States)

    Zoladz, Phillip R; Woodson, James C; Haynes, Vernon F; Diamond, David M

    2010-01-01

    The persistent intrusion of remote traumatic memories in people with post-traumatic stress disorder (PTSD) may contribute to the impairment of their ongoing hippocampal and prefrontal cortical functioning. In the current work, we have developed a rodent analogue of the intrusive memory phenomenon. We studied the influence of the activation of a remote traumatic memory in rats on their ability to retrieve a newly formed hippocampus-dependent memory. Adult male Sprague-Dawley rats were given inhibitory avoidance (IA) training, and then 24 h or 1, 6 or 12 months later, the same rats were trained to learn, and then remember across a 30-min delay period, the location of a hidden escape platform in the radial-arm water maze (RAWM). When IA-trained rats spent the 30-min delay period in the IA apparatus, they exhibited intact remote (1-year old) memory of the shock experience. More importantly, activation of the rats' memory of the shock experience profoundly impaired their ability to retrieve the newly formed spatial memory of the hidden platform location in the RAWM. Our finding that reactivation of a remote emotional memory exerted an intrusive effect on new spatial memory processing in rats provides a novel approach toward understanding how intrusive memories of traumatic experiences interfere with ongoing cognitive processing in people with PTSD.

  10. PSYCHOMETRIC PROPERTY OF FATIGUE SEVERITY SCALE AND CORRELATION WITH DEPRESSION AND QUALITY OF LIFE IN CIRRHOTICS

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    Danusa ROSSI

    2017-10-01

    Full Text Available ABSTRACT BACKGROUND: Fatigue is a common complaint in cirrhotic patients and may be considered a debilitating symptom with negative impact on quality of life. Research on its etiology and treatment has been hampered by the lack of relevant and reproducible measures of fatigue. OBJECTIVE: To evaluate the psychometric properties of the Fatigue Severity Scale (FSS in cirrhotic patients and to correlate with depressive symptomatology and quality of life. METHODS: Cross-sectional study with a convenience sample of 106 cirrhotic patients, aged between 18 and 70 years, both genders, literate, pre and post liver transplantation in outpatient follow-up. Internal consistency, reproducibility, discriminant validity, criterion validity, construct validity, responsiveness criterion, depressive symptomatology and quality of life were evaluated through questionnaires between January and October 2015. RESULTS: The mean age was 54.75±9.9 years, 65.1% male and 32.1% of the sample had cirrhosis due to hepatitis C virus. The mean FSS score was 4.74±1.64. Cronbach’s alpha was 0.93, and the Intraclass Correlation Coefficient was 0.905 (95% CI: 0.813-0.952. For discriminant validity, FSS differentiated scores from different groups (P=0.009 and presented a correlation with the Modified Fatigue Impact Scale (r=0.606, P=0.002. FSS correlated significantly and positively with depressive symptomatology and correlated negatively with the SF-36 domains for construct validity. For responsiveness, no significant changes were observed in the fatigue scores in the pre and post-liver transplantation periods (P=0.327. CONCLUSION: FSS showed good psychometric performance in the evaluation of fatigue in patients with cirrhosis. Fatigue presented a strong correlation with depressive symptomatology and quality of life.

  11. Treating hepatic encephalopathy in cirrhotic patients admitted to ICU with sodium phenylbutyrate: a preliminary study.

    Science.gov (United States)

    Weiss, Nicolas; Tripon, Simona; Lodey, Marion; Guiller, Elsa; Junot, Helga; Monneret, Denis; Mayaux, Julien; Brisson, Hélène; Mallet, Maxime; Rudler, Marika; Imbert-Bismut, Françoise; Thabut, Dominique

    2018-04-01

    Hepatic encephalopathy (HE) influences short-term and long-term prognoses. Recently, glycerol phenylbutyrate (PB), that lowers ammonia by providing an alternate pathway to urea for waste nitrogen excretion, has shown that it was effective in preventing the occurrence of HE in RCT. The aim was to assess the benefits of sodium PB in cirrhotic patients admitted to ICU for overt HE, in terms of ammonia levels decrease, neurological improvement, and survival. Cirrhotic patients who presented with overt HE, ammonia levels >100 μmol/L, and did not display any contra-indication were included. Sodium PB was administered at 200 mg/kg/day. Control group included historical controls treated by standard therapy, matched for age, sex, MELD score, and severity of HE. Eighteen patients were included and treated with sodium PB (age: 59 [45-68], male gender: 15 [83%], Child-Pugh B: 8 [44%], Child-Pugh C: 10 [56%], and MELD score: 16 [13-23]). Ammonia levels significantly decreased in the PB as compared to the control group from inclusion to 12 h and from inclusion to 48 h (P = 0.0201 and P = 0.0230, respectively). The proportion of patients displaying neurological improvement was only higher in the PB-treated group as compared to controls at ICU discharge (15 [83%] vs. 9 [50%], P = 0.0339). ICU discharge survival was significantly higher in patients treated with PB (17 [94%] vs. 9 [50%], P = 0.0017). In cirrhotic patients with overt HE, sodium PB could be effective in reducing ammonia levels and might be effective in improving neurological status and ICU discharge survival. More extensive data, especially a RCT, are mandatory. © 2017 Société Française de Pharmacologie et de Thérapeutique.

  12. Wall shear stress in portal vein of cirrhotic patients with portal hypertension.

    Science.gov (United States)

    Wei, Wei; Pu, Yan-Song; Wang, Xin-Kai; Jiang, An; Zhou, Rui; Li, Yu; Zhang, Qiu-Juan; Wei, Ya-Juan; Chen, Bin; Li, Zong-Fang

    2017-05-14

    To investigate wall shear stress (WSS) magnitude and distribution in cirrhotic patients with portal hypertension using computational fluid dynamics. Idealized portal vein (PV) system models were reconstructed with different angles of the PV-splenic vein (SV) and superior mesenteric vein (SMV)-SV. Patient-specific models were created according to enhanced computed tomography images. WSS was simulated by using a finite-element analyzer, regarding the blood as a Newtonian fluid and the vessel as a rigid wall. Analysis was carried out to compare the WSS in the portal hypertension group with that in healthy controls. For the idealized models, WSS in the portal hypertension group (0-10 dyn/cm 2 ) was significantly lower than that in the healthy controls (10-20 dyn/cm 2 ), and low WSS area (0-1 dyn/cm 2 ) only occurred in the left wall of the PV in the portal hypertension group. Different angles of PV-SV and SMV-SV had different effects on the magnitude and distribution of WSS, and low WSS area often occurred in smaller PV-SV angle and larger SMV-SV angle. In the patient-specific models, WSS in the cirrhotic patients with portal hypertension (10.13 ± 1.34 dyn/cm 2 ) was also significantly lower than that in the healthy controls ( P portal hypertension, the low WSS area extended to wider levels and the magnitude of WSS reached lower levels, thereby being more prone to disturbed flow occurrence. Cirrhotic patients with portal hypertension show dramatic hemodynamic changes with lower WSS and greater potential for disturbed flow, representing a possible causative factor of PV thrombosis.

  13. Non-cirrhotic portal hypertension in HIV mono-infected patients.

    Science.gov (United States)

    Jackson, Belinda D; Doyle, Joseph S; Hoy, Jennifer F; Roberts, Stuart K; Colman, John; Hellard, Margaret E; Sasadeusz, Joseph J; Iser, David M

    2012-09-01

    Unexplained liver injury including fibrosis and portal hypertension has rarely been reported among patients with HIV in the absence of co-infection with hepatitis B (HBV) or hepatitis C (HCV). We describe a series of HIV mono-infected patients with evidence of non-cirrhotic portal hypertension. HIV-infected patients with evidence of portal hypertension who were anti-HBV and anti-HCV negative and HBV and HCV RNA polymerase chain reaction (PCR) negative were identified from patients managed by the Victorian statewide HIV referral service located at The Alfred Hospital, Melbourne. Portal hypertension was defined as either radiological or endoscopic evidence of varices, portal vein flow obstruction, or elevated hepatic venous pressure gradient (HPVG). Five patients were found to have portal hypertension. These patients were male, aged 41 to 65 years, with known duration of HIV infection between 11 to 25 years. All had been treated with antiretroviral therapy, including didanosine. Tests for metabolic, autoimmune, and hereditary causes of liver disease failed to establish an etiology for the liver injury. All had radiological or endoscopic findings of varices, and four patients had radiological features of portal vein obstruction or flow reversal. Only one patient underwent HPVG measurement, which was elevated. Non-invasive fibrosis assessment revealed increased liver stiffness in three (out of four) patients, and no cirrhotic features were found on those who underwent liver biopsy. To our knowledge, this is the largest published series of non-cirrhotic portal hypertension in HIV mono-infected patients in Australia. Further research is needed to understand what relationship, if any, HIV or its treatments might have on liver injury over time. © 2012 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

  14. Comparative study of bacterial infection prevalence between cirrhotic patients with and without upper gastrointestinal bleeding

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    Delvone Almeida

    Full Text Available Bacterial infection is a frequent complication in patients with chronic liver disease, mainly during the advanced stages. There is evidence that the main factors that contribute to a predisposition to infection in cirrhotic patients are related to hepatic failure with consequent immunodeficiency. Invasive procedures (diagnostic or therapeutic can predispose to bacterial infections, and upper gastrointestinal bleeding (UGB is considered a potentially important risk factor. A group of cirrhotic patients (child B and C Pugh groups were evaluated retrospectively by chart reviews regarding the prevalence of bacterial infection during hospitalization to determine whether UGB was a risk factor. An infection was considered present if a specific organ system was identified or if fever (>38ºC persisted for more than 24 hours with associated leukocytosis. Spontaneous bacterial peritonitis was based on classical criteria. Eighty-nine patients were evaluated. Fourty-six patients presented with UGB, and 43 patients had no UGB (control. There were infections recorded in 25/46 (54% patients with UGB, and 15/43 (35% in those without UGB (p=0.065. The ratio of the number of infections/admitted patients, was significantly larger in the group with UGB (0.78 ± 0.89 vs. 0.39 ± 0.62; p=0.028 since patients had more than one infection. In the UGB group compared to non UGB group, ascites was more frequent (67% vs. 42%; p=0.027; they were more likely to have undergone endoscopic procedures (p<0.001 and the mean ± SD for platelets count was smaller (96,114 ± 57,563 vs. 145,674 ± 104,083; p=0.007. The results show that UGB is an important contribution to bacterial infection among Child B and C cirrhotic patients.

  15. Transjugular Intrahepatic Portosystemic Shunt before Abdominal Surgery in Cirrhotic Patients: A Retrospective, Comparative Study

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    Evelyne Vinet

    2006-01-01

    Full Text Available Surgery in cirrhotic patients is associated with high morbidity and mortality related to portal hypertension and liver insufficiency. Therefore, preoperative portal decompression is a logical approach to facilitate abdominal surgery and hopefully to improve postoperative survival. The present study evaluated the clinical outcomes of 18 patients (mean age 58 years with cirrhosis (seven alcoholics and 11 nonalcoholics who underwent transjugular intrahepatic portosystemic shunt (TIPS placement before antrectomy (n=5, colectomy (n=10, small-bowel resection (n=1, pancreatectomy (n=1 and nephrectomy (n=1. TIPS was performed a mean (± SD of 72±21 days before surgery and induced a marked mean decrease in portohepatic gradient from 21.4±3.9 mmHg to 8.4±3.4 mmHg. Cirrhotic patients (n=17 who underwent elective abdominal surgery without preoperative TIPS placement were used as the control group. Both groups were matched for age, etiology of cirrhosis, indications for surgery, type of surgery and coagulation parameters. The mean Pugh score was significantly higher in the TIPS group (7.7 versus 6.2. No significant differences were observed for operative blood loss, postoperative complications, duration of hospitalization and one-month (83% versus 88% or one-year (54% versus 63% cumulative survival rate. Analysis using the Cox proportional hazards model showed that neither TIPS placement nor preoperative Pugh score were independent predictors for survival. The present study suggests that preoperative TIPS placement does not improve postoperative evolution after abdominal surgery in cirrhotic patients with good or moderately impaired liver function.

  16. Significant long-term, but not short-term, hippocampal-dependent memory impairment in adult rats exposed to alcohol in early postnatal life.

    Science.gov (United States)

    Goodfellow, Molly J; Lindquist, Derick H

    2014-09-01

    In rodents, ethanol exposure in early postnatal life is known to induce structural and functional impairments throughout the brain, including the hippocampus. Herein, rat pups were administered one of three ethanol doses over postnatal days (PD) 4-9, a period of brain development comparable to the third trimester of human pregnancy. As adults, control and ethanol rats were trained and tested in a variant of hippocampal-dependent one-trial context fear conditioning. In Experiment 1, subjects were placed into a novel context and presented with an immediate footshock (i.e., within ∼8 sec). When re-exposed to the same context 24 hr later low levels of conditioned freezing were observed. Context pre-exposure 24 hr prior to the immediate shock reversed the deficit in sham-intubated and unintubated control rats, enhancing freezing behavior during the context retention test. Even with context pre-exposure, however, significant dose-dependent reductions in contextual freezing were seen in ethanol rats. In Experiment 2, the interval between context pre-exposure and the immediate shock was shortened to 2 hr, in addition to the standard 24 hr. Ethanol rats trained with the 2 hr, but not 24 hr, interval displayed retention test freezing levels roughly equal to controls. Results suggest the ethanol rats can encode a short-term context memory and associate it with the aversive footshock 2 hr later. In the 24 hr ethanol rats the short-term context memory is poorly transferred or consolidated into long-term memory, we propose, impeding the memory's subsequent retrieval and association with shock. © 2014 Wiley Periodicals, Inc.

  17. The anorectic effect of GLP-1 in rats is nutrient dependent.

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    Darleen Sandoval

    Full Text Available GLP-1-induced insulin secretion from the β-cell is dependent upon glucose availability. The purpose of the current study was to determine whether CNS GLP-1 signaling is also glucose-dependent. We found that fasting blunted the ability of 3(rd cerebroventricularly (i3vt-administered GLP-1 to reduce food intake. However, fasted animals maintained the anorexic response to melanotan II, a melanocortin receptor agonist, indicating a specific effect of fasting on GLP-1 action. We also found that i3vt administration of leptin, which is also decreased with fasting, was not able to potentiate GLP-1 action in fasted animals. However, we did find that CNS glucose sensing is important in GLP-1 action. Specifically, we found that i3vt injection of 2DG, a drug that blocks cellular glucose utilization, and AICAR which activates AMPK, both blocked GLP-1-induced reductions in food intake. To examine the role of glucokinase, an important CNS glucose sensor, we studied glucokinase-heterozygous knockout mice, but found that they responded normally to peripherally administered GLP-1 and exendin-4. Interestingly, oral, but not i3vt or IP glucose potentiated GLP-1's anorectic action. Thus, CNS and peripheral fuel sensing are both important in GLP-1-induced reductions in food intake.

  18. The Mitochondria-Targeted Antioxidant SkQ1 Downregulates Aryl Hydrocarbon Receptor-Dependent Genes in the Retina of OXYS Rats with AMD-Like Retinopathy

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    M. L. Perepechaeva

    2014-01-01

    Full Text Available The mitochondria-targeted antioxidant SkQ1 is a novel drug thought to retard development of age-related diseases. It has been shown that SkQ1 reduces clinical signs of retinopathy in senescence-accelerated OXYS rats, which are a known animal model of human age-related macular degeneration (AMD. The aim of this work was to test whether SkQ1 affects transcriptional activity of AhR (aryl hydrocarbon receptor and Nrf2 (nuclear factor erythroid 2-related factor 2, which are considered as AMD-associated genes in the retina of OXYS and Wistar rats. Our results showed that only AhR and AhR-dependent genes were sensitive to SkQ1. Dietary supplementation with SkQ1 decreased the AhR mRNA level in both OXYS and Wistar rats. At baseline, the retinal Cyp1a1 mRNA level was lower in OXYS rats. SkQ1 supplementation decreased the Cyp1a1 mRNA level in Wistar rats, but this level remained unchanged in OXYS rats. Baseline Cyp1a2 and Cyp1b1 mRNA expression was stronger in OXYS than in Wistar rats. In the OXYS strain, Cyp1a2 and Cyp1b1 mRNA levels decreased as a result of SkQ1 supplementation. These data suggest that the Cyp1a2 and Cyp1b1 enzymes are involved in the pathogenesis of AMD-like retinopathy of OXYS rats and are possible therapeutic targets of SkQ1.

  19. The ethanol-induced stimulation of rat duodenal mucosal bicarbonate secretion in vivo is critically dependent on luminal Cl-.

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    Anna Sommansson

    Full Text Available Alcohol may induce metabolic and functional changes in gastrointestinal epithelial cells, contributing to impaired mucosal barrier function. Duodenal mucosal bicarbonate secretion (DBS is a primary epithelial defense against gastric acid and also has an important function in maintaining the homeostasis of the juxtamucosal microenvironment. The aim in this study was to investigate the effects of the luminal perfusion of moderate concentrations of ethanol in vivo on epithelial DBS, fluid secretion and paracellular permeability. Under thiobarbiturate anesthesia, a ∼30-mm segment of the proximal duodenum with an intact blood supply was perfused in situ in rats. The effects on DBS, duodenal transepithelial net fluid flux and the blood-to-lumen clearance of 51Cr-EDTA were investigated. Perfusing the duodenum with isotonic solutions of 10% or 15% ethanol-by-volume for 30 min increased DBS in a concentration-dependent manner, while the net fluid flux did not change. Pre-treatment with the CFTR inhibitor CFTRinh172 (i.p. or i.v. did not change the secretory response to ethanol, while removing Cl- from the luminal perfusate abolished the ethanol-induced increase in DBS. The administration of hexamethonium (i.v. but not capsazepine significantly reduced the basal net fluid flux and the ethanol-induced increase in DBS. Perfusing the duodenum with a combination of 1.0 mM HCl and 15% ethanol induced significantly greater increases in DBS than 15% ethanol or 1.0 mM HCl alone but did not influence fluid flux. Our data demonstrate that ethanol induces increases in DBS through a mechanism that is critically dependent on luminal Cl- and partly dependent on enteric neural pathways involving nicotinic receptors. Ethanol and HCl appears to stimulate DBS via the activation of different bicarbonate transporting mechanisms.

  20. Sex-dependent behavioral changes in rat offspring after in utero administration of a single low dose PBDE 47

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    Kuriyama, S.N.; Talsness, C.E.; Chahoud, I. [Charite Univ. Medical School Berlin (Germany). Inst. of Clinical Pharmacology and Toxicology, Dept. Toxicology, Campus Benjamin Franklin

    2004-09-15

    Increasing levels of polybrominated diphenyl ethers (PBDEs) in environmental and human samples has resulted in intensive discussion regarding possible hazard identification and risk assessment in the last years. In rodents, exposure to PBDE mixtures or single congeners has resulted in a mixed induction of CYP450- dependent enzymes, showing increased activity of hepatic EROD and PROD. In addition, genotoxicity has been observed in recombination assays, and neurotoxicity has been reported in mice exposed during development. Acute and sub-chronic exposures of mice and rats to a PBDE mixture (DE-71) cause dose-dependent reductions in serum concentrations of thyroxin (T4), and stressinduced elevations in plasma corticosterone. Further, some hydroxylated metabolites of PBDE congeners exhibit a higher potency in vivo than T4 in competitive binding to human transthyretin (TTR), the transport protein mediating transfer of thyroid hormones across the placenta and into the brain. The available information in the literature clearly indicates that PBDEs are potent neurotoxicants, causing effects at doses lower than that able to disrupt thyroid hormone profiles and change CYP 450 activities. Neurobehavior effects, which includes defects in learning and memory, and changes in nicotinic receptors were found at doses starting at 0.45 ppm in mouse (9). The congeners, PBDE 47 and PBDE 99, have also been shown to cause permanent aberrations in spontaneous behavior in mice which was more pronounced with increasing age. PBDE 47 is the most predominant congener found in environmental and human samples, including human breast milk. Its presence in breast milk highlights the importance of evaluating possible effects following early developmental exposure and because this period represents a critical time which an organism is extremely susceptible to minor changes in hormonal milieu. Variances in terms of time point and concentration of exposure to steroids can lead to an organizational

  1. Argon inhalation attenuates retinal apoptosis after ischemia/reperfusion injury in a time- and dose-dependent manner in rats.

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    Felix Ulbrich

    Full Text Available Retinal ischemia and reperfusion injuries (IRI permanently affect neuronal tissue and function by apoptosis and inflammation due to the limited regenerative potential of neurons. Recently, evidence emerged that the noble gas Argon exerts protective properties, while lacking any detrimental or adverse effects. We hypothesized that Argon inhalation after IRI would exert antiapoptotic effects in the retina, thereby protecting retinal ganglion cells (RGC of the rat's eye.IRI was performed on the left eyes of rats (n = 8 with or without inhaled Argon postconditioning (25, 50 and 75 Vol% for 1 hour immediately or delayed after ischemia (i.e. 1.5 and 3 hours. Retinal tissue was harvested after 24 hours to analyze mRNA and protein expression of Bcl-2, Bax and Caspase-3, NF-κB. Densities of fluorogold-prelabeled RGCs were analyzed 7 days after injury in whole-mounts. Histological tissue samples were prepared for immunohistochemistry and blood was analyzed regarding systemic effects of Argon or IRI. Statistics were performed using One-Way ANOVA.IRI induced RGC loss was reduced by Argon 75 Vol% inhalation and was dose-dependently attenuated by lower concentrations, or by delayed Argon inhalation (1504±300 vs. 2761±257; p<0.001. Moreover, Argon inhibited Bax and Bcl-2 mRNA expression significantly (Bax: 1.64±0.30 vs. 0.78±0.29 and Bcl-2: 2.07±0.29 vs. 0.99±0.22; both p<0.01, as well as caspase-3 cleavage (1.91±0.46 vs. 1.05±0.36; p<0.001. Expression of NF-κB was attenuated significantly. Immunohistochemistry revealed an affection of Müller cells and astrocytes. In addition, IRI induced leukocytosis was reduced significantly after Argon inhalation at 75 Vol%.Immediate and delayed Argon postconditioning protects IRI induced apoptotic loss of RGC in a time- and dose-dependent manner, possibly mediated by the inhibition of NF-κB. Further studies need to evaluate Argon's possible role as a therapeutic option.

  2. Balloon occlusion retrograde transvenous obliteration of gastric varices in two-cirrhotic patients with portal vein thrombosis

    Energy Technology Data Exchange (ETDEWEB)

    Borhei, Peyman; Kim, Seung Kwon; Zukerman, Darryl A [Interventional Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis (United States)

    2014-02-15

    This report describes two non-cirrhotic patients with portal vein thrombosis who underwent successful balloon occlusion retrograde transvenous obliteration (BRTO) of gastric varices with a satisfactory response and no complications. One patient was a 35-year-old female with a history of Crohn's disease, status post-total abdominal colectomy, and portal vein and mesenteric vein thrombosis. The other patient was a 51-year-old female with necrotizing pancreatitis, portal vein thrombosis, and gastric varices. The BRTO procedure was a useful treatment for gastric varices in non-cirrhotic patients with portal vein thrombosis in the presence of a gastrorenal shunt.

  3. Repeated courses of transarterial embolization with polyvinyl alcohol particles: 'long life elixir' in a cirrhotic patient with unresectable hepatocellular carcinoma.

    Science.gov (United States)

    Marelli, Laura; Shusang, Vibhakorn; Senzolo, Marco; Cholongitas, Evangelos; Goode, Antony; Yu, Dominic; Patch, David W; Burroughs, Andrew K

    2007-04-01

    Chemoembolization improves survival in selected cirrhotic patients with hepatocellular carcinoma, but prolonged survival is unusual. In this study, a 70-year-old cirrhotic patient, who had a histologically proven hepatocellular carcinoma of 5 cm diameter, embolization with polyvinyl alcohol particles alone, without chemotherapeutic agent, has resulted in continued survival, of 5 years to date, with virtual elimination of residual hypervascularity following 10 sessions of embolization, and with continued patency of the injected branch of the hepatic artery. Provided liver function is maintained, embolization alone appears a feasible long term and effective therapy for unresectable hepatocellular carcinoma.

  4. Portal venous blood flow while breath-holding after inspiration or expiration and during normal respiration in controls and cirrhotics

    International Nuclear Information System (INIS)

    Sugano, Shigeo; Yamamoto, Kunihiro; Sasao, Ken-ichiro; Watanabe, Manabu

    1999-01-01

    In this study, we used magnetic resonance (MR) imaging to measure portal blood flow in 12 healthy controls and 17 cirrhotics while they were breath-holding after inspiration and after expiration. We then compared the results with measurements made during normal respiration in the healthy controls and cirrhotics. Blood flow in the main portal vein under basal fasting conditions was quantitated using the cine phase-contrast MR velocity mapping method. Three measurements were made on one occasion, as follows: throughout the cardiac cycle during normal respiration, with the subject breath-holding after maximal inspiration, and with the subject breath-holding after maximal expiration. During normal respiration, portal blood flow was 1.3±0.2 l/min in controls vs 1.0±0.1 l/min in cirrhotics (P<0.0001); while subjects were breath-holding after inspiration, portal blood flow was 1.0±0.2 l/min in controls vs 0.9±0.1 l/min in cirrhotics; and while subjects were breath-holding after expiration, portal blood flow was 1.5±0.2 l/min in controls vs 1.1±0.2 l/min in cirrhotics (P<0.0001). The differences were primarily due to changes in flow velocity. When the magnitude of these hemodynamic changes in the three respiratory conditions was compared in controls and cirrhotics, analysis of variance (ANOVA) showed a significant difference (P<0.0001). In controls, portal blood flow decreased during maximal inspiration relative to flow during normal respiration (-24.6±8.3%). Changes in portal blood flow in controls were greater than in cirrhotics (-13.5±4.5%) (P<0.0001); however, the difference in blood flow increase associated with maximal expiration between the two groups (+11.8±9.4% vs +5.9±11.5%) was not significant. We found that the respiration-induced hemodynamic variation in portal blood flow was less in cirrhotics than in the healthy controls. Portal blood flow measurements made during normal respiration using MR imaging closely reflect nearly physiologic conditions

  5. Portal venous blood flow while breath-holding after inspiration or expiration and during normal respiration in controls and cirrhotics

    Energy Technology Data Exchange (ETDEWEB)

    Sugano, Shigeo; Yamamoto, Kunihiro; Sasao, Ken-ichiro; Watanabe, Manabu [Saiseikai Wakakusa Hospital, Yakohama (Japan)

    1999-07-01

    In this study, we used magnetic resonance (MR) imaging to measure portal blood flow in 12 healthy controls and 17 cirrhotics while they were breath-holding after inspiration and after expiration. We then compared the results with measurements made during normal respiration in the healthy controls and cirrhotics. Blood flow in the main portal vein under basal fasting conditions was quantitated using the cine phase-contrast MR velocity mapping method. Three measurements were made on one occasion, as follows: throughout the cardiac cycle during normal respiration, with the subject breath-holding after maximal inspiration, and with the subject breath-holding after maximal expiration. During normal respiration, portal blood flow was 1.3{+-}0.2 l/min in controls vs 1.0{+-}0.1 l/min in cirrhotics (P<0.0001); while subjects were breath-holding after inspiration, portal blood flow was 1.0{+-}0.2 l/min in controls vs 0.9{+-}0.1 l/min in cirrhotics; and while subjects were breath-holding after expiration, portal blood flow was 1.5{+-}0.2 l/min in controls vs 1.1{+-}0.2 l/min in cirrhotics (P<0.0001). The differences were primarily due to changes in flow velocity. When the magnitude of these hemodynamic changes in the three respiratory conditions was compared in controls and cirrhotics, analysis of variance (ANOVA) showed a significant difference (P<0.0001). In controls, portal blood flow decreased during maximal inspiration relative to flow during normal respiration (-24.6{+-}8.3%). Changes in portal blood flow in controls were greater than in cirrhotics (-13.5{+-}4.5%) (P<0.0001); however, the difference in blood flow increase associated with maximal expiration between the two groups (+11.8{+-}9.4% vs +5.9{+-}11.5%) was not significant. We found that the respiration-induced hemodynamic variation in portal blood flow was less in cirrhotics than in the healthy controls. Portal blood flow measurements made during normal respiration using MR imaging closely reflect nearly

  6. Segmental-dependent membrane permeability along the intestine following oral drug administration: Evaluation of a triple single-pass intestinal perfusion (TSPIP) approach in the rat.

    Science.gov (United States)

    Dahan, Arik; West, Brady T; Amidon, Gordon L

    2009-02-15

    In this paper we evaluate a modified approach to the traditional single-pass intestinal perfusion (SPIP) rat model in investigating segmental-dependent permeability along the intestine following oral drug administration. Whereas in the traditional model one single segment of the intestine is perfused, we have simultaneously perfused three individual segments of each rat intestine: proximal jejunum, mid-small intestine and distal ileum, enabling to obtain tripled data from each rat compared to the traditional model. Three drugs, with different permeabilities, were utilized to evaluate the model: metoprolol, propranolol and cimetidine. Data was evaluated in comparison to the traditional method. Metoprolol and propranolol showed similar P(eff) values in the modified model in all segments. Segmental-dependent permeability was obtained for cimetidine, with lower P(eff) in the distal parts. Similar P(eff) values for all drugs were obtained in the traditional method, illustrating that the modified model is as accurate as the traditional, throughout a wide range of permeability characteristics, whether the permeability is constant or segment-dependent along the intestine. Three-fold higher statistical power to detect segmental-dependency was obtained in the modified approach, as each subject serves as his own control. In conclusion, the Triple SPIP model can reduce the number of animals utilized in segmental-dependent permeability research without compromising the quality of the data obtained.

  7. MR and magnetisation transfer imaging in cirrhotic and fatty livers

    International Nuclear Information System (INIS)

    Alanen, A.; Komu, M.; Leino, R.; Toikkanen, S.

    1998-01-01

    Purpose: To determine whether low-field MR fat/water separation and magnetisation transfer (MT) techniques are useful in studying the livers of patients with parenchymal liver diseases in vivo. Material and Methods: MR and MT imaging of the liver in 33 patients (14 with primary biliary cirrhosis, 15 with alcohol-induced liver disease, and 4 with fatty liver) was performed by means of the fat/water separation technique at 0.1 T. The relaxation time T1 and the MT contrast (MTC) parameter of liver and spleen tissue were measured, and the relative proton density fat content N(%) and MTC of the liver were calculated from the separate fat and water images. The value of N(%) was also compared with the percentage of fatty hepatocytes at histology. Results: The relaxation rate R1 of liver measured from the magnitude image, and the difference in the value of MTC measured form the water image compared with the one measured from the fat and water magnitude image, both depended linearly on the value of N(%). The value of N(%) correlated significantly with the percentage of the fatty hepatocytes. In in vivo fatty tissue, fat infiltration increased both the observed relaxation rate R1 and the measured magnetisation ratio (the steady state magnetisation M s divided by the equilibrium magnetisation M o , M s /M o ) and consequently decreased the MT efficiency measured in a magnitude MR image. The amount of liver fibrosis did not correlate with the value of MTC measured after fat separation. Conclusion: Our results in studying fatty livers with MR imaging and the MT method show that the fat/water separation gives more reliable parametric results. Characterisation of liver cirrhosis by means of the MTC parameter is not reliable, even after fat separation. (orig.)

  8. Mild Thyroid Hormone Insufficiency During Development Compromises Activity-Dependent Neuroplasticity in the Hippocampus of Adult Male Rats

    Data.gov (United States)

    U.S. Environmental Protection Agency — behavioral measures of learning and memory in adult offspring of rats treated with thyroid hormone synthesis inhibitor, propylthiouracil. Electrophysiological...

  9. Leptin-induced endothelium-dependent vasorelaxation of peripheral arteries in lean and obese rats: role of nitric oxide and hydrogen sulfide.

    Directory of Open Access Journals (Sweden)

    Anna Jamroz-Wiśniewska

    Full Text Available Adipose tissue hormone leptin induces endothelium-dependent vasorelaxation mediated by nitric oxide (NO and endothelium-derived hyperpolarizing factors (EDHF. Previously it has been demonstrated that in short-term obesity the NO-dependent and the EDHF-dependent components of vascular effect of leptin are impaired and up-regulated, respectively. Herein we examined the mechanism of the EDHF-dependent vasodilatory effect of leptin and tested the hypothesis that alterations of acute vascular effects of leptin in obesity are accounted for by chronic hyperleptinemia. The study was performed in 5 groups of rats: (1 control, (2 treated with exogenous leptin for 1 week to induce hyperleptinemia, (3 obese, fed highly-palatable diet for 4 weeks, (4 obese treated with pegylated superactive rat leptin receptor antagonist (PEG-SRLA for 1 week, (5 fed standard chow and treated with PEG-SRLA. Acute effect of leptin on isometric tension of mesenteric artery segments was measured ex vivo. Leptin relaxed phenylephrine-preconstricted vascular segments in NO- and EDHF-dependent manner. The NO-dependent component was impaired and the EDHF-dependent component was increased in the leptin-treated and obese groups and in the latter group both these effects were abolished by PEG-SRLA. The EDHF-dependent vasodilatory effect of leptin was blocked by either the inhibitor of cystathionine γ-lyase, propargylglycine, or a hydrogen sulfide (H2S scavenger, bismuth (III subsalicylate. The results indicate that NO deficiency is compensated by the up-regulation of EDHF in obese rats and both effects are accounted for by chronic hyperleptinemia. The EDHF-dependent component of leptin-induced vasorelaxation is mediated, at least partially, by H2S.

  10. [Role of splenectomy in the treatment of non-cirrhotic portal hypertension: about 3 cases].

    Science.gov (United States)

    Belhamidi, Mohamed Said; Hammi, Salah Eddine; Bouzroud, Mohamed; Benmoussa, Mustapha; Ali, Abdelmounaim Ait; Bounaim, Ahmed

    2017-01-01

    Non-cirrhotic portal hypertension was first described by Guido BANTI in 1898 as a condition characterized by the association of portal hypertension with splenomegaly, anemia and healthy liver. The diagnosis was based on abdominal ultrasound, splenoportography and liver biopsy. Our study aimed to evaluate the role of splenectomy in non-cirrhotic portal hypertension. We conducted a retrospective study of 3 patients (2 women and 1 man) treated by our staff over the period January 2010 -September 2016. The diagnosis of idiopathic portal hypertension was based on the following criteria: portal hypertension, the presence of oesophageal varices associated with splenomegaly, the absence of cirrhosis or of other liver disorders responsible of portal hypertension. All patients underwent splenectomy. Outcome after splenectomy was marked by the standardization of clinical, radiological and biological signs of this disease associated with the absence of oesophageal varices recurrence. Splenectomy associated with ligation of oesophageal varices may be sufficient to treat this syndrome and especially its consequences without using splenorenal bypass.

  11. Structural and functional cerebral impairments in cirrhotic patients with a history of overt hepatic encephalopathy

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    Chen, Hua-Jun [Jiangsu Key Laboratory of Molecular Imaging and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009 (China); Zhu, Xi-Qi [Jiangsu Key Laboratory of Molecular Imaging and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009 (China); Department of Radiology, The Second Hospital of Nanjing, Medical School of Southeast University, Nanjing 210002 (China); Shu, Hao [Department of Neurology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009 (China); Yang, Ming; Zhang, Yi; Ding, Jie; Wang, Yu [Jiangsu Key Laboratory of Molecular Imaging and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009 (China); Teng, Gao-Jun, E-mail: gjteng@vip.sina.com [Jiangsu Key Laboratory of Molecular Imaging and Functional Imaging, Department of Radiology, Zhongda Hospital, Medical School of Southeast University, Nanjing 210009 (China)

    2012-10-15

    Objective: Diffuse brain atrophy has been observed in cirrhotic patients and recent reports have revealed the persistence of cognitive impairment after clinical resolution of overt hepatic encephalopathy. We sought to explore the continued influence of overt hepatic encephalopathy on neurological function by measuring brain resting-state inherent connectivity, based on an investigation of structural abnormalities. Methods: Neuropsychological tests and structural and functional magnetic resonance scanning were conducted in 20 healthy controls and 21 cirrhotic patients with a history of overt hepatic encephalopathy. The analysis of voxel-based morphometry and functional connectivity were performed to detect the alterations in brain structure and function, respectively. Results: Patients showed significantly worse performance in neuropsychological tests as compared with controls, despite apparently normal mental status. Analysis of voxel-based morphometry revealed a decrease in gray matter volume primarily in the midline regions, bilateral insular cortex and caudates, left parahippocampal gyrus, and right cerebellum posterior lobe, while the volume of the bilateral thalamus showed an increase. Of these regions, the posterior cingulate cortex with peak atrophy was selected as the origin for the analysis of functional connectivity. Typical patterns of a default mode network were identified in both groups. Decreased functional connectivity was found in the medial prefrontal gyrus, left inferior parietal lobule, and left middle temporal gyrus in the patients. Conclusions: Both functional and structural impairments were evident after apparent recovery from overt hepatic encephalopathy, demonstrating that brain dysfunction induced by hepatic encephalopathy persisted after clinical resolution and provided a basis for further evolution of the disease.

  12. Structural and functional cerebral impairments in cirrhotic patients with a history of overt hepatic encephalopathy

    International Nuclear Information System (INIS)

    Chen, Hua-Jun; Zhu, Xi-Qi; Shu, Hao; Yang, Ming; Zhang, Yi; Ding, Jie; Wang, Yu; Teng, Gao-Jun

    2012-01-01

    Objective: Diffuse brain atrophy has been observed in cirrhotic patients and recent reports have revealed the persistence of cognitive impairment after clinical resolution of overt hepatic encephalopathy. We sought to explore the continued influence of overt hepatic encephalopathy on neurological function by measuring brain resting-state inherent connectivity, based on an investigation of structural abnormalities. Methods: Neuropsychological tests and structural and functional magnetic resonance scanning were conducted in 20 healthy controls and 21 cirrhotic patients with a history of overt hepatic encephalopathy. The analysis of voxel-based morphometry and functional connectivity were performed to detect the alterations in brain structure and function, respectively. Results: Patients showed significantly worse performance in neuropsychological tests as compared with controls, despite apparently normal mental status. Analysis of voxel-based morphometry revealed a decrease in gray matter volume primarily in the midline regions, bilateral insular cortex and caudates, left parahippocampal gyrus, and right cerebellum posterior lobe, while the volume of the bilateral thalamus showed an increase. Of these regions, the posterior cingulate cortex with peak atrophy was selected as the origin for the analysis of functional connectivity. Typical patterns of a default mode network were identified in both groups. Decreased functional connectivity was found in the medial prefrontal gyrus, left inferior parietal lobule, and left middle temporal gyrus in the patients. Conclusions: Both functional and structural impairments were evident after apparent recovery from overt hepatic encephalopathy, demonstrating that brain dysfunction induced by hepatic encephalopathy persisted after clinical resolution and provided a basis for further evolution of the disease

  13. Does protein energy malnutrition affect the outcome in Tunisian cirrhotic patients?

    Science.gov (United States)

    Ennaifer, Rym; Cheikh, Myriam; Romdhane, Haifa; Sabbagh, Safa; Ben Nejma, Houda; Bougassas, Wassila; Bel Hadj, Najet

    2016-02-01

    Malnutrition is commonly seen in cirrhotic patients and has been shown to adversely affect outcome. However, it remains associated with the severity of cirrhosis. Therefore, its role as an independent prognostic factor is still under debate. The aims of our study were to determine the prevalence of malnutrition in cirrhotic patients and determine whether this condition was an independent prognostic factor. We prospectively analyzed the nutritional status of 104 consecutive patients with cirrhosis Subjective global nutritional assessment (SGA) and anthropometry [dry body mass index (BMI), triceps skinfold (TSF), arm muscle circumference (AMC)] were used for the evaluation of the nutritional status. Complications of cirrhosis during follow-up and patient's survival were recorded. Global survival and survival without complications was studied by Kaplan Meier method and using Log Rank test. Prevalence of malnutrition ranged from 16.3 and 62.5% according to the method of nutritional assessment used. Survival without complications was reduced in malnourished patients. This difference was significant when assessing malnutrition by dry BMI (p=0.001). In multivariate analysis, malnutrition defined by dry BMImalnutrition was an independent predictor of complications in cirrhosis. However, it did not appear as an independent prognostic factor for global survival. These results raise again difficulties to clarify whether malnutrition influence itself the prognosis of cirrhosis or if it is only related to the severity of cirrhosis.

  14. Embolization of portal-systemic shunts in cirrhotic patients with chronic recurrent hepatic encephalopathy

    International Nuclear Information System (INIS)

    Sakurabayashi, Shin; Sezai, Shuichi; Yamamoto, Yoshihiro; Hirano, Masanori; Oka, Hiroshi

    1997-01-01

    Purpose. To evaluate the efficacy of embolization of portal-systemic shunts in cirrhotic patients with chronic recurrent hepatic encephalopathy (CRHE). Methods. Seven cirrhotic patients with CRHE refractory to medical treatment (3 men and 4 women, mean age 66 years) were studied. Five patients had splenorenal shunts, 1 had a gastrorenal shunt, and 1 had an intrahepatic portal vein-hepatic vein shunt. Shunt embolization was performed using stainless steel coils, with a percutaneous transhepatic portal vein approach in 4 patients and a transrenal vein approach in 3 patients. Results. After embolization, the shunt disappeared in 4 patients on either ultrasound pulsed Doppler monitoring or portography. Complications observed in the 7 patients were fever, transient pleural effusion, ascites, and mild esophageal varices. For 3-6 months after embolization, the 4 patients whose shunts disappeared showed minimal or no reappearance of a shunt, and had no recurrence of encephalopathy. The serum ammonia levels decreased and electroencephalograms also improved. One of the 4 patients, who developed mild esophageal varices, required no treatment. Treatment was effective in 3 of the 4 patients (75%) who underwent embolization via a transhepatic portal vein. Conclusion. Transvascular embolization of shunts improved the outcome in 4 of 7 patients. The most effective embolization was achieved via the percutaneous transhepatic portal vein approach

  15. Changes in cardiac output and incidence of volume overload in cirrhotics receiving 20% albumin infusion.

    Science.gov (United States)

    Shasthry, Saggere M; Kumar, Manoj; Khumuckham, Jelen S; Sarin, Shiv Kumar

    2017-08-01

    Patients with cirrhosis are prone to develop volume over load, have increased capillary permeability and latent or overt cardiomyopathy. Whether albumin infusion causes volume overload in cirrhotics has not been adequately studied. Ninety nine consecutive cirrhotic patients receiving 1gm per kg albumin infusion were evaluated for development of volume overload. Clinical, echocardiographic and haemodynamic changes were closely monitored during and after albumin infusion. Thirty (30.30%) patients developed volume overload. Patients with higher BMI (P=.003), lower CTP (P=.01) and MELD (P=.034) were more often associated with the development of volume overload. Though baseline diastolic dysfunction was present in 82.8% of the patients, it did not influence the development of volume overload or changes in the cardiac output. The cardiac output increased significantly after albumin infusion (4.9±1.554 L/min to 5.86±1.85 L/min, Palbumin infusion develop volume overload, specially, those with higher BMI and lower severity of liver disease. Cardiac output increases after albumin infusion, and, baseline diastolic dysfunction has little effect on the development of volume overload or changes in cardiac output. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. Efficacy of CT portography in the evaluation of cirrhotic patients for hepatocellular carcinoma

    International Nuclear Information System (INIS)

    Oliver, J.H. III; Baron, R.L.; Dodd, G.D. III; Carr, B.I.; Van Thiel, D.

    1991-01-01

    CT portography (CTAP) is sensitive in the detection of liver neoplasms. However, this paper reports on a high technical failure rate in cirrhotic patients and the authors review the usefulness of CTAP in these patients at risk for hepatoma. To date, the authors have evaluated 43 cirrhotic patients with CTAP with use of 120-150 mL of 60% iodinated contrast material at 1.0-1.5 mL/sec. Scans were evaluated for the presence and enhancement of collateral vessels. Lover parenchyma enhancement was evaluated as homogeneous or heterogeneous. The degree of enhancement was categorized as poor, moderate, or good based on maximal postcontrast attenuation. A determination of the presence and location of flow artifacts simulating thrombus in the portal vein was made. Twenty of 43 examination were technical failures, with 6 portosystemic shunts and large varices siphoning contrast material in 7. In 7 of the failures, no varices or shunts were present. Twenty-three of 43 examinations had acceptable enhancement, but 9 had heterogeneous regions of decreased enhancement, not due to tumor, that could obscure or be confused with small tumor foci

  17. The evaluation of the right inferior phrenic artery diameter in cirrhotic patients.

    Science.gov (United States)

    Esen, Kaan; Balci, Yuksel; Tok, Sermin; Ucbilek, Enver; Kara, Engin; Kaya, Omer

    2017-09-01

    The purpose of this study is to evaluate the relationship between right inferior phrenic artery diameter and portal hypertension in cirrhotic patients. CT examinations of 38 patients with chronic liver disease (patient group) and 40 patients without any liver disease (control group) were evaluated. The right inferior phrenic artery diameter of the patient and control group were measured. CT findings of portal hypertension, which were accepted as ascites, collaterals, splenomegaly and portal vein diameter greater than 13 mm, were determined and scored in the patient group. Patients obtained scores between one and four with respect to portal hypertension findings, and the scores were compared with phrenic artery diameters. Child-Pugh and MELD scores of the patients were also calculated. The mean diameter of the right inferior phrenic artery in the patient group was larger than that in the control group (p phrenic artery diameter of the patients with score 1 was significantly different from those with score 2 (p = 0.028), score 3 (p = 0.001) and score 4 (p = 0.005). We found a linear and moderate relationship between phrenic artery diameter values and Child-Pugh scores (p = 0.012, r = 0.405). Dilatation of the right inferior phrenic artery in cirrhotic patients may be a nonspecific sign of developing portal hypertension.

  18. Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats

    Science.gov (United States)

    Choi, Miyeon; Lee, Seung Hoon; Wang, Sung Eun; Ko, Seung Yeon; Song, Mihee; Choi, June-Seek; Duman, Ronald S.; Son, Hyeon

    2015-01-01

    Ketamine produces rapid antidepressant-like effects in animal assays for depression, although the molecular mechanisms underlying these behavioral actions remain incomplete. Here, we demonstrate that ketamine rapidly stimulates histone deacetylase 5 (HDAC5) phosphorylation and nuclear export in rat hippocampal neurons through calcium/calmodulin kinase II- and protein kinase D-dependent pathways. Consequently, ketamine enhanced the transcriptional activity of myocyte enhancer factor 2 (MEF2), which leads to regulation of MEF2 target genes. Transfection of a HDAC5 phosphorylation-defective mutant (Ser259/Ser498 replaced by Ala259/Ala498, HDAC5-S/A), resulted in resistance to ketamine-induced nuclear export, suppression of ketamine-mediated MEF2 transcriptional activity, and decreased expression of MEF2 target genes. Behaviorally, viral-mediated hippocampal knockdown of HDAC5 blocked or occluded the antidepressant effects of ketamine both in unstressed and stressed animals. Taken together, our results reveal a novel role of HDAC5 in the actions of ketamine and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of ketamine. PMID:26647181

  19. Cholecalciferol attenuates perseverative behavior associated with developmental alcohol exposure in rats in a dose-dependent manner.

    Science.gov (United States)

    Idrus, N M; Happer, J P; Thomas, J D

    2013-07-01

    Alcohol is a known teratogen that is estimated to affect 2-5% of the births in the U.S. Prenatal alcohol exposure can produce physical features such as facial dysmorphology, physiological alterations such as cell loss in the central nervous system (CNS), and behavioral changes that include hyperactivity, cognitive deficits, and motor dysfunction. The range of effects associated with prenatal alcohol exposure is referred to as fetal alcohol spectrum disorders (FASD). Despite preventative measures, some women continue to drink while pregnant. Therefore, identifying interventions that reduce the severity of FASD is critical. This study investigated one such potential intervention, vitamin D3, a nutrient that exerts neuroprotective properties. The present study determined whether cholecalciferol, a common vitamin D3 nutritional supplement, could serve as a means of mitigating alcohol-related learning deficits. Using a rat model of FASD, cholecalciferol was given before, during, and after 3rd trimester equivalent alcohol exposure. Three weeks after cholecalciferol treatment, subjects were tested on a serial spatial discrimination reversal learning task. Animals exposed to ethanol committed significantly more errors compared to controls. Cholecalciferol treatment reduced perseverative behavior that is associated with developmental alcohol exposure in a dose-dependent manner. These data have important implications for the treatment of FASD and suggest that cholecalciferol may reduce some aspects of FASD. This article is part of a Special Issue entitled 'Vitamin D Workshop'. Copyright © 2012 Elsevier Ltd. All rights reserved.

  20. Light at night acutely impairs glucose tolerance in a time-, intensity- and wavelength-dependent manner in rats.

    Science.gov (United States)

    Opperhuizen, Anne-Loes; Stenvers, Dirk J; Jansen, Remi D; Foppen, Ewout; Fliers, Eric; Kalsbeek, Andries

    2017-07-01

    Exposure to light at night (LAN) has increased dramatically in recent decades. Animal studies have shown that chronic dim LAN induced obesity and glucose intolerance. Furthermore, several studies in humans have demonstrated that chronic exposure to artificial LAN may have adverse health effects with an increased risk of metabolic disorders, including type 2 diabetes. It is well-known that acute exposure to LAN affects biological clock function, hormone secretion and the activity of the autonomic nervous system, but data on the effects of LAN on glucose homeostasis are lacking. This study aimed to investigate the acute effects of LAN on glucose metabolism. Male Wistar rats were subjected to i.v. glucose or insulin tolerance tests while exposed to 2 h of LAN in the early or late dark phase. In subsequent experiments, different light intensities and wavelengths were used. LAN exposure early in the dark phase at ZT15 caused increased glucose responses during the first 20 min after glucose infusion (p light of 50 and 150 lx induced greater glucose responses than 5 and 20 lx, whereas all intensities other than 5 lx reduced locomotor activity. Green light induced glucose intolerance, but red and blue light did not, suggesting the involvement of a specific retina-brain pathway. Together, these data show that exposure to LAN has acute adverse effects on glucose metabolism in a time-, intensity- and wavelength-dependent manner.

  1. Zinc supplementation in rats impairs hippocampal-dependent memory consolidation and dampens post-traumatic recollection of stressful event.

    Science.gov (United States)

    Contestabile, Antonio; Peña-Altamira, Emiliano; Virgili, Marco; Monti, Barbara

    2016-06-01

    Zinc is a trace element important for synaptic plasticity, learning and memory. Zinc deficiency, both during pregnancy and after birth, impairs c