AMCHP Issue Brief: Environmental Scan: State Title V Program Response to Autism Spectrum Disorder and Other Developmental Disabilities, December 2009

The increasing incidence of children identified and diagnosed with Autism Spectrum Disorders (ASD) and other developmental disabilities (DD) poses a major challenge to Title V and other programs as they try to meet the diverse and sometimes complex needs of these children. However, those state that have initiated coordinated efforts to meet the needs of these children cross systems have had the opportunity to form and/or strengthen relationships with new partners. In addition, these coordinated efforts will allow states to develop new policies, programs and financing mechanisms addressing the health of children with ASD, which may also strengthen the system of care for all Children and Youth with Special Health Care Needs.

Backflow-induced asymmetric collapse of disclination lines in liquid crystals

We present experiments where opposed pairs of planar parallel disclination lines of topological strength s=±1 move due to their mutual attraction. Our measurements show that their motion is clearly asymmetric, with +1 defects moving up to twice as fast as -1 ones. This is a clear indication of backflow, given the intrinsic isotropic elasticity of our system. A phenomenological model is able to account for the experimental observations by renormalizing the orientational diffusivity estimated from the velocity of each defect.

Public health significance of bipolar disorder: implications for early intervention and prevention.

OBJECTIVES: Early intervention and preventive strategies have become major targets of research and service development in psychiatry over the last few years. Compared to schizophrenia, bipolar disorder (BD) has received limited attention in this regard. In this paper, we review the available literature in order to explore the public health significance of BD and the extent to which this may justify the development of early intervention strategies for this disorder. METHODS: The main computerized psychiatric literature databases were accessed. This included Medline and PsychInfo, using the following keywords: bipolar, early intervention, staging model, burden, caregiver, public health, and manic depression. RESULTS: BD is often recurrent and has an impact that goes well beyond symptomatic pathology. The burden it incurs is linked not only to its cardinal clinical features, but also to cognitive dysfunction, poor functional outcome, poor physical health, high rate of comorbidities, and suicide. At a societal level, BD induces enormous direct and indirect costs and has a major impact on caregivers. The available literature reveals a usually long delay between illness onset and the start of treatment, and the absence of specific guidelines for the treatment of the early phase of BD. CONCLUSIONS: Considering the major impact of BD on patients and society, there is an urgent need for the development of early intervention strategies aimed at earlier detection and more specific treatment of the early phase of the disorder.

Social and temporal organization in an ant colony

Ant colonies are known for their complex and efficient social organization that com-pletely lacks hierarchical structure. However, due to methodological difficulties in follow¬ing all ants of a colony, it was until now impossible to investigate the social and temporal organization of colonies. We developed a tracking system that allows tracking the posi¬tions and orientations of several hundred individually labeled ants continuously, providing for the first time quantitative long term data on all individuals of a colony. These data permit reconstructing trajectories, activity patterns and social networks of all ants in a colony and enable us to investigate ant behavior quantitatively in previously unpreceded ways. By analyzing the spatial positions and social interactions of all ants in six colonies for 41 days we show that ant colonies are organized in groups of nurses, nest patrollers and foragers. Workers of each group were highly interconnected and occupied similar spa¬tial locations in the nest. Groups strongly segregated spatially, and were characterized by unique behavioral signatures. Nurses spent most of their time on the brood. Nest patrollers frequently visited the rubbish pile, and foragers frequently visited the forag¬ing arena. In addition nurses were on average younger than nest patrollers who were, in turn, younger than foragers. We further show that workers had a preferred behav¬ioral trajectory and moved from nursing to nest patrolling, and from nest patrolling to foraging. By analyzing the activity patterns of all ants we show that only a third of all workers in a colony exhibit circadian rhythms and that these rhythms shortened by on av¬erage 42 minutes in constant darkness, thereby demonstrating the presence of a functional endogenous clock. Most rhythmic workers were foragers suggesting that rhythmicity is tightly associated with task. Nurses and nest patrollers were arrhythmic which most likely reflects plasticity of the circadian clock, as isolated workers in many species exhibit circadian rhythmicity. Altogether our results emphasize that ant colonies, despite their chaotic appearance, repose on a strong underlying social and temporal organization. - Les colonies de fourmis sont connues pour leur organisation sociale complexe et effi-cace, charactérisée par un manque absolu de structure hiérarchique. Cependant, puisqu'il est techniquement très difficile de suivre toutes les fourmis d'une colonie, il a été jusqu'à maintenant impossible d'étudier l'organisation sociale et temporelle des colonies de four-mis. Nous avons développé un système qui permet d'extraire en temps réel à partir d'images vidéo les positions et orientations de plusieurs centaines de fourmis marquées individuellement. Nous avons pu ainsi générer pour la première fois des données quanti-tatives et longitudinales relatives à des fourmis appartenant à une colonie. Ces données nous ont permis de reconstruire la trajectoire et l'activité de chaque fourmi ainsi que ses réseaux sociaux. Ceci nous a permis d'étudier de manière exhaustive et objective le com-portement de tous les individus d'une colonie. En analysant les données spatiales et les interactions sociales de toutes les fourmis de six colonies qui ont été filmées pendant 41 jours, nous montrons que les fourmis d'une même colonie se répartissent en trois groupes: nourrices, patrouilleuses et approvisionneuses. Les fourmis d'un même groupe interagis-sent fréquemment et occupent le même espace à l'intérieur du nid. L'espace propre à un groupe se recoupe très peu avec celui des autres. Chaque groupe est caractérisé par un comportement typique. Les nourrices s'affairent surtout autour du couvain. Les pa-trouilleuses font de fréquents déplacements vers le tas d'ordures, et les approvisionneuses sortent souvent du nid. Les nourrices sont en moyenne plus jeunes que les patrouilleuses qui, à leur tour, sont plus jeunes que les approvisionneuses. De plus, nous montrons que les ouvrières changent de tâche au cours de leur vie, passant de nourrice à patrouilleuse puis à approvisionneuse. En analysant l'activité de chaque fourmi, nous montrons que seulement un tiers des ouvrières d'une colonie présente des rythmes circadiens et que ces rythmes diminuent en moyenne de 42 minutes lorsqu'il y a obscurité constante, ce qui démontre ainsi la présence d'une horloge endogène. De plus, la plupart des approvi¬sionneuses ont une activité rythmique alors que les nourrices et patrouilleuses présentent une activité arythmique, ce qui suggère que la rythmicité est étroitement associée à la tâche. L'arythmie des nourrices et patrouilleuses repose probablement sur une plasticité de l'horloge endogène car des ouvrières de nombreuses espèces font preuve d'une ryth¬micité circadienne lorsqu'elles sont isolées de la colonie. Dans l'ensemble nos résultats révèlent qu'une colonie de fourmis se fonde sur une solide organisation sociale et tem¬porelle malgré son apparence chaotique.

The function of a new regulator of epidermal differentiation, HOP, and pathomechanisms underlying epidermolytic hyperkeratosis

The process of epidermal differentiation involves proliferation, differentiation, migration and maturation of keratinocytes to form an impermeable barrier against water loss and outside environment. It is controlled by highly balanced regulatory machinery, involving many molecules that are still under investigation.Homeobox proteins are involved in body patterning and morphogenesis of organs and are studied as potentially good candidates to regulate this process. In the first project we investigated the role of a protein named HOP which belongs to a group of homeobox proteins. Even if HOP is a small protein almost completely composed of the homeodomain and without DNA binding capacity, it is considered as transcriptional regulator in different tissues. HOP interacts with serum response factor (SRF) and histone deacetylase type 2 (HDAC2). By microarray analysis we found that HOP expression increases in cultured human primary keratinocytes (NHK) which undergo calcium-induced differentiation. HOP protein was localized in granular layer of the epidermis of healthy individuals. Lack of HOP was demonstrated in psoriatic lesions, whereas a strong expression was demonstrated in the lesional skin of patients affected with lichen planus (LP). Since LP is characterized by hypergranulosis while psoriatic lesions by progressive lack of the granular layer, the obtained data indicated that HOP might have a potential function in granular layer of epidermis. To investigate HOP function, we inhibited its expression by using HOP specific StealthRNAi and we overexpressed HOP using lentiviral vectors in differentiating NHK. The conclusion of both experiments indicated that HOP positively regulates the expression of late differentiation markers, such as profilaggrin, loricrin and transglutaminase 1. The in vitro data were next confirmed in vivo using HOP knockout mouse model.The second part of my study involved analysis of mechanisms underlying the pathogenesis of epidermolytic hyperkeratosis (EHK). EHK is a genetic disorder characterized by erythema, skin blistering, keratinocyte hyperproliferation and hyperkeratosis. EHK is caused by mutations in keratin 1 or 10 (K1, K10) which are major structural proteins of differentiated keratinocytes and participate in the cellular scaffold formation. To investigate how the structural proteins carrying mutations alter cellular signaling, we established an in vitro model for EHK by overexpression of one of the most common K10 mutations reported so far (K10R156H), in primary human keratinocytes. In order to mimic the in vivo situation, mutated keratinocytes growing on silicone membranes were subjected to mechanical stretch. We observed strong collapse of KIF in K10R156H keratinocytes when subjected to stretch for 30 minutes. Our data demonstrated stronger activation of p38, a member of MAPK stress signaling pathways, in K10R156H when compared to control cells. We demonstrated also that K10R156H keratinocytes showed an induction of TNF-α and RANTES release in response to stretch.Taken together these studies characterize a novel regulator of epidermal differentiation - HOP and demonstrate new aspects implicated in the pathogenesis of EHK.

Early clarification processes in clients presenting with borderline personality disorder: Relations with symptom level and change

Clarification-Oriented Psychotherapy (COP), an integrative treatment form with a basis in process-experiential psychotherapy, is particularly relevant for clients with Personality Disorders (PDs). We argue here that two related core therapeutic COP principles, "dual action regulation" and "interactional games" have consequences for symptom severity and therapeutic outcome for clients with PDs. A high quality COP clarification process requires that client's interactional games may be quickly assessed and treated in all (preferably early) therapy sessions. These processes can be observed and measured using the observer-rated Bochum Process and Relationship Rating Scales (BPRRS) which measure both clients' and therapists' contributions to the quality of the clarification processes engaged in therapy. This measure has been successfully applied to COP-therapies, but not, as yet, to therapies other than experiential, nor to specific client populations such as borderline personality disorder. The present study is a first attempt to evaluate the application of COP processes to other therapies and populations. We measured action regulation and interactional games using the BPRRS during intake sessions of a 10-session psychodynamic treatment of borderline personality disorder for a total of N = 30 clients and N = 8 therapists. Significant relationships were found between the client's degree of interactional games and both pretherapy symptom level and symptom change across therapy. These results are discussed in the context of Clarification-Oriented Psychotherapy, and more generally Person-Centered and Process-Experiential Psychotherapies. The potential relevance of the findings for psychodynamic psychotherapists are explored as well as the potential usefulness of taking into account a detailed analysis of interactional games for the training of psychotherapists working with any model of therapy working with clients presenting with BPD.

Congenital disorder of glycosylation type Id (CDG Id): phenotypic, biochemical and molecular characterization of a new patient.

Congenital disorders of glycosylation (CDG) are a family of multisystem inherited disorders caused by defects in the biosynthesis of N- or O-glycans. Among the many different subtypes of CDG, the defect of a mannosyltransferase encoded by the human ALG3 gene (chromosome 3q27) is known to cause CDG Id. Six patients with CDG Id have been described in the literature so far. We further delineate the clinical, biochemical, neuroradiological and molecular features of CDG Id by reporting an additional patient bearing a novel missense mutation in the ALG3 gene. All patients with CDG Id display a slowly progressive encephalopathy with microcephaly, severe psychomotor retardation and epileptic seizures. They also share some typical dysmorphic features but they do not present the multisystem involvement observed in other CDG syndromes or any biological marker abnormalities. Unusually marked osteopenia is a feature in some patients and may remain undiagnosed until revealed by pathological fractures. Serum transferrin screening for CDG should be extended to all patients with encephalopathy of unknown origin, even in the absence of multisystem involvement.

Cono-spondylar dysplasia: Clinical, radiographic, and molecular findings of a previously unreported disorder.

We report on a consanguineous Arab family in which three sibs had an unusual skeletal dysplasia characterized by anterior defects of the spine leading to severe lumbar kyphosis and marked brachydactyly with cone epiphyses. The clinical phenotype also included dysmorphic facial features, epilepsy, and developmental delay. This constellation likely represents a previously undescribed skeletal dysplasia, most probably inherited in an autosomal recessive pattern. A homozygosity mapping approach has thus far failed to unearth the responsible gene as the region shared by these three sibs is 27.7 Mb in size and contains over 200 genes with no obvious candidate.

Randomized Trial of prophylactic granulocyte colony-stimulating factor during rapid COJEC induction in pediatric patients with high-risk neuroblastoma: the European HR-NBL1/SIOPEN study.

Purpose To reduce the incidence of febrile neutropenia during rapid COJEC (cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide given in a rapid delivery schedule) induction. In the High-Risk Neuroblastoma-1 (HR-NBL1) trial, the International Society of Paediatric Oncology European Neuroblastoma Group (SIOPEN) randomly assigned patients to primary prophylactic (PP) versus symptom-triggered granulocyte colony-stimulating factor (GCSF; filgrastim). Patients and Methods From May 2002 to November 2005, 239 patients in 16 countries were randomly assigned to receive or not receive PPGCSF. There were 144 boys with a median age of 3.1 years (range, 1 to 17 years) of whom 217 had International Neuroblastoma Staging System (INSS) stage 4 and 22 had stage 2 or 3 MYCN-amplified disease. The prophylactic arm received a single daily dose of 5 μg/kg GCSF, starting after each of the eight COJEC chemotherapy cycles and stopping 24 hours before the next cycle. Chemotherapy was administered every 10 days regardless of hematologic recovery, provided that infection was controlled. Results The PPGCSF arm had significantly fewer febrile neutropenic episodes (P = .002), days with fever (P = .004), hospital days (P = .017), and antibiotic days (P = .001). Reported Common Toxicity Criteria (CTC) graded toxicity was also significantly reduced: infections per cycle (P = .002), fever (P < .001), severe leucopenia (P < .001), neutropenia (P < .001), mucositis (P = .002), nausea/vomiting (P = .045), and constipation (P = .008). Severe weight loss was reduced significantly by 50% (P = .013). Protocol compliance with the rapid induction schedule was also significantly better in the PPGCSF arm shown by shorter time to completion (P = .005). PPGCSF did not adversely affect response rates or success of peripheral-blood stem-cell harvest. Following these results, PPG-GSF was advised for all patients on rapid COJEC induction.

Rationale and first results of developing at-risk (prodromal) criteria for bipolar disorder.

Bipolar affective disorder (BD) is a severe, recurrent and disabling disorder with devastating consequences for individuals, families and society. Although these hazards and costs provide a compelling rationale for development of early detection and early intervention strategies in BD, the development of at-risk criteria for first episode mania is still in an early stage of development. In this paper we review the literature with respect to the clinical, neuroantomical and neuropsychological data, which support this goal. We also describe our recently developed bipolar at-risk criteria (BAR). This criteria comprises the peak age range of the first onset of bipolar disorder, genetic risk, presenting with sub-threshold mania, cyclothymic features or depressive symptoms. An initial pilot evaluation of the BAR criteria in 22 subjects indicated conversion rates to proxies of first-episode mania of 23% within 265 days on average, and high specificity and sensitivity of the criteria. If prospective studies confirm the validity of the BAR criteria, then the criteria would have the potential to open up new avenues of research for indicated prevention in BD and might therefore offer opportunities to ameliorate the severity of, or even prevent BD.