Ellen M. Flanagan

Elevation of the neurotoxin quinolinic acid occurs following spinal cord trauma

Excitatory amino acid neurotoxicity and the inflammatory response are suspected as mediators of some of the pathological sequelae occurring as a result of spinal cord injury. Here we report temporal and regional increases of the NMDA receptor agonist, quinolinic acid (QUIN), in an experimental model of spinal contusion injury. These changes occurred at a time when the blood-brain barrier is known to be dysfunctional and the activation state and density of microglia and macrophages are increased. Thus, alterations in tissue QUIN levels may occur as a result of secondary activation of CNS inflammatory cells or from peripherally derived sources across a damaged blood-brain barrier.

The Bispectral Index in the Diagnosis of Perioperative Stroke: A Case Report and Discussion

We discuss a case where the bispectral index (BIS; Aspect Medical, Natick, MA) was the earliest indicator of acute perioperative stroke during the removal of an Abiomed BVS 5000 ® (Penn State Cardiovascular Center, Hershey, PA) left ventricular assist device (LVAD). Up to 3% of cardiac surgical patients suffer serious, typically embolic, neurological complications, with an associated 20% mortality rate (1). The opportunity to make an earlier diagnosis may help improve outcome in this group as novel therapeutic options become available.

Quinolinic Acid in Neurological Disease: Opportunities for Novel Drug Discovery

Publisher Summary Quinolinic acid is found throughout nature in organisms ranging from bacteria to humans. Chemically this compound is known as pyridine-2,3-dicarboxylic acid. The biosynthetic pathways for quinolinic acid and nicotinamide adenine dinucleotide (NAD) appear to be conserved evolutionarily. The neurotoxicity of quinolinic acid has been demonstrated in vivo and in vitro. Quinolinic acid toxicity has been demonstrated most often through its direct intrastriatal injection. considerable reasons exist to suspect that quinol in k acid may be an important mediator in the primary phase of inflammatory brain disease and may be important in the secondary phase of brain injury following a variety of insults to the central nervous system (CNS). However, the real test for the importance of quinolinic acid will be the application of quinolinate synthesis inhibitors, possibly at the level of kynurenine hydroxylase or kynureninase, to human disease. However, such inhibitors are not presently available. Several advantages will aid us in that task. First, the enzymes of the macrophage pathway are largely present in the liver and should be amenable to testing potential inhibitors. Second, cultures of human macrophages are readily obtained and flux can be determined on a relevant cell type. Third, animal models of elevated quinolinate biosynthesis are available in which the in vivo efficacy of inhibitors can be evaluated.

The regulation of quinolinic acid in human immunodeficiency virus-infected monocytes

Quinolinic acid (Quin) is thought to underlie cognitive and motor dysfunctions for a variety of neurological disorders. Specifically, in human immunodeficiency virus (HIV)-associated dementia, Quin levels correlate with the degree of neurological dysfunction observed in affected individuals. Since recent data from our laboratories suggest that both HIV-1 infection and activation of brain macrophages are required for the development of neurotoxicity we examined Quin production during virus infection and immune activation. HIV-1 infection of monocytes induced low levels of Quin while lipopolysaccharide (LPS) or interferon-gamma (IFN-gamma) activation of the virus-infected cells elicited 10-fold higher levels. The combined effects of LPS and IFN-gamma for Quin production in HIV-infected monocytes was identical to each factor added alone. Little or no Quin was detected in unstimulated uninfected monocytes. LPS or IFN-gamma activation of uninfected monocytes produced substantially higher levels of Quin than found in similarly stimulated HIV-1-infected monocytes. These results were at variance to the production of tumor necrosis factor-alpha (TNF-alpha). Here, a 2-to 5-fold increase in TNF-alpha levels were observed in culture fluids of LPS-activated HIV-infected cells when compared to similarly stimulated uninfected monocytes. The effect of LPS-induced Quin production by HIV-infected monocytes was not altered by primary human astrocytes. These data suggest that Quin levels seen in HIV dementia are a reflection of macrophage/ microglial activation seen during advanced clinical disease. These findings could help explain, in part, why few HIV-1-infected brain macrophages can give rise to significant neurological impairments.

A radiometric assay for kynurenine 3-hydroxylase based on the release of 3H2O during hydroxylation of L-[3,5-3H]kynurenine.

A rapid and sensitive assay for kynurenine 3-hydroxylase (KH) has been developed. This radiometric assay is based on the enzymatic synthesis of tritiated water from L-[3,5-3H]kynurenine during the hydroxylation reaction. Radiolabeled water is quantified following selective adsorption of the isotopic substrate and its metabolite with activated charcoal. The assay is suitable for detecting 0.1 pmol enzyme activity per minute per milligram protein in tissues displaying low levels of the enzyme. The amount of water produced in the reaction, as calculated from the tritium released, was stoichiometric with the 3-hydroxykynurenine product detected by HPLC. Rat liver KH was characterized by cofactor specificity and kinetic parameters. NADPH was preferred over NADH as coreductant in the reaction. Tetrahydrobiopterin was not a cofactor. The tissue distribution of KH activity in the rat suggested that the majority of active enzyme is located in liver and kidney. Detectable amounts were found in several other tissues, including brain which had low but significant levels of activity in every region assayed.

Self-care as a professional imperative: physician burnout, depression, and suicide

PurposeBurnout has been identified in approximately half of all practicing physicians, including anesthesiologists. In this narrative review, the relationship between burnout, depression, and suicide is explored, with particular attention to the anesthesiologist. Throughout this review, we highlight our professional imperative regarding this epidemic.SourceThe authors searched the existing English language literature via PubMed from 1986 until present using the search terms physician burnout, depression, and suicide, with particular attention to studies regarding anesthesiologists and strategies to address these problems.Principal findingsBurnout and depression have increased among physicians, while the rate of suicide has remained relatively the same. There are many factors associated with burnout and depression as well as many causes. Certain individual factors include sex, amount of social support, and mental health history. Systems factors that play a role in burnout and depression include work compression, demands of electronic health records, production pressure, and lack of control over one’s professional life. Medical license applications include questions that reinforce the stigma of psychological stresses and discourage physicians from seeking appropriate care.ConclusionThe concept of physician well-being is multidimensional and includes factors related to each physician as an individual as well as to the working environment. Anesthesiologists must actively engage in self-care. Anesthesiology practices and healthcare organizations should evaluate the balance between demands they place on physicians and the resources provided to sustain an engaged, productive, and satisfied physician workforce. National efforts must be rallied to support physicians seeking help for physical and psychological health problems.RésuméObjectifOn a constaté un épuisement professionnel chez près de la moitié des médecins en pratique, anesthésiologistes y compris. Dans ce compte rendu narratif, la relation entre l’épuisement professionnel, la dépression et le suicide est explorée, en portant une attention particulière à l’anesthésiologiste. Ce faisant, notre impératif professionnel quant à cette épidémie est précisé.SourceLes auteurs ont effectué une recherche dans la littérature de langue anglaise existante dans la banque de données PubMed de 1986 à nos jours à l’aide des termes suivants: physician burnout, depression et suicide (soit épuisement professionnel, dépression et suicide), en attachant une attention particulière aux études s’intéressant aux anesthésiologistes et aux stratégies employées pour gérer ces problèmes.Constatations principalesL’épuisement professionnel et la dépression sont en hausse parmi les médecins, alors que le taux de suicide demeure relativement stable. Les associations avec et les causes d’épuisement professionnel et de dépression sont nombreuses et comprennent des facteurs individuels tels que le sexe, l’étendue du soutien social et les antécédents de santé mentale. Parmi les facteurs systémiques qui jouent un rôle dans l’épuisement professionnel et la dépression, citons les compressions professionnelles, les exigences des dossiers médicaux électroniques, la pression de production et le manque de contrôle sur la vie professionnelle. Les formulaires de postulation pour la licence médicale comportent des questions qui renforcent le stigmatisme rattaché aux stress psychologiques et découragent les médecins de chercher des soins adaptés.ConclusionLe concept de bien-être du médecin est multidimensionnel et comprend des facteurs liés à chaque médecin en tant qu’individu, mais également à l’environnement de travail. Les anesthésiologistes doivent faire un effort pour prendre soin d’eux-mêmes. Les pratiques d’anesthésiologie et les organismes de soins de santé devraient évaluer l’équilibre entre les exigences qu’ils fixent aux médecins et les ressources à disposition pour soutenir une population de médecins engagés, productifs et satisfaits. Les efforts nationaux doivent être rassemblés afin de soutenir au mieux les médecins demandant de l’aide pour des problèmes de santé physique ou psychologique.

The neurotoxin quinolinic acid is increased in spinal cords of mice with herpes simplex virus encephalitis.

Following retroperitoneal, intradermal inoculation of mice with HSV-1, signs of encephalomyelitis (hind-limb paralysis, flaccid tail and loss of bladder control) appeared 6-7 days later. Levels of quinolinic acid (QUIN; determined by gas chromatography with mass-spectrometry), rose approximately 40-fold in mice with encephalomyelitis, primarily in the spinal cord. Live virus could also be grown from homogenates of the affected spinal cords. Time-course studies, demonstrated that the increase in QUIN coincided with the appearance of encephalomyelitis. Large increases in indoleamine dioxygenase activity were observed in spinal cords from the affected mice, suggesting that the QUIN was synthesized within the spinal cord. It is, therefore, possible that QUIN may contribute to the pathology of HSV-1 encephalomyelitis.