Genetic Markers of IgG Influence The Outcome of Infection with Hepatitis C Virus

We examined the role that immunoglobulin GM and KM allotypes—genetic markers of γ and κ chains, respectively—play in the outcome of hepatitis C virus (HCV) infection in white Americans. A total of 119 persons who had cleared HCV and 111 with persistent HCV infection were genotyped for the presence of several GM and KM determinants. Persistent HCV infection was more than three times as likely (odds ratio, 3.50; P = .01) in subjects who were carriers of the GM3 allele than in those who were noncarriers. These results show that particular GM alleles may be important determinants of the outcome of HCV infection

GM Allotypes and COVID-19. A Pilot Study Performed on Sicilian Patients

Several studies suggest that genetic variants that influence the onset, maintenance and resolution of the immune response might be fundamental in predicting the evolution of COVID-19. In the present paper, we analysed the distribution of GM allotypes (the genetic markers of immunoglobulin γ chains) in symptomatic and asymptomatic COVID-19 patients and in healthy controls, all born and residing in Sicily. Indeed, the role played by GM allotypes in immune responses and infection control is well known. Our findings show that the GM23 allotype is significantly reduced in healthy controls. Interestingly, in a previous study, Sicilians carrying the GM23 allotype were associated with the risk of developing a symptomatic Human Cytomegalovirus infection. However, a note of caution should be considered, due to the small sample size of patients and controls

Brief isoflurane administration as an adjunct treatment to control organophosphate-induced convulsions and neuropathology

Organophosphate-based chemical agents (OP), including nerve agents and certain pesticides such as paraoxon, are potent acetylcholinesterase inhibitors that cause severe convulsions and seizures, leading to permanent central nervous system (CNS) damage if not treated promptly. The current treatment regimen for OP poisoning is intramuscular injection of atropine sulfate with an oxime such as pralidoxime (2-PAM) to mitigate cholinergic over-activation of the somatic musculature and autonomic nervous system. This treatment does not provide protection against CNS cholinergic overactivation and therefore convulsions require additional medication. Benzodiazepines are the currently accepted treatment for OP-induced convulsions, but the convulsions become refractory to these GABAA agonists and repeated dosing has diminishing effectiveness. As such, adjunct anticonvulsant treatments are needed to provide improved protection against recurrent and prolonged convulsions and the associated excitotoxic CNS damage that results from them. Previously we have shown that brief, 4-min administration of 3%–5% isoflurane in 100% oxygen has profound anticonvulsant and CNS protective effects when administered 30 min after a lethal dose of paraoxon. In this report we provide an extended time course of the effectiveness of 5% isoflurane delivered for 5 min, ranging from 60 to 180 min after a lethal dose of paraoxon in rats. We observed substantial effectiveness in preventing neuronal loss as shown by Fluoro-Jade B staining when isoflurane was administered 1 h after paraoxon, with diminishing effectiveness at 90, 120 and 180 min. In vivo magnetic resonance imaging (MRI) derived T2 and mean diffusivity (MD) values showed that 5-min isoflurane administration at a concentration of 5% prevents brain edema and tissue damage when administered 1 h after a lethal dose of paraoxon. We also observed reduced astrogliosis as shown by GFAP immunohistochemistry. Studies with continuous EEG monitoring are ongoing to demonstrate effectiveness in animal models of soman poisoning

Metabolic acetate therapy improves phenotype in the tremor rat model of Canavan disease

Genetic mutations that severely diminish the activity of aspartoacylase (ASPA) result in the fatal brain dysmyelinating disorder, Canavan disease. There is no effective treatment. ASPA produces free acetate from the concentrated brain metabolite, N-acetylaspartate (NAA). Because acetyl coenzyme A is a key building block for lipid synthesis, we postulated that the inability to catabolize NAA leads to a brain acetate deficiency during a critical period of CNS development, impairing myelination and possibly other aspects of brain development. We tested the hypothesis that acetate supplementation during postnatal myelination would ameliorate the severe phenotype associated with ASPA deficiency using the tremor rat model of Canavan disease. Glyceryltriacetate (GTA) was administered orally to tremor rats starting 7 days after birth, and was continued in food and water after weaning. Motor function, myelin lipids, and brain vacuolation were analyzed in GTA-treated and untreated tremor rats. Significant improvements were observed in motor performance and myelin galactocerebroside content in tremor rats treated with GTA. Further, brain vacuolation was modestly reduced, and these reductions were positively correlated with improved motor performance. We also examined the expression of the acetyl coenzyme A synthesizing enzyme acetyl coenzyme A synthase 1 and found upregulation of expression in tremor rats, with a return to near normal expression levels in GTA-treated tremor rats. These results confirm the critical role played by NAA-derived acetate in brain myelination and development, and demonstrate the potential usefulness of acetate therapy for the treatment of Canavan disease

N-Acetylaspartate in the CNS: From neurodiagnostics to neurobiology

The brain is unique among organs in many respects, including its mechanisms of lipid synthesis and energy production. The nervous systemspecific metabolite N-acetylaspartate (NAA), which is synthesized from aspartate and acetyl-coenzyme A in neurons, appears to be a key link in these distinct biochemical features of CNS metabolism. During early postnatal central nervous system (CNS) development, the expression of lipogenic enzymes in oligodendrocytes, including the NAA-degrading enzyme aspartoacylase (ASPA), is increased along with increased NAA production in neurons. NAA is transported from neurons to the cytoplasm of oligodendrocytes, where ASPA cleaves the acetate moiety for use in fatty acid and steroid synthesis. The fatty acids and steroids produced then go on to be used as building blocks for myelin lipid synthesis. Mutations in the gene for ASPA result in the fatal leukodystrophy Canavan disease, for which there is currently no effective treatment. Once postnatal myelination is completed, NAA may continue to be involved in myelin lipid turnover in adults, but it also appears to adopt other roles, including a bioenergetic role in neuronal mitochondria. NAA and ATP metabolism appear to be linked indirectly, whereby acetylation of aspartate may facilitate its removal from neuronal mitochondria, thus favoring conversion of glutamate to alpha ketoglutarate which can enter the tricarboxylic acid cycle for energy production. In its role as a mechanism for enhancing mitochondrial energy production from glutamate, NAA is in a key position to act as a magnetic resonance spectroscopy marker for neuronal health, viability and number. Evidence suggests that NAA is a direct precursor for the enzymatic synthesis of the neuron specific dipeptide N-acetylaspartylglutamate, the most concentrated neuropeptide in the human brain. Other proposed roles for NAA include neuronal osmoregulation and axon-glial signaling. We propose that NAA may also be involved in brain nitrogen balance. Further research will be required to more fully understand the biochemical functions served by NAA in CNS development and activity, and additional functions are likely to be discovered

N-Acetylaspartate reductions in brain injury: impact on post-injury neuroenergetics, lipid synthesis, and protein acetylation

N-Acetylaspartate (NAA) is employed as a non-invasive marker for neuronal health using proton magnetic resonance spectroscopy (MRS). This utility is afforded by the fact that NAA is one of the most concentrated brain metabolites and that it produces the largest peak in MRS scans of the healthy human brain. NAA levels in the brain are reduced proportionately to the degree of tissue damage after traumatic brain injury (TBI) and the reductions parallel the reductions in ATP levels. Because NAA is the most concentrated acetylated metabolite in the brain, we have hypothesized that NAA acts in part as an extensive reservoir of acetate for acetyl coenzyme A synthesis. Therefore, the loss of NAA after TBI impairs acetyl coenzyme A dependent functions including energy derivation, lipid synthesis and protein acetylation reactions in distinct ways in different cell populations. The enzymes involved in synthesizing and metabolizing NAA are predominantly expressed in neurons and oligodendrocytes respectively, and therefore some proportion of NAA must be transferred between cell types before the acetate can be liberated, converted to acetyl coenzyme A and utilized. Studies have indicated that glucose metabolism in neurons is reduced, but that acetate metabolism in astrocytes is increased following TBI, possibly reflecting an increased role for non-glucose energy sources in response to injury. NAA can provide additional acetate for intercellular metabolite trafficking to maintain acetyl CoA levels after injury. Here we explore changes in NAA, acetate and acetyl coenzyme A metabolism in response to brain injury

Hepatitis C Virus Core Protein Discriminates Between the Two IgG2 Allotypes

Immunoglobulin GM allotypes, genetic markers of IgG, are associated with the outcome of hepatitis C virus (HCV) infection, but the underlying mechanisms are not completely understood. HCV has evolved mechanisms for decreasing the efficacy of the host immune response. One such strategy might involve the scavenging of the Fcγ domain of the anti-HCV IgG antibodies by its Fcγ-receptor–like core protein and thus interfering with the Fcγ-mediated host defense mechanisms. We tested the hypothesis that GM allotypes modulate this viral strategy through differential binding to the core protein. Here we show that the absorbance values for binding to the core protein were higher for GM23+IgG2 than for GM23− IgG2 (p = 0.027), a finding that at least in part explains the involvement of GM allotypes in the outcome of HCV infection. These findings also contribute toward our understanding of the mechanisms that maintain strong linkage disequilibrium between particular GM alleles