A deprivation index for health planning in Canada.

Administrative databases in the Canadian health sector do not contain socio-economic information. To facilitate the monitoring of social inequalities for health planning, this study proposes a material and social deprivation index for Canada. After explaining the concept of deprivation, we describe the methodological aspects of the index and apply it to the example of premature mortality (i.e. death before the age of 75). We illustrate variations in deprivation and the links between deprivation and mortality nationwide and in different geographic areas including the census metropolitan areas (CMAs) of Toronto, Montréal and Vancouver; other CMAs; average-size cities, referred to as census agglomerations (CAs); small towns and rural communities; and five regions of Canada, namely Atlantic, Quebec, Ontario, the Prairies and British Columbia. Material and social deprivation and their links to mortality vary considerably by geographic area. We comment on the results as well as the limitations of the index and its advantages for health planning.

Serotoninergic system in dementia of the Alzheimer type. Abnormal forms of 5-hydroxytryptophan and serotonin in cerebrospinal fluid.

Serotonin (5-HT), its precursor 5-hydroxytryptophan (5-HTP), and its major metabolite 5-hydroxyindoleacetic acid (5-HIAA) were measured in the cerebrospinal fluid (CSF) of 14 patients with dementia of the Alzheimer type (DAT) and in nine controls by high-performance liquid chromatography with a novel multisensor coulometric detection system. Concentrations of both 5-HT and 5-HIAA detected by this system were lower than the concentrations obtained using conventional amperometric detection. This difference was caused by coelution of compounds that could be resolved from 5-HT and 5-HIAA by the multisensor coulometric system. One of the coelution compounds, observed in DAT but not in control CSF, behaved like a partially oxidized 5-HT. A compound behaving like partially oxidized 5-HTP was also observed in DAT CSF. Concentrations of 5-HTP, 5-HT, and 5-HIAA were lower in DAT CSF than in a corresponding fraction of control CSF. These results indicate involvement of the serotoninergic system in DAT and might lead to development of a diagnostic test for DAT.

Simultaneous measurements of tryptophan and its metabolites, kynurenine and serotonin, in the superficial layers of the spinal dorsal horn. A study in normal and arthritic rats.

It has been demonstrated that 5-hydroxytryptamine (5-HT) is not the only neuroactive metabolite of tryptophan (TRP) in the CNS. The presence of kynurenine (KYN) and its metabolites has been reported in the brain of several mammalian species and the neuroactive properties of these compounds are now well established. In the present study, we report the identification of KYN in the superficial layers of the rat spinal dorsal horn. KYN was measured simultaneously with TRP. 5-hydroxytryptophan, 5-HT, 5-hydroxyindoleacetic acid and 5-HT-O-sulfate by means of liquid chromatography with coulometric electrode array detection. The results observed in the normal rat and in an animal model of persistent pain, the arthritic rat, are discussed in view of the hypothesis relating to the involvement of the bulbospinal serotonergic system in pain mechanisms and of the possible participation of KYN and its metabolites in these mechanisms.

Cerebrospinal fluid constituents of cat vary with susceptibility to motion sickness.

Six female cats, varying in susceptibility to motion sickness, were implanted with chronic cannulae in the rostral portion of the fourth ventricle. The cats were then challenged with a motion sickness-inducing stimulus. Samples of cerebrospinal fluid were withdrawn before and after emesis or 30 min of motion if emesis did not occur and again on control (no motion) days. The samples were analyzed by HPLC with an array of 16 coulometric detectors. Thirty-six compounds were identified in the samples. Baseline levels of DOPAC, MHPGSO4, uric acid, DA, 5-HIAA and HVA were lower on motion and control days in cats which became motion sick when compared with cats which did not become motion sick. None of the identified compounds varied as a function of either exposure to motion or provocation of emesis. It is concluded that susceptibility to motion sickness is a manifestation of individual differences related to fundamental neurochemical composition.

EC array sensor concepts and data.

The use of multiple parameter assays of entire metabolic pathways is potentially a powerful tool for unraveling mechanisms of disorders or drug action and classification of neurological diseases. Coulometric electrode series array sensors, coupled with liquid chromatography (n-ELC), provide a route to multiplying the resolving power of conventional LC by factors of 10 to 50. Since the original description of the n-ELC concept by Matson et al. (1), fundamental issues of optimizing sensor design and integration with computer controlled LC systems have been addressed. Femtogram level potential time (ET) separations can now be performed for multiple components in both isocratic and gradient modes. A 56-component isocratic method for the study of the kynurenine system in Huntington's Disease (HD) is presented as an indication of the analytical definitions and nomenclature used to qualify an n-ELC procedure, and an indication of the implications of multiparameter data bases on data handling and experimental design.

A multidimensional approach to analysis of cerebrospinal fluid biogenic amines in schizophrenia: I. Comparisons with healthy control subjects and neuroleptic-treated/unmedicated pairs analyses.

Recent hypotheses and findings indicate that measurements of interactions between cerebrospinal fluid (CSF) biogenic amine systems, rather than measurement of CSF biogenic amine metabolites, better correlate with clinically important findings in schizophrenia. To test hypotheses, we used a recent technological advance in high performance liquid chromatography with electrochemical detection and combined it with multivariate statistical analyses to study biogenic amine concentrations in CSF in schizophrenia. This approach enabled the study of the interactions of several metabolites of each of the three major neurotransmitter pathways (dopaminergic, noradrenergic, and serotonergic) to test existing hypotheses regarding the neurobiochemical basis of schizophrenia. Twenty biogenic amines, their metabolites, and other compounds from 24 medication-free schizophrenic patients and 12 normal control subjects were simultaneously measured using a recently developed technique of gradient high performance liquid chromatography coupled with a 16-channel electrochemical array detector. After covariation for storage time, results of a stepwise discriminant function analysis comparing the control and patient groups identified tryptophan, tryptophol, and epinephrine as discriminating variables. Hotelling's paired T2 test from a subgroup of schizophrenic patients studied while they were and were not receiving neuroleptic treatment did not yield any significant differences between subgroups. A discussion of the findings and a comparison with previous studies of CSF biogenic amines in schizophrenia are presented.

Uric acid in the aqueous humor and tears of retinoblastoma patients.

PURPOSE: Malignancy can be associated with high levels of catabolic products. We performed a two-part study. Part 1 measured levels of uric acid and xanthine in the aqueous humor of eyes with malignant and nonmalignant diagnoses. Part 2 measured the levels of uric acid in tears of retinoblastoma patients. If compounds in high concentrations inside the eye could be detected outside the eye, via diffusion, in high concentrations in the tears, then a tear screening test for retinoblastoma could be developed. METHODS: High-performance liquid chromatography measured levels of uric acid and xanthine in aqueous humor samples of patients with retinoblastoma, melanoma, Coats' disease, adult cataract, and congenital cataract. Tear sampling was performed on patients with retinoblastoma and on normal eyes, and samples were assayed for uric acid. RESULTS: Part 1--Uric acid was elevated in the aqueous humor of eyes with retinoblastoma, melanoma, and Coats' disease compared with eyes with cataracts. Xanthine was elevated in retinoblastoma and Coats' disease and was lower in adult and congenital cataracts and melanoma. Part 2-No significant difference was found in the concentrations of uric acid in the tears of patients with retinoblastoma and those of normal patients. CONCLUSIONS: High levels of uric acid and xanthine present in the aqueous humor of patients with malignancy are consistent with the destructive nature of these conditions. Although uric acid was not elevated in the tears of retinoblastoma patients, continued investigation into substances that might be measurably different in the tears may yield a useful screening test in the future.

Monoamines in the brain cerebrospinal fluid of facial pain patients.

The purpose of the study was to assay monoamines in cerebrospinal fluid (CSF) obtained from the trigeminal cistern of 64 patients with intractable facial pain. The CSF was analyzed for homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and 3-methoxy-4-hydroxyphenylglycol (MHPG), end-product markers of activity for the dopamine, serotonin, and norepinephrine systems, respectively. HVA averaged 121 ng/mL in these facial pain patients, compared to 150 to 550 ng/mL in 10 studies of ventricular brain CSF in assorted psychiatric and pain patients. 5-HIAA averaged 29 to ng/mL in our facial pain patients compared to 60 to 120 ng/mL in nine studies of ventricular brain CSF in assorted psychiatric and neurological patients. Trigeminal cistern CSF MHPG averaged 9 ng/mL, similar to the range of 13 studies of lumbar CSF of assorted psychiatric and pain diagnoses. These results indicate that (1) the electrochemical detection method provides a unique way of accurately measuring nanogram concentrations of multiple monoamines in a little as 0.25 mL of CSF; (2) trigeminal cistern and posterior fossa brain CSF monoamine metabolites reflect a different profile of dopaminergic and serotonergic functioning in these facial pain patients from that previously reported with lumbar CSF measurements of other patients; and (3) trigeminal sensory ganglion or brain dopamine and serotonin systems may be concomitantly dysfunctional in intractable facial pain.

Validation of a deprivation index for public health: a complex exercise illustrated by the Quebec index.

INTRODUCTION: Despite the widespread use of deprivation indices in public health, they are rarely explicitly or extensively validated, owing to the complex nature of the exercise. METHODS: Based on the proposals of British researchers, we sought to validate Quebec's material and social deprivation index using criteria of validity (content, criterion and construct validity), reliability and responsiveness, as well as other properties relevant to public health (comprehensibility, objectivity and practicality). RESULTS: We reviewed the international literature on deprivation indices, as well as publications and uses of the Quebec index, to which we added factual data. CONCLUSION: Based on the review, it appears that the Quebec index responds favourably to the proposed validation criteria and properties. However, additional validations are required to better identify the contextual factors associated with the index.

TITRE: Valider un indice de défavorisation en santé publique : un exercice complexe, illustré par l'indice québécois. INTRODUCTION: Malgré l'usage répandu d'indices de défavorisation en santé publique, leur validation est rarement abordée de manière explicite ou élaborée, car il s'agit là d'un exercice complexe. MÉTHODOLOGIE: En nous fondant sur les propositions de chercheurs britanniques, nous avons cherché à valider l'indice québécois de défavorisation matérielle et sociale en utilisant des critères de validité (validité de contenu, validité sur critère et validité de construit), de fiabilité, de sensibilité et d'autres propriétés pertinentes en santé publique (intelligibilité, objectivité et praticabilité). RÉSULTATS: Nous avons passé en revue la littérature internationale sur les indices de défavorisation ainsi que les publications et les utilisations de l'indice québécois et nous avons ajouté des données factuelles. CONCLUSION: Après examen, il appert que l'indice québécois répond favorablement aux critères et propriétés de validation proposés. Des validations additionnelles s'imposent toutefois afin de mieux cerner les facteurs contextuels associés à cet indice.

Quebec Integrated Chronic Disease Surveillance System (QICDSS), an innovative approach.

INTRODUCTION: With the growing burden of chronic diseases, surveillance will play an essential role in improving their prevention and control. The Institut national de santé publique du Québec has developed an innovative chronic disease surveillance system, the Quebec Integrated Chronic Disease Surveillance System (QICDSS). We discuss the primary features, strengths and limitations of this system in this report. METHODS: The QICDSS was created by linking five health administrative databases. Updated annually, it currently covers the period from January 1, 1996, to March 31, 2012. The operational model comprises three steps: (1) extraction and linkage of health administrative data according to specific selection criteria; (2) analysis (validation of case definitions essentially) and production of surveillance measures; and (3) data interpretation, submission and dissemination of information. The QICDSS allows the surveillance of the following chronic diseases: diabetes, cardiovascular diseases, respiratory diseases, osteoporosis, osteoarticular diseases, mental disorders, Alzheimer's disease and related disorders. The system also lends itself to the analysis of multimorbidity and polypharmacy. RESULTS: For 2011-2012, the QICDSS contained information on 7 995 963 Quebecers with an average age of 40.8 years. Of these, 95.3% met at least one selection criterion allowing the application of case definitions for chronic disease surveillance. The actual proportion varied with age, from 90.1% for those aged 19 years or less to 99.3% for those aged 65 years or over. CONCLUSION: The QICDSS provides a way of producing population-based data on the chronic disease burden, health services and prescription drug uses. The system facilitates the integrated study of several diseases in combination, an approach rarely implemented until now in the context of population surveillance. The QICDSS possesses all the essential features of a surveillance system and supports the dissemination of information to public health decision-makers for future actions.

TITRE: Le Système intégré de surveillance des maladies chroniques du Québec (SISMACQ), une approche novatrice. INTRODUCTION: Avec l'accroissement du fardeau des maladies chroniques, la surveillance est fondamentale pour améliorer la prévention et la prise en charge de ces dernières. L'Institut national de santé publique du Québec a donc développé un système novateur de surveillance des maladies chroniques, le Système intégré de surveillance des maladies chroniques du Québec (SISMACQ), dont les principales caractéristiques, les forces et les limites sont présentées ici. MÉTHODOLOGIE: Le SISMACQ est le résultat du jumelage de cinq fichiers médicoadministratifs. Mises à jour annuellement, ses données couvrent actuellement la période du 1er janvier 1996 au 31 mars 2012. Trois étapes en caractérisent le modèle opérationnel : 1) l'extraction et le jumelage des données médico-administratives grâce à divers critères de sélection; 2) les analyses (principalement la validation des définitions) et la production des mesures de surveillance et 3) l'interprétation, le dépôt et la diffusion de l'information. Le SISMACQ permet actuellement l'étude des maladies chroniques suivantes : diabète, maladies cardiovasculaires, maladies respiratoires, ostéoporose, maladies ostéoarticulaires, troubles mentaux et Alzheimer et maladies apparentées. Il permet également l'analyse de la multimorbidité et de la polypharmacie. RÉSULTATS: Pour 2011-2012, le SISMACQ contenait des données sur 7 995 963 Québécois, et leur moyenne d'âge était de 40,8 ans. Parmi eux, 95,3 % répondaient à au moins un critère de sélection permettant l'application de définitions de cas pour la surveillance des maladies chroniques. Cette proportion variait avec l'âge : de 90,1 % chez les Québécois de 19 ans et moins à 99,3 % chez ceux de 65 ans et plus. CONCLUSION: Le SISMACQ permet la production de données, à l'échelle de la population, sur le fardeau de plusieurs maladies chroniques, sur l'utilisation des services de santé et sur la consommation de médicaments. Il rend possible l'étude intégrée de la combinaison de plusieurs maladies, une approche jusqu'à présent rarement mise en oeuvre dans un contexte de surveillance populationnelle. Le SISMACQ répond aux attributs essentiels d'un système de surveillance et aide à la diffusion de l'information auprès des décideurs en vue d'actions en santé publique.

Analysis of phytoestrogens and polyphenols in plasma, tissue, and urine using HPLC with coulometric array detection.

The study of phytoestrogens in food sources and their metabolism, effects, and mechanism of action in animals requires very selective and often sensitive analytical techniques. We have applied coulometric array detection, which uses a series of flow-through electrochemical sensors each providing 100% electrolytic efficiency, for measurement of a variety of phytochemicals in complex matrices. Recent work has involved the resolution of coumestrol (COM), daidzein (DE), daidzin (DI), diethylstilbestrol (DES), enterodiol (ED), enterolactone (EL), equol (EQ), estradiol (E2), estriol (E3), estrone (E), genistein (GE), and quercetin (QE). Binary gradient reversed-phase (C18) chromatography was used with a sodium acetate buffer (pH 4.8)-methanol-acetonitrile solvent system. Eight coulometric sensors were set at 260, 320, 380, 440, 500, 560, 620, and 680 mV (vs Pd reference). Compounds were resolved in 30 min via both their oxidation/reduction characteristics and chromatographic behavior. Respective maximal oxidation potentials (mV) were: COM = 380; DE = 500; DI = 620; DES = 440; ED = 620; EL = 620; EQ = 560; E2 = 560; E3 = 560; E1 = 560; GE = 500; and QE = 260 with limits of detection of 5-50 pg. Uterine tissue homogenates (30 mg/ml in Tris-EDTA) and plasma from Sprague-Dawley rats sacrificed 1 hr after sc injection with either vehicle, dimethylsulfoxide, 10 microg DES, or 1.0 mg EQ were analyzed before and after enzymatic hydrolysis with beta-glucuronidase/sulfatase. Urine samples from humans receiving a Boston-area diet with or without soy protein isolate supplements were also analyzed. Ethanol extracts were evaporated and reconstituted in 20% methanol before HPLC analysis. DE, ED, EL, EQ, and GE were determined in urine with less than 5% (R.S.D.) intraassay imprecision and 85%-102% recovery. Levels (ng/ml) of GE (1.8), QE (11.2), and EQ (1.7) were found in control plasma before hydrolysis and GE (293), QE (183), and EQ (22) after hydrolysis. Higher concentrations, corresponding to sc injection, in free and total EQ were found in both tissue and plasma.

Monoamines and their precursors and metabolites in the chicken brain, pineal, and retina: regional distribution and day/night variations.

Levels of norepinephrine, epinephrine, dopamine, and serotonin (5-HT) and their precursors [tyrosine, L-3,4-dihydroxyphenylalanine, tryptophan, and 5-hydroxytryptophan (5-HTP)] and metabolites [3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), homovanillic acid, 3-methoxy-4-hydroxyphenylglycol, and 5-hydroxyindoleacetic acid (5-HIAA)] were determined concurrently in samples of chick retina, pineal gland, and nine selected areas of the brain (optic lobes, thalamus, hypothalamus, optic chiasm, pons/medulla, cerebellum, neostriatum/ectostriatum, hyperstriatum, and basal forebrain) using HPLC coupled with a coulometric electrode array detection system. The norepinephrine level was highest in the pineal gland, but it was also widely distributed throughout the chick brain, with the thalamus and hypothalamus showing substantial levels. The dopamine level was highest in the basal forebrain. The epinephrine level was highest in the hypothalamus. The thalamus and hypothalamus showed the highest levels of 5-HT. Daytime levels (1100 h) of these compounds were compared with levels in chicks killed in the middle of the dark phase (2300 h). In the brain areas examined, no day/night variations in levels of norepinephrine, epinephrine, dopamine, or 5-HT were seen, although significant nocturnal changes in levels of their metabolites were observed in some areas. Pineal levels of 5-HIAA decreased significantly at night. The retina showed significant nocturnal increases in 5-HTP, 5-HT, and 5-HIAA levels. Retinal levels of 3-MT and DOPAC were significantly decreased at night.

Urinary metanephrine and normetanephrine determined without extraction by using liquid chromatography and coulometric array detection.

We describe a procedure for the direct measurement of metanephrine (MN) and normetanephrine (NMN) in hydrolyzed urine, using HPLC with coulometric array detection. Acid-hydrolyzed samples were diluted and filtered before separation by isocratic reversed-phase ion-pair chromatography. Eight serial coulometric sensors, set at incrementally increasing anodic potentials, were used to screen lower-oxidizing interferences and provide stepwise oxidation of the metanephrines. Voltammetric behavior across three adjacent sensors was used to assess resolution and aid in peak identification. Values obtained in commercial controls were consistently within the specified target range. Variability, expressed as CV, was 5.45-9.22% between runs and 1.60-4.52% within-run for both compounds. The limit of detection was 2.6 micrograms/L for MN and 2.8 micrograms/L for NMN, with a linear response to 15.0 mg/L for both analytes. Results from patients' samples correlated well with those by a method involving dual ion-exchange extraction (r = 0.963, n = 82 for MN; r = 0.9768, n = 83 for NMN). This procedure provided high selectivity and objective peak purity information while greatly simplifying sample preparation.

Analysis of phenolic and flavonoid compounds in juice beverages using high-performance liquid chromatography with coulometric array detection.

Analysis of phenolics and flavonoids in juice beverages using reversed-phase HPLC with coulometric array detection is described. Sixteen serial coulometric detectors were used for on-line resolution of co-eluting compounds and generation of voltammetric data. Within each class of compounds, oxidation potential corresponded to specific substitution patterns where: catechol < methoxycatechol < monohydroxyl < methoxyl. Twenty-seven standard compounds were resolved in a 45-min run. The limits of detection were in the low ng/ml range with a linear response range of at least three orders of magnitude. Intra-run retention time variation was < 1% (R.S.D.) and adjacent sensor response ratios varied by < 5% (R.S.D.). The utility of this technique in generating multivariate data for differentiation of juices and juice mixtures is shown.

Simultaneous measurement of monoamines, metabolites and amino acids in brain tissue and microdialysis perfusates.

A high-performance liquid chromatographic method with coulometric array electrochemical detection is described for the simultaneous analysis of monoamines, their metabolites and o-phthalaldehyde (OPA)-derivatized amino acids. This method has been used to examine metabolite levels in both striatal tissue homogenates and striatal microdialysis perfusates. An aliquot of sample was initially analyzed for monoamines and metabolites by isocratic elution and electrochemical detection on a serial electrode array of eight coulometric flow-through graphite electrodes (0 to 490 mV; 70-mV increment). The remaining sample was derivatized pre-column with OPA-beta-mercaptoethanol and after column switching was analyzed for amino acids on a second isocratic system with electrochemical detection on four electrodes. Metabolites were then identified based on their retention time as well as electrochemical behavior across the arrays. The analysis, derivatization procedure, column switching, data reduction and peak identification were fully automated. The limit of detection for striatal tissue homogenates was approximately 1.38 ng/g wet weight for the monoamines and 8.25 ng/g wet weight for amino acids. The limit of detection for striatal perfusates was approximately 2.5 pg per 20-microliters sample for the monoamines and 15 pg per 20-microliters sample for the amino acids with analysis completed within 25 min making it ideal for microdialysis samples.

Kynurenine pathway measurements in Huntington's disease striatum: evidence for reduced formation of kynurenic acid.

Recent evidence suggests that there may be overactivation of the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptors in Huntington's disease (HD). Tryptophan metabolism by the kynurenine pathway produces both quinolinic acid, an NMDA receptor agonist, and kynurenic acid, an NMDA receptor antagonist. In the present study, multiple components of the tyrosine and tryptophan metabolic pathways were quantified in postmortem putamen of 35 control and 30 HD patients, using HPLC with 16-sensor electrochemical detection. Consistent with previous reports in HD putamen, there were significant increases in 5-hydroxyindoleacetic acid, 5-hydroxytryptophan, and serotonin concentrations. Within the kynurenine pathway, the ratio of kynurenine to kynurenic acid was significantly (p less than 0.01) increased twofold in HD patients as compared with controls, consistent with reduced formation of kynurenic acid in HD. CSF concentrations of kynurenic acid were significantly reduced in HD patients as compared with controls and patients with other neurologic diseases. Because kynurenic acid is an endogenous inhibitor of excitatory neurotransmission and can block excitotoxic degeneration in vivo, a relative deficiency of this compound could directly contribute to neuronal degeneration in HD.

n-Electrode three-dimensional liquid chromatography with electrochemical detection for determination of neurotransmitters.

Coulometric electrodes in series have been used with liquid chromatography with electrochemical detection to increase selectivity and resolution for the direct analysis of tissue neurotransmitters. Use of three coulometric sensors for electrochemical modification, selectivity, and peak identification has been expanded into "gate" cells of three or four coulometric electrodes that allow elimination of all electrochemically irreversible substances, and "array" cells of up to 15 coulometric electrodes for separation of co-eluting compounds by their current/voltage characteristics. On-column sensitivity of the sensor arrays is 0.4 to 4 pg. Gate cell selectivity favors electrochemically reversible compounds over irreversible ones, e.g., 3-methoxy-4-hydroxyphenylglycol vs ascorbate, by a factor of up to 10(4). Resolution across the multi-electrode array cells allows separation of co-eluting compounds with half-wave potentials differing by as little as 30 to 40 mV. Cells with three to 15 electrodes have been used to measure monoamines and metabolites in brain; monoamines directly in serum filtrate; and the state of oxidation of 5-hydroxytryptamine and 5-hydroxytryptophan in cerebrospinal fluid of patients with Alzheimer's disease.

Retinoblastoma aqueous humor: aromatic amino acids.

Aqueous humor from children with retinoblastoma obtained at enucleation and from eyes with adult cataracts were assayed with electrochemical liquid chromatography (Model 5500 Coulochem electrode array system) for metabolites of tyrosine, tryptophan metabolic pathways, catecholamine degradation pathways and ascorbate. More than 20 metabolites were identified in human aqueous for the first time. High levels of ascorbate were found in aqueous of eyes with adult cataracts (254, 336 ng/ml). Tyrosine metabolism in both sets of eyes was through dopamine. Vandylmandelic acid (VMA), homovanillic acid (HVA), and 3-methoxy, 4-hydroxyphenylglycol (MHPG) were all detected in retinoblastoma eyes. Although eyes with either adult cataracts or childhood retinoblastoma convert tryptophan through the serotonin pathway, retinoblastoma eyes metabolize tryptophan through the kynurenine pathway to a greater degree than adult cataract eyes.

Acetaminophen toxicity to cultured rat embryos.

We tested the effects of acetaminophen on cultured rat embryo development. When added directly to culture media at 300 microM, a concentration approximately twice the human therapeutic blood level, acetaminophen caused abnormalities in the cultured embryos. Sera from both rats and monkeys following gavage with acetaminophen were also toxic to cultured embryos. The sera toxicities were related to acetaminophen concentrations, and the toxicity could be removed by serum dialysis. With regard to the metabolism of acetaminophen, glutathione levels in the yolk sac decreased in a concentration related fashion with addition of the drug. Also, buthionine sulfoximine, an inhibitor of glutathione synthesis, appeared to enhance acetaminophen embryo toxicity, and N-acetylcysteine, a glutathione precursor, appeared to protect embryos from acetaminophen toxicity. These results suggested that acetaminophen embryo toxicity resulted from direct exposure of embryos to acetaminophen and not a maternal metabolite.