Cholesterol 25-hydroxylase is a metabolic switch to constrain T cell-mediated inflammation in the skin.

Interleukin-27 (IL-27) is an immunoregulatory cytokine whose essential function is to limit immune responses. We found that the gene encoding cholesterol 25-hydroxylase (Ch25h) was induced in CD4+ T cells by IL-27, enhanced by transforming growth factor­ß (TGF-ß), and antagonized by T-bet. Ch25h catalyzes cholesterol to generate 25-hydroxycholesterol (25OHC), which was subsequently released to the cellular milieu, functioning as a modulator of T cell response. Extracellular 25OHC suppressed cholesterol biosynthesis in T cells, inhibited cell growth, and induced nutrient deprivation cell death without releasing high-mobility group box 1 (HMGB1). This growth inhibitory effect was specific to actively proliferating cells with high cholesterol demand and was reversed when extracellular cholesterol was replenished. Ch25h-expressing CD4+ T cells that received IL-27 and TGF-ß signals became refractory to 25OHC-mediated growth inhibition in vitro. Nonetheless, IL-27­treated T cells negatively affected viability of bystander cells in a paracrine manner, but only if the bystander cells were in the early phases of activation. In mouse models of skin inflammation due to autoreactive T cells or chemically induced hypersensitivity, genetic deletion of Ch25h or Il27ra led to worse outcomes. Thus, Ch25h is an immunoregulatory metabolic switch induced by IL-27 and dampens excess bystander T effector expansion in tissues through its metabolite derivative, 25OHC. This study reveals regulation of cholesterol metabolism as a modality for controlling tissue inflammation and thus represents a mechanism underlying T cell immunoregulatory functions.

African swine fever: a global factor affecting agricultural markets over the medium term.

The African swine fever (ASF) outbreak in the People's Republic of China (China) is affecting regional and global meat and feed markets with potential impacts on vegetable oils, biofuels and even pharmaceuticals. Using the Aglink-Cosimo modelling system, the authors adopt three different scenarios to assess the impacts of ASF in China, South-East Asia and the world. The simulation results show a range of possible effects for agricultural commodity markets, notably a large initial protein gap that will be filled by higher production of both eggs and non-pork meats (poultry, beef and sheep/goat) in China and by pork imports from international markets. The results suggest a fast and near complete closure of the protein gap, reflecting China's low responsiveness of meat demand to prices. A sizeable share of the protein gap could remain unfilled if the necessary import infrastructure for meat, with gapless cold chains and efficient and comprehensive sanitary controls, is not set up as assumed in the scenarios. Not filling the protein gap would also leave domestic meat prices at permanently high levels, which could even translate into higher overall inflation rates. The simulations further suggest that an ASF pandemic would drive a lasting wedge between plant protein and animal protein prices, both locally and internationally. Oil meal prices will be particularly adversely affected, whereas pork and poultry will see a significant price rise. Countries that import the former and export the latter are likely to become the main beneficiaries of an ASF pandemic, benefiting from lower input prices and higher output prices for potentially large volumes of exports.

Le foyer de peste porcine africaine (PPA) survenu en République populaire de Chine (Chine) affecte les marchés régionaux et mondiaux de viande et d'aliments fourragers et a également un impact potentiel sur les huiles végétales, les bio-carburants voire les produits pharmaceutiques. En s'appuyant sur le système de modélisation Aglink-Cosimo, les auteurs ont élaboré trois scénarios différents pour évaluer les impacts de la PPA en Chine, en Asie du Sud-Est et dans le monde entier. Les résultats de la simulation font apparaître un large éventail d'effets sur les marchés de produits agricoles, en particulier un déficit protéique initial majeur qui sera compensé par une augmentation de la production d'oeufs et de viande issue d'autres animaux que le porc (volaille, boeuf, mouton et chèvre) en Chine, et par des importations de viande de porc à partir des marchés internationaux. Ces résultats semblent indiquer une élimination rapide et quasiment complète du déficit protéique, traduisant une faible réactivité aux prix de la demande chinoise en viande. Une part non négligeable du déficit protéique pourrait ne pas être comblée si les infrastructures nécessaires pour les importations de viande, avec des chaînes du froid ininterrompues et des inspections sanitaires complètes ne sont pas en place comme le prévoient les scénarios. Le maintien d'un déficit protéique aurait également pour effet de pousser les prix de la viande locale à des niveaux durablement élevés, ce qui pourrait se traduire par une hausse générale de l'inflation. Les simulations indiquent par ailleurs qu'une pandémie de PPA pourrait induire un écart de prix durable entre les protéines végétales et animales, aussi bien localement qu'au niveau international. Les prix des farines de tourteaux seraient particulièrement affectés tandis que les prix de la viande de porc et de volaille connaîtraient une hausse significative. Les pays importateurs de farines de tourteaux et exportateurs de viande de porc et de volaille seront probablement les principaux gagnants en cas de pandémie de PPA, bénéficiant de prix d'intrants bas et de prix d'extrants élevés sur des volumes potentiellement importants d'exportations.

El brote de peste porcina africana en la República Popular de China (China) está afectando a los mercados regionales y mundiales de carne y piensos y puede tener repercusión en los de aceites vegetales, biocombustibles e incluso productos farmacéuticos. Los autores aplican el sistema de modelización Aglink-Cosimo a tres hipótesis distintas para estudiar los efectos de la peste porcina africana a la escala de China, el Sudeste asiático y el mundo entero. Los resultados de la simulación revelan todo un conjunto de posibles efectos sobre los mercados de productos agrícolas, empezando por un gran déficit de proteínas que se cubrirá con una mayor producción tanto de huevos como de carnes no porcinas (avícola, vacuna y ovina/caprina) en China y con la importación de carne porcina a través de los mercados internacionales. Los resultados parecen indicar asimismo una rápida y cuasi completa corrección del déficit de proteínas, lo que pone de relieve que en China la demanda de carne es poco reactiva a los precios. Es posible que una parte considerable del déficit de proteínas quedara por cubrir en caso de que la infraestructura necesaria para las importaciones de carne, con cadenas de frío ininterrumpidas y controles sanitarios eficientes y exhaustivos, no correspondiera a los supuestos contemplados en las hipótesis. El hecho de no cubrir el déficit de proteínas también mantendría en niveles continuamente elevados los precios de la carne en el país, lo que podría incluso hacer subir las tasas de inflación generales. Las simulaciones llevan a pensar además que una pandemia de peste porcina africana induciría un desfase duradero entre los precios de las proteínas vegetales y los de las proteínas animales, tanto en el país como a nivel internacional. El precio de los piensos de aceite, en particular, se vería afectado negativamente, mientras que el de la carne porcina y la avícola sufrirían un sustancial aumento. Los países que importan los primeros y exportan las segundas serían presumiblemente los principales beneficiarios de una pandemia de peste porcina africana, pues saldrían ganando con el menor precio de los insumos y el mayor precio de los productos finales, que podrían exportar en grandes cantidades.

Basement membrane zone IgE deposition is associated with bullous pemphigoid disease severity and treatment results.

BACKGROUND: A subset of patients with bullous pemphigoid (BP) show deposition of IgE in the basement membrane zone (BMZ), yet the relationship between BMZ IgE and the clinical presentation of BP remains unclear. OBJECTIVES: To investigate the relationship between IgE deposition, IgE levels in serum, and disease severity in patients with BP. METHODS: We investigated IgE autoantibodies in 53 patients with BP by direct immunofluorescence (DIF), indirect immunofluorescence and enzyme-linked immunosorbent assay. RESULTS: Of 53 patients with BP, 23 (43%) had IgE deposition, 10 (19%) of whom were IgE+ and 13 (25%) IgE± according to DIF analyses. Erosion/blister (E/B) Bullous Pemphigoid Disease Area Index (BPDAI) scores were significantly higher in IgE+ patients than in IgE- patients (n = 15), while no significant differences were found for urticaria/erythema BPDAI scores. IgE+ and IgE± patients took longer to reduce their E/B BPDAI score by 75% after systemic corticosteroid treatment. BP180-IgE levels were significantly higher among IgE+ patients than IgE± or IgE- patients (n = 10). Total IgE levels in the serum and blood eosinophil counts did not differ between IgE+, IgE± and IgE- patients. A significant correlation was detected between BP180-IgG and BP180-IgE, but not between BPDAI scores and any of BP180-IgG, BP180-IgE or blood eosinophil count. CONCLUSIONS: IgE deposition in the BMZ is associated with higher E/B BPDAI scores and longer treatment periods. We conclude that IgE binding in the BMZ may contribute to BP pathogenesis by promoting blister formation. What's already known about this topic? BP180-IgE autoantibodies have an important role in the pathogenesis of bullous pemphigoid (BP). A subset of patients with BP display deposition of IgE within the basement membrane zone (BMZ) of skin tissue. What does this study add? Patients with in vivo IgE deposition in the BMZ displayed higher erosion/blister Bullous Pemphigoid Disease Area Index (BPDAI) scores, while urticaria/erythema BPDAI scores were not significantly different. Patients with in vivo IgE deposition in the BMZ took longer to reduce their erosion/blister BPDAI score by 75% after systemic corticosteroid treatment. BP180-specific IgE levels in serum were higher among patients with linear IgE deposition in the BMZ than in those with granular or no IgE deposition.

Managing the challenges of a highly pathogenic avian influenza H5N8 outbreak in Uganda: a case study.

In 2016-2017, the H5N8 strain of highly pathogenic avian influenza (HPAI) spread worldwide and Uganda reported the first occurrence of the disease in its poultry and wild birds. Genetic analysis revealed that the virus clusters with 2.3.4.4 group B strains from birds in central and southern Asia, and thus forms part of the 2.3.4.4 group B clade. Since Uganda is in the path of two major migratory bird flyways, it is likely that infected migratory wild birds played a crucial role in the introduction of H5N8 HPAI viruses into Uganda. The outbreaks happened in the districts of Wakiso, Masaka and Kalangala and affected domestic and wild birds. A One Health Multisectoral Coordination Committee, consisting of a National Task Force, Technical Working Groups and District Disaster Management Committees, was immediately activated to coordinate the preparedness and response efforts to control the disease. In all the affected districts, surveillance was intensified on both domestic and wild birds; biosecurity measures were increased; and movement controls, culling, cleaning, disinfection and safe disposal of carcasses were implemented. Awareness of the disease was raised through education materials, leaflets and brochures distributed to farmers. Finally, Uganda successfully controlled the H5N8 outbreak, using its national preparedness and response mechanisms and through collaboration with international partners. The emergence and spread of this virus strain in Uganda and other parts of Africa poses a significant threat to the poultry industry and food security.

En 2016­2017, le sous-type H5N8 du virus de l'influenza aviaire hautement pathogène (IAHP) s'est propagé dans le monde entier. En Ouganda, les premiers cas ont été notifiés chez les volailles et dans l'avifaune. Une analyse génétique a montré que le virus causal était relié aux souches 2.3.4.4 de groupe B trouvées chez des oiseaux d'Asie centrale et du Sud et qu'il appartenait donc au clade 2.3.4.4 des virus du groupe B. L'Ouganda se trouvant sur le tracé de deux voies majeures de migration d'oiseaux, les espèces sauvages d'oiseaux migrateurs ont probablement joué un rôle déterminant dans l'introduction des virus H5N8 de l'IAHP en Ouganda. Les foyers se sont déclarés dans les districts de Wakiso, Masaka et Kalangala, affectant des espèces aviaires domestiques et sauvages. Un Comité de coordination multisectoriel Une seule santé a aussitôt été créé, composé d'un groupe de travail national, de plusieurs groupes techniques d'experts et de comités locaux de gestion des urgences, afin d'assurer la coordination des activités de préparation et de réponse pour lutter contre la maladie. La surveillance des oiseaux domestiques et de l'avifaune a été intensifiée dans tous les districts affectés ; les mesures de biosécurité ont été renforcées ; les mouvements d'animaux ont été soumis à un contrôle ; enfin, des mesures d'abattage, de nettoyage/désinfection et d'élimination sécurisée des cadavres ont été introduites. Une campagne de sensibilisation à la maladie a été organisée avec la distribution aux éleveurs de matériels pédagogiques, dépliants et brochures d'information. L'Ouganda a finalement réussi à contrôler ce foyer dû au virus H5N8 en appliquant les mécanismes nationaux de préparation et de réponse, avec la collaboration de ses partenaires internationaux. L'émergence et la propagation de cette souche virale en Ouganda et dans d'autres régions d'Afrique font peser une lourde menace sur le secteur des productions avicoles ainsi que sur la sécurité alimentaire.

En los años 2016 y 2017 la cepa H5N8 del virus de la influenza aviar altamente patógena (IAAP) se diseminó por el mundo entero y Uganda notificó su primera aparición en las poblaciones de aves salvajes y de corral del país. El análisis genético reveló que el virus se agrupa con cepas 2.3.4.4 del grupo B que se encuentran en aves de Asia central y meridional, de donde se sigue que forma parte del clado 2.3.4.4 del grupo B. Toda vez que por el territorio ugandés pasan dos grandes rutas migratorias, es probable que, en el curso de sus migraciones, ciertas aves salvajes infectadas hayan tenido un papel decisivo en la introducción en el país del virus H5N8 de la IAAP. Los brotes tuvieron lugar en los distritos de Wakiso, Masaka y Kalangala y afectaron a aves tanto domésticas como salvajes. Inmediatamente se activó un comité de coordinación multisectorial de Una sola salud, formado por un grupo de trabajo nacional más una serie de grupos de trabajos técnicos y de comités de distrito de «gestión de catástrofes¼, que tenía por cometido coordinar las actividades de preparación y respuesta para combatir la enfermedad. En todos los distritos afectados se intensificó la vigilancia de las aves domésticas y salvajes, se reforzaron las medidas de seguridad biológica y se instituyeron medidas de control de los movimientos, sacrificio sanitario, limpieza, desinfección y eliminación segura de los animales muertos. También se repartieron entre los productores material pedagógico, prospectos y folletos con el objetivo de dar mejor a conocer la enfermedad. A la postre Uganda, gracias a sus mecanismos nacionales de preparación y respuesta, aunados a la colaboración con contrapartes internacionales, logró controlar el brote causado por el virus H5N8. La aparición y propagación de esta cepa vírica en Uganda y otras partes de África supone una importante amenaza para el sector avícola y la seguridad alimentaria.

Assessment of biological, psychological and adherence factors in the prediction of step-down treatment for patients with well-controlled asthma.

BACKGROUND AND OBJECTIVE: Inhaled corticosteroids (ICS) and inhaled corticosteroids combined with long-acting beta2-agonist (ICS/LABA) are standard treatments for asthma. However, factors that might help reduce medication in well-controlled asthma are unknown. We classified problems of asthma patients into biological, psychological and adherence factors, and investigated factors associated with the indication and failure of a medication step-down treatment. METHODS: Two hundred twenty two well-controlled asthma patients receiving ICS or ICS/LABA were assessed for physical and psychiatric problems and followed up for one year from adjustment of their treatment step. Factor B was defined as a presence of chronic upper airway complications. Factor P was defined as presence of psychiatric complications such as sleep disorder, depression, anxiety and somatoform disorders. Factor A was defined as poor adherence to ICS or ICS/LABA inhaler of 75% or less. Success in step-down treatment was defined as maintenance of well-controlled status for over one year after step-down. RESULTS: Factor B was the most important single negative predictive factor for indication for step-down treatment (Odds ratio; 0.19). Factor A increased the risk of failure to maintain step-down treatment most significantly by 23-fold, and factor B increased it by 11-fold. The combination of factors B and A increased failure by 24-fold, factors P and A by 21-fold, all three factors by 36-fold. Factor P only interacted with the other factors to reduce chances of stepping down, but did not constitute a problem factor when present alone. CONCLUSION AND CLINICAL RELEVANCE: The evaluation of biological, psychological and adherence problems may lead to a more proactive and targeted approach to step-down treatment for patients with well-controlled asthma.

Epitope analysis of antidesmoglein 1 autoantibodies from patients with pemphigus foliaceus across different activity stages.

BACKGROUND: Pemphigus foliaceus (PF) and pemphigus vulgaris (PV) are closely related, but clinically distinct, autoimmune blistering diseases caused by autoantibodies against desmoglein (Dsg)1 and Dsg3, respectively. Using ethylenediaminetetraacetic acid (EDTA)-treated Dsg3 enzyme-linked immunosorbent assay (ELISA) we have shown that the proportion of anti-Dsg3 antibodies against calcium-dependent epitopes decreased upon shifting to the inactive phase in patients with PV. OBJECTIVES: To analyse the epitope profiles of anti-Dsg1 antibodies across the different activity stages of PF. METHODS: We evaluated five patients with PF who retained high serum levels of anti-Dsg1 antibodies in the inactive phase. Sera were obtained in both the active and inactive phases, and were analysed by EDTA-treated and exfoliative toxin-treated ELISAs. To map the epitopes of anti-Dsg1 antibodies, immunoprecipitation-immunoblotting was performed using a set of Dsg1/Dsg2 domain-swapped molecules. RESULTS: Anti-Dsg1 antibodies against the calcium-dependent epitopes of Dsg1 were the predominant antibodies in both the active and inactive phases. The proportion of anti-Dsg1 antibodies against the calcium-dependent epitopes did not change upon shifting to the inactive phase. The results of immunoprecipitation-immunoblotting showed that most of the anti-Dsg1 antibodies bound to the extracellular domains (EC)1-2 of Dsg1. CONCLUSIONS: In patients with PF, the calcium-dependent epitopes on EC1 and EC2 of Dsg1 contained definitively pathogenic and nonpathogenic epitopes. The disease activity might be differentially controlled by the antibodies between PF and PV depending on the presence or absence of the nonpathogenic epitope.

Origin and evolution of highly pathogenic H5N1 avian influenza in Asia.

Outbreaks of highly pathogenic avian influenza caused by H5N1 viruses were reported almost simultaneously in eight neighbouring Asian countries between December 2003 and January 2004, with a ninth reporting in August 2004, suggesting that the viruses had spread recently and rapidly. However, they had been detected widely in the region in domestic waterfowl and terrestrial poultry for several years before this, and the absence of widespread disease in the region before 2003, apart from localised outbreaks in the Hong Kong Special Autonomous Region (SAR), is perplexing. Possible explanations include limited virus excretion by domestic waterfowl infected with H5N1, the confusion of avian influenza with other serious endemic diseases, the unsanctioned use of vaccines, and the under-reporting of disease as a result of limited surveillance. There is some evidence that the excretion of the viruses by domestic ducks had increased by early 2004, and there is circumstantial evidence that they can be transmitted by wild birds. The migratory birds from which viruses have been isolated were usually sick or dead, suggesting that they would have had limited potential for carrying the viruses over long distances unless subclinical infections were prevalent. However, there is strong circumstantial evidence that wild birds can become infected from domestic poultry and potentially can exchange viruses when they share the same environment. Nevertheless, there is little reason to believe that wild birds have played a more significant role in spreading disease than trade through live bird markets and movement of domestic waterfowl. Asian H5N1 viruses were first detected in domestic geese in southern China in 1996. By 2000, their host range had extended to domestic ducks, which played a key role in the genesis of the 2003/04 outbreaks. The epidemic was not due to the introduction and spread of a single virus but was caused by multiple viruses which were genotypically linked to the Goose/GD/96 lineage via the haemagglutinin gene. The H5N1 viruses isolated from China, including the Hong Kong SAR, between 1999 and 2004 had a range of genotypes and considerable variability within genotypes. The rising incidence and widespread reporting of disease in 2003/04 can probably be attributed to the increasing spread of the viruses from existing reservoirs of infection in domestic waterfowl and live bird markets leading to greater environmental contamination. When countries in the region started to report disease in December 2003, others were alerted to the risk and disease surveillance and reporting improved. The H5N1 viruses have reportedly been eliminated from three of the nine countries that reported disease in 2003/04, but they could be extremely difficult to eradicate from the remaining countries, owing to the existence of populations and, possibly, production and marketing sectors, in which apparently normal birds harbour the viruses.

Determination of effects of antiepileptic drugs on SNAREs-mediated hippocampal monoamine release using in vivo microdialysis.

1. To elucidate possible mechanisms underlying the effects of carbamazepine (CBZ), valproate (VPA) and zonisamide (ZNS) on neurotransmitter exocytosis, the interaction between these three antiepileptic drugs (AEDs) and botulinum toxins (BoNTs) on basal, Ca(2+)- and K(+)-evoked release of dopamine (DA) and serotonin (5-HT) were determined by microdialysis in the hippocampus of freely moving rats. 2. Basal release of monoamine was decreased by pre-microinjection of the syntaxin inhibitor, BoNT/C, but only weakly affected by the synaptobrevin inhibitor, BoNT/B. Ca(2+)-evoked release was inhibited by BoNT/C selectively. K(+)-evoked release was reduced by BoNT/B predominantly and BoNT/C weakly. 3. Perfusion with low and high concentrations of CBZ and ZNS increased and decreased basal monoamine release, respectively. Perfusion with VPA increased basal 5-HT release concentration-dependently, whereas basal DA release was affected by VPA biphasic concentration-dependently, similar to CBZ and ZNS. This stimulatory action of AEDs on basal release was inhibited by BoNT/C predominantly. 4. Ca(2+)-evoked monoamine release was increased by low concentrations of CBZ, ZNS and VPA, but decreased by high concentrations. These effects of the AEDs on Ca(2+)-evoked release were inhibited by BoNT/C, but not by BoNT/B. 5. K(+)-evoked monoamine release was reduced by AEDs concentration-dependently. The inhibitory effect of these three AEDs on K(+)-evoked release was inhibited by BoNT/B, but not by BoNT/C. 6. These findings suggest that the therapeutic-relevant concentration of CBZ, VPA and ZNS affects exocytosis of DA and 5-HT, the enhancement of syntaxin-mediated monoamine release during resting stage, and the inhibition of synaptobrevin-mediated release during depolarizing stage.

Increased constriction of the ductus arteriosus with combined administration of indomethacin and L-NAME in fetal rats.

We studied age-related changes and the caliber of the ductus arteriosus (DA) after two-pathway inhibition of prostaglandin E(2) and nitric oxide (NO) by the combined administration of indomethacin, a cyclooxygenase inhibitor, and N(G)-nitro-L-arginine methyl ester (L-NAME), an NO synthase inhibitor, in fetal rats. Pregnant rats from day 18 to 21 of gestation were used. They were administered indomethacin orally (3 mg/kg) 3 h before cesarean section, and then L-NAME (50 mg/kg) was injected intraperitoneally 3 h before the rats were killed. Using rapid-freezing and shaving methods, the caliber of the DA in fetal rats was measured. Compared with the indomethacin alone group, indomethacin plus L-NAME further constricted the DA after indomethacin and L-NAME were simultaneously administered 3 h before the rats were sacrificed. The extent of the final DA constriction was almost equal to the addition of each effect of indomethacin and L-NAME. We concluded that the magnitude of DA constriction following indomethacin plus L-NAME was due to the additive effects of these agents, suggesting a possible method to treat patent DA in premature infants.

Pharmacological discrimination between effects of carbamazepine on hippocampal basal, Ca(2+)- and K(+)-evoked serotonin release.

To elucidate mechanisms of hippocampal serotonin release and possible mechanisms of clinical action of carbamazepine (CBZ), we determined interaction between antagonists of N-type (omega-conotoxin GVIA:GVIA), P-type (omega-agatoxin IVA:IVA) Ca(2+) channels, Na(+) channel (tetrodotoxin: TTX) and CBZ on hippocampal basal, Ca(2+)- and K(+)-evoked serotonin releases, using microdialysis in freely moving rats. Basal release was reduced by TTX, GVIA and IVA (GVIA>IVA). Ca(2+)-evoked release was reduced by GVIA but unaffected by TTX and IVA. K(+)-evoked release was reduced by TTX, GVIA and IVA (GVIA

Sociomedical aspects of epileptic patients: their employment and marital status.

We examined the employment and marital status of adult patients with epilepsy who did not have mental retardation and who had been treated at Hirosaki University Hospital, Hirosaki, Japan, for more than 5 years. The present study included 278 patients (142 males and 136 females) ranging from 20 to 60 years of age. We investigated the occupational status of the subjects and found that 168 had permanent jobs, but 41 patients were unemployed at the time of this survey. The proportion of the patients whose seizures were controlled at the time of this survey was 68% (114/168) in the group having permanent jobs, and 22% (9/41) in the unemployed group. Forty cases answered that they had resigned from their jobs due to occurrence of epileptic seizures. Of these patients, 13 were dismissed and 27 resigned voluntarily due to the potential for seizures. As to relationship between jobs and neuropsychiatric complications, the incidence of a past history of psychotic states in the unemployed group was significantly higher than that in the employed group. As to marital status, 13 males and 16 females (n = 29) had experienced divorce. Seven cases (two males and five females) had answered that epilepsy had been the reason for their divorce. We conclude that epilepsy or epileptic seizures have various negative effects on the patient's social life.

Adenosine receptor subtypes modulate two major functional pathways for hippocampal serotonin release.

To clarify the mechanisms of interaction between adenosine A(1) receptor (A1-R) and adenosine A(2) receptor (A2-R) on neurotransmitter release, this study determined the functional interactions among adenosine receptors (AD-Rs), voltage-sensitive Ca(2+) channels (VSCCs), protein kinases (PKs), and synaptic proteins [N-ethylmaleimide-sensitive factor (NSF) attachment protein (SNAP) receptors] on hippocampal serotonin release using in vivo microdialysis in freely moving rat. Basal serotonin release was regulated by two functional complexes: N-type VSCC (N-VSCC)/calcium-phospholipid-dependent protein kinase (PKC)/syntaxin (major pathway) and P-type VSCC (P-VSCC)/cyclic AMP-dependent protein kinase (PKA)/synaptobrevin (minor pathway). However, K(+)-evoked serotonin release was regulated by N-VSCC/PKC/syntaxin (minor pathway) and P-VSCC/PKA/synaptobrevin (major pathway). A1-R antagonists increased basal serotonin release, which was reduced by inhibitors of N-VSCC, PKC, and syntaxin predominantly and by inhibitors of PKA and synaptobrevin weakly, but was not affected by P-VSCC inhibitor. In the presence of A1-R antagonist, A2-R agonists increased basal serotonin release, which was inhibited by inhibitors of P-VSCC, PKA, and synaptobrevin predominantly and reduced by inhibitors of N-VSCC, PKC, and syntaxin weakly. Under the condition of activation of adenylate cyclase in the absence of A1-R antagonists, A2-R agonists increased basal serotonin release. A1-R antagonist and A2-R agonist enhanced K(+)-evoked serotonin release, which was inhibited by inhibitors of P-VSCC, PKA, and synaptobrevin predominantly. These results suggest that an activation of A1-R suppresses serotonin release via inhibition of both N-VSCC/PKC/syntaxin and P-VSCC/PKA/synaptobrevin pathways, and an activation of A2-R stimulates serotonin release via enhancement of the P-VSCC/PKA/synaptobrevin pathway. Therefore, PKA activity plays an important role in the interaction between A1-R and A2-R on hippocampal serotonin release.

Use of illegal drugs among mothers across racial/ethnic groups in the United States: a multi-level analysis of individual and community level influences.

OBJECTIVE: To obtain adjusted one-year prevalence estimates and compare multi-level correlates of marijuana, cocaine, crack, or heroin use among 4,678 mothers of minor children in the United States across racial/ethnic populations. METHODS: The study used publicly available data from the 1997 National Household Survey on Drug Abuse. Hierarchical generalized linear modeling (HGLM) procedures were used to test drug use variation among non-Hispanic White, non-Hispanic Black, and Hispanic mothers across US neighborhoods. RESULTS: Black mothers were 40% less likely to use illegal drugs than were White mothers, and Hispanic mothers were 72% less likely than were White mothers to use drugs, after adjusting for demographic and community covariates. Drug use was found to vary across neighborhoods for all racial/ethnic groups. This study identified a positive association between the likelihood of mothers using illegal drugs and their living in neighborhoods with a higher occurrence of drug use. CONCLUSION: To compare drug use across racial/ethnic groups, it is necessary to account for the confounding effects of covariates. Additional research is needed to determine whether non-drug using mothers chose to live in neighborhoods with a lower concentration of drug use, whether residence in these neighborhoods decreases the likelihood of mothers using drugs, or if a reciprocal relationship exists. The mechanisms that link individual drug use and neighborhood characteristics merit further investigation.

Biphasic response of the ductus arteriosus to combined administration of indomethacin and L-NAME in fetal rats.

We studied the combined effects of indomethacin, a cyclooxygenase inhibitor, and N(G)-nitro-L-arginine methyl ester (L-NAME), a nitric oxide (NO) synthase inhibitor, on the patency of the ductus arteriosus (DA) in fetal rats. Pregnant rats were administered indomethacin (3 mg/kg) orally 3 h before cesarean section, and then L-NAME (5 and 50 mg/kg), D-NAME, an enantiomer of L-NAME (50 mg/kg), or methylene blue, a soluble guanylate cyclase inhibitor (100 mg/kg), was injected intraperitoneally at various times before the cesarean section. Using rapid freezing and shaving methods, the calibers of the DA were measured. Compared with the indomethacin alone group, L-NAME caused a rapid and marked increase in the DA caliber 0.5 h after injection in fetal rats in which the DA was constricted by treatment with indomethacin. Subsequently, the transient ductal dilatation was completely reversed by 3 h after the L-NAME injection. Methylene blue also caused a biphasic response, but D-NAME did not affect the DA caliber. We conclude that the inhibition of both cyclooxygenase (indomethacin) and NO synthase (L-NAME) or NO action (methylene blue) causes a biphasic effect on the DA caliber in fetal rats.

Effects of butorphanol and carprofen on the minimal alveolar concentration of isoflurane in dogs.

OBJECTIVE: To evaluate the effects of butorphanol and carprofen, alone and in combination, on the minimal alveolar concentration (MAC) of isoflurane in dogs. DESIGN: Randomized complete-block crossover study. ANIMALS: 6 healthy adult dogs. PROCEDURE: Minimal alveolar concentration of isoflurane was determined following administration of carprofen alone, butorphanol alone, carprofen and butorphanol, and neither drug (control). Anesthesia was induced with isoflurane in oxygen, and MAC was determined by use of a tail clamp method. Three hours prior to induction of anesthesia, dogs were fed a small amount of canned food without any drugs (control) or with carprofen (2.2 mg/kg of body weight [1 mg/lb]). Following initial determination of MAC, butorphanol (0.4 mg/kg [0.18 mg/lb], i.v.) was administered, and MAC was determined again. Heart rate, respiratory rate, indirect arterial blood pressure, endtidal partial pressure of CO2, and saturation of hemoglobin with oxygen were recorded at the time MAC was determined. RESULTS: Mean +/- SD MAC of isoflurane following administration of butorphanol alone (1.03 +/- 0.22%) or carprofen and butorphanol (0.90 +/- 0.21%) were significantly less than the control MAC (1.28 +/- 0.14%), but MAC after administration of carprofen alone (1.20 +/- 0.13%) was not significantly different from the control value. The effects of carprofen and butorphanol on the MAC of isoflurane were additive. There were not any significant differences among treatments in regard to cardiorespiratory data. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that administration of butorphanol alone or in combination with carprofen significantly reduces the MAC of isoflurane in dogs; however, the effects of butorphanol and carprofen are additive, not synergistic.

Dysfunction of M-channel enhances propagation of neuronal excitability in rat hippocampus monitored by multielectrode dish and microdialysis systems.

To explore the pathogenesis of benign familial neonatal convulsions (BFNC), we determined effects of KCNQ-related M-channels (KCNQ-channels) on hippocampal glutamate (Glu) and gamma-aminobutyric acid (GABA) releases using microdialysis, and propagation of evoked field-potentials (FP) using multielectrode (64-ch)-dish system as two-dimensional monitoring. KCNQ-channel inhibitor, Dup996, enhanced hippocampal K(+)-evoked Glu and GABA releases without affecting basal releases of them. Dup996 unaffected FP-amplitude, but enhanced FP-propagation. The GABA(A)-receptor antagonist, bicuculline, enhanced the stimulatory effects of Dup996 on FP-propagation, however, this stimulatory effects of Dup996 were abolished by the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/glutamate-receptor antagonist, DNQX. These results suggest that the occurrence of BFNC cannot be produced by KCNQ-channel dysfunction alone, but by reciprocal action between impaired KCNQ-channel and other unknown elements (possibly dysfunction of inhibitory neurotransmission system).

Role of nitric oxide in regulating the ductus arteriosus caliber in fetal rats.

The role of nitric oxide (NO) on the ductus arteriosus (DA) patency was examined in fetal rats at various stages of gestation. N(G)-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg, i.p.), an NO synthase (NOS) inhibitor, or indomethacin (3 mg/kg, p.o.), a cyclooxygenase inhibitor, was administered at 3 hr before cesarean section to pregnant rats ranging from day 17 to day 21 of gestation. Dams were decapitated and the fetuses were obtained by cesarean section. The fetuses were rapidly frozen in an acetone-dry ice mixture. Using rapid-freezing and shaving methods, the calibers of the DA and pulmonary artery were measured. The constrictive effect of L-NAME on the fetal DA caliber was stronger than that of indomethacin in 19-day-old and immature fetuses. In near-term fetuses, the constrictive effects of L-NAME were reduced, while indomethacin caused marked DA constriction. We conclude that endogenous NO may play a major role in regulating the patency of the DA in earlier fetal stages, while dilator prostaglandins may play a greater role in regulating the ductal patency in the near-term fetus.

Effects of carbamazepine on acetylcholine release and metabolism.

To clarify the mechanisms of action of carbamazepine (CBZ), we investigated the effects of CBZ on acetylcholine (ACh) release and metabolism in rat striatum and hippocampus. Acute administration of effective dose of CBZ (25 mg/kg) increased both striatal and hippocampal extracellular levels of ACh, whereas a supraeffective dose of CBZ (50 mg/kg) did not affect the levels and a toxic dose of CBZ (100 mg/kg) decreased the extracellular ACh levels in both brain regions. Both acute and chronic administrations of CBZ (25 and 50 mg/kg, mg/kg per day) increased intracellular ACh levels in striatum and hippocampus. The striatal intracellular ACh levels were decreased by both acute and chronic administrations of CBZ (100 mg/kg, mg/kg per day), whereas the hippocampal intracellular ACh levels were not affected. The effective CBZ concentration did not affect cholinesterase activity, whereas supraeffective CBZ concentration reduced it weakly. Effective dose of CBZ enhanced ACh release and synthesis; however, supraeffective doses of CBZ reduced ACh release and synthesis without enhancement of ACh degradation, indicating that CBZ has biphasic effects on ACh release and synthesis. Thus, the present findings, the slight stimulation of ACh function by effective dose of CBZ, are involved, at least partially, in the antiepileptic and mood stabilizing mechanisms of action of CBZ.