Stochastic simulations of polymer growth and isomerization in the polymerization of propylene catalyzed by Pd-based diimine catalysts.

A model is presented that employs a stochastic approach to the simulation of polyolefin chain growth and isomerization. The model is applied to propylene polymerization catalyzed by Pd-based diimine catalysts. The stochastic approach links the microscopic (quantum chemical) approach with modeling of the macroscopic systems.

DFT studies on the copolymerization of alpha-olefins with polar monomers: ethylene-methyl acrylate copolymerization catalyzed by a Pd-based diimine catalyst.

Gradient-corrected density functional theory has been used to study the elementary reactions for the copolymerization of ethylene with methyl acrylate catalyzed by Pd-based diimine catalysts, modeled by the generic complex N(wedge)N-Pd(n-C(3)H(7))(+), with N(wedge)N = -NHCHCHNH-. The steric effects in the real systems are discussed on the basis of the calculations for the catalyst with N(wedge)N = -NArCRCRNAr-, R = CH(3), and Ar = C(6)H(3)(i-Pr(2)) and the previous calculations on ethylene/propylene polymerization. Considerations have been given to the different possible acrylate complexes, as well as the transition states and the products (agostic complexes and the alternative chelates) for two acrylate insertion paths (1,2 and 2,1).

Evidence for a serotonin transporter deficit in experimental acute liver failure.

It has been suggested that alterations of serotonin transport may be implicated in the pathogenesis of the neuropsychiatric symptoms encountered in acute liver failure. In order to address this issue, microdialysate concentrations of serotonin, its precursor L-tryptophan and metabolite 5-hydroxyindoleacetic acid (5-HIAA) as well as brain regional distribution of serotonin transporter ([3H]-citalopram) sites were measured in rats with acute liver failure resulting from hepatic devascularization. A significant loss of [3H]-citalopram sites was observed in dorsal Raphe nucleus, in frontal and frontoparietal cortices as well as in substantia nigra of rats with severe encephalopathy resulting from acute liver failure.

Loss of noradrenaline transporter sites in frontal cortex of rats with acute (ischemic) liver failure.

There is increasing evidence that central noradrenaline (NA) transport mechanisms are implicated in the central nervous system complications of acute liver failure. In order to assess this possibility, binding sites for the high affinity NA transporter ligand [3H]-nisoxetine were measured by quantitative receptor autoradiography in the brains of rats with acute liver failure resulting from hepatic devascularization and in appropriate controls. In vivo microdialysis was used to measure extracellular brain concentrations of NA.

Effect of portacaval anastomosis on glutamine synthetase protein and gene expression in brain, liver and skeletal muscle.

The effects of chronic liver insufficiency resulting from end-to-side portacaval anastomosis (PCA) on glutamine synthetase (GS) activities, protein and gene expression were studied in brain, liver and skeletal muscle of male adult rats. Four weeks following PCA, activities of GS in cerebral cortex and cerebellum were reduced by 32% and 37% (p<0.05) respectively whereas GS activities in muscle were increased by 52% (p<0.

Mild hypothermia delays the onset of coma and prevents brain edema and extracellular brain glutamate accumulation in rats with acute liver failure.

Mild hypothermia is effective in the prevention of brain edema associated with cerebral ischemia and traumatic brain injury. Brain edema is also a serious complication of acute liver failure (ALF). To assess the effectiveness of hypothermia in ALF, groups of rats were subjected to hepatic devascularization (portacaval anastomosis, followed 48 hours later by hepatic artery ligation), and body temperatures were maintained at either 35 degrees C (hypothermic) or 37 degrees C (normothermic).

Manganese deposition in basal ganglia structures results from both portal-systemic shunting and liver dysfunction.

Background & Aims: Manganese (Mn) deposition could be responsible for the T(1)-weighted magnetic resonance signal hyperintensities observed in cirrhotic patients. These experiments were designed to assess the regional specificity of the Mn increases as well as their relationship to portal-systemic shunting or hepatobiliary dysfunction.

Methods: Mn concentrations were measured in (1) brain samples from basal ganglia structures (pallidum, putamen, caudate nucleus) and cerebral cortical structures (frontal, occipital cortex) obtained at autopsy from 12 cirrhotic patients who died in hepatic coma and from 12 matched controls; and from (2) brain samples (caudate/putamen, globus pallidus, frontal cortex) from groups (n = 8) of rats either with end-to-side portacaval anastomosis, with biliary cirrhosis, or with fulminant hepatic failure as well as from sham-operated and normal rats.

L-ornithine-L-aspartate lowers plasma and cerebrospinal fluid ammonia and prevents brain edema in rats with acute liver failure.

Brain edema sufficient to cause intracranial hypertension and brain herniation remains a major cause of mortality in acute liver failure (ALF). Studies in experimental animal models of ALF suggest a role for ammonia in the pathogenesis of both encephalopathy and brain edema in this condition. As part of a series of studies to evaluate the therapeutic efficacy of ammonia-lowering agents, groups of rats with ALF caused by hepatic devascularization were treated with L-ornithine-L-aspartate (OA), an agent shown previously to be effective in reducing blood ammonia concentrations in both experimental and human chronic liver failure.

L-ornithine-L-aspartate in experimental portal-systemic encephalopathy: therapeutic efficacy and mechanism of action.

Strategies aimed at the lowering of blood ammonia remain the treatment of choice in portal-systemic encephalopathy (PSE). L-ornithine-L-aspartate (OA) has recently been shown to be effective in the prevention of ammonia-precipitated coma in humans with PSE. These findings prompted the study of mechanisms of the protective effect of OA in portacaval-shunted rats in which reversible coma was precipitated by ammonium acetate administration (3.

Selective increases of extracellular brain concentrations of aromatic and branched-chain amino acids in relation to deterioration of neurological status in acute (ischemic) liver failure.

Previous reports based on studies in brain tissue from humans and experimental animals suggest that aromatic amino acids (AAAs) and branched-chain amino acids (BCAA's) accumulate in brain in acute liver failure. In order to assess these changes in relation to the severity of neurological impairment and to the degree of hyperammonemia, AAAs and BCAAs were measured in vivo by cerebral microdialysis in frontal cortex of rats at various stages during the development of hepatic encephalopathy due to acute liver failure resulting from portacaval anastomosis followed by hepatic artery ligation. Extracellular brain concentrations of AAAs and of valine and leucine were elevated 2 to 4-fold following hepatic devascularization and these increases were significantly correlated to arterial ammonia concentration (r= 0.

Evidence for altered central noradrenergic function in experimental acute liver failure in the rat.

These is increasing evidence to suggest that central noradrenergic mechanisms may contribute to the central nervous system manifestations of acute liver failure. To further elucidate this possibility, extracellular brain concentrations of the monoamines, noradrenaline (NA), dopamine (DA), and serotonin, were measured by high-performance liquid chromatography with electrochemical detection in microdialysates from the extracellular compartment of frontal cortex in rats with acute (ischemic) liver failure at various times during the progression of encephalopathy and brain edema, as well as in obligate control groups of animals. In addition, binding sites for the noradrenergic receptor subtype ligands, [3H]-prazosin (alpha1 sites), [3H]-RX821002 (alpha2 sites), and [125]I-iodopindolol (beta sites), were assessed using quantitative receptor autoradiography in regions of the brains of rats at coma stage of acute liver failure and of control groups of animals.

Ornithine transcarbamylase deficiency: pathogenesis of the cerebral disorder and new prospects for therapy.

Ornithine Transcarbamylase (OTC) is a key urea cycle enzyme. Congenital OTC deficiencies in humans result in hyperammonemia and a spectrum of neurological symptoms including hypotonia, seizures and mental retardation. Neuropathologic evaluation reveals cerebral atrophy, ventricular enlargement and Alzheimer type II astrocytosis.

Decreased glutamate transporter (GLT-1) expression in frontal cortex of rats with acute liver failure.

It has been suggested that reduced astrocytic uptake of neuronally released glutamate contributes to the pathogenesis of hepatic encephalopathy in acute liver failure. In order to further address this issue, the recently cloned and sequenced astrocytic glutamate transporter GLT-1 was studied in brain preparations from rats with ischemic liver failure induced by portacaval anastomosis followed 24 h later by hepatic artery ligation and from appropriate sham-operated controls. GLT-1 expression was studied using reverse transcriptase-polymerase chain reaction (RT-PCR).

Selective loss of binding sites for the glutamate receptor ligands [3H]kainate and (S)-[3H]5-fluorowillardiine in the brains of rats with acute liver failure.

There is increasing evidence that alterations of glutamatergic function are implicated in the pathogenesis of central nervous system consequences of acute liver failure. The aim of the study was to assess the integrity of glutamate receptors in the brain in experimental ischemic liver failure using quantitative receptor autoradiography and the selective ligands [3H]MK801 (for N-methyl-D-aspartate [NMDA] sites), [3H]5-fluorowillardiine (for non-NMDA, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid [AMPA] subclass sites), and [3H]kainate (for non-NMDA, kainate subclass sites). At coma stages of encephalopathy, a selective loss of up to 60% of binding sites for the kainate- and AMPA-receptor ligands was observed in cerebral cortical and hippocampal structures as well as in the hypothalamus and cerebellum.

Neuroactive amino acids and glutamate (NMDA) receptors in frontal cortex of rats with experimental acute liver failure.

It has been proposed that alterations of excitatory and inhibitory amino acids play a role in the pathogenesis of hepatic encephalopathy in acute liver failure. To evaluate this possibility, in vivo cerebral microdialysis was used to sample extracellular concentrations of amino acids in the frontal cortex of unanesthetized rats at various times during the progression of encephalopathy resulting from acute liver failure. Liver failure was induced by portacaval anastomosis followed 24 hours later by hepatic artery ligation.

Free and esterified coenzyme A in the liver and muscles of chronically hyperammonemic mice treated with sodium benzoate.

Ammonia toxicity and relative sodium benzoate toxicity alters the energy metabolism, leading to a decrease of adenosine triphosphate and free coenzyme A levels. The object of the present study was to analyze the hepatic and muscular acyl-coenzyme A profiles in chronically hyperammonemic mice treated with varying doses of the sodium benzoate. An enzymatic method was used for the measurement of free coenzyme A, acetyl-coenzyme A, and medium and long chain acyl-coenzyme A.

Tissue acylcarnitine and acyl-coenzyme A profiles in chronically hyperammonemic mice treated with sodium benzoate and supplementary L-carnitine.

The aim of the present study, was to establish the hepatic profile of acyl-coenzyme A (acyl-CoA) in relation to the hepatic profile of acylcarnitines in chronically hyperammonemic spf mice (hereditary deficiency in ornithine transcarbamylase) treated with sodium benzoate alone or in combination with L-carnitine. The muscular profile of the acylcarnitines and the stability of sarcolemma were also assessed in the same mice. Following administration of sodium benzoate, we observed decreases in hepatic total and free coenzyme A and in acetyl-CoA, which was accompanied by an increase in hepatic acyl-CoA.

A profile of cerebral and hepatic carnitine, ammonia, and energy metabolism in a model of organic aciduria: BALB/cByJ mouse with short-chain acyl-CoA dehydrogenase deficiency.

Spontaneous animal models of inborn errors of metabolism are valuable tools for defining the pathogenesis of these disorders and also the mechanism of various therapeutic approaches. In the present study, we have employed BALB/cByJ mice with an autosomal recessive deficiency of short-chain acyl-CoA dehydrogenase (SCAD). These animals were characterized by a marked urinary excretion of ethylmalonic and methylsuccinic acids along with butyrylglycine.

[Carnitine levels in muscle in mice with hyperammonemia: effect of treatment with sodium benzoate].

The object of this study was to measure carnitine levels in skeletal muscles of experimental mice with acute, subacute, and chronic hyperammonemia, with or without sodium benzoate treatment. Normal Swiss-ICR mice in which acute hyperammonemia was created through intraperitoneal injection of ammonium acetate showed a significant decrease in free carnitine in the skeletal muscles. The same phenomenon was observed in spf mice with chronic congenital hyperammonemia caused by an X-linked deficiency of liver ornithine transcarbamylase.

[Profile of hepatic and muscular acylcarnitines in chronically hyperammonemic mice after an acute treatment with sodium benzoate: dose-response study].

Sodium benzoate is conjugated with glycine in the liver and the kidney, which may cause the elimination of one mole of alpha-amino N for each mole of benzoate administered. However, muscle does not possess the enzyme activity to form benzoylglycine. The object of this study was to identify the secondary effects of acute sodium benzoate treatment on the concentrations of carnitine in liver and muscle when the glycine availability in these tissues is still assured.

[Hypocarnitinemia in patients affected by a primary defect of ammonia metabolism treated with sodium benzoate].

We have studied the plasma and urinary levels of free and esterified carnitine in 18 patients affected by a primary defect of ammonia metabolism, which had been managed with or without a therapy of sodium benzoate. None of these patients presented with any acute neurologic or digestive symptoms during the study. Our group of non-treated patients showed an increase in the levels of plasma esterified carnitine and an elevation of urinary concentration of free carnitine, while the levels of urinary esterified carnitine clearly approached the superior limits of normal values.

Plasma and urinary levels of carnitine in different experimental models of hyperammonemia and the effect of sodium benzoate treatment.

The effect of hyperammonemia on plasma and urinary levels of carnitine was studied in different groups of +/Y (normal) and spf/Y (chronically hyperammonemic) mice. Experimental models of acute and subacute hyperammonemia were prepared in +/Y and spf/Y mice by the use of ammonium acetate ip injections and arginine-free diets, respectively. In acute hyperammonemia, the plasma levels of both free and acylcarnitines increased significantly whereas acyl/free carnitine ratio was decreased, indicating a mobilization of carnitine from the storage sites.