No abstract

Neurological dysfunction, seizures and brain atrophy occur in a broad spectrum of acute and chronic neurological diseases. In certain instances, over-stimulation of N-methyl-D-aspartate receptors has been implicated. Quinolinic acid (QUIN) is an endogenous N-methyl-D-aspartate receptor agonist synthesized from L-tryptophan via the kynurenine pathway and thereby has the potential of mediating N-methyl-D-aspartate neuronal damage and dysfunction. Conversely, the related metabolite, kynurenic acid, is an antagonist of N-methyl-D-aspartate receptors and could modulate the neurotoxic effects of QUIN as well as disrupt excitatory amino acid neurotransmission. In the present study, markedly increased concentrations of QUIN were found in both lumbar cerebrospinal fluid (CSF) and post-mortem brain tissue of patients with inflammatory diseases (bacterial, viral, fungal and parasitic infections, meningitis, autoimmune diseases and septicaemia) independent of breakdown of the blood-brain barrier. The concentrations of kynurenic acid were also increased, but generally to a lesser degree than the increases in QUIN. In contrast, no increases in CSF QUIN were found in chronic neurodegenerative disorders, depression or myoclonic seizure disorders, while CSF kynurenic acid concentrations were significantly lower in Huntington's disease and Alzheimer's disease. In inflammatory disease patients, proportional increases in CSF L-kynurenine and reduced L-tryptophan accompanied the increases in CSF QUIN and kynurenic acid. These responses are consistent with induction of indoleamine-2,3-dioxygenase, the first enzyme of the kynurenine pathway which converts L-tryptophan to kynurenic acid and QUIN. Indeed, increases in both indoleamine-2,3-dioxygenase activity and QUIN concentrations were observed in the cerebral cortex of macaques infected with retrovirus, particularly those with local inflammatory lesions. Correlations between CSF QUIN, kynurenic acid and L-kynurenine with markers of immune stimulation (neopterin, white blood cell counts and IgG levels) indicate a relationship between accelerated kynurenine pathway metabolism and the degree of intracerebral immune stimulation. We conclude that inflammatory diseases are associated with accumulation of QUIN, kynurenic acid and L-kynurenine within the central nervous system, but that the available data do not support a role for QUIN in the aetiology of Huntington's disease or Alzheimer's disease. In conjunction with our previous reports that CSF QUIN concentrations are correlated to objective measures of neuropsychological deficits in HIV-1-infected patients, we hypothesize that QUIN and kynurenic acid are mediators of neuronal dysfunction and nerve cell death in inflammatory diseases. Therefore, strategies to attenuate the neurological effects of kynurenine pathway metabolites or attenuate the rate of their synthesis offer new approaches to therapy.

The purpose of this study was to ascertain COVID-19 transmission dynamics among Latino communities nationally. Methods: We compared predictors of COVID-19 cases and deaths between disproportionally Latino counties (17.8% Latino population) and all other counties through May 11, 2020. Adjusted rate ratios (aRRs) were estimated using COVID-19 cases and deaths via zero-inflated binomial regression models. Results: COVID-19 diagnoses rates were greater in Latino counties nationally (90.9 vs. 82.0 per 100,000). In multivariable analysis, COVID-19 cases were greater in Northeastern and Midwestern Latino counties (aRR: 1.42, 95% CI: 1.11e1.84, and aRR: 1.70, 95% CI: 1.57e1.85, respectively). COVID-19 deaths were greater in Midwestern Latino counties (aRR: 1.17, 95% CI: 1.04e1.34). COVID-19 diagnoses were associated with counties with greater monolingual Spanish speakers, employment rates, heart disease deaths, less social distancing, and days since the first reported case. COVID-19 deaths were associated with household occupancy density, air pollution, employment, days since the first reported case, and age (fewer <35 yo). Conclusions: COVID-19 risks and deaths among Latino populations differ by region. Structural factors place Latino populations and particularly monolingual Spanish speakers at elevated risk for COVID-19 acquisition.

were compared between disproportionately (>13%) black and all other (<13% black) counties. Rate ratios were calculated and population attributable fractions (PAF) were estimated using COVID-19 cases and deaths via zero-inflated negative binomial regression model. National maps with countylevel data and an interactive scatterplot of COVID-19 cases were generated. ResultsNearly ninety-seven percent of disproportionately black counties (656/677) reported a case and 49% (330/677) reported a death versus 81% (1987/2,465) and 28% (684/ 2465), respectively, for all other counties. Counties with higher proportions of black people have higher prevalence of comorbidities and greater air pollution. Counties with higher proportions of black residents had more COVID-19 diagnoses (RR 1.24, 95% CI 1.17-1.33) and deaths (RR 1.18, 95% CI 1.00-1.40), after adjusting for county-level characteristics such as age, poverty, comorbidities, and epidemic duration. COVID-19 deaths were higher in disproportionally black rural and small metro counties. The PAF of COVID-19 diagnosis due to lack of health insurance was 3.3% for counties with <13% black residents and 4.2% for counties with >13% black residents.

Accumulation of L-kynurenine and quinolinic acid (QUIN) in the brain occurs after either ischemic brain injury or after systemic administration of pokeweed mitogen. Although conversion of L-[13C6]tryptophan to [13C6]-QUIN has not been demonstrated in brain either from normal gerbils or from gerbils given pokeweed mitogen, direct conversion in brain tissue does occur 4 days after transient cerebral ischemia. Increased activities of enzymes distal to indoleamine-2,3-dioxygenase may determine whether L-kynurenine is converted to QUIN. One day after 10 min of cerebral ischemia, the activities of kynureninase and 3-hydroxy-3,4-dioxygenase were increased in the hippocampus, but local QUIN levels and the activities of the indoleamine-2,3-dioxygenase and kynurenine-3-hydroxylase were unchanged. By days 2 and 4 after ischemia, however, the activities of all these enzymes in the hippocampus as well as QUIN levels were significantly increased. Kynurenine aminotransferase activity in the hippocampus was unchanged on days 1 and 2 after ischemia but was decreased on day 4, at a time when local kynurenic acid levels were unchanged. A putative precursor of QUIN, [13C6]anthranilic acid, was not converted to [13C6]QUIN in the hippocampus of either normal or 4-day post-ischemic gerbils. Gerbil macrophages stimulated by endotoxin in vitro converted L-[13C6]tryptophan to [13C6]QUIN. Kinetic analysis of kynurenine-3-hydroxylase activity in the cerebral cortex of postischemic gerbils showed that Vmax increased, without changes in Km. Systemic administration of pokeweed mitogen increased indoleamine-2,3-dioxygenase and kynureninase activities in the brain without significant changes in kynurenine-3-hydroxylase or 3-hydroxyanthranilate-3,4-dioxygenase activities. Increases in kynurenine-3-hydroxylase activity, in conjunction with induction of indoleamine-2,3-dioxygenase, kynureninase, and 3-hydroxyanthranilate-3,4-dioxygenase in macrophage infiltrates at the site of brain injury, may explain the ability of postischemic hippocampus to convert L-[13C6]tryptophan to [13C6]QUIN.