Challenge of transition in the socio-professional insertion of youngsters with neurodisabilities.

Objective: To evaluate the activities of patients with neurodisabilities and assess their insertion problems in the professional world. Methods: It is based on medical records of 267 patients (224 with neurodevelopmental diseases and 43 with neuromuscular diseases), aged 16-25 years, followed in the transition clinic of young adults in the neurorehabilitation services of a tertiary center. Results: Nearly half of them (46.8%) were in a protected environment, 37.08% studied and only 3.4% worked. Their studies are much longer and they are less in university than Swiss people of same age. The competitiveness criteria are no mental retardation and to be completely independent. Finally, 29.2% reported work problems, the foremost being the lack of adaptation in the workplace. Conclusion: These results highlight the need to increase the integration of young adults with neuromotor disorders in the labor market.

Suivi neurodéveloppemental à 5ans des extrêmes prématurés et détection des difficultés sur le plan des fonctions exécutives [Detection of executive function disorders with a standard neurodevelopmental follow-up of premature children].

INTRODUCTION: A significant proportion of prematurely born children encounter behavioral difficulties, such as attention deficit or hyperactivity, which could be due to executive function disorders. AIMS: To examine whether the standard neurodevelopmental assessment offered to premature children in Switzerland recognizes executive function disorders. METHODS: The study population consisted of 49 children born before 29 weeks of gestation who were examined between 5 and 6 years of age with a standard assessment, with additional items to assess executive functioning. Children with severe neurodevelopmental impairment were excluded (mental retardation, cerebral palsy, autism). Standard assessment consisted in the Kaufman Assessment Battery for Children (K-ABC), which comprises three subscales: sequential processes (analysis of sequential information), simultaneous processes (global analysis of visual information), and composite mental processes (CMP) (result of the other two scales), as well as a behavioral evaluation using the standardized Strengths and Difficulties Questionnaire (SDQ). Executive functioning was assessed with tasks evaluating visual attention, divided attention, and digit memory as well as with a specialized questionnaire, the Behavior Rating Index of Executive Functions (BRIEF), which evaluates several aspects of executive function (regulation, attention, flexibility, working memory, etc). RESULTS: Children were divided according to their results on the three K-ABC scales (< or>85), and the different neuropsychological tasks assessing executive function were compared between the groups. The CMP did not differentiate children with executive difficulties, whereas a score<85 on the sequential processes was significantly associated with worse visual and divided attention. There was a strong correlation between the SDQ and the BRIEF questionnaires. For both questionnaires, children receiving psychotherapy had significantly higher results. Children who presented behavioral problems assessed with the SDQ presented significantly higher scores on the BRIEF. CONCLUSION: A detailed analysis of the standard neurodevelopmental assessment allows the identification of executive function disorders in premature children. Children who performed below 85 on the sequential processes of the K-ABC had significantly more attentional difficulties on the neuropsychological tasks and therefore have to be recognized and carefully followed. Emotional regulation had a strong correlation with behavioral difficulties, which were suitably assessed with the SDQ, recognized by the families, and treated.

Syttyminen ja palamisen eteneminen partikkelikerroksessa

Syttymistä ja palamisen etenemistä partikkelikerroksessa tutkitaan paloturvallisuuden parantamista sekä kiinteitä polttoaineita käyttävien polttolaitteiden toiminnan tuntemista ja kehittämistä varten. Tässä tutkimuksessa on tavoitteena kerätä yhteen syttymiseen ja liekkirintaman etenemiseen liittyviä kokeellisia ja teoreettisia tutkimustuloksia, jotka auttavat kiinteäkerrospoltto- ja -kaasutus-laitteiden kehittämisessä ja suunnittelussa. Työ on esitutkimus sitä seuraavalle kokeelliselle ja teoreettiselle osalle. Käsittelyssä keskitytään erityisesti puuperäisiin polttoaineisiin. Hiilidioksidipäästöjen vähentämistavoitteet sekä kiinteiden jätteiden energiakäytön lisääminen ja kaatopaikalle viennin vähentäminen aiheuttavat lähitulevaisuudessa kerrospolton lisääntymistä. Kuljetusmatkojen optimoinnin takia joudutaan rakentamaan melko pieniä polttolaitoksia, joissa kerrospolttotekniikka on edullisin vaihtoehto. Syttymispisteellä tarkoitetaan Semenovin määritelmän mukaan tilaa ja ajankohtaa, jolloin polttoaineen ja hapen reaktioissa muodostuva nettoenergia aikayksikössä on yhtäsuuri kuin ympäristöön siirtyvä nettoenergiavirta. Itsesyttyminen tarkoittaa syttymistä ympäristön lämpötilan tai paineen suurenemisen seurauksena. Pakotettu syttyminen tapahtuu, kun syttymispisteen läheisyydessä on esimerkiksi liekki tai hehkuva kiinteä kappale, joka aiheuttaa paikallisen syttymisen ja syttymisrintaman leviämisen muualle polttoaineeseen. Kokeellinen tutkimus on osoittanut tärkeimmiksi syttymiseen ja syttymisrintaman etenemiseen vaikuttaviksi tekijöiksi polttoaineen kosteuden, haihtuvien aineiden pitoisuuden ja lämpöarvon, partikkelikerroksen huokoisuuden, partikkelien koon ja muodon, polttoaineen pinnalle tulevan säteilylämpövirran tiheyden, kaasun virtausnopeuden kerroksessa, hapen osuuden ympäristössä sekä palamisilman esilämmityksen. Kosteuden lisääntyminen suurentaa syttymisenergiaa ja -lämpötilaa sekä pidentää syttymisaikaa. Mitä enemmän polttoaine sisältää haihtuvia aineita sitä pienemmässä lämpötilassa se syttyy. Syttyminen ja syttymisrintaman eteneminen ovat sitä nopeampia mitä suurempi on polttoaineen lämpöarvo. Kerroksen huokoisuuden kasvun on havaittu suurentavan palamisen etenemisnopeutta. Pienet partikkelit syttyvät yleensä nopeammin ja pienemmässä lämpötilassa kuin suuret. Syttymisrintaman eteneminen nopeutuu partikkelien pinta-ala - tilavuussuhteen kasvaessa. Säteilylämpövirran tiheys on useissa polttosovellutuksissa merkittävin lämmönsiirtotekijä, jonka kasvu luonnollisesti nopeuttaa syttymistä. Ilman ja palamiskaasujen virtausnopeus kerroksessa vaikuttaa konvektiiviseen lämmönsiirtoon ja hapen pitoisuuteen syttymisvyöhykkeellä. Ilmavirtaus voi jäähdyttää ja kuumankaasun virtaus lämmittää kerrosta. Hapen osuuden kasvaminen nopeuttaa syttymistä ja liekkirintaman etenemistä kunnes saavutetaan tila, jota suuremmilla virtauksilla ilma jäähdyttää ja laimentaa reaktiovyöhykettä. Palamisilman esilämmitys nopeuttaa syttymisrintaman etenemistä. Syttymistä ja liekkirintaman etenemistä kuvataan yleensä empiirisillä tai säilyvyysyhtälöihin perustuvilla malleilla. Empiiriset mallit perustuvat mittaustuloksista tehtyihin korrelaatioihin sekä joihinkin tunnettuihin fysikaalisiin lainalaisuuksiin. Säilyvyysyhtälöihin perustuvissa malleissa systeemille määritetään massan, energian, liikemäärän ja alkuaineiden säilymisyhtälöt, joiden nopeutta kuvaavien siirtoyhtälöiden muodostamiseen käytetään teoreettisella ja kokeellisella tutkimuksella saatuja yhtälöitä. Nämä mallinnusluokat ovat osittain päällekkäisiä. Pintojen syttymistä kuvataan usein säilyvyysyhtälöihin perustuvilla malleilla. Partikkelikerrosten mallinnuksessa tukeudutaan enimmäkseen empiirisiin yhtälöihin. Partikkelikerroksia kuvaavista malleista Xien ja Liangin hiilipartikkelikerroksen syttymiseen liittyvä tutkimus ja Gortin puun ja jätteen polttoon liittyvä reaktiorintaman etenemistutkimus ovat lähimpänä säilyvyysyhtälöihin perustuvaa mallintamista. Kaikissa malleissa joudutaan kuitenkin yksinkertaistamaan todellista tapausta esimerkiksi vähentämällä dimensioita, reaktioita ja yhdisteitä sekä eliminoimalla vähemmän merkittävät siirtomekanismit. Suoraan kerrospolttoa ja -kaasutusta palvelevia syttymisen ja palamisen etenemisen tutkimuksia on vähän. Muita tarkoituksia varten tehtyjen tutkimusten polttoaineet, kerrokset ja ympäristöolosuhteet poikkeavat yleensä selvästi polttolaitteiden vastaavista olosuhteista. Erikokoisten polttoainepartikkelien ja ominaisuuksiltaan erilaisten polttoaineiden seospolttoa ei ole tutkittu juuri ollenkaan. Polttoainepartikkelien muodon vaikutuksesta on vain vähän tutkimusta.Ilman kanavoitumisen vaikutuksista ei löytynyt tutkimuksia.

Etude de la toxicité hépatique de la cocaïne associée à de l'alcool: Effets de l'éthanol sur le métabolisme de la cocaïne dan les hépatocytes de rat en suspension et dans un modèle enzymatique humain

Le but essentiel de notre travail a été d?étudier la capacité du foie, premier organe de métabolisation des xénobiotiques, à dégrader la cocaïne en présence d?éthanol, à l?aide de deux modèles expérimentaux, à savoir un modèle cellulaire (les hépatocytes de rat en suspension) et un modèle acellulaire (modèle reconstitué in vitro à partir d?enzymes purifiées de foie humain). La première partie a pour objectifs de rechercher les voies de métabolisation de la cocaïne qui sont inhibées et / ou stimulées en présence d?éthanol, sur hépatocytes isolés de rat. Dans ce but, une méthode originale permettant de séparer et de quantifier simultanément la cocaïne, le cocaéthylène et huit de leurs métabolites respectifs a été développée par Chromatographie Phase Gazeuse couplée à la Spectrométrie de Masse (CPG / SM). Nos résultats préliminaires indiquent que l?éthanol aux trois concentrations testées (20, 40 et 80 mM) n?a aucun effet sur la cinétique de métabolisation de la cocaïne. Notre étude confirme que l?addition d?éthanol à des cellules hépatiques de rat en suspension supplémentées en cocaïne résulte en la formation précoce de benzoylecgonine et de cocaéthylène. L?apparition retardée d?ecgonine méthyl ester démontre l?activation d?une deuxième voie de détoxification. La production tardive d?ecgonine indique une dégradation de la benzoylecgonine et de l?ecgonine méthyl ester. De plus, la voie d?oxydation intervenant dans l?induction du stress oxydant en produisant de la norcocaïne est tardivement stimulée. Enfin, notre étude montre une métabolisation complète de la concentration initiale en éthanol par les hépatocytes de rat en suspension. La deuxième partie a pour but de déterminer s?il existe d?autres enzymes que les carboxylesterases formes 1 et 2 humaines ayant une capacité à métaboliser la cocaïne seule ou associée à de l?éthanol. Pour ce faire, une méthode de micropurification par chromatographie liquide (Smart System®) a été mise au point. Dans le cadre de nos dosages in situ de la cocaïne, du cocaéthylène, de la benzoylecgonine, de l?acide benzoïque et de la lidocaïne, une technique par Chromatographie Liquide Haute Performance couplée à une Détection par Barrette de Diode (CLHP / DBD) et une méthode de dosage de l?éthanol par Chromatographie Phase Gazeuse couplée à une Détection par Ionisation de Flamme équipée d?un injecteur à espace de tête (espace de tête CPG / DIF) ont été développées. La procédure de purification nous a permis de suspecter la présence d?autres enzymes que les carboxylesterases formes 1 et 2 de foie humain impliquées dans le métabolisme de la cocaïne et déjà isolées. A partir d?un modèle enzymatique reconstitué in vitro, nos résultats préliminaires indiquent que d?autres esterases que les formes 1 et 2 de foie humain sont impliquées dans l?élimination de la cocaïne, produisant benzoylecgonine et ecgonine méthyl ester. De plus, nous avons montré que les sensibilités de ces enzymes à l?éthanol sont variables.<br/><br/>The main purpose of our work was to study the ability of the liver, as the first organ to metabolise xenobiotic substances, to degrade cocaine in the presence of ethanol. In order to do this, we used two experimental models, namely a cellular model (rat liver cells in suspension) and an a-cellular model (model reconstructed in vitro from purified human liver enzymes). The purpose of the first part of our study was to look for cocaine metabolising processes which were inhibited and / or stimulated by the presence of ethanol, in isolated rat liver cells. With this aim in mind, an original method for simultaneously separating and quantifying cocaine, cocaethylene and eight of their respective metabolites was developed by Vapour Phase Chromatography coupled with Mass Spectrometry (VPC / MS). Our preliminary results point out that ethanol at three tested concentrations (20, 40 et 80 mM) have no effect on the kinetic of metabolisation of cocaine. Our study confirms that the addition of alcohol to rat liver cells in suspension, supplemented with cocaine, results in the premature formation of ecgonine benzoyl ester and cocaethylene. The delayed appearance of ecgonine methyl ester shows that a second detoxification process is activated. The delayed production of ecgonine indicates a degradation of the ecgonine benzoyl ester and the ecgonine methyl ester. Moreover, the oxidising process which occurs during the induction of the oxidising stress, producing norcocaine, is stimulated at a late stage. Finally, our study shows the complete metabolisation of the initial alcohol concentration by the rat liver cells in suspension. The second part consisted in determining if enzymes other than human carboxylesterases 1 and 2, able to metabolise cocaine on its own or with alcohol, existed. To do this, a micropurification method us ing liquid phase chromatography (Smart System®) was developed. A technique based on High Performance Liquid Chromatography coupled with a Diode Array Detection (HPLC / DAD) in the in situ proportioning of cocaine, cocaethylene, ecgonine benzoyl ester, benzoic acid and lidocaine, and a method for proportioning alcohol by quantifying the head space using Vapour Phase Chromatography coupled with a Flame Ionisation Detection (head space VPC / FID) were used. The purification procedure pointed to the presence of enzymes other than the human liver carboxylesterases, forms 1 and 2, involved in the metabolism of cocaine and already isolated. The preliminary results drawn from an enzymatic model reconstructed in vitro indicate that human liver carboxylesterases, other than forms 1 and 2, are involved in the elimination of cocaine, producing ecgonine benzoyl ester and ecgonine methyl ester. Moreover, we have shown that the sensitivity of these enzymes to alcohol is variable.

Propagation of the Ignition Front against Airflow in Packed Beds of Wood Particles

Combustion of wood is increasing because of the needs of decreasing the emissions of carbon dioxide and the amount of waste going to landfills. Wood based fuels are often scattered on a large area. The transport distances should be short enough to prevent too high costs, and so the size of heating and power plants using wood fuels is often rather small. Combustion technologies of small-size units have to be developed to reach efficient and environmentally friendly energy production. Furnaces that use different packed bed combustion or gasification techniques areoften most economic in small-scale energy production. Ignition front propagation rate affects the stability, heat release rate and emissions of packed bed combustion. Ignition front propagation against airflow in packed beds of wood fuels has been studied. The research has been carried out mainly experimentally. Theoretical aspects have been considered to draw conclusions about the experimental results. The effects of airflow rate, moisture content of the fuel, size, shape and density of particles, and porosity of the bed on the propagation rate of the ignition front have been studied. The experiments were carried out in a pot furnace. The fuels used in the experiments were mainly real wood fuels that are often burned in the production of energy. The fuel types were thin wood chips, saw dust, shavings, wood chips, and pellets with different sizes. Also a few mixturesof the above were tested. Increase in the moisture content of the fuel decreases the propagation rates of the ignition front and makes the range of possible airflow rates narrower because of the energy needed for the evaporation of water and the dilution of volatile gases due to evaporated steam. Increase in the airflow rate increases the ignition rate until a maximum rate of propagation is reached after which it decreases. The maximum flame propagation rate is not always reached in stoichiometric combustion conditions. Increase in particle size and density transfers the optimum airflow rate towards fuel lean conditions. Mixing of small and large particles is often advantageous, because small particles make itpossible to reach the maximum ignition rate in fuel rich conditions, and large particles widen the range of possible airflow rates. A correlation was found forthe maximum rate of ignition front propagation in different wood fuels. According to the correlation, the maximum ignition mass flux is increased when the sphericity of the particles and the porosity of the bed are increased and the moisture content of the fuel is decreased. Another fit was found between sphericity and porosity. Increase in sphericity decreases the porosity of the bed. The reasons of the observed results are discussed.

Nivel de aceptabilidad para cinco variedades de uva de mesa en el mercado español

Con el objetivo de evaluar el nivel de aceptabilidad con relación a distintas variedades de uva de mesa, la Unidad de Comercialización y Divulgación Agraria del Departamento de Economía y Ciencias Sociales Agrarias (E.T.S.I.Agrónomos), de la Universidad Politécnica de Madrid, realizó la presente investigación en julio de 1999. Se utilizó el análisis sensorial en Sala de Catas como herramienta para la evaluación del nivel de aceptabilidad de cinco variedades de uva de mesa. Se puso énfasis en conocer las posibles diferencias de carácter sensorial entre las variedades Flame Seedless, Cardinal, Superior Seedless, Victoria y Redgloble, variedades que coinciden en su época de cosecha en España. En los análisis hechos, las variedades Cardinal y Superior Seedless fueron las más preferidas en comparación con Flame Seedless, Victoria y Redgloble. La variedad Superior Seedless fue muy valorada por su ausencia de semillas, además de su buen sabor, lo que la torna de gran potencial para el mercado español. El sabor, seguido de la jugosidad, fueron los elementos determinantes en el proceso de aceptación de la uva.

Indicadores cognitivos del proceso de envejecimiento en las personas con síndrome de Down

Fundamentos: el aumento de la esperanza de vida en las personas con síndrome de Down plantea nuevos interrogantes sobre el proceso de su envejecimiento. La revisión bibliográfica sobre el tema muestra acuerdo sobre algunos aspectos diferenciales respecto a la población con discapacidad psíquica y la población general. Entre ellos, destacamos dos: a) la precocidad del inicio del proceso y b) el aumento de la probabilidad de desarrollar un envejecimiento patológico a causa de la demencia tipo Alzheimer. El objetivo del presente estudio se centra en la aportación de datos que ayuden a delimitar los posibles indicadores del declive cognitivo de las personas adultas con síndrome de Down relacionados con un posible deterioro propio de la demencia tipo Alzheimer. Método: el estudio se realiza en una muestra de 84 personas adultas con discapacidad psíquica, 42 de las cuales presentan el síndrome de Down. La media de edad se sitúa entorno a los 40 años y su nivel de retraso mental es medio. Se aplica de forma longitudinal en un período de dos años el test d’Aptituds Cognitives per a Deficiència del 65% (Castelló, Carrillo y Barnosell, 1996). Se utiliza un diseño factorial mixto de medidas repetidas controlando las variables etiología, edad cronológica, nivel de retraso mental y paso del tiempo. Resultados: se observa con el paso del tiempo, un declive cognitivo significativo de las personas con síndrome de Down de más de 38 años y nivel de retraso mental ligero respecto al grupo con discapacidad psíquica de referencia. Los indicadores cognitivos se sitúan preferentemente en las áreas de lenguaje y coordinación visomotora. Conclusiones: las personas con síndrome de Down de más de 38 años y nivel de retraso mental ligero manifiestan una probabilidad mayor de desarrollar un declive cognitivo relacionado con un probable deterioro propio de la demencia Alzheimer.

Autosomal dominant dopa-responsive parkinsonism in a multigenerational Swiss family.

AIM: To describe a large family with autosomal dominant parkinsonism. BACKGROUND: Seven genes are directly implicated in autosomally inherited parkinsonism. However, there are several multigenerational large families known with no identifiable mutation. MATERIAL AND METHODS: Family members were evaluated clinically, by history and chart review. Genetic investigation included SCA2, SCA3, UCHL1, SNCA, LRRK2, PINK1, PRKN, PGRN, FMR1 premutation, and MAPT. The proband underwent brain fluorodopa PET (FD-PET) scan, and one autopsy was available. RESULTS: Eleven patients had a diagnosis of Parkinson's disease (PD), nine women. Mean age of onset was 52 with tremor-predominant dopa-responsive parkinsonism. Disease progression was slow but severe motor fluctuations occurred. One patient required subthalamic nucleus deep-brain stimulation with a good motor outcome. One patient had mental retardation, schizophrenia and became demented, and another patient was demented. Three patients and also two unaffected subjects had mild learning difficulties. All genetic tests yielded negative results. FD-PET showed marked asymmetric striatal tracer uptake deficiency, consistent with PD. Pathological examination demonstrated no Lewy bodies and immunostaining was negative for alpha-synuclein. CONCLUSION: Apart from a younger age of onset and a female predominance, the phenotype was indistinguishable from sporadic tremor-predominant PD, including FD-PET scan results. As known genetic causes of autosomal dominant PD were excluded, this family harbors a novel genetic defect.

Tuberous sclerosis: literature review and case report

Tuberous sclerosis (TS) or Bourneville"s disease is a rare, multisystemic genetic disorder. It involves alterations to ectodermal and mesodermal cell differentiation and proliferation, causing benign hamartomatous tumors, neurofibromas and angiofibromas in the brain and other vital organs including the kidney, heart, eyes, lungs, skin and mucosa. It also affects the central nervous system and produces neurological dysfunctions such as seizures, mental retardation and behavior disorders. Tuberous (rootshaped) growths develop in the brain, and calcify over time, becoming hard and sclerotic, hence the name given to the disease. Although inheritance is autosomal dominant, 60-70% of cases occur through spontaneous mutations. The disease is related to some mutations or alterations in two genes, named TSC1 and TSC2. Discovered in 1997, TSC1 is located on chromosome 9q34 and produces a protein called hamartin. TSC2, discovered in 1993, is located on chromosome 16p13 and produces a protein called tuberin. The prevalence of the disease is 1/6000-10,000 live newborns, and it is estimated that there are 1-2 million sufferers worldwide. This paper presents a literature review and a family case report of a mother and two of her daughters with oral features of TS

Cross-validation of methods used for analysis of MTBE and other gasoline components in groundwater.

Head space gas chromatography with flame-ionization detection (HS-GC-FID), ancl purge and trap gas chromatography-mass spectrometry (P&T-GC-MS) have been used to determine methyl-tert-butyl ether (MTBE) and benzene, toluene, and the ylenes (BTEX) in groundwater. In the work discussed in this paper measures of quality, e.g. recovery (94-111%), precision (4.6 - 12.2%), limits of detection (0.3 - 5.7 I~g L 1 for HS and 0.001 I~g L 1 for PT), and robust-ness, for both methods were compared. In addition, for purposes of comparison, groundwater samples from areas suffering from odor problems because of fuel spillage and tank leakage were analyzed by use of both techniques. For high concentration levels there was good correlation between results from both methods.

Kaasunpolton tutkimuslaitteiston mittausten suunnittelu

Tämä diplomityö on Lappeenrannan teknillisessä yliopistossa aloitetun kaasunpolttotutkimushankkeen ensimmäinen tutkimusjakso. Tutkimushanketta varten on LTY:n voimalaitostekniikan koepolttolaboratoriossa rakennettu kaasunpolton tutkimuslaitteisto, jolla tässä diplomityössä perehdytään kaasuliekin lämpötilan mittausmenetelmiin, lämmönsiirtoon ja syntyviin päästöihin neste- ja maakaasupoltossa. Hankkeen toisessa tutkimusjaksossa laitteistolla tutkitaan regenaratiivista polttoa, ja polttoaineena käytetään neste- ja maakaasun lisäksi muita kaasuja kuten vetyä ja erilaisia seoskaasuja. Kaasunpolttotutkimushankkeen kokonaistavoitteena on pienentää kaasunpoltossa syntyviä NOx-päästöjä ja parantaa palamishyötysuhdetta ja tätä kautta pienentää laitteiston kokoa ja vähentää hiilidioksidipäästöjä.

Neuropathogenesis in glutaric aciduria type I and methylmalonic aciduria

Glutaric aciduria type-I (GA-I) and methylmalonic aciduria (MMA-uria) are two neurometabolic diseases manifesting in neonatal period and early childhood. They belong to the group of organic acidurias and are caused by defects in the catabolism of amino acids, leading to massive accumulation of toxic metabolites in the body and severe brain injury. Therapeutic strategies are mainly based on reversing catabolic state during metabolic crisis and dietary protein restriction that both aim to prevent extra production of toxic metabolites. Specific and neuroprotective treatments are missing because the mechanisms of brain damage in these diseases are only poorly understood. The principal objective of my work was to develop in vitro models for both diseases aiming at elucidation of toxic effects of the main metabolites accumulating in GA-I (glutaric acid (GA) and 3-hydroxy glutaric acid (3-OHGA)) and MMA-uria (methylmalonic acid (MMA), propionic acid (PA) and 2-methylcitric acid (2-MCA)) on developing brain cells, and to study the cellular pathways targeted by these deleterious effects in order to find new therapeutic potentials. We used re-aggregated embryonic rat brain cells in organotypic 3D cultures, which were exposed to toxic metabolites at different developing stages of the cultures. In parallel, we studied the cellular localization of the defected enzyme in GA-I, glutaryl-CoA dehydrogenase (GCDH), in the brain and peripheral tissues of rats in adulthood and during embryonic development. GCDH expression: GCDH showed a strong neuronal expression in embryonic central and peripheral nervous system. In the adult brain, GCDH expression was exclusively neuronal with the strongest signal in cerebral cortex and Purkinje cells. GCDH expression was homogenous in embryonic peripheral organs with high levels in intestinal mucosa at late stages. Strong GCDH expression was also observed in liver and intestinal mucosa and with lower intensity in muscles, convoluted renal tubules and renal collecting tubes in adult peripheral organs. GA-I and MMA-uria in vitro models: 3-OHGA (for GA-I) and 2-MCA (for MMA-uria) showed the most deleterious effects at early stages of the cultures with morphological and biochemical alterations and induction of cell death. 3-OHGA and 2-MCA caused astrocytic cell suffering reflected by astrocytic fiber loss and swelling and retardation in oligodendrocytic maturation and/or differentiation. High ammonium increase concomitant with glutamine decrease was observed in these cultures. Neurons were not substantially affected. Our studies revealed that brain-cell generated ammonia may play a role in the neuropathogenesis of these diseases. Thus, developing neuroprotective strategies that target ammonium toxicity in the brain of GA-I and MMA-uria patients might be important according to our findings. -- L'acidurie glutarique de type I (GA-I) et l'acidurie méthylmalonique (MMA-urie) sont deux maladies neurométaboliques se manifestant durant la période néonatale ou la petite enfance, et qui appartiennent aux aciduries organiques. Elles sont causées par des défauts dans le catabolisme des acides aminés, conduisant à une accumulation des métabolites toxiques dans le corps et aussi des lésions cérébrales sévères. Le traitement est limité à une prise en charge d'urgence pendant la crise métabolique et à une diète restreinte en protéines naturelles. Des traitements spécifiques, neuroprotecteurs manquent principalement parce que les mécanismes conduisant aux lésions cérébrales dans ces maladies sont peu connus. L'objectif principal de mon travail était d'élucider les effets toxiques des métabolites accumulés dans GA-I (l'acide glutarique (GA) et l'acide 3-hydroxyglutarique (3-OHGA)) et MMA-uria (l'acide méthylmalonique (MMA), l'acide propionique (PA) et l'acide 2-méthylcitrique(2-MCA) sur les cellules du cerveau ainsi que les voies cellulaires impliquées, dans le but de trouver de potentielles nouvelles stratégies thérapeutiques. Nous avons utilisé un modèle in vitro de cultures 3D de cellules de cerveau d'embryons de rat (en développement) en les exposant aux métabolites toxiques à différents stades de développement des cultures. En parallèle, nous avons étudié la localisation cellulaire de l'enzyme déficiente dans GA-I, la CoA-glutarly déshydrogénase (GCDH), dans le cerveau et les organes périphériques des rats adultes et pendant le développement embryonnaire. L'expression de GCDH: GCDH a montré une expression neuronale forte dans le système nerveux chez l'embryon et le cerveau adulte. L'expression était homogène dans les organes périphériques avec une forte expression dans l'intestin. Les modèles in vitro de GA-I et MMA-uria : 3-OHGA en modèle GA-I et 2-MCA en modèle MMA-uria ont montré les effets délétères les plus importants avec des altérations morphologiques des cellules et biochimiques dans le milieu de culture et l'induction de mort cellulaire non-apoptotique (3-OHGA) ou apoptotique (2-MCA). 3-OHGA et 2-MCA ont provoqué une souffrance astrocytaire avec perte des fibres et gonflement et un retard de maturation et/ou de différentiation des oligodendrocytes. Une augmentation importante d'ammonium avec une diminution concomitante de glutamine a été observée dans les cultures. Les neurones n'étaient pas vraiment affectés. Nos études ont révélé que l'ammonium généré par les cellules cérébrales pourrait jouer un rôle dans la neuropathogenèse de ces deux maladies. Par conséquent, développer des stratégies neuroprotectrices ciblant la toxicité de l'ammonium dans le cerveau des patients atteints de GA-I ou MMA-urie pourrait être très important selon nos résultats.

Dysregulated ADAM10-Mediated Processing of APP during a Critical Time Window Leads to Synaptic Deficits in Fragile X Syndrome.

The Fragile X mental retardation protein (FMRP) regulates neuronal RNA metabolism, and its absence or mutations leads to the Fragile X syndrome (FXS). The β-amyloid precursor protein (APP) is involved in Alzheimer's disease, plays a role in synapse formation, and is upregulated in intellectual disabilities. Here, we show that during mouse synaptogenesis and in human FXS fibroblasts, a dual dysregulation of APP and the α-secretase ADAM10 leads to the production of an excess of soluble APPα (sAPPα). In FXS, sAPPα signals through the metabotropic receptor that, activating the MAP kinase pathway, leads to synaptic and behavioral deficits. Modulation of ADAM10 activity in FXS reduces sAPPα levels, restoring translational control, synaptic morphology, and behavioral plasticity. Thus, proper control of ADAM10-mediated APP processing during a specific developmental postnatal stage is crucial for healthy spine formation and function(s). Downregulation of ADAM10 activity at synapses may be an effective strategy for ameliorating FXS phenotypes.

An unusual cause of high anion gap metabolic acidosis: pyroglutamic acidemia. A case report.

Pyroglutamic acidemia is an uncommon metabolic disorder, which is usually diagnosed at early ages. The mechanism of action is thought to be glutathione depletion, and its clinical manifestations consist of hemolytic anemia, mental retardation, ataxia, and chronic metabolic acidosis. However, an acquired form has been described in adult patients, who usually present with confusion, respiratory distress, and high anion gap metabolic acidosis (HAGMA). It is also associated with many conditions, including chronic acetaminophen consumption. A 68-year-old white male, with chronic acetaminophen use presented to our service on multiple occasions with severe HAGMA. The patient was admitted to the intensive care unit and required mechanical ventilation and aggressive supportive measures. After ruling out the most frequent etiologies for his acid-base disorder and considering the long history of Tylenol ingestion, his 5-oxiproline (pyroglutamic acid) levels were sent to diagnose pyroglutamic acidemia. Clinicians need to be aware of this cause for metabolic acidosis since it might be a more common metabolic disturbance in compromised patients than would be expected. Subjects with HAGMA that cannot be explained by common causes should be tested for the presence of 5-oxoproline. Discontinuation of the offending drug is therapeutic.

Hypertension artérielle et oeil

Résumé L'hypertension artérielle systémique est répandue dans la population et représente un facteur de risque cardiovasculaire majeur de morbidité et de mortalité. La rétinopathie hypertensive est l'atteinte la plus fréquente. Les signes au fond d'oeil sont la vasoconstriction et des signes indirects d'ischémie localisée de la rétine comme les hémorragies rétiniennes, les exsudats mous et durs. Elle peut contribuer à l'aggravation de la rétinopathie diabétique. Les complications oculaires fréquentes sont les hémorragies sous-conjonctivales et les occlusions veineuses. Plus rares mais plus graves sont les neuropathies optiques ischémiques et les occlusions artérielles rétiniennes ou choroïdiennes. Un dépistage est conseillé en cas d'hypertension mal contrôlée ou aiguë, de diabète, ou de toutes autres plaintes visuelles récentes. Abstract Systemic hypertension is widely spread in the general population. It is recognised as a major risk factor for cardiovascular morbidity and mortality. Hypertensive retinopathy is the most common manifestation. Initial changes are retinal arteriolar vasoconstriction and findings such as flame or blot hemorrhages, cotton wool spots and hard exsudates resulting from localised retinal ischemia. Ocular complications of high blood pressure (HBP) are subconjunctival hemorrhages and retinal vein occlusions. Hypertensive retinopathy contributes to worsening of diabetic retinopathy. Less common but more threatening are ischemic optic neuropathy and retinal arterial occlusions. Screening is recommended in case of severe systemic hypertension, diabetes, or any complain of recent visual disturbances.