Methanol-induced monoamine changes in hypothalamus and striatum of albino rats

This paper suggests that like ethanol, methanol also produces certain changes in the steady state level of monoamines in hypothalamus and striatum of albino rats. Though, the toxic manifestations of methanol are attributed to the metabolic end product of methanol viz. formic acid by several workers, we report here that the methanol-induced brain monoamine changes, at least, could be attributed to the direct action of methanol rather than to its metabolic end products like formaldehyde or formate. Studies in the steady state level of rat brain monoamines have shown that after methanol administration (3 g/kg), there is severe depletion of dopamine level in striatum but a significant increase in the level of dopamine, serotonin and 5-hydroxy indole acetic acid in hypothalamus. At the same time, norepinephrine and epinephrine levels are reduced in hypothalamus as well as in striatum. These effects do not seem to be induced by metabolic acidosis. The changes in monoamine levels are very well correlated with the blood and brain level of methanol as evidenced by maintaining a higher methanol level either by simultaneous administration of ethanol or by blocking methanol metabolism by pretreatment with 4-methyl pyrazole and 3-amino-1,2,4-triazole. It is thus postulated that monoamine changes induced by methanol appear to be the direct effect of methanol per se on the monoaminergic neuronal membranes.     

Circulating testosterone in pure motor stroke

Serum LH, FSH and testosterone were quantitated in 9 patients with pure motor stroke within 24-48 h of its reported onset. High circulating LH with normal or low testosterone was noted in 8 of them. In response to an intravenous bolus of GnRH, the LH responses were exaggerated in all, but the FSH responses in 7 of them were comparable to those in eugonadal age matched controls. The rise in testosterone following 2000U hCG daily for 3 consecutive days was insignificant in the patients group compared to the controls. The data suggest normally operative pituitary testicular feed-back but decreased Leydig cell response in pure motor stroke.     

Effect of isopropanol on rat brain monoamine levels

Changes in monoamines were studied in discrete areas of brain with varying dose of isopropanol. Acute administration of isopropanol (0.463 g/kg, 0.925 g/kg and 1.85 g/kg) decreased dopamine level in hypothalamus, pons medulla and cerebral cortex and whereas it was increased in striatum and cerebellum. Noradrenaline level was reduced in all the brain areas studied. Adrenaline level was increased in hypothalamus, striatum, midbrain and pons medulla, and decreased in hippocampus and cerebral cortex. Serotonin level was increased in hypothalamus, midbrain, pons-medulla and cerebral cortex, and decreased in striatum and hippocampus. These changes were dose-dependent. It is concluded that isopropanol causes changes in brain monoamine content that this effect is not the same in all the regions of the brain.     

Immune reactions associated with silicone-based ventriculo-peritoneal shunt malfunctions in children

The implantation of ventriculo-peritoneal (VP) shunting systems is the most commonly performed neurological procedure in children with hydrocephalus. Although the overall complication risk is low, the cumulative risk of shunt failure is high and unfortunately results in a high prevalence of revision surgeries. In this study, we explored the concept that some pediatric patients may develop an immune response to either the proteins attached to the silicone implant surface or to the biomaterial itself, and that this reaction may contribute to VP shunt failure in some individuals. The data displays that the sterile shunt malfunction group had a higher rate of protein deposition and increased levels of autoantibodies to the extracted surface proteins as compared to individuals with functioning shunting systems. The precise nature of the shunt-bound proteins that serve as antigens in this experiment have not yet been determined. The data also indicated that some individuals develop antibodies to polymeric substances that cross-react with partially polymerized acrylamide. The detection of significant amounts of shunt-bound protein, antibody responses to these proteins and to polymeric substances suggest that an immunological response to these proteins may play a role in the mechanism behind sterile shunt malfunctions.     

Helicobacter hepaticus hydrogenase mutants are deficient in hydrogen-supported amino acid uptake and in causing liver lesions in A/J mice

Helicobacter hepaticus, a causative agent of chronic hepatitis and hepatocellular carcinoma in mice, expresses a nickel-containing hydrogen-oxidizing hydrogenase enzyme. Growth of a hyaB gene-targeted mutant was unaffected by the presence of hydrogen, unlike the wild-type strain, which showed an enhanced growth rate when supplied with H(2). Hydrogenase activities in H. hepaticus were constitutive and not dependent on the inclusion of H(2) during growth. Addition of nickel during growth significantly stimulated both urease (for wild-type and hyaB) and hydrogenase (for wild-type) activities. In a 5-h period, the extent of (14)C-labeled amino acid uptake by the wild type was markedly enhanced in the presence of hydrogen and was >5-fold greater than that of the hyaB mutant strain. In the presence of H(2), the short-term whole-cell amino acid uptake V(max) of the parent strain was about 2.2-fold greater than for the mutant, but the half-saturation affinity for amino acid transport was the same for the parent and mutant strain. The liver- and cecum-colonizing abilities of the strains was estimated by real-time PCR quantitation of the H. hepaticus-specific cytolethal distending toxin gene and showed similar animal colonization for the hyaB mutant and the wild type. However, at 21 weeks postinoculation, the livers from mice inoculated with wild type exhibited moderate lobular lymphoplasmacytic hepatitis with hepatocytic coagulative necrosis, but the hydrogenase mutants exhibited no histological evidence of lobular inflammation or necrosis.     

Requirement of hydD, hydE, hypC and hypE genes for hydrogenase activity in Helicobacter pylori

Helicobacter pylori possesses a membrane-bound, nickel containing, hydrogen uptake hydrogenase enzyme; its synthesis requires structural as well as accessory proteins, the latter needed for the complete maturation of the enzyme. Our lab previously characterized mutants in the accessory hyp genes, hypA, hypB, hypD and hypF that were all severely affected for hydrogenase activity, and in some cases (hypA and hypB mutants) also affected for urease activity. This finding prompted us to disrupt the two remaining unstudied hyp genes of H. pylori, hypC and hypE, in order to see if the same pleiotropic effect would be observed. In both mutants hydrogenase activity was abolished but urease activity remained unaffected. Addition of 5 microM nickel into the growth medium partially restored the hydrogenase activity in the hypE mutant and to a lesser extent in the hypC mutant. In addition, we also disrupted the genes HP0634 (referred as hydD in the H. pylori 26695 genome database) and HP0635 (whose function was unknown, referred to here as hydE) to address their possible roles in the hydrogenase synthesis/maturation process. In both cases, hydrogenase activities were abolished and addition of nickel could not restore the activity, suggesting that these proteins are involved in the hydrogenase synthesis process rather than in nickel mobilization/insertion steps.     

Congenital leukaemia in Down Syndrome--a case report

A 17 days old male infant, who had features of Down Syndrome, presented with fever, refusal to feed and seizures. He had papular, crusted skin lesions, moderate hepatosplenomegaly and a rapid downhill course. Peripheral blood and bone marrow aspirate showed features of acute leukaemia. Congenital Leukaemia is a rare malignancy associated with a very poor prognosis. Paradoxically, many cases of Congenital Leukaemia, especially in infants with Down Syndrome, show spontaneous remission.     

Neurochemical and behavioural correlates in cassava-induced neurotoxicity in rats

Chronic cyanide intoxication from cassava has been implicated as the cause for a degenerative neuropathy known widely as tropical ataxic neuropathy. An attempt has been made in this study to identify the specific cause for neuropathy caused by cassava using Wistar strain albino rats as the experimental animal model. The results of cassava fed animals were compared with control animals, animals given cyanide, malnourished animals and malnourished animals fed cyanide, to identify the causative factors. This study revealed that though the behavioural pattern in motor coordination of the cassava fed animals was similar to the other groups studied, the neurochemical basis for the observed behavioural pattern was unique for cassava. Hence the neurotoxicity of cassava could be attributed to unmetabolized linamarin, more than its nutritional status and/or cyanide toxicity.     

Effects of avasimibe on cytochrome P450 2C9 expression in vitro and in vivo.

Avasimibe, an acyl-CoA:cholesterol acyltransferase inhibitor, has been previously shown to be a potent inducer of CYP3A4 and multiple drug resistance protein 1. We have further characterized the drug interaction potential of avasimibe by studying the inductive and inhibitory effect of this compound on major drug-metabolizing enzymes. Enzymes known to be involved in the metabolism of drugs likely to be coadministered with avasimibe, such as CYP1A1/2, CYP2C, and CYP2B6, were evaluated further by microarray analysis, Western immunoblotting, and activity assays, using rifampicin and beta-naphthoflavone as positive controls. No change was observed in CYP1A1/2 mRNA or activity levels after avasimibe treatment. Differential induction of CYP2C9- and CYP2B6-immunoreactive protein and activity was observed depending on drug concentration and donor. Microarray analysis showed a similar increase in CYP2C and CYP2B6 mRNA levels. The inhibition potential of avasimibe on the major drug-metabolizing enzymes was assessed using pooled human liver microsomes. Avasimibe inhibited CYP2C9 (IC50 2.9 microM), CYP1A2 (IC50 13.9 microM), and CYP2C19 (IC50 26.5 microM). A clinical drug interaction study was conducted to determine whether avasimibe might interact with the CYP2C9 substrate warfarin. Volunteers received 750 mg of avasimibe and showed a 54.2% reduction in trough concentrations of S-warfarin and decreased prothrombin times by 12, 15, 19, and 21% on days 6 through 9, respectively. These results demonstrate that avasimibe's inductive spectrum resembles that of rifampin.