Pharmacokinetics, biodistribution and toxicology of novel cell-penetrating peptides.

Cell-penetrating peptides (CPPs) have been used in basic and preclinical research in the past 30 years to facilitate drug delivery into target cells. However, translation toward the clinic has not been successful so far. Here, we studied the pharmacokinetic (PK) and biodistribution profiles of Shuttle cell-penetrating peptides (S-CPP) in rodents, combined or not with an immunoglobulin G (IgG) cargo. We compared two enantiomers of S-CPP that contain both a protein transduction domain and an endosomal escape domain, with previously shown capacity for cytoplasmic delivery. The plasma concentration versus time curve of both radiolabelled S-CPPs required a two-compartment PK analytical model, which showed a fast distribution phase (t1/2α ranging from 1.25 to 3 min) followed by a slower elimination phase (t1/2ß ranging from 5 to 15 h) after intravenous injection. Cargo IgG combined to S-CPPs displayed longer elimination half-life, of up to 25 h. The fast decrease in plasma concentration of S-CPPs was associated with an accumulation in target organs assessed at 1 and 5 h post-injection, particularly in the liver. In addition, in situ cerebral perfusion (ISCP) of L-S-CPP yielded a brain uptake coefficient of 7.2 ± 1.1 µl g-1 s-1, consistent with penetration across the blood-brain barrier (BBB), without damaging its integrity in vivo. No sign of peripheral toxicity was detected either by examining hematologic and biochemical blood parameters, or by measuring cytokine levels in plasma. In conclusion, S-CPPs are promising non-toxic transport vectors for improved tissue distribution of drug cargos in vivo.

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

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

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

Impact of diabetes and gender on survival after acute myocardial infarction in the Province of Quebec, Canada--a population-based study.

AIMS: To examine the impact of diabetes, gender and their interaction on 30-day, 1-year and 5-year post-acute myocardial infarction (AMI) mortality in three age groups (20-64, 65-74 and > or = 75 years). METHODS: Retrospective analysis including 23 700 patients aged > or = 20 years (22% with diabetes) admitted to hospital for a first AMI in any hospital in the Province of Quebec, Canada, between April 1995 and March 1997. Administrative databases were used to identify patients and assess outcomes. RESULTS: Regarding 30-day mortality, there was non-significant interaction between diabetes and gender. Women aged < 75 years had, independently of diabetes status, at least a 38% (P < 0.05) higher mortality than their male counterparts after adjustment for socio-economic status and co-morbid conditions. Gender difference disappeared, however, after controlling for in-hospital complications. Regarding 1-year mortality (31-365 days), there was no significant gender disparity for all age groups. During the 5-year follow-up, no gender differences were seen in any age group, except for younger (< 65 years) women with diabetes, who had a 52% (P = 0.004) higher mortality than men after controlling for co-variables. This female disadvantage was demonstrated by a significant interaction between diabetes and gender in patients aged < 65 years (P = 0.009). CONCLUSIONS: The higher 30-day mortality post-AMI in younger (20-64 years) and middle-aged (65-74 years) women compared with men was not influenced by diabetes status. However, during the 5-year follow-up, the similar gender mortality observed in patients without diabetes seemed to disappear in younger patients with diabetes, which may be explained by the deleterious, long-term, post-AMI impact of diabetes in younger women.

[Structural and functional neuroanatomy of attention-deficit hyperactivity disorder (ADHD)]. / Neuroanatomie structurelle et fonctionnelle du trouble déficitaire d'attention avec ou sans hyperactivité (TDAH).

INTRODUCTION: Attention-deficit hyperactivity disorder (ADHD) is a common and impairing neuropsychiatric disorder with preschool onset. ADHD occurs in approximately 3-9% of the childhood population. There is a much higher incidence rate in boys who are around three times more likely than girls to be diagnosed. Approximately 30-60% of individuals diagnosed with ADHD in youth have symptoms that persist into adulthood. LITERATURE FINDINGS: Three subtypes of the disorder have been proposed in the current clinical view of ADHD: inattentive, hyperactive-impulsive and combined type. Numerous problems are associated with ADHD: poor academic performance, learning disorders, subtle cognitive deficits, conduct disorders, antisocial personality disorder, poor social relationships, and a higher incidence of anxiety and depression symptoms into adulthood. Researchers have emphasized poor behavioural inhibition as the central impairment of the disorder. From the neuropsychological viewpoint, impairment of the "hot" affective aspects of executive functions, like behavioural inhibition and attention and the more cognitive, "cool" aspects of executive functions like self-regulation, working memory, planning, and cognitive flexibility, are often reported by studies on ADHD. The hot executive functions are associated with ventral and medial regions of the prefrontal cortex (including the anterior cingulated cortex) and named "hotbrain" and the cool executive functions are associated with the dorsolateral prefrontal cortex and are called "coolbrain". DISCUSSION: Convergent data from neuroimaging, neuropsychology, genetics and neurochemical studies consistently point to the involvement of the frontostriatal network as a likely contributor to the pathophysiology of ADHD. This network involves the lateral prefrontal cortex, the dorsal anterior cingulate cortex, the caudate nucleus and putamen. Moreover, a growing literature demonstrates abnormalities affecting other cortical regions and the cerebellum. The exploratory brain regions of interest in which abnormalities have been identified, but that were not predicted by cognitive models of ADHD, are the temporal lobe, parietal lobe, occipital lobe and lateral ventricles. Anatomical studies suggest widespread reductions in volume throughout the cerebrum and cerebellum, while functional imaging studies suggest that affected individuals activate more diffuse areas than controls during the performance of cognitive tasks. More precisely, reductions in volume have been observed in the total cerebral volume, the prefrontal cortex, the basal ganglia (striatum), the dorsal anterior cingulate cortex, the corpus callosum and the cerebellum. Furthermore, hypoactivation of the dorsal anterior cingulate cortex, the frontal cortex and the basal ganglia (striatum) have also been reported. The paradigms mostly used in functional magnetic resonance imaging (fMRI) are tasks of motor inhibition, interference and attention such as the go/no-go, "stop-signal" and the Stroop. CONCLUSION: This review provides an overview of the main imaging studies that investigated the neurobiological substrate of ADHD. Some guidelines for future functional magnetic imaging studies are also suggested.

[Development of self-regulation and inhibition in children exhibiting attention deficit disorder with or without hyperactivity (ADHD)]. / Développement de l'autorégulation et de l'inhibition chez des enfants présentant un trouble déficitaire de l'attention avec ou sans hyperactivité (TDAH).

INTRODUCTION: Self-regulation shares several affinities with executive functions. However, the specificity of self-regulation deficits in attention deficit/hyperactivity disorder (ADHD) remains unclear. The typical child starts around the age of four to develop a self-control mechanism along with an internal language that allows the child to modulate impulsively. Conversely, a child with ADHD seems to have greater difficulties delaying or retaining an action or response. OBJECTIVE: In this study we aim to evaluate self-regulation of comprehension in ADHD. RESULTS: Our results show that children with ADHD fail to recognize inconsistencies in presented stories at a rate ranging between 72 (eight years) and 54% (ten years). We also found a positive correlation between a better control of self-regulation and our behavioral inhibition measurement. The attentional deficits exhibited through markedly longer reaction times to continuous performance test (CPT) could be responsible for a poor ability to self-regulate. Fast reaction times were found to be associated with increased vigilance/attention that in turn would permit better self-regulation. Furthermore, our findings show that older subjects with ADHD have shorter reaction times to CPT approaching this group to the typical children. DISCUSSION: This suggests that improvement overtime in self-regulation processes may be attributed to the associated development of vigilance/attention in children with ADHD. Improved vigilance/attention would result in optimal reaction times during tasks that require self-regulation. In addition, our findings suggest that subjects with ADHD have developmental trajectories similar to those observed in healthy subjects. CONCLUSION: In the present study, the lack of a comparison group does not allow us to conclude if such trajectory is delayed compared to typical subjects. Finally, there was no significant relation between the degree of intelligence and the rate of self-regulation, which makes it possible to distinguish the two functions. However, in ADHD self-regulation is favourably influenced by age as observed in developmental studies on typical children. Thus, maturation independent of intelligence, influences self-regulation processes.

Molecular cloning and characterization of bovine prostaglandin E2 receptors EP2 and EP4: expression and regulation in endometrium and myometrium during the estrous cycle and early pregnancy.

Prostaglandins (PGs) play important functions in the reproductive system, and PGE(2) appears necessary for recognition of pregnancy. We have found that PGE(2) is able to increase cAMP generation in the bovine endometrium. There are two PGE(2) receptors (EP), EP2 and EP4, that are coupled to adenylate cyclase to generate cAMP, but these receptors have not been studied in the bovine. We have cloned and characterized bovine EP2 and EP4 receptors and studied their expression in the uterus. The amino acid sequences of bovine EP2 and EP4 possess a high degree (>80%) of identity with the other mammalian homologs. EP2 is expressed in most tissues, and EP4 is expressed only in intestine and testis. EP2 mRNA and protein are expressed in endometrium and myometrium during the estrous cycle, whereas EP4 is undetectable. The Western analysis indicates that EP2 is maximally expressed in both endometrium and myometrium between d 10 and 18 of the estrous cycle. Immunohistochemical localization reveals that EP2 protein is expressed in all cell types of endometrium and myometrium. On d 18, pregnancy up-regulates EP2 protein, primarily in endometrial stroma and myometrial smooth muscle cells. In conclusion, EP2 is the major cAMP-generating PGE(2) receptor expressed and regulated in the bovine uterus during the estrous cycle and early pregnancy.

Interferon-tau stimulates granulocyte-macrophage colony-stimulating factor gene expression in bovine lymphocytes and endometrial stromal cells.

Interferon-tau (IFN-tau), the antiluteolytic signal produced by the trophoblast prior to implantation in ruminants, exhibits immunomodulatory properties. It stimulates the production of prostaglandin (PG) E(2) in bovine endometrial cells via the induction of cyclooxygenase-2 (COX-2). We previously demonstrated that preconditioning lymphocytes with PGE(2) increases the expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine that promotes conceptus growth and survival. Our goal in the present study was to evaluate the impact of IFN-tau on the expression of GM-CSF in bovine peripheral blood lymphocytes (PBL) and endometrial epithelial and stromal cells. Changes in PGE(2) production and mRNA levels of COX-2 were also studied in PBL in response to IFN-tau. Gene expression was estimated by semiquantitative reverse transcription-polymerase chain reaction and Northern analysis. The expression of GM-CSF in PBL was stimulated by treatment with IFN-tau. Furthermore, GM-CSF mRNA levels were increased after preconditioning PBL for 3 days with IFN-tau, followed by a 12-h restimulation without IFN-tau. Inhibition rather than stimulation of PGE(2) production and COX-2 expression in PBL during treatment with IFN-tau suggests a direct effect on GM-CSF expression. Moreover, GM-CSF expression was stimulated in uterine stromal cells in response to IFN-tau. This study provides the first evidence for stimulation of GM-CSF expression by IFN-tau in both leukocytes and endometrial stromal cells. In view of the role of GM-CSF on fetal growth and survival, these results support the hypothesis that the conceptus mediates accommodation mechanisms in the uterus during early pregnancy by modulating the expression of beneficial cytokines at the fetomaternal interface.

Prostaglandin E2 regulates both interleukin-2 and granulocyte-macrophage colony-stimulating factor gene expression in bovine lymphocytes.

Prostaglandin E2 (PGE2) is known to inhibit interleukin-2 (IL-2) production by human peripheral blood lymphocytes (PBL) and to increase granulocyte-macrophage colony-stimulating factor (GM-CSF). In many species with hemochorial placentation, down-regulation of IL-2 appears necessary to impede early embryonic demise, whereas up-regulation of GM-CSF increases embryonic growth and survival. It is not known whether the same mechanisms are involved in a species with a less invasive placenta. PGE2 is synthesized during early bovine gestation by the endometrium and by the embryo, and it may therefore be involved in regulating IL-2 and GM-CSF in this species. Our goal was to evaluate the impact of PGE2 on cellular proliferation and on IL-2 and GM-CSF gene expression in bovine PBL. Incorporation of [3H]thymidine was used to study DNA synthesis. Gene expression was estimated by semiquantitative polymerase chain reaction using bovine-specific primers and by Northern analysis using amplified bovine cDNAs as probes. The DNA synthesis and IL-2 mRNA levels of bovine PBL stimulated by concanavalin A (ConA) were greatly reduced by PGE2 in direct-treatment studies. Under the same conditions, GM-CSF gene expression was also inhibited. However, pretreatment of PBL for 72 h with ConA and PGE2, followed, after washing, by an incubation with ConA alone for 12 h resulted in reduced DNA synthesis, stable expression of IL-2, and a dramatic increase of GM-CSF mRNA levels. This is the first evidence in the bovine model that direct treatment with PGE2 down-regulates IL-2 and GM-CSF mRNA levels and that preconditioning with PGE2 stimulates GM-CSF gene expression. We propose that PGE2, either from embryonic or from endometrial compartments, induces bovine PBL to undergo functional changes, affecting cellular proliferation and cytokine production in order to accommodate the developing conceptus.