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Previous studies have demonstrated abnormalities of intracellular electrolyte content and sodium transport in leukocytes of patients with fulminant hepatic failure. The current study was undertaken to establish whether similar abnormalities were present in patients with encephalopathy from advanced cirrhosis. Results from 19 patients with advanced cirrhosis showed values for the leukocyte total sodium efflux-rate constant were significantly reduced in patients, 3.02 +/- 1 SEM 0.12 h-1, compared to control values, 3.80 +/- 0.06 h-1. This reduction was due primarily to a lowering of the ouabain-sensitive component of sodium efflux, a measure of Na,K-ATPase activity. In comparison, leukocytes from patients with fulminant hepatic failure show a greater inhibition of the ouabain-sensitive component of sodium efflux with a raised ouabain-insensitive efflux. Although cirrhosis has generally been associated with potassium depletion, the intracellular potassium content of the cirrhotic patients' leukocytes was normal. Since the leukocyte is considered to be a good cell model and because abnormalities of sodium transport have been shown in the leukocytes of these patients, it is likely that similar abnormalities of sodium transport are present in other organs, including the brain.
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PMID:Abnormalities in the leukocyte sodium pump in advanced cirrhosis. 726 13

Variceal bleeding remains an important complication in extrahepatic portal vein thrombosis (EPVT). As for portal hypertension due to other etiologies, an elective treatment to decrease the risk of subsequent rebleeding is warranted. The results of the Sugiura-Futagawa procedure (SP) in 38 patients with variceal bleeding secondary to EPVT are reported: 20 women and 18 men, with a mean age of 28 +/- 2 years (SEM). Thirty-seven patients were classified as Child-Pugh class A, and one patient as class B. In terms of diagnosis, 45% of patients had idiopathic EPVT, and 18% had associated hypercoagulability disorders; 52% of patients had associated splenic vein thrombosis. The SP was completed in two surgical stages in 18 patients and in one surgical stage in 14; 6 patients had only the abdominal stage. One patient had mild postoperative encephalopathy, and three patients rebled at long-term follow-up study. There were two operative deaths. Actuarial survival was 70% at 64 months. It is concluded that the SP is an excellent alternative for patients with variceal bleeding secondary to EPVT.
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PMID:Surgical management of extrahepatic portal hypertension and variceal bleeding. 804 30

In experimental hepatic encephalopathy and hyperammonemia, extracellular levels of glutamate are increased in hippocampus and cerebral cortex. It has been suggested that overstimulation of glutamate receptors causes a pathological entry of calcium into neurons via receptor-operated (NMDA- and AMPA-type) or voltage-dependent calcium channels leading to calcium overload and cell death. Neurodegeneration as a result of exposure to excitotoxins, including glutamate, can be localized and quantified using 45CaCl2 autoradiography. This approach was used to study cerebral calcium accumulation in rabbits with acute liver failure and acute hyperammonemia. Acute liver failure was induced in 6 rabbits, acute hyperammonemia in 4 rabbits; 4 control rabbits received sodium-potassium-acetate. At the start of the experiment 500 microCi 45CaCl2 was given intravenously. After development of severe encephalopathy, the animals were killed by decapitation. All rabbits with acute liver failure or acute hyperammonemia developed severe encephalopathy, after 13.2 +/- 1.7 and 19.3 +/- 0.5 hours respectively (mean +/- SEM). Plasma ammonia levels were 425 +/- 46 and 883 +/- 21 mumol/l, respectively (p < 0.05). Control rabbits maintained normal plasma ammonia levels (13 +/- 5 mumol/l), demonstrated normal behaviour throughout the study and were sacrificed after 16 hours. 45Ca(2+)-autoradiograms of 40 microns brain sections were analyzed semiquantitatively using relative optical density and computerized image analysis. As compared to background levels 45Ca was not increased in hippocampus or any other brain area of rabbits with severe encephalopathy from acute liver failure or acute hyperammonemia. This suggests that, despite increased extracellular brain glutamate levels in these conditions, glutamate neurotoxicity was not important for the development of encephalopathy in these rabbits.
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PMID:45CaCl2 autoradiography in brain from rabbits with encephalopathy from acute liver failure or acute hyperammonemia. 807 63

To study the molecular basis of ammonia toxicity, highly reproducible models of acute liver failure and acute hyperammonemia in the rabbit were developed. Acute liver failure was induced by two-stage liver devascularization, and acute hyperammonemia by prolonged ammonia infusion such that the plasma ammonia pattern found in acute liver failure was simulated. Clinical symptoms, spectral analysis of the EEG, biochemistry (blood gases, renal function, electrolytes and markers of hepatic injury) and the presence of cerebral edema were studied. During acute liver failure severe encephalopathy developed after 10.2 +/- 1.9 h (n = 6, mean +/- SEM). Other liver-failure-associated abnormalities were cerebral edema, lactic acidosis, renal dysfunction, hypothermia and septicemia. During acute hyperammonemia, severe encephalopathy developed after 18.2 +/- 0.4 h (n = 6, mean +/- SEM). Other abnormalities found were cerebral edema and lactic acidosis. In both animal models comparable EEG changes were observed (a decrease in mean dominant frequency and theta-activity, and an increase in delta activity). However, these changes were not statistically significant, and non-specific as they also occurred in control rabbits despite their clinical wellbeing. This study demonstrates in the rabbit the similarity between encephalopathy due to acute ischemic liver failure and that due to hyperammonemia. An observed difference in hyperammonemia-induced encephalopathy was pronounced ataxia, which did not occur during acute liver failure, whereas hypothermia, sepsis and renal failure occurred exclusively in acute liver failure. Our models appear satisfactory for the study of hepatic encephalopathy and ammonia toxicity.
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PMID:Encephalopathy from acute liver failure and from acute hyperammonemia in the rabbit. A clinical and biochemical study. 817 26

Depo cytarabine (DTC 101 [formerly identified as Depo/Ara-C]) is a slow-releasing, depot formulation in which cytarabine is encapsulated within the aqueous compartments of microscopic (DepoFoam) particles. A phase I trial of DTC 101, given intraventricularly, was conducted in patients with leptomeningeal metastasis. Nine patients were given 1 to 7 cycles of DTC 101 in doses ranging from 25 to 125 mg that were administered via an Ommaya reservoir into the lateral ventricle. The dose-limiting toxic reaction was encephalopathy that occurred at the 125-mg dose level. All toxic episodes but one were transient and reversible, with the total duration of toxicity lasting from 1 to 7 days. The ventricular concentration of free cytarabine released from DTC 101 into cerebrospinal fluid decreased biexponentially with an initial half-life of 7.2 +/- 1.7 (+/- SEM) hours and a terminal half-life of 140 +/- 49 hours. The cerebrospinal fluid was cleared of malignant cells within 3 weeks of initial therapy in five of six cytologically evaluable patients. The duration of response ranged from 2 to more than 14 weeks, with a median of over 11 weeks. In conclusion, DTC 101 appears to be a pharmacologically attractive agent for use against leptomeningeal metastasis. The toxic episodes that occur with this therapy are well tolerated by patients.
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PMID:Treatment of leptomeningeal metastasis with intraventricular administration of depot cytarabine (DTC 101). A phase I study. 844 4

Therapeutic modulation of the increased GABAergic tone in chronic hepatic encephalopathy (HE) by the benzodiazepine receptor (BR) antagonist flumazenil (F) has led to conflicting results in humans and animal models for HE. The BR inverse agonist sarmazenil (S) has only been used in animal models of acute HE. Therefore we investigated the effects of intravenous injection of F and S in dogs with chronic HE 8 to 12 weeks after placement of a portocaval shunt and 40% hepatectomy (n=7), compared to sham-operated pair-fed controls (n=7). The HE dogs had hyperammonemia (298 +/- 48 microM v 33 +/- 3 before surgery (mean +/- SEM)) and signs of HE at the start of the experiments (0.9 +/- 0.1 (scale 0-4)). Three (S3) and 8 (S8) mg/kg of S resulted in a significant improvement of encephalopathy (grade 0.9 +/- 0.2 immediately before v 0.5 +/- 0.1 after injection (S3) and 0.7 +/- 0.1 v 0.3 +/- 0.1 (S8)) and increase in mean dominant frequency of the EEG (MDF; 9.1 +/- 0.7 Hz v 11.1 +/- 0.3 (S3) and 8.9 +/- 0.5 v 11.0 +/- 0.3 (S8)) in HE dogs, whereas 15 mg/kg of S, 3 and 8 mg/kg of F, and the vehicle had no significant effects. The efficacy of S in these dogs is consistent with an increased GABAergic tone in the pathogenesis of chronic HE. The lack of effects of F makes a role for endogenous benzodiazepines herein unlikely.
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PMID:Improvement of chronic hepatic encephalopathy in dogs by the benzodiazepine-receptor partial inverse agonist sarmazenil, but not by the antagonist flumazenil. 980 68

The aim of this study was to investigate whether hypercortisolism in dogs with congenital portosystemic shunts disappeared after surgical closure of the shunts concomitantly with recovery from hepatic encephalopathy. We examined 22 dogs before and four weeks after partial surgical closure of a single, large congenital portosystemic shunt (PSS). Parameters measured to characterise the basal activity of the pituitary-adrenal axis were the cortisol:creatinine (c/c) ratio in home-sampled urine and total and free cortisol in plasma. The binding characteristics of cortisol binding globulin (CBG) in pooled pre- and postoperative plasma were also determined. Ammonia and bile acid concentrations were measured in plasma to characterise the liver perfusion and function. Clinical symptoms relevant to liver function, cortisol excess, and hepatic encephalopathy were recorded semiquantitatively using a standardized questionnaire. The dogs had hypercortisolism before surgery, which had normalized four weeks later. The pre- and postoperative concentrations (means +/- SEM) were, respectively, 238+/-45 nM and 126+/-19 nM for total cortisol, 15.5+/-2.6 nM and 8.4+/-1.3 nM for free cortisol in plasma, 13.4+/-4.3 x 10(-6) and 3.9+/-0.4 x 10(-6) for c/c in urine. The pre- and postoperative Bmax values of CBG were 41 and 79, and Kd values were 3.8 and 5.5. The concentrations of ammonia were 217+/-23 microM and 32+/-3.1 microM, and of bile acids 1 10+/-33 and 11.1+/-2.0 microM, respectively. We conclude that there is a close relation between portosystemic encephalopathy and hypercortisolism in dogs with PSS and that both deviations resolve completely within four weeks of closure of the shunt.
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PMID:Fast resolution of hypercortisolism in dogs with portosystemic encephalopathy after surgical shunt closure. 1008 14

Activation of microglia/macrophages is important in neonatal hypoxic-ischemic (HI) brain injury. Based on experimental studies, we identified macrophage/microglia-derived mediators with potential neurotoxic effects after neonatal HI and examined them in cerebrospinal fluid (CSF) from newborn infants after birth asphyxia. Galectin-3 is a novel inflammatory mediator produced by microglia/macrophages. Galectin-3 is chemotactic for inflammatory cells and activates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase resulting in production and release of reactive oxygen species (ROS). Matrix metalloproteinase-9 (MMP-9) is a tissue-degrading protease expressed by activated microglia in the immature brain after HI. Both galectin-3 and MMP-9 contribute to brain injury in animal models for neonatal HI. Quinolinic acid (QUIN) is a neurotoxic N-methyl-D-aspartate (NMDA) receptor agonist also produced by activated microglia/macrophages. Galectin-3 and MMP-9 were measured by ELISA and QUIN by mass spectrometry. Asphyxiated infants (n=20) had higher levels of galectin-3 (mean (SEM) 2.64 (0.43) ng/mL) and QUIN (335.42 (58.9) nM) than controls (n=15) (1.36 (0.46) ng/mL and 116.56 (16.46) nM, respectively), p<0.05 and p<0.01. Infants with septic infections (n=10) did not differ from controls. Asphyxiated infants with abnormal outcome had higher levels of galectin-3 (3.96 (0.67) ng/mL) than those with normal outcome (1.76 (0.32) ng/mL), p=0.02, and the difference remained significant in the clinically relevant group of infants with moderate encephalopathy. MMP-9 was detected in few infants with no difference between groups. The potentially neurotoxic macrophage/microglia-derived mediators galectin-3 and QUIN are increased in CSF after birth asphyxia and could serve as markers and may contribute to injury.
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PMID:Microglia/macrophage-derived inflammatory mediators galectin-3 and quinolinic acid are elevated in cerebrospinal fluid from newborn infants after birth asphyxia. 2380 98


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