Early ACCESS (EA) – Early Hearing Detection and Intervention (EHDI) Questions and Answers Summary

This is a six page document of Qusetions and Answer for Early Hearing Detecting and Inventation.

Intervention of carbonate components in petrogenesis of the pyroxene nephelinites from the Jbel Saghro (Anti-Atlas, Morocco)

The Jbel Saghro alkaline complex was emplaced close to the eastern edge of the Moroccan Anti-Atlas. Within the northern part, two types of nephelinite were recognized [Ibhi and Nachit, 1999 and lbhi, 2000]. The first type (olivine-rich nephelinite) constitutes the main volcanic mass south of the Bou Gafer granit (fig. 1), where the volcanism had been active at least during 2 Ma, between 9.6 and 7.5 +/- 0.1 Ma [Berrahma et al., 1993]. The second group outcrops in the north (Foum El Kouss). It consists of pyroxene nephelinites which are younger (2.9 +/- 0.1 Ma) [Berrahma et al., 1993], and bears carbonatitic xenoliths, melteigitic pyroxenites and metasomatised peridotite xenoliths. Geochemically, the pyroxene nephelinite is highly enriched in LILE compared with the first one. The mineralogical and geochemical characteristics may be explained by the incorporation of carbonatitic and melteigitic pyroxenite segregates of carbonatitic affinity.

Immune response to MMTV infection.

Mouse mammary tumor virus (MMTV) has developed a strategy of exploitation of the immune response. It infects dendritic cells and B cells and requires this infection to establish an efficient chronic infection. This allows transmission of infection to the mammary gland, production in milk and infection of the next generation via lactation. The elaborate strategy developed by MMTV utilizes several key elements of the normal immune response. Starting with the infection and activation of dendritic cells and B cells leading to the expression of a viral superantigen followed by professional superantigen-mediated priming of naive polyclonal T cells by dendritic cells and induction of superantigen-mediated T cell B cell collaboration results in long-lasting germinal center formation and production of long-lived B cells that can later carry the virus to the mammary gland epithelium. Later in life it can induce transformation of mammary gland epithelium by integrating close to proto-oncogenes leading to their overexpression. Genes encoding proteins of the Wnt-pathway are preferential targets. This review will put these effects in the context of a normal immune response and summarize important facts on MMTV biology.

Age vs. Experience: Evaluation of a Video Feedback Intervention for Newly Licensed Teen Drivers, TPF-5(207), 2013

This project examines the effects of age, experience, and video-based feedback on the rate and type of safety-relevant events captured on video event recorders in the vehicles of three groups of newly licensed young drivers: 1. 14.5- to 15.5-year-old drivers who hold a minor school license (see Appendix A for the provisions of the Iowa code governing minor school licenses); 2. 16-year-old drivers with an intermediate license who are driving unsupervised for the first time; 3. 16-year-old drivers with an intermediate license who previously drove unsupervised for at least four months with a school license. METHODS: The young drivers’ vehicles were equipped with an event-triggered video recording device for 24 weeks. Half of the participants received feedback regarding their driving, and the other half received no feedback at all and served as a control group. The number of safety-relevant events per 1,000 miles (i.e., “event rate”) was analyzed for 90 participants who completed the study. RESULTS: On average, the young drivers who received the video-based intervention had significantly lower event rates than those in the control group. This finding was true for all three groups. An effect of experience was seen for drivers in the control group; the 16-year-olds with driving experience had significantly lower event rates than the 16-year-olds without experience. When the intervention concluded, an increase in event rate was seen for the school license holders, but not for either group of 16-year-old drivers. There is strong evidence that giving young drivers video-based feedback, regardless of their age or level of driving experience, is effective in reducing the rate of safety-relevant events relative to a control group who do not receive feedback. Specific comparisons with regard to age and experience indicated that the age of the driver did not have an effect on the rate of safety-events, while experience did. Young drivers with six months or more of additional experience behind the wheel had nearly half as many safety-relevant events as those without that experience.

Microbial influences on epithelial integrity and immune function as a basis for inflammatory diseases.

Certain autoimmune diseases as well as asthma have increased in recent decades, particularly in developed countries. The hygiene hypothesis has been the prevailing model to account for this increase; however, epidemiology studies also support the contribution of diet and obesity to inflammatory diseases. Diet affects the composition of the gut microbiota, and recent studies have identified various molecules and mechanisms that connect diet, the gut microbiota, and immune responses. Herein, we discuss the effects of microbial metabolites, such as short chain fatty acids, on epithelial integrity as well as immune cell function. We propose that dysbiosis contributes to compromised epithelial integrity and disrupted immune tolerance. In addition, dietary molecules affect the function of immune cells directly, particularly through lipid G-protein coupled receptors such as GPR43.

Antibody-mediated and cellular immune responses induced in naive volunteers by vaccination with long synthetic peptides derived from the Plasmodium vivax circumsporozoite protein.

Plasmodium vivax circumsporozoite (CS) protein is a leading malaria vaccine candidate. We describe the characterization of specific immune responses induced in 21 malaria-naive volunteers vaccinated with long synthetic peptides derived from the CS protein formulated in Montanide ISA 720. Both antibody- and cell-mediated immune responses were analyzed. Antibodies were predominantly of IgG1 and IgG3 isotypes, recognized parasite proteins on the immunofluorescent antibody test, and partially blocked sporozoite invasion of hepatoma cell lines in vitro. Peripheral blood mononuclear cells from most volunteers (94%) showed IFN-γ production in vitro upon stimulation with both long signal peptide and short peptides containing CD8+ T-cell epitopes. The relatively limited sample size did not allow conclusions about HLA associations with the immune responses observed. In summary, the inherent safety and tolerability together with strong antibody responses, invasion blocking activity, and the IFN-γ production induced by these vaccine candidates warrants further testing in a phase II clinical trial.

Motivational intervention to reduce cannabis use in young people with psychosis: a randomized controlled trial.

Background: Cannabis use has a negative impact on psychosis. Studies are needed to explore the efficacy of psychological interventions to reduce cannabis use in psychosis. Our aim is to study the efficacy of a specific motivational intervention on young cannabis users suffering from psychosis. Methods: Participants (aged less than 35 years) were randomly assigned to treatment as usual (TAU) alone, or treatment as usual plus motivational intervention (MI + TAU). TAU was comprehensive and included case management, early intervention and mobile team when needed. Assessments were completed at baseline and at 3, 6 and12 months follow-up. Results: Sixty-two participants (32 TAU and 30 MI + TAU) were included in the study. Cannabis use decreased in both groups at follow-up. Participants who received MI in addition to TAU displayed both a greater reduction in number of joints smoked per week and greater confidence to change cannabis use at 3 and 6 months follow-up, but differences between groups were nonsignificant at 12 months. Conclusions: MI is well accepted by patients suffering from psychosis and has a short-term impact on cannabis use when added to standard care. However, the differential effect was not maintained at 1-year follow-up. MI appears to be a useful active component to reduce cannabis use which should be integrated in routine clinical practice.

Normal pathogen-specific immune responses mounted by CTLA-4-deficient T cells: a paradigm reconsidered.

CTLA-4 is a critical negative regulator of T cell responses and CTLA-4-deficient (CTLA-4(-/-)) mice die of a lymphproliferative disease. Nevertheless, RAG-2-deficient mice reconstituted with a mixture of CTLA-4(-/-) and normal (CTLA-4(+/+)) bone marrow survive in the absence of any signs of disease, although 50% of their T cells do not express CTLA-4. Using such mixed chimeras, we analyzed the role of CTLA-4 in specific T cell responses to lymphocytic choriomeningitis virus, Leishmania major and mouse mammary tumor virus, which cause acute, chronic and persistent infections, respectively. The populations of antigen-specific CTLA-4(-/-)CD4(+) and CTLA-4(-/-)CD8(+) T cells became activated, expanded and contracted indistinguishably from CTLA-4(+/+)CD4(+) and CTLA-4(+/+)CD8(+) T cells after infection with all three pathogens. Thus, CTLA-4 is not involved in the down-regulation of specific T cell responses and peripheral deletion in a T cell-autonomous fashion.

Persistent infection of arenaviruses : molecular mechanisms and pathogenesis

Arenaviruses are enveloped negative single strand RNA viruses that include a number of important human pathogens. The most prevalent human pathogen among the arenaviruses is the Old World arenavirus Lassa virus (LASV) which is endemic in West Africa from Senegal to Cameroon. LASV is the etiologic agent of a severe viral hemorrhagic fever named Lassa fever whose mortality rate can reach 30% in hospitalized patients. One of the hallmarks of fatal arenavirus infection in humans is the absence of an effective innate and adaptive immune response. In nature, arenaviruses are carried by rodents which represent the natural reservoirs as well as the vectors for transmission. In their natural rodent reservoir, arenaviruses have the ability to establish persistent infection without any overt signs and symptoms of pathology. We believe that the modulation of the host cell's innate immunity by arenaviruses is a key determinant for persistence in the natural host and for the pathogenesis in man. In this thesis, we studied the interaction of arenaviruses with two main branches of the host's innate anti-viral defense, the type I interferon (IFN) system and virus-induced mitochondrial apoptosis. The arenavirus nucleoprotein (NP) is responsible for the anti-IFN activity of arenaviruses. Specifically, NP blocks the activation and the nuclear translocation of the transcription factor interferon regulatory factor 3 (IRF3) which leads to type I IFN production. LASV and the prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) NPs contain a 3'-5'exoribonuclease domain in the C terminal part that has been linked to the anti-IFN activity of NP. In the first project, we sought to identify cellular component(s) of the type I IFN induction pathway targeted by the viral NP. Our study revealed that LCMV NP prevents the activation of IRF3 by blocking phosphorylation of the transcription factor. We found that LCMV NP specifically targets the IRF-activating kinase IKKs, and this specific binding is conserved within the Arenaviridae. We could also demonstrate that LCMV NP associates with the kinase domain of IKKs involving NP's C-terminal region. Lastly, we showed that the binding of LCMV NP inhibits the kinase activity of IKKs. This study allowed the discovery of a new cellular interacting partner of arenavirus NP. This newly described association may play a role in the anti-IFN activity of arenaviruses but potentially also in other aspects of arenavirus infection. For the second project, we investigated the ability of arenaviruses to avoid and/or suppress mitochondrial apoptosis. As persistent viruses, arenaviruses evolved a "hit and stay" survival strategy where the apoptosis of the host cell would be deleterious. We found that LCMV does not induce mitochondrial apoptosis at any time during infection. Specifically, no caspase activity, no cytochrome c release from the mitochondria as well as no cleavage of poly (ADP-ribose) polymerase (PARP) were detected during LCMV infection. Interestingly, we found that virus-induced mitochondrial apoptosis remains fully functional in LCMV infected cells, while the induction of type IIFN is blocked. Since both type IIFN production and virus- induced mitochondrial apoptosis critically depend on the pattern recognition receptor (PRR) RIG-I, we examined the role of RIG-I in apoptosis in LCMV infected cells. Notably, virus- induced mitochondrial apoptosis in LCMV infected cells was found to be independent of RIG- I and MDA5, but still depended on MAVS. Our study uncovered a novel mechanism by which arenaviruses alter the host cell's pro-apoptotic signaling pathway. This might represent a strategy arenaviruses developed to maintain this branch of the innate anti-viral defense in absence of type I IFN response. Taken together, these results allow a better understanding of the interaction of arenaviruses with the host cell's innate immunity, contributing to our knowledge about pathogenic properties of these important viruses. A better comprehension of arenavirus virulence may open new avenues for vaccine development and may suggest new antiviral targets for therapeutic intervention against arenavirus infections. - Les arenavirus sont des virus enveloppés à ARN simple brin qui comportent un grand nombre de pathogènes humains. Le pathogène humain le plus important parmi les arenavirus est le virus de Lassa qui est endémique en Afrique de l'Ouest, du Sénégal au Cameroun. Le virus de Lassa est l'agent étiologique d'une fièvre hémorragique sévère appelée fièvre de Lassa, et dont le taux de mortalité peut atteindre 30% chez les patients hospitalisés. L'une des caractéristiques principales des infections fatales à arenavirus chez l'Homme est l'absence de réponse immunitaire innée et adaptative. Dans la nature, les arenavirus sont hébergés par différentes espèces de rongeur, qui représentent à la fois les réservoirs naturels et les vecteurs de transmission des arenavirus. Dans leur hôte naturel, les arenavirus ont la capacité d'établir une infection persistante sans symptôme manifeste d'une quelconque pathologie. Nous pensons que la modulation de système immunitaire inné de la cellule hôte par les arenavirus est un paramètre clé pour la persistance au sein de l'hôte naturel, ainsi que pour la pathogenèse chez l'Homme. L'objectif de cette thèse était d'étudier l'interaction des arenavirus avec deux branches essentielles de la défense antivirale innée de la cellule hôte, le système interféron (IFN) de type I et l'apoptose. La nucléoprotéine virale (NP) est responsable de l'activité anti-IFN des arenavirus. Plus spécifiquement, la NP bloque 1'activation et la translocation nucléaire du facteur de transcription IRF3 qui conduit à la production des IFNs de type I. La NP du virus de Lassa et celle du virus de la chorioméningite lymphocytaire (LCMV), l'arénavirus prototypique, possèdent dans leur extrémité C-terminale un domaine 3'-5' exoribonucléase qui a été associé à l'activité anti-IFN de ces protéines. Dans un premier projet, nous avons cherché à identifier des composants cellulaires de la cascade de signalisation induisant la production d'IFNs de type I qui pourraient être ciblés par la NP virale. Nos recherches ont révélé que la NP de LCMV empêche 1'activation d'IRF3 en bloquant la phosphorylation du facteur de transcription. Nous avons découvert que la NP de LCMV cible spécifiquement la kinase IKKe, et que cette interaction spécifique est conservée à travers la famille des Arenaviridae. Notre étude a aussi permis de démontrer que la NP de LCMV interagit avec le domaine kinase d'IKKe et que l'extrémité C-terminale de la NP est impliquée. Pour finir, nous avons pu établir que l'association avec la NP de LCMV inhibe l'activité kinase d'IKKe. Cette première étude présente la découverte d'un nouveau facteur cellulaire d'interaction avec la NP des arenavirus. Cette association pourrait jouer un rôle dans l'activité anti-IFN des arénavirus, mais aussi potentiellement dans d'autres aspects des infections à arénavirus. Pour le second projet, nous nous sommes intéressés à la capacité des arénavirus à éviter et/ou supprimer l'apoptose mitochondriale. En tant que virus persistants, les arénavirus ont évolué vers une stratégie de survie "hit and stay" pour laquelle l'apoptose de la cellule hôte serait néfaste. Nous avons observé qu'à aucun moment durant l'infection LCMV n'induit l'apoptose mitochondriale. Spécifiquement, aucune activité de caspase, aucune libération mitochondriale de cytochrome c ainsi qu'aucun clivage de la polymerase poly(ADP-ribose) (PARP) n'a été détecté pendant l'infection à LCMV. Il est intéressant de noter que l'apoptose mitochondriale induite par les virus reste parfaitement fonctionnelle dans les cellules infectées par LCMV, alors que l'induction de la réponse IFN de type I est bloquée dans les mêmes cellules. La production des IFNs de type I et l'apoptose mitochondriale induite par les virus dépendent toutes deux du récepteur de reconnaissance de motifs moléculaires RIG-I. Nous avons, par conséquent, investigué le rôle de RIG-I dans l'apoptose qui a lieu dans les cellules infectées par LCMV lorsqu'on les surinfecte avec un autre virus pro-apoptotique. En particulier, l'apoptose mitochondriale induite par les surinfections s'est révélée indépendante de RIG-I et MDA5, mais dépendante de MAVS dans les cellules précédemment infectées par LCMV. Notre étude démontre ainsi l'existence d'un nouveau mécanisme par lequel les arénavirus altèrent la cascade de signalisation pro-apoptotique de la cellule hôte. Il est possible que les arénavirus aient développé une stratégie permettant de maintenir fonctionnelle cette branche de la défense antivirale innée en l'absence de réponse IFN de type I. En conclusion, ces résultats nous amènent à mieux comprendre l'interaction des arénavirus avec l'immunité innée de la cellule hôte, ce qui contribue aussi à améliorer notre connaissance des propriétés pathogéniques de ces virus. Une meilleure compréhension des facteurs de virulence des arénavirus permet, d'une part, le développement de vaccins et peut, d'autre part, servir de base pour la découverte de nouvelles cibles thérapeutiques utilisées dans le traitement des infections à arénavirus.

Longevity differs among sexes but is not affected by repeated immune activation in voles (Microtus arvalis)

Investment of resources in immune defences, despite obvious short-term benefits, may be detrimental to long-term maintenance and thus decrease longevity in absence of parasites. In addition, females and males may differ in immune investment and intrinsic longevity because they are subjected to different degrees of sexual competition and extrinsic mortality. In order to test if sex-specific investment in mounting an immune response reduced longevity, we compared the longevity of captive male and female common voles Microtus arvalis regularly challenged with keyhole limpet haemocyanin, an antigen which elicits the production of antibodies, to the longevity of voles injected with the corresponding antigen-free buffer (phosphate-buffered saline). Injections were repeated every 28 days to mimic a chronic infection. The magnitude of immune response did not vary between males and females and did not affect longevity. Overall, females lived longer than males, independently of the immune challenge. Thus, the long-term costs of immunity seem small in voles. The longevity pattern is consistent with the prediction that male-biased predation or parasitism in the wild causes reduced intrinsic lifespan, but this reduction is not mediated by a decrease in male immunity