Association between education and quality of diabetes care in Switzerland

PURPOSE: Low socioeconomic status is associated with higher prevalence of diabetes, worse outcomes, and worse quality of care. We explored the relationship between education, as a measure of socioeconomic status, and quality of care in the Swiss context. PATIENTS AND METHODS: Data were drawn from a population-based survey of 519 adults with diabetes during fall 2011 and summer 2012 in a canton of Switzerland. We assessed patients and diabetes characteristics. Eleven indicators of quality of care were considered (six of process and five of outcomes of care). After bivariate analyses, regression analyses adjusted for age, sex, and diabetic complications were performed to assess the relationship between education and quality of care. RESULTS: Of 11 quality-of-care indicators, three were significantly associated with education: funduscopy (patients with tertiary versus primary education were more likely to get the exam: odds ratio, 1.8; 95% confidence interval [CI], 1.004-3.3) and two indicators of health-related quality of life (patients with tertiary versus primary education reported better health-related quality of life: Audit of Diabetes-Dependent Quality of Life: β=0.6 [95% CI, 0.2-0.97]; SF-12 mean physical component summary score: β=3.6 [95% CI, 0.9-6.4]). CONCLUSION: Our results suggest the presence of educational inequalities in quality of diabetes care. These findings may help health professionals focus on individuals with increased needs to decrease health inequalities.

A MODEL OF CREATINE DEFICIENCY SYNDROMES IN 3D BRAIN CELL CULTURES BY KNOCKDOWN OF GAMT AND SLC6A8 GENES

La créatine joue un rôle essentiel dans le métabolisme cellulaire par sa conversion, par la creatine kinase, en phosphocreatine permettant la régénération de l'ATP. La synthèse de créatine, chez les mammifères, s'effectue par une réaction en deux étapes impliquant Γ arginine: glycine amidinotransférase (AGAT) et la guanidinoacétate méthyltransférase (GAMT). L'entrée de créatine dans les cellules s'effectue par son transporteur, SLC6A8. Les déficiences en créatine, dues au déficit en GAMT, AGAT ou SLC6A8, sont fréquentes et caractérisées par une absence ou une forte baisse de créatine dans le système nerveux central. Alors qu'il est connu que AGAT, GAMT et SLC6A8 sont exprimés par le cerveau, les conséquences des déficiences en créatine sur les cellules nerveuses sont peu comprises. Le but de ce travail était de développer de nouveaux modèles expérimentaux des déficiences en Cr dans des cultures 3D de cellules nerveuses de rat en agrégats au moyen de l'interférence à l'ARN appliquée aux gènes GAMT et SLC6A8. Des séquences interférentes (shRNAs) pour les gènes GAMT et SLC6A8 ont été transduites par des vecteurs viraux AAV (virus adéno-associés), dans les cellules nerveuses en agrégats. Nous avons ainsi démontré une baisse de l'expression de GAMT au niveau protéique (mesuré par western blot), et ARN messager (mesuré par qPCR) ainsi qu'une variation caractérisitique de créatine et guanidinoacétate (mesuré par spectrométrie de masse). Après avoir validé nos modèles, nous avons montré que les knockdown de GAMT ou SLC6A8 affectent le développement des astrocytes et des neurones ou des oligodendrocytes et des astrocytes, respectivement, ainsi qu'une augmentation de la mort cellulaire et des modifications dans le pattern d'activation des voies de signalisation impliquant caspase 3 et p38 MAPK, ayant un rôle dans le processus d'apoptose. - Creatine plays essential roles in energy metabolism by the interconversion, by creatine kinase, to its phosphorylated analogue, phosphocreatine, allowing the regeneration of ATP. Creatine is synthesized in mammals by a two step mechanism involving arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT). Creatine is taken up by cells by a specific transporter, SLC6A8. Creatine deficiency syndromes, due to defects in GAMT, AGAT and SLC6A8, are among the most frequent inborn errors of metabolism, and are characterized by an absence or a severe decrease of creatine in central nervous system, which is the main tissue affected. While it is known that AGAT, GAMT and SLC6A8 are expressed in CNS, many questions remain on the specific effects of AGAT, GAMT and SLC6A8 deficiencies on brain cells. Our aim was to develop new experimental models of creatine deficiencies by knockdown of GAMT and SLC6A8 genes by RNAi in 3D organotypic rat brain cell cultures in aggregates. Specific shRNAs for the GAMT and SLC6A8 genes were transduced in brain cell aggregates by adeno-associated viruses (AAV). The AAV-transduced shRNAs were able to efficiently knockdown the expression of our genes of interest, as shown by a strong decrease of protein by western blotting, a decrease of mRNA by qPCR or characteristic variations of creatine and guanidinoacetate by tandem mass spectrometry. After having validated our experimental models, we have also shown that GAMT and SLC6A8 knockdown affected the development of astrocytes and neurons or oligodendrocytes and astrocytes, respectively. We also observed an increase of cell death and variations in activation pattern of caspase 3 and p38 MAPK pathways, involved in apoptosis, in our experimental model.

Regulation of the vascular gap junctions in a mouse model of intimal hyperplasia

Objective: Intimal hyperplasia (IH) is one of the leading causes of failure¦after vascular interventions. It involves the proliferation of smooth muscle¦cells (SMCs) and the production of extracellular fibrous matrix. Gap junctional¦communication, mediated by membrane connexins (Cx), participates to the¦control of proliferation and migration. In human and mice vessels, endothelial¦cells (ECs) express Cx37, Cx40 and Cx43, whereas SMCs are coupled by Cx43.¦We previously reported that Cx43 was increased in the SMCs of a human vein¦during the development of IH.¦In our experimental model of mice carotid artery ligation (CAL), luminal¦narrowing occurred by SMCs-rich neointima after 2-4 weeks of ligation.¦This experimental model of mice allows us to decipher the regulation of the¦cardiovascular connexins in the mouse.¦Methods: C57BL/6 mice were anesthetized and the left common carotid artery¦was dissected through a neck incision and ligated near the carotid bifurcation.¦The mice were then euthanized at 7, 14 and 28 days. Morphometric analyses¦were then performed with measurements of total area, lumen and intimal area¦and media thickness. Western blots, immunocytochemistry and quantitative¦RT-PCR were performed for Cx43, Cx40 and Cx37.¦Results: All animals recovered with no symptom of stroke. Morphometric¦analysis demonstrated that carotid ligation resulted in an initial increase (after¦7 days) of the total vessel area followed by its reduction (after 28 days). This¦phenomena was associated with a progressive increase in the intimal area and a¦consecutive decrease of the lumen. The media thickness was also increased after¦14 and 28 days. This neointima formation was associated to a marked increase¦in the expression of Cx43 at both protein and RNA levels. Concomitantly,¦Cx40 and Cx37 protein expression were reduced in the endothelium. This was¦confirmed by en face analyses showing reduced Cx37 and Cx40 levels in the¦endothelial cells covering the lesion.¦Conclusion: This study assessed the regulation of the cardiovascular connexins¦in the development of IH. This model will allow us to characterize the¦involvement of gap junctions in the IH. In turn, this understanding is¦instrumental for the development of new therapeutical tools, as well as for¦the evaluation of the effects of drugs and gene therapies of this disease for which¦there is no efficient therapy available.

Altered expression of beta-galactosidase-1-like protein 3 (Glb1l3) in the retinal pigment epithelium (RPE)-specific 65-kDa protein knockout mouse model of Leber's congenital amaurosis

Purpose: In this study, we investigated the expression of the gene encoding beta-galactosidase (Glb)-1-like protein 3 (Glb1l3), a member of the glycosyl hydrolase 35 family, during retinal degeneration in the retinal pigment epithelium (RPE)-specific 65-kDa protein knockout (Rpe65(-/-)) mouse model of Leber congenital amaurosis (LCA). Additionally, we assessed the expression of the other members of this protein family, including beta-galactosidase-1 (Glb1), beta-galactosidase-1-like (Glb1l), and beta-galactosidase-1-like protein 2 (Glb1l2).Methods: The structural features of Glb1l3 were assessed using bioinformatic tools. mRNA expression of Glb-related genes was investigated by oligonucleotide microarray, real-time PCR, and reverse transcription (RT) -PCR. The localized expression of Glb1l3 was assessed by combined in situ hybridization and immunohistochemistry.Results: Glb1l3 was the only Glb-related member strongly downregulated in Rpe65(-/-) retinas before the onset and during progression of the disease. Glb1l3 mRNA was only expressed in the retinal layers and the RPE/choroid. The other Glb-related genes were ubiquitously expressed in different ocular tissues, including the cornea and lens. In the healthy retina, expression of Glb1l3 was strongly induced during postnatal retinal development; age-related increased expression persisted during adulthood and aging.Conclusions: These data highlight early-onset downregulation of Glb1l3 in Rpe65-related disease. They further indicate that impaired expression of Glb1l3 is mostly due to the absence of the chromophore 11-cis retinal, suggesting that Rpe65 deficiency may have many metabolic consequences in the underlying neuroretina.

Explaining Fiscal Balances with a Simultaneous Equation Model of Revenue and Expenditure : A Case Study of Swiss Cantons Using Panel Data

Empirical literature on the analysis of the efficiency of measures for reducing persistent government deficits has mainly focused on the direct explanation of deficit. By contrast, this paper aims at modeling government revenue and expenditure within a simultaneous framework and deriving the fiscal balance (surplus or deficit) equation as the difference between the two variables. This setting enables one to not only judge how relevant the explanatory variables are in explaining the fiscal balance but also understand their impact on revenue and/or expenditure. Our empirical results, obtained by using a panel data set on Swiss Cantons for the period 1980-2002, confirm the relevance of the approach followed here, by providing unambiguous evidence of a simultaneous relationship between revenue and expenditure. They also reveal strong dynamic components in revenue, expenditure, and fiscal balance. Among the significant determinants of public fiscal balance we not only find the usual business cycle elements, but also and more importantly institutional factors such as the number of administrative units, and the ease with which people can resort to political (direct democracy) instruments, such as public initiatives and referendum.

The ALK-F1174L activating mutation is tumorigenic in MONC-1 neural crest stem cells in an orthotopic murine model of neuroblastoma

Background: Activating mutations of the anaplastic lymphoma receptor tyrosine kinase gene (ALK) were identified in both somatic and familial neuroblastoma. The most common somatic mutation, F1174L, is associated with NMYC amplification and displayed an efficient transforming activity in vivo. In addition, both AKL-F1174L and NMYC were shown cooperate in neuroblastoma tumorigenesis in animal models. To analyse the role of ALK mutations in the oncogenesis of neuroblastoma, ALK wt and various ALK mutants were transduced in murine neural crest stem cells (MONC1). Methods: ALK-wt, and F1174L, and R1275Q mutants were stably expressed by retroviral infection using the pMIGR1 vector in the murine neural crest stem cell line MONC-1, previously immortalised with v-myc, and further implanted subcutaneously or orthotopically in nude mice. Results: Both MONC1-ALK-F1174L and -R1275Q cells displayed a rapid tumour forming capacity upon subcutaneous injection in nude mice compared to control MONC1-MIGR or MONC1 cells. Interestingly, the transforming capacity of the F1174L mutant was much more potent compared to that of R1275Q mutant in murine neural crest stem cells, while ALK-wt was not tumorigenic. In addition, mice implanted orthotopically in the left adrenal gland with MONC1-ALK-F1174L cells developed highly aggressive tumours in 100% of mice within three weeks, while MONC1-Migr or MONC1 derived tumours displayed a longer latency and a reduced tumour take. Conclusions: The activating ALK-F1174L mutant is highly tumorigenic in neural crest stem cells. Nevertheless, we cannot exclude a functional implication of the v-myc oncogene used for MONC1 cells immortalisation. Indeed, the control MONC1-Migr and MONC1 cells were also able to derive subcutaneous and orthotopic tumours, although with considerable reduced efficiency. Further investigations using neural crest stem cell lacking exogenous myc expression are currently on way to assess the exclusive role of ALK mutations in NB oncogenesis.

Evidence for an episodic model of protein sequence evolution.

The evolution of protein function appears to involve alternating periods of conservative evolution and of relatively rapid change. Evidence for such episodic evolution, consistent with some theoretical expectations, comes from the application of increasingly sophisticated models of evolution to large sequence datasets. We present here some of the recent methods to detect functional shifts, using amino acid or codon models. Both provide evidence for punctual shifts in patterns of amino acid conservation, including the fixation of key changes by positive selection. Although a link to gene duplication, a presumed source of functional changes, has been difficult to establish, this episodic model appears to apply to a wide variety of proteins and organisms.

Detection of neuronal activity and metabolism in a model of dehydration-induced anorexia in rats at 14.1 T using manganese-enhanced MRI and 1H MRS.

In this study, hypothalamic activation was performed by dehydration-induced anorexia (DIA) and overnight food suppression (OFS) in female rats. The assessment of the hypothalamic response to these challenges by manganese-enhanced MRI showed increased neuronal activity in the paraventricular nuclei (PVN) and lateral hypothalamus (LH), both known to be areas involved in the regulation of food intake. The effects of DIA and OFS were compared by generating T-score maps. Increased neuronal activation was detected in the PVN and LH of DIA rats relative to OFS rats. In addition, the neurochemical profile of the PVN and LH were measured by (1) H MRS at 14.1T. Significant increases in metabolite levels were measured in DIA and OFS relative to control rats. Statistically significant increases in γ-aminobutyric acid were found in DIA (p=0.0007) and OFS (p<0.001) relative to control rats. Lactate increased significantly in DIA (p=0.03), but not in OFS, rats. This work shows that manganese-enhanced MRI coupled to (1) H MRS at high field is a promising noninvasive method for the investigation of the neural pathways and mechanisms involved in the control of food intake, in the autonomic and endocrine control of energy metabolism and in the regulation of body weight.

Anti-vascular endothelial growth factor acts on retinal microglia/macrophage activation in a rat model of ocular inflammation.

PURPOSE: To evaluate whether anti-vascular endothelial growth factor (VEGF) neutralizing antibodies injected in the vitreous of rat eyes influence retinal microglia and macrophage activation. To dissociate the effect of anti-VEGF on microglia and macrophages subsequent to its antiangiogenic effect, we chose a model of acute intraocular inflammation. METHODS: Lewis rats were challenged with systemic lipopolysaccharide (LPS) injection and concomitantly received 5 µl of rat anti-VEGF-neutralizing antibody (1.5 mg/ml) in the vitreous. Rat immunoglobulin G (IgG) isotype was used as the control. The effect of anti-VEGF was evaluated at 24 and 48 h clinically (uveitis scores), biologically (cytokine multiplex analysis in ocular media), and histologically (inflammatory cell counts on eye sections). Microglia and macrophages were immunodetected with ionized calcium-binding adaptor molecule 1 (IBA1) staining and counted based on their differential shapes (round amoeboid or ramified dendritiform) on sections and flatmounted retinas using confocal imaging and automatic quantification. Activation of microglia was also evaluated with inducible nitric oxide synthase (iNOS) and IBA1 coimmunostaining. Coimmunolocalization of VEGF receptor 1 and 2 (VEGF-R1 and R2) with IBA1 was performed on eye sections with or without anti-VEGF treatment. RESULTS: Neutralizing rat anti-VEGF antibodies significantly decreased ocular VEGF levels but did not decrease the endotoxin-induced uveitis (EIU) clinical score or the number of infiltrating cells and cytokines in ocular media (interleukin [IL]-1β, IL-6, tumor necrosis factor [TNF]-α, and monocyte chemoattractant protein [MCP]-1). Eyes treated with anti-VEGF showed a significantly decreased number of activated microglia and macrophages in the retina and the choroid and decreased iNOS-positive microglia. IBA1-positive cells expressed VEGF-R1 and R2 in the inflamed retina. CONCLUSIONS: Microglia and macrophages expressed VEGF receptors, and intravitreous anti-VEGF influenced the microglia and macrophage activation state. Taking into account that anti-VEGF drugs are repeatedly injected in the vitreous of patients with retinal diseases, part of their effects could result from unsuspected modulation of the microglia activation state. This should be further studied in other ocular pathogenic conditions and human pathology.

The quality of primary care in a country with universal health care coverage

Cet article a été réalisé dans le but d'évaluer la qualité des soins fournie à une population âgée de 50 à 80 ans suivie dans 4 policliniques médicales universitaires de Suisse, à savoir Bâle, Zurich, Genève et Lausanne. Nous avons sélectionné 37 indicateurs de qualité qui ont été développés et préalablement évalués au Etats-Unis. Ces indicateurs ont été divisés en 2 sous-groupes distincts : les indicateurs de prévention et les indicateurs concernant les facteurs de risque cardiovasculaires.¦L'étude a inclus des patients âgés de 50 à 80 ans avec un suivi d'un minimum de 1 an par un médecin dans l'une des policliniques de Suisse. Nous avons limité notre étude à ce groupe d'âge, afin d'avoir une prévalence élevée de facteur de risque cardiovasculaire et plus d'indications à des tests de dépistages. Les dossiers médicaux des patients ont été sélectionnés selon un mode aléatoire en prenant 250 dossiers par centre.¦L'enjeu principal de cette étude était de déterminer le niveau de soins fournis en Suisse dans les policliniques médicales universitaires. Il a été également possible de mettre en évidence les secteurs de prévention pour lesquels le taux d'application est encore insuffisant. Nous avons par la même occasion comparé nos résultats à ceux obtenus aux Etats-Unis, sachant que ce pays a un système d'évaluation de la qualité des soins qui fournit chaque années des statistiques à ce sujet.¦Les résultats de notre étude montrent qu'en Suisse les adultes reçoivent 69% des mesures de prévention recommandées mais que ces taux diffèrent d'un indicateur à l'autre. Les indicateurs à propos de la tension artérielle et de la mesure du poids (les 2 95%) ont plus souvent été réalisés durant les consultations que les indicateurs concernant l'arrêt du tabagisme (72%), les cancers du sein (40%), du colon (35%) et la vaccination annuelle contre la grippe (35.2% chez les patients de >65 ans et 29.3% chez les patient de <65 ans avec une maladie chronique). 83% des patients reçoivent les mesures préventives concernant les facteurs de risque cardiovasculaire, avec >75% pour l'hypertension, le diabète et la dyslipidémie. Cependant, l'examen des pieds est effectué chez seulement 50% des patients présentant un diabète.¦De même, nous avons pu démontrer que les femmes (65.3%) et les personnes âgées de plus de 65 ans (68.0%) reçoivent moins de mesures préventives que les hommes (72.2%) et les personnes plus jeunes (70.1%).¦Ce travail de recherche a donc permis de mettre en évidence les domaines de la prévention encore insuffisamment proposés aux patients et de rendre attentif le personnel médical sur le fait qu'il existe en Suisse des groupes de personnes qui reçoivent moins de prévention que d'autres groupes. Dans le futur, l'accent devrait être d'avantage mis durant les études de médecine et lors de la formation post-graduée sur les mesures préventives pas assez exploitées en Suisse en particulier le dépistage des cancers et la vaccination annuelle contre la grippe.

Die Reichweite von Theorien als Indikator für ihre Umsetzbarkeit in der Praxis [The scope as an indicator of the applicability of nursing theories to practice]

In der Pflegewissenschaft geben der Einsatz von Theorien und der daraus folgende Gewinn immer wieder Anlass zu Diskussionen. Ein Hauptvorwurf ist, dass Pflegetheorien als sehr abstrakt und wenig praxisnah gelten. Jedoch gibt es wenige Indikatoren, um das Abstraktionsniveau von Theorien und die damit verbundene Reichweite zu bestimmen. Im vorliegenden Artikel werden Fragen basierend auf die Definitionen und Grundannahmen von Theorien erstellt. Damit werden anschließend drei ausgesuchte Theorien auf ihr Abstraktionsniveau und Reichweite untersucht. Es wurden 18 Fragen zu den drei Bereichen ,,Zweck der Theorie", ,,Aufgabe der Theorie" und ,,Beschreibung der Theorie" entwickelt. Diese 18 Fragen wurden auf die Theorie der Adaptation von Sister Callista Roy, die Theorie zur Unsicherheit von Merle M. Mishel und die Theorie der Omnipräsenz von Krebs von Maya Shaha angewendet. [The use of nursing theories and their associated benefits remain an area of repeated discussion in nursing. One of the main objections is that nursing theories are abstract and therefore cannot be easily applied to practice. However, only few indicators exist to help identify a theory's level of abstraction or its scope. In this article, questions based on definitions and assumptions of theories have been developed. These questions have then been applied to three selected theories to investigate their level of abstraction and scope. A total of 18 questions divided into three domains were developed. The three categories were: ,,the purpose of the theory", ,,the aim of the theory" and ,,the description of the theory". The theory of Adaptation by Sister Callista Roy, the Theory of Uncertainty by Merle M. Mishel and the Theory of the Omnipresence of Cancer by Maya Shaha were selected to be analysed following the three domains with the 18 questions.]

The neurobiological basis of prefrontal cortex impairment in the phencyclidine model of schizophrenia : convergent reduction of synaptic glutamate release, energy metabolism and cognitive performance

RÉSUMÉ : Le traitement répété à la phencyclidine (PCP), un bloqueur du récepteur NMDA (NMDAR), reproduit chez les rongeurs une partie de la symptomatologie typique de la schizophrénie. Le blocage prolongé du NMDAR par la PCP mime une hypofunction du NMDAR, une des principales altérations supposées exister dans les cerveaux des patients schizophréniques. Le but de notre étude était d'examiner les conséquences neurochimiques, métaboliques et fonctionnelles du traitement répété à la phencyclidine in vivo, au niveau du cortex préfrontal (cpf), une région cérébrale qui joue un rôle dans les déficits cognitifs observés chez les patients schizophréniques. Pour répondre à cette question, les rats ou les souris ont reçu chaque jour une injection soit de PCP (5 mg/kg), soit de solution saline, pendant 7 ou 14 jours. Les animaux ont ensuite été sacrifiés au moins 24 heures après le dernier traitement. Des tranches aiguës du cpf ont été préparées rapidement, puis stimulées avec une concentration élevée de KCI, de manière à induire une libération de glutamate à partir des terminaisons synaptiques excitatrices. Les résultats montrent que les tranches du cpf des animaux traités à la PCP ont libéré une quantité de glutamate significativement inférieure par rapport à celles des animaux contrôle. Ce déficit de libération a persisté 72 heures après la fin du traitement, tandis qu'il n'était pas observé dans le cortex visuel primaire, une autre région corticale. En outre, le traitement avec des antipsychotiques, l'halopéridol ou l'olanzapine, a supprimé le déficit induit par la PCP. Le même déficit de libération a été remarqué sur des synaptosomes obtenus à partir du cpf des animaux traités à la phenryclidine. Cette observation indique que la PCP induit une modification plastique adaptative du mécanisme qui contrôle la libération du glutamate dans les terminaisons synaptiques. Nous avons découvert que cette modification implique la sous-régulation d'un NMDAR présynaptique, qui serait doué d'un rôle d'autorécepteur stimulateur de la libération du glutamate. Grâce à des tests comportementaux conduits en parallèle et réalisés pour évaluer la fonctionnalité du cpf, nous avons observé chez les souris traitées à la PCP une flexibilité comportementale réduite lors d'un test de discrimination de stimuli visuels/tactiles. Le déficit cognitif était encore présent 4 jours après la dernière administration de PCP. La technique de l'autoradiographie quantitative du [14C]2-deoxyglucose a permis d'associer ce déficit à une réduction de l'activité métabolique cérébrale pendant le déroulement du test, particulièrement au niveau du cpf. Dans l'ensemble, nos résultats suggèrent que le blocage prolongé du NMDAR lors de l'administration répétée de PCP produit un déficit de libération du glutamate au niveau des terminaisons synaptiques excitatrices du cpf. Un tel déficit pourrait être provoqué par la sousrégulation d'un NMDAR présynaptique, qui aurait une fonction de stimulateur de libération; la transmission excitatrice du cpf s'en trouverait dans ce cas réduite. Ce résultat est en ligne avec l'activité métabolique et fonctionnelle réduite du cpf et l'observation de déficits cognitifs induits lors de l'administration de la PCP. ABSTRACT : Sub-chronic treatment with phencyclidine (PCP), an NMDA receptor (NMDAR) channel blocker, reproduces in rodents part of the symptomatology associated to schizophrenia in humans. Prolonged pharmacological blockade of NMDAR with PCP mimics NMDAR hypofunction, one of the main alterations thought to take place in the brains of schizophrenics. Our study was aimed at investigating the neurochemical, metabolic and behavioral consequences of repeated PCP administration in vivo, focusing on the functioning of the prefrontal cortex (pfc), a brain region highly relevant for the cognitive deficits observed in schizophrenic patients. Rats or mice received a daily administration of either PCP (5 mg/kg) or saline for 7 or 14 days. At least 24 hours after the last treatment the animals were sacrificed. Acute slices of the pfc were quickly prepared and challenged with high KCl to induce synaptic glutamate release. Pfc slices from PCP-treated animals released significantly less glutamate than slices from salinetreated animals. The deficit persisted 72 hours after the end of the treatment, while it was not observed in another cortical region: the primary visual cortex. Interestingly, treatment with antipsychotic drugs, either haloperidol or olanzapine, reverted the glutamate release defect induced by PCP treatment. The same release defect was observed in synaptosomes prepared from the pfc of PCP-treated animals, indicating that PCP induces a plastic adaptive change in the mechanism controlling glutamate release in the glutamatergic terminals. We discovered that such change most likely involves the down-regulation of a newly identified, pre-synaptic NMDAR with stimulatory auto-receptor function on glutamate release. In parallel sets of behavioral experiments challenging pfc function, mice sub-chronically treated with PCP displayed reduced behavioral flexibility (reversal learning) in a visual/tactile-cued discrimination task. The cognitive deficit was still evident 4 days after the last PCP administration and was associated to reduced brain metabolic activity during the performance of the behavioral task, notably in the pfc, as determined by [14C]2-deoxyglucose quantitative autoradiography. Clverall, our findings suggest that prolonged NMDAR blockade by repeated PCP administration results in a defect of glutamate release from excitatory afferents in the pfc, possibly ascribed to down-regulation of apre-synaptic stimulatory NMDAR. Deficient excitatory neurotransmission in the pfc is consistent with the reduced metabolic and functional activation of this area and the observed PCP-induced cognitive deficits.

The Impact of Personality and Culture on the Job Demands-Control Model of Job Stress

Among the various work stress models, one of the most popular has been the job demands-control (JDC) model developed by Karasek (1979), which postulates that work-related strain is highest under work conditions characterized by high demands and low autonomy. The absence of social support at work further increases negative outcomes. This model, however, does not apply equally to all individuals and to all cultures. This review demonstrates how various individual characteristics, especially some personality dimensions, influence the JDC model and could thus be considered buffering or moderator factors. Moreover, we review how the cultural context impacts this model as suggested by results obtained in European, American, and Asian contexts. Yet there are almost no data from Africa or South America. More crosscultural studies including populations from these continents would be valuable for a better understanding of the impact of the cultural context on the JDC model.

The role of C-Jun N-terminal kinase in a mouse model of intracerebral hemorrhage

Background: Intracerebral hemorrhage (ICH) is a subtype of stroke characterized by a haematoma within the brain parenchyma resulting from blood vessel rupture and with a poor outcome. In ICH, the blood entry into the brain triggers toxicity resulting in a substantial loss of neurons and an inflammatory response. At the same time, blood-brain barrier (BBB) disruption increases water content (edema) leading to growing intracranial pressure, which in turn worsens neurological outcome. Although the clinical presentation is similar in ischemic and hemorrhagic stroke, the treatment is different and the stroke type needs to be determined beforehand by imaging which delays the therapy. C-Jun N-terminal kinases (JNKs) are a family of kinases activated in response to stress stimuli and involved in several pathways such as apoptosis. Specific inhibition of JNK by a TAT-coupled peptide (XG-102) mediates strong neuroprotection in several models of ischemic stroke in rodents. Recently, we have observed that the JNK pathway is also activated in a mouse model of ICH, raising the question of the efficacy of XG-102 in this model. Method: ICH was induced in the mouse by intrastriatal injection of bacterial collagenase (0,1 U). Three hours after surgery, animals received an intravenous injection of 100 mg/kg of XG-102. The neurological outcome was assessed everyday until sacrifice using a score (from 0 to 9) based on 3 behavioral tests performed daily until sacrifice. Then, mice were sacrificed at 6 h, 24 h, 48 h, and 5d after ICH and histological studies performed. Results: The first 24 h after surgery are critical in our ICH mice model, and we have observed that XG-102 significantly improves neurological outcome at this time point (mean score: 1,8 + 1.4 for treated group versus 3,4+ 1.8 for control group, P<0.01). Analysis of the lesion volume revealed a significant decrease of the lesion area in the treated group at 48h (29+ 11mm3 in the treated group versus 39+ 5mm3 in the control group, P=0.04). XG-102 mainly inhibits the edema component of the lesion. Indeed, a significant inhibition Journal of Cerebral Blood Flow & Metabolism (2009) 29, S490-S493 & 2009 ISCBFM All rights reserved 0271-678X/09 $32.00 www.jcbfm.com of the brain swelling was observed in treated animals at 48h (14%+ 13% versus 26+ 9% in the control group, P=0.04) and 5d (_0.3%+ 4.5%versus 5.1+ 3.6%in the control group, P=0.01). Conclusions: Inhibition of the JNK pathway by XG- 102 appears to lead to several beneficial effects. We can show here a significant inhibition of the cerebral edema in the ICH model providing a further beneficial effect of the XG-102 treatment, in addition to the neuroprotection previously described in the ischemic model. This result is of interest because currently, clinical treatment for brain edema is limited. Importantly, the beneficial effects observed with XG-102 in models of both stroke types open the possibility to rapidly treat stroke patients before identifying the stroke subtype by imaging. This will save time which is precious for stroke outcome.