AIM:To investigate the neuroprotective potential of ciclosporin during acute liver failure. We evaluated the effect of intrathecally administered ciclosporin on intracranial pressure, brain water content and aquaporin...AIM:To investigate the neuroprotective potential of ciclosporin during acute liver failure. We evaluated the effect of intrathecally administered ciclosporin on intracranial pressure, brain water content and aquaporin-4 expression in a rat model with acute hyperammonaemia.METHODS:Twenty-four male Wistar rats with portacaval anastomosis were randomised into four groups receiving ciclosporin or vehicle and ammonia or saline infusion. Ciclosporin or vehicle was given intrathecally prior to the ammonia or saline infusion. The ammonia or saline infusion was given intravenously for 4 h,while intracranial pressure and arterial pressure was recorded. At the end of the experiment, cerebral cortex and cerebellar brain tissue was analysed for water and aquaporin-4 content.RESULTS:The following intracranial pressures were found at the end of the experiment:ammonia + ciclosporin:10.0±1.7 mmHg, ammonia + vehicle:6.8±1.0mmHg, saline + ciclosporin:3.1±0.5 mmHg, saline +vehicle:3.3 ± 0.6 mmHg. Ammonia infusion had a significant effect on intracranial pressure and brain water content, which both were higher in the groups receiving ammonia(P<0.001, two-way analysis of variance). Treatment with ciclosporin resulted in relevant tissue concentrations of ciclosporin(>0.2 micromolar)but did not reduce intracranial pressure after 4 h. Furthermore, ciclosporin did not attenuate the increase in cerebral water content, and did not affect aquaporin-4expression.CONCLUSION:Intrathecal administration of ciclosporin does not attenuate intracranial hypertension or brain oedema in rats with portacaval anastomosis and 4 h of ammonia infusion.展开更多
Glucose is derived from three sources： intestinal absorption, glycogenolysis, and gluconeogenesis.Hypoglycemia in child is often attributed to depletion of glycogen stores. However, recently, congenital hyperinsulini...Glucose is derived from three sources： intestinal absorption, glycogenolysis, and gluconeogenesis.Hypoglycemia in child is often attributed to depletion of glycogen stores. However, recently, congenital hyperinsulinism becomes an important cause of hypoglycaemia in early infancy.展开更多
Hepatic encephalopathy is suspected in non-cirrhotic cases of encephalopathy because the symptoms are accompanied by hyperammonaemia. Some cases have been misdiagnosed as psychiatric diseases and consequently patients...Hepatic encephalopathy is suspected in non-cirrhotic cases of encephalopathy because the symptoms are accompanied by hyperammonaemia. Some cases have been misdiagnosed as psychiatric diseases and consequently patients hospitalized in psychiatric institutions or geriatric facilities. Therefore, the importance of accurate diagnosis of this disease should be strongly emphasized. A 68-year-old female patient presented to the Emergency Room with confusion, lethargy, nausea and vomiting. Examination disclosed normal vital signs. Neurological examination revealed a minimally responsive woman without apparent focal deficits and normal reflexes. She had no history of hematologic disorders or alcohol abuse. Her brain TC did not demonstrate any intracranial abnormalities and electroencephalography did not reveal any subclinical epileptiform discharges. Her ammonia level was > 400 mg/d L(reference range < 75 mg/d L) while hepatitis viral markers were negative. The patient was started on lactulose, rifaximin and low-protein diet.On the basis of the doppler ultrasound and abdomen computed tomography angiography findings, the decision was made to attempt portal venography which confirmed the presence of a giant portal-systemic venous shunt. Therefore, mechanic obliteration of shunt by interventional radiology was performed. As a consequence, mesenteric venous blood returned to hepatopetally flow into the liver, metabolic detoxification of ammonia increased and hepatic encephalopathy subsided. It is crucial that physicians immediately recognize the presence of non-cirrhotic encephalopathy, in view of the potential therapeutic resolution after accurate diagnosis and appropriate treatments.展开更多
The interplay between glucose metabolism and that of the two other primary nutrient classes, amino acids and fatty acids is critical for regulated insulin secretion. Mitochondrial metabolism of glucose, amino acid and...The interplay between glucose metabolism and that of the two other primary nutrient classes, amino acids and fatty acids is critical for regulated insulin secretion. Mitochondrial metabolism of glucose, amino acid and fatty acids generates metabolic coupling factors(such as ATP, NADPH, glutamate, long chain acyl-CoA and diacylglycerol) which trigger insulin secretion. The observation of protein induced hypoglycaemia in patients with mutations in GLUD1 gene, encoding the enzyme glutamate dehydrogenase(GDH) and HADH gene, encoding for the enzyme short-chain 3-hydroxyacyl-CoA dehydrogenase has provided new mechanistic insights into the regulation of insulin secretion by amino acid and fatty acid metabolism. Metabolic signals arising from amino acid and fatty acid metabolism converge on the enzyme GDH which integrates both signals from both pathways and controls insulin secretion. Hence GDH seems to play a pivotal role in regulating both amino acid and fatty acid metabolism.展开更多
AIM： To assess whether portacaval anastomosis （PCA） in rats affects the protein expression and/or activity of glutaminase in kidneys, intestines and in three brain areas of cortex, basal ganglia and cerebellum and ...AIM： To assess whether portacaval anastomosis （PCA） in rats affects the protein expression and/or activity of glutaminase in kidneys, intestines and in three brain areas of cortex, basal ganglia and cerebellum and to explain the neurological alterations found in hepatic encephalopathy （HE）. METHODS： Sixteen male Wistar rats weighing 250-350 g were grouped into sham-operation control （n=8） or portacaval shunt （n = 8）. Twenty-eight days after the procedure, the animals were sacrificed. The duodenum, kidney and brain were removed, homogenised and mitochondria were isolated. Ammonia was measured in brain and blood. Phosphate-activated glutaminase （PAG） activity was determined by measuring ammonia production following incubation for one hour at 37 ℃ with O-phthalaldehyde （OPA） and specific activity expressed in units per gram of protein （pkat/g of protein）. Protein expression was measured by immunoblotting. RESULTS： Duodenal and kidney PAG activities together with protein content were significantly higher in PCA group than in control or sham-operated rats （duodenum PAG activity was 976.95±268.87μkat/g of protein in PCA rats vs 429.19±126.92.μkat/g of protein in shamoperated rats; kidneys PAG activity was 1259.18±228.79 μkat/g protein in PCA rats vs 669.67±400.8 μkat/g of protein in controls, P〈0.05; duodenal protein content： 173% in PCA vs sham-operated rats; in kidneys the content of protein was 152% in PCA vs sham-operated rats）. PAG activity and protein expression in PCA rats were higher in cortex and basal ganglia than those in shamoperated rats （cortex： 6646.6 ±1870.4 μkat/g of protein vs 3573.8± 2037.4 μkat/g of protein in control rats, P〈 0.01; basal ganglia, PAG activity was 3657.3± 1469.6 μkat/g of protein in PCA rats vs 2271.2±384 μkat/g of protein in sham operated rats, P〈0.05; In the cerebellum, the PAG activity was 2471.6±701.4 μkat/g of protein vs 1452.9 ±567.8 μkat/g of protein in the PCA and sham rats, respectively, P〈0.05; content of protein： cerebral cortex： 162% ±40% vs 100% ± 26%, P〈 0.009; and basal ganglia： 140% ±39% vs 100% ±14%, P〈0.05; but not in cerebellum： 100% ±25% vs 100% ± 16%, P= ns）. CONCLUSION： Increased PAG activity in kidney and duodenum could contribute significantly to the hyperammonaemia in PCA rats, animal model of encephalopathy. PAG is increased in non-synaptic mitochondria from the cortex and basal ganglia and could be implicated in the pathogenesis of hepatic encephalopathy. Therefore, PAG could be a possible target for the treatment of HE or liver dysfunction.展开更多
文摘AIM:To investigate the neuroprotective potential of ciclosporin during acute liver failure. We evaluated the effect of intrathecally administered ciclosporin on intracranial pressure, brain water content and aquaporin-4 expression in a rat model with acute hyperammonaemia.METHODS:Twenty-four male Wistar rats with portacaval anastomosis were randomised into four groups receiving ciclosporin or vehicle and ammonia or saline infusion. Ciclosporin or vehicle was given intrathecally prior to the ammonia or saline infusion. The ammonia or saline infusion was given intravenously for 4 h,while intracranial pressure and arterial pressure was recorded. At the end of the experiment, cerebral cortex and cerebellar brain tissue was analysed for water and aquaporin-4 content.RESULTS:The following intracranial pressures were found at the end of the experiment:ammonia + ciclosporin:10.0±1.7 mmHg, ammonia + vehicle:6.8±1.0mmHg, saline + ciclosporin:3.1±0.5 mmHg, saline +vehicle:3.3 ± 0.6 mmHg. Ammonia infusion had a significant effect on intracranial pressure and brain water content, which both were higher in the groups receiving ammonia(P<0.001, two-way analysis of variance). Treatment with ciclosporin resulted in relevant tissue concentrations of ciclosporin(>0.2 micromolar)but did not reduce intracranial pressure after 4 h. Furthermore, ciclosporin did not attenuate the increase in cerebral water content, and did not affect aquaporin-4expression.CONCLUSION:Intrathecal administration of ciclosporin does not attenuate intracranial hypertension or brain oedema in rats with portacaval anastomosis and 4 h of ammonia infusion.
基金This study was supported by a grant from the Beijing Natural Science Foundation, China （No. 7092085）.
文摘Glucose is derived from three sources： intestinal absorption, glycogenolysis, and gluconeogenesis.Hypoglycemia in child is often attributed to depletion of glycogen stores. However, recently, congenital hyperinsulinism becomes an important cause of hypoglycaemia in early infancy.
文摘Hepatic encephalopathy is suspected in non-cirrhotic cases of encephalopathy because the symptoms are accompanied by hyperammonaemia. Some cases have been misdiagnosed as psychiatric diseases and consequently patients hospitalized in psychiatric institutions or geriatric facilities. Therefore, the importance of accurate diagnosis of this disease should be strongly emphasized. A 68-year-old female patient presented to the Emergency Room with confusion, lethargy, nausea and vomiting. Examination disclosed normal vital signs. Neurological examination revealed a minimally responsive woman without apparent focal deficits and normal reflexes. She had no history of hematologic disorders or alcohol abuse. Her brain TC did not demonstrate any intracranial abnormalities and electroencephalography did not reveal any subclinical epileptiform discharges. Her ammonia level was > 400 mg/d L(reference range < 75 mg/d L) while hepatitis viral markers were negative. The patient was started on lactulose, rifaximin and low-protein diet.On the basis of the doppler ultrasound and abdomen computed tomography angiography findings, the decision was made to attempt portal venography which confirmed the presence of a giant portal-systemic venous shunt. Therefore, mechanic obliteration of shunt by interventional radiology was performed. As a consequence, mesenteric venous blood returned to hepatopetally flow into the liver, metabolic detoxification of ammonia increased and hepatic encephalopathy subsided. It is crucial that physicians immediately recognize the presence of non-cirrhotic encephalopathy, in view of the potential therapeutic resolution after accurate diagnosis and appropriate treatments.
文摘The interplay between glucose metabolism and that of the two other primary nutrient classes, amino acids and fatty acids is critical for regulated insulin secretion. Mitochondrial metabolism of glucose, amino acid and fatty acids generates metabolic coupling factors(such as ATP, NADPH, glutamate, long chain acyl-CoA and diacylglycerol) which trigger insulin secretion. The observation of protein induced hypoglycaemia in patients with mutations in GLUD1 gene, encoding the enzyme glutamate dehydrogenase(GDH) and HADH gene, encoding for the enzyme short-chain 3-hydroxyacyl-CoA dehydrogenase has provided new mechanistic insights into the regulation of insulin secretion by amino acid and fatty acid metabolism. Metabolic signals arising from amino acid and fatty acid metabolism converge on the enzyme GDH which integrates both signals from both pathways and controls insulin secretion. Hence GDH seems to play a pivotal role in regulating both amino acid and fatty acid metabolism.
基金Supported by funding from the Spanish Ministry of Health (grants # PI040384 and # 03/155-2002) awarded to the Spanish Network of Hepatic Encephalopathy Research and a grant from PAI (CTS-532)
文摘AIM： To assess whether portacaval anastomosis （PCA） in rats affects the protein expression and/or activity of glutaminase in kidneys, intestines and in three brain areas of cortex, basal ganglia and cerebellum and to explain the neurological alterations found in hepatic encephalopathy （HE）. METHODS： Sixteen male Wistar rats weighing 250-350 g were grouped into sham-operation control （n=8） or portacaval shunt （n = 8）. Twenty-eight days after the procedure, the animals were sacrificed. The duodenum, kidney and brain were removed, homogenised and mitochondria were isolated. Ammonia was measured in brain and blood. Phosphate-activated glutaminase （PAG） activity was determined by measuring ammonia production following incubation for one hour at 37 ℃ with O-phthalaldehyde （OPA） and specific activity expressed in units per gram of protein （pkat/g of protein）. Protein expression was measured by immunoblotting. RESULTS： Duodenal and kidney PAG activities together with protein content were significantly higher in PCA group than in control or sham-operated rats （duodenum PAG activity was 976.95±268.87μkat/g of protein in PCA rats vs 429.19±126.92.μkat/g of protein in shamoperated rats; kidneys PAG activity was 1259.18±228.79 μkat/g protein in PCA rats vs 669.67±400.8 μkat/g of protein in controls, P〈0.05; duodenal protein content： 173% in PCA vs sham-operated rats; in kidneys the content of protein was 152% in PCA vs sham-operated rats）. PAG activity and protein expression in PCA rats were higher in cortex and basal ganglia than those in shamoperated rats （cortex： 6646.6 ±1870.4 μkat/g of protein vs 3573.8± 2037.4 μkat/g of protein in control rats, P〈 0.01; basal ganglia, PAG activity was 3657.3± 1469.6 μkat/g of protein in PCA rats vs 2271.2±384 μkat/g of protein in sham operated rats, P〈0.05; In the cerebellum, the PAG activity was 2471.6±701.4 μkat/g of protein vs 1452.9 ±567.8 μkat/g of protein in the PCA and sham rats, respectively, P〈0.05; content of protein： cerebral cortex： 162% ±40% vs 100% ± 26%, P〈 0.009; and basal ganglia： 140% ±39% vs 100% ±14%, P〈0.05; but not in cerebellum： 100% ±25% vs 100% ± 16%, P= ns）. CONCLUSION： Increased PAG activity in kidney and duodenum could contribute significantly to the hyperammonaemia in PCA rats, animal model of encephalopathy. PAG is increased in non-synaptic mitochondria from the cortex and basal ganglia and could be implicated in the pathogenesis of hepatic encephalopathy. Therefore, PAG could be a possible target for the treatment of HE or liver dysfunction.
