Mental health problems are increasing in Swedish adolescents and mortality rates are higher in this age group than among younger. 10-20% of all adolescents suffer from a chronic medical condition (CC). Few protective factors (PF) and clustering of health-risk behaviours (HRB) are frequent among adolescents with CCs. One of the most common CC in Swedish adolescents is type 1 diabetes mellitus (T1DM). Metabolic control often deteriorates during adolescence, especially in girls. Poor metabolic control is associated with increased risk for long-term complications, of which cognitive problems are common. However, the implication of cognitive/executive problems in patients with T1DM has not been sufficiently studied. Neither has the impact of neurodevelopmental problems (NDP), such as ADHD, on HRB in adolescents with CCs been analysed. Methods: In paper I and II the questionnaire ”Life and Health in Youth” was distributed to all students in year nine and year two of the upper secondary school in the county of Sörmland, 2008 (n=5771) and 2011 (n=5550). Adolescents with CCs were compared to healthy peers with regard to PFs and HRBs. In paper III, the ”Five to Fifteen” questionnaire was used in 175 paediatric patients with T1DM. Patients with indications of NDPs were compared with patients without such problems with regard to metabolic control. In paper IV, the BRIEF questionnaire and the ADHD Rating Scale as well as data from the Swedish Childhood Diabetes Registry was used in 241 adolescents with T1DM. Patients with indications of executive problems were compared with patients without such problems with regard to diabetes control. Results: CCs were associated with few PFs and clustered HRBs. The combination of CCs and low numbers of PFs was found to be associated with an increased risk of clustered HRBs. In the presence of coexisting ADHD the pattern of few PFs and clustering of HRBs was aggravated. ADHD was more common among adolescents with other CCs. Definite memory and learning problems as well as mild executive problems were associated with poor metabolic control, especially among adolescents. Executive problems were also associated with many outpatient visits and low physical activity. Girls with T1DM tended to self-report executive problems to a larger extent than boys, while parents more often reported these problems in boys. Conclusion: Knowledge about factors influencing treatment adherence and life in general is essential in the work with chronically ill adolescents. Focus must be put on enhancing PFs in order to avoid HRBs. Identification of coexisting NDPs, such as ADHD, is crucial, since such problems can adversely influence treatment adherence, HRBs and school achievements

Thesis (MScSportSc)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Autism Spectrum Disorder (ASD) has been described as a neuro-developmental disorder influencing the social interaction and communication skills of individuals. Those with ASD have been observed to experience sensory input challenges, which could result in motor delays. Descriptive research was conducted with two case studies, who were boys aged 6- and 8-years, diagnosed with ASD. The purpose of the study was to design and implement a Sensory-Motor Integration (SMI) programme for each boy and to assess the effect it had on the sensory motor skills of the boys over time. At the start of the intervention, the boys were assessed with three neuro-developmental and diagnostic evaluations (Social Communication Questionnaire, Autism Diagnostic Interview Revised and Autism Diagnostic Observation Schedule-2nd Edition) conducted by a psychiatrist to re-affirm their previous ASD diagnoses. The two boys (Subject A and Subject G) participated in individualised sessions of 30 minutes each, twice a week for seven months. The SMI programme focused on vestibular and somato-sensory (proprioceptor) variables. The Quick Neurological Screening Test-3 (QNST III) and the Sensory Input Systems Screening Test (SISST) were used to evaluate the latter at baseline. These were repeated regularly, every 4 to 5 weeks, over the 7-month period and included a retention test of 5 weeks. Based on the results from the subtests of the motor skill tests, a self-designed SMI programme was integrated into the planning of the intervention programme for each boy according to their sensory-motor needs. Subject A showed improvement in the following vestibular subtests in the QNST-III: Stand on one leg (67%) and Tandem walk (83%) and retaining his standard from the Post-test to the Retention test. For muscle tone ability and proprioception, the Arm and leg extension subtest also demonstrated improvement (67%) from the Pre-to the Post-test. The results of the subtest were not retained over the retention period and increased only slightly being 33% from the baseline score. The proprioceptive function of Subject A showed great improvement in the following QNSTIII subtests: Finger to nose (67%), Rapidly reversing repetitive hand movements (88%) and Left and right discrimination (67%). The results of vestibular-related subtests for Subject G showed improvement in the following: Stand on one leg (33%) and the Arm and leg extension task (33%). Some of the scores of Subject G started in the functional category of “severe discrepancy”; however there was improvement in the following proprioceptionrelated subtests: Finger to nose (43%), Thumb and finger circles (20%), and Reversing repetitive hand movements (86%). Although Subject G showed gradual improvement over time, his two sensory systems struggled to integrate with the more complex tasks. The outcome of the individualised SMI programmes showed that the sensory-motor skills improved by enhancing the stimulation of their vestibular and somato-sensory (proprioception) function. Regarding the SISST, Subject A progressed from a ‘fail’ to ‘pass’, in the following test items: the Tonic Labyrinthine Supine (TLS), Tonic Labyrinthine Prone (TLP), Positive Support Reflex (PSR) and the Ocular Alignment test items. Results from the Vestibular test for both Subject A and Subject G appeared to be ‘hypo-vestibular’ (under-stimulated) according to the Post- Rotary Nystagmus test (PRN) score at baseline. These scores were inconsistent during the intervention. The only test item to show positive improvement for Subject G was the Equilibrium Reactions. Lastly, both Subject A and Subject G remained in the ‘fail’ category for Kinaesthesis, which may indicate their ongoing poor proprioception and spatial orientation. There is a need for further research in the area of sensory-motor individualised programmes for children with ASD. Suggestions for future research interventions are to conduct the individualised programmes either over a longer period of time and more frequently at three times a week. / AFRIKAANSE OPSOMMING: Outisme Spektrum Versteuring (OSV) word beskryf as 'n neuro-ontwikkelingsversteuring wat die sosiale interaksie en kommunikasie van individue beïnvloed. Daar is waargeneem dat diegene met OSV, uitdagings met betrekking tot sensoriese insette ervaar, wat kan lei tot motoriese agterstande. Beskrywende navorsing is toegepas met twee gevalle-studies. Die ouderdom van die twee seuns wat met outisme gediagnoseer was, was 6- en 8-jaar oud. Die doel van die studie was om ʼn Sensories-Motoriese Integrasie (SMI) program te ontwikkel en te implementeer as intervensie wat op elk van die seuns spesifiek toegespits is. Die intervensie-program het voorsiening gemaak om aan die uitvoering van bepaalde motoriese vaardighede aandag te skenk en om die uitwerking daarvan oor die 7-maande tydperk te assesseer. Die twee seuns (Geval A en Geval G) het individuele sessies van 30 minute elk twee keer per week bygewoon. Die SMI program het op die vestibulêre en somato-sensoriese (proprioseptor) sisteme gefokus om hul vermoë en vordering waar te neem. Aan die begin van die studie is drie neuro-ontwikkelings- en diagnostiese meetinstrumente (SCQ, ADIR-R en ADOS) deur 'n psigiater gelei om die vorige OSV diagnose van die seuns te bevestig. Die “Quick Neurological Screening Test” (QNST III) en die “Sensory Input Systems Screening Test“ (SISST) is benut om hul aanvangsvermoë as basislyn te bepaal. Hierdie toetse was gereeld herhaal, elke 4 tot 5 weke oor ʼn tydperk van 7 maande en het ʼn retensie toets van 5 weke ingesluit. Op grond van die resultate van die sub-toetse van die vermelde motoriese vaardigheidstoetse, is die self-ontwerpte SMI intervensie-program vir elke seun, volgens sy persoonlike sensoriese-motoriese behoeftes, beplan. Geval A het verbetering getoon in die volgende QNST-III sub-toets: Staan op een been (67%) en Tandemloop (83%), en handhaaf sy standaard vanaf die na-toets tot en met die retensie toets. Vir spiertonus en propriosepsie, het die Arm- en been-ekstensie sub-toets ook ʼn verbetering (67%) van die voor-toets tot die na-toets getoon. Die resultaat van hierdie subtoets is nie oor die hele tydperk gehandhaaf nie, en het net effens verhoog (33%) van die basislyn telling. Die proprioseptiewe funksie van Geval A het 'n groot verbetering in die volgende QNST-III sub-toetse getoon: Vinger na neus (67%), Vinnige omkeer, herhalende hand bewegings (88%) en Links en regs diskriminasie (67%). Geval G se resultate vir die vestibulêre-verwante sub-toetse het verbetering in die volgende getoon: Een been staan (33%) en Arm- en Been-ekstensie (33%). Sommige van die resultate van Geval G het op 'n ernstige diskripansie begin, maar daar was verbetering in die volgende proprioseptiewe verwante sub-toetse: Vinger na neus (43%), Duim en vinger sirkels (20%) en Vinnige omkeer, herhalende hand bewegings (86%). Ten spyte daarvan dat Geval G ʼn geleidelike verbetering oor tyd getoon het, het sy twee sensoriese stelsels gesukkel om met die meer komplekse take met mekaar te integreer. Die uitkoms van die geïndividualiseerde SMI programme het getoon dat die sensoriesemotoriese vaardighede by beide seuns verbeter as gevolg van die verbeterde stimulering van hul vestibulêre en somato-sensoriese (proprioseptiewe) funksie. Die SSIST resultate toon dat Geval A van ‘druip’ na ‘slaag’ in die volgende toetsitems gevorder het: Tonic Labyrinthine Supine (TLS), Tonic Labyrinthine Prone (TLP), Positive Support Reflex (PSR) en die Ocular Alignment toetsitems. Resultate van die vestibulêre toets, blyk dit dat sowel Geval A as Geval G ‘hipo-vestibulêr’ (onder-gestimuleer) was volgens die “Post-Rotary Nystagmus toets” (PRN) meting wat by die basislyn toetsing behaal is. Hierdie tellings was veranderlik tydens die intervensie. Die enigste toetsitem wat ʼn positiewe verbetering by Geval G getoon het, was die Ekwilibriumsreaksie. Laastens, beide Geval A en Geval G het in die ‘druip’ kategorie vir Kinestese gebly wat daarop dui dat hul swak propriosepsie en ruimtelike oriëntasie steeds teenwoordig was. Daar is 'n behoefte aan verdere navorsing op die gebied van sensoriese-motoriese individuele programme vir kinders met OSV. Toekomstige navorsing wat individuele programme benut, moet oorweeg om die intervensie oor ʼn langer tydperk (bv. een jaar) te laat geskied met meer sessies per week (bv. drie sessies).

Methyl-CpG-binding protein 2 (MeCP2 is) is an epigenetic regulator that binds to methylated DNA. Initially identified as transcriptional repressor, MeCP2 also binds to different proteins functioning as gene activator. Importantly, MecCP2 gene mutations and changes in MeCP2 levels are associated to several forms of mental retardation and autism-related disorders; including Rett, a neurodevelopmental disorder affecting primarily girls. While brain MeCP2 was considered to be exclusively neuronal, this regulator is also present in glia. We found that oligodendrocytes, the myelinating cells of the central nervous system (CNS), express particularly high MeCP2 levels at a developmental stage that precedes their final maturation. Moreover, downregulation of MeCP2 levels by treatment of immature oligodendrocytes with small interference RNA (siRNA), reduced the expression of 14 kDa myelin basic protein (MBP) and MOG, two markers of mature oligodendrocytes. These observations raise the possibility that oligodendrocytes have a direct participation in Rett syndrome and other autism-related disorders.

As politicas de apoio a criancas com Transtornos do Neurodesenvolvimento precisam que seus cuidadores sejam responsaveis por prover o ensino especial necessario para o manejo dos problemas de comportamento e evitar que sejam objeto de rejeicao social em funcao de seus deficits comportamentais. Essa carga de trabalho pode acarretar impacto a saude mental e qualidade de vida dos cuidadores e justifica a importancia de estudos voltados para o mapeamento de tais dificuldades, afim de sustentar propostas de prevencao e intervencao destinadas a este publico. Este estudo, de corte transversal, teve como objetivo identificar associacoes entre os problemas de comportamento de criancas com Transtornos do Neurodesenvolvimento e a saude mental e qualidade de seus cuidadores, alem de descrever as praticas parentais educativas utilizadas. A amostra foi composta por 91 diades cuidadorescriancas. Todas as criancas (idade entre 3 e 18 anos) estavam matriculadas em escolas da rede publica do municipio de Barueri-SP como aluno com necessidade educacional especial e apresentavam laudo diagnostico de Deficiencia Intelectual (DI) idiopatica, Transtorno do Espectro Autista ou Sindrome de Down comorbido com DI. Para a avaliacao comportamental infantil foi empregada a Escala de Comportamentos Aberrantes, o Inventario de Problemas de Comportamento e o Inventario dos Comportamentos de Criancas e Adolescentes. Para a avaliacao dos cuidadores, aplicou-se o Inventario de Autoavaliacao para Adultos de 18 a 59 anos, o Instrumento abreviado de avaliacao de qualidade de vida (WHOQOL-Bref) e o World-Safe CORE para as praticas parentais. As analises demonstram nao haver diferenca na saude mental do cuidador em funcao do diagnostico de seu filho. A avaliacao comportamental dos cuidadores evidenciou que suas dificuldades internalizantes foram as areas mais impactadas pelos problemas de comportamento infantis. Entre 3,4% e 20% da variancia dos indicadores de saude mental dos cuidadores foi significativamente explicada pelas queixas externalizantes da crianca, especialmente hiperatividade e agressividade, e as dificuldades internalizantes infantis, principalmente o retraimento. As dificuldades comportamentais infantis nao foram preditores da qualidade de vida total dos cuidadores. Ja a frequencia de comportamento agressivo da crianca foi preditor do Dominio Psicologico do WHOQOLBref. Quanto as praticas parentais, muitos reportaram utilizar metodos coercitivos para tentar controlar o comportamento de seus filhos. As queixas internalizantes dos cuidadores, especialmente Ansiedade/ Depressao e Queixas Somaticas, devem ser alvo de atencao das iniciativas em saude. Assim propostas de intervencao para melhoria da saude mental poderiam ser destinadas a todos os cuidadores independente do diagnostico clinico de seus filhos, dado que muitos reportaram o uso de estrategias coercitivas e que seus problemas de comportamento sao similares / Policies to support children with Neurodevelopmental Disorders need their caregivers to be responsible for providing the special education in order to manage behavioral problems and avoid social rejection due to their child behavioral difficulties. This caregiver\'s workload can impact one\'s mental health and quality of life therefore supporting the importance of studies aimed to investigate this impact in order to support prevention and intervention programs for this specific public. This crosssectional study aimed to identify associations between the behavioral problems of children with Neurodevelopmental Disorders and the mental health and quality of life of their caregivers, as well as to describe their parental practices. The sample consisted of 91 caregiver and child. All children (Aged between 3 and 18 years) were enrolled in public schools in the city of Barueri-SP as students with special educational needs and diagnostic reports of Idiopathic Intellectual Disability (ID), Autism Spectrum Disorder and Down Syndrome comorbid with ID. For the child\'s behavioral assessment, the following questionnaires were used: Aberrant Behavior Checklist, Behavior Problems Inventory and Child Behavior Checklist. For the caregiver\'s evaluation were used the Adult Self-Report, the World Health Organization Quality of Life Instruments (WHOQOL-Bref) and the World-Safe CORE for parental practices. The analysis shows that there is no difference in the caregiver\'s mental health due to their child\'s diagnosis. The caregiver\'s behavioral evaluation demonstrated that their internalizing difficulties are the most impacted area due to their children\'s behavioral problems. Between 3.4% and 20% of the variance on the caregiver\'s assessment were significantly predicted by child\'s externalizing complaints, mainly hyperactivity and aggressiveness, and the child\'s internalizing difficulties, especially social withdrawal. Caregiver\'s overall quality of life were not predicted by child\'s behavioral difficulties, whereas the frequency of child\'s aggressive behavior predicts 4% of variance on the Psychological Domain of WHOQOL-Bref. Regarding parental practices, many caregivers reported the use of coercive methods to try to control their children\'s behavior. Caregiver\'s internalizing problems, especially Anxiety/ Depression and Somatic Complaints, should be addressed by health initiatives. Thus, interventions for improving mental health could be targeted to all caregivers regardless their child\'s clinical diagnosis, given that many of them have reported using coercive measures and the similarity of their behavioral problems

The causes and neurodevelopmental outcomes of children exposed to drugs and/or alcohol prenatally are presented. The incidence of this population is rising rapidly and appearing in increasing numbers on the caseloads of speech-language pathologists. Topics include prevalence, common drugs, Neonatal Abstinence Syndrome, longer-term neurodevelopmental outcomes, and treatment challenges.

No description available.

No description available.

SYNGAP1 haploinsufficiency is one of the most common monogenic causes of nonsyndromic moderate to severe intellectual disability (NSID) and autism (Hamdan et al., 2009; Pinto et al., 2010). De novo truncating or frameshift mutations in the SYNGAP1 gene lead to the loss of the encoded protein Synaptic GTPase activating protein (SynGAP), one of the most abundant of postsynaptic proteins (Hamdan et al., 2011). SynGAP, present at excitatory and inhibitory synapses (Kim et al., 1998), acts as a key regulator of highly conserved signaling pathways linked to AMPA- and NMDA-receptor dependent plasticity at the post synaptic density (Krapivisky et al., 2004; Vazquez et al., 2004). The Syngap mouse model has been extensively used to understand the pathophysiology underlying abnormal SynGAP-mediated signaling. Syngap heterozygous (het) mice demonstrate a range of physiological and behavioural abnormalities from development to adulthood (Komiyama et al., 2002; Muhia et al., 2010). However, recent advances in techniques for genome manipulation have allowed for the generation of rat models of neurodevelopmental disorders, including Syngap; enabling phenotypes to be validated across species and to address cognitive and social dysfunction, using paradigms that are more difficult to assess in mice. In this study, we examined the pathophysiology associated with a heterozygous deletion of the C2 and catalytic GAP domain of the protein, in Long-Evans rats (het). In contrast with het mice, het rats do not present with hyperactivity and can be habituated to an open field environment. To examine associative recognition memory, we tested the rats in five spontaneous exploration tasks for short-term and long-term memory, object-recognition (OR), object-location (OL), object-place (OP), object-context (OC) and object-place-context (OPC). Both groups were able to perform short-term memory tasks, but only wild type rats performed above chance in OL with a 24hour delay, suggesting deficits in long- term spatial memory. We also tested if partial loss of the GAP domain in SynGAP affects social behaviour in rats and we found that het rats exhibited impaired short- term social memory, with no signs of social isolation. These findings do not fully recapitulate previous abnormalities reported in the mouse model of SYNGAP1 haploinsufficiency, suggesting that some key behavioural phenotypes may be species-specific. Furthermore, based on physiological deficits that Syngap het mice exhibit, such as alterations in mEPSC/mIPSC amplitude and frequency and evoked cortical hyperexcitability in vitro (Guo et al., 2009; Ozkan et al., 2014), we also aimed to test if in vivo neuronal activity and circuit properties are altered. Using two-photon calcium imaging in awake mice, we focused on two areas of the cortex; a primary sensory area, the binocular region of the visual cortex (V1), and an association area, the medial posterior parietal cortex (PPC). Both areas have been found to maintain activity during visual discrimination tasks but to present with divergent activity trajectories (Harvey et al., 2012; Goard et al., 2016). We found preliminary evidence that neurons in layer 2-3 of the PPC of Syngap mice are hypoactive in basal conditions when animals are still in the dark, compared to wild type controls. When we assessed whether that changes when animals are running, we found that during locomotion neurons of both genotypes increase their activity, consistent with previous findings in wild type mice (McGinley et al., 2015; Pakan et al., 2016). However, this response gain is exaggerated in Syngap het neurons of the PPC. In contrast to above findings in PPC, results in V1 show that layer 2-3 neurons are hyperactive during both behavioural states, suggesting seemingly different computations of these two cortical areas. This work provides the first evidence for a dysregulated neuronal circuit in vivo in both visual and parietal cortex of Syngap mice, two areas critical for sensory processing that has been found to be affected in individuals with NSID and autism (Joosten and Bundy, 2010). We also provide first evidence of the effect of loss of SynGAP activity in behaviour of rats, complimenting existing data in the literature in a species-specific manner and providing greater insight into sensory and cognitive dysfunction associated with dysregulation in SynGAP-mediated signaling.

At the age of 13, the 2:1 ratio becomes evident. It entails the fact that after puberty, twice as many females as compared to males suffer from depressive episodes. Much research has been conducted to highlight key contributing factors that aid in the onset and the timing of the 2:1 ratio. Many researchers emphasize hormonal influences and the onset of puberty as key contributors, with theories such as the gonadic theory andthe interactional hypothesis both highlighting the role of hormones in the existence and the emergence of the 2:1 ratio during adolescence. Furthermore, a large variety of researchers emphasize females increased stress sensitivity and stress reactivity as key contributors to the 2:1 ratio. Critically, research concerning hormonal- and stress-related factors will be included. However, an additional focus will be on neurodevelopmental sex differences. This, as brain-based sex differences have been paid too little attention in theories and models concerning the emergence of the 2:1 ratio during adolescence. Results from research conducted to unravel the mystery of sex differences within the adolescent brain emphasize the impact of sex hormones on the maturational sexual differentiation occurring within the adolescent brain. It has been hypothesized that increases in female adolescent depression might occur in accordance with upsurges in peripheral estrogen levels, during puberty. This seems to suggest that there is an interaction between the effects of circulating ovarian hormones in relation to both sexual differentiation in brain organization and depression susceptibility. Hence, the point of this essay is to delineate key contributing factors that potentially govern the existence and onset of the 2:1 ratio during adolescence by emphasizing the areas of (a) sex-based neurodevelopmental factors, (b) hormonal factors and (c) stress-related factors.

An important quest in genomics since the publication of the first complete human genome in 2003 has been its functional annotation. DNA holds the instructions to the production of the components necessary for the life of cells and organisms. A complete functional catalog of genomic regions will help the understanding of the cell body and its dynamics, thus creating links between genotype and phenotypic traits. The need for annotations prompted the development of several bioinformatic methods. In the context of promoter and first exon predictors, the majority of models relies principally on structural and chemical properties of the DNA sequence. Some of them integrate information from epigenomic and transcriptomic data as secondary features. Current genomic research asserts that reference genome annotations are far from being fully annotated (human organism included).Physicians rely on reference genome annotations and functional databases to understand disorders with genetic basis, and missing annotations may lead to unresolved cases. Because of their complexity, neurodevelopmental disorders are under study to figure out all genetic regions that are involved. Besides functional validation on model organisms, the search for genotype-phenotype association is supported by statistical analysis, which is typically biased towards known functional regions.This thesis addresses the use of an in-silico integrative analysis to improve reference genome annotations and discover novel functional regions associated with neurodevelopemental disorders. The contributions outlined in this document have practical applications in clinical settings. The presented bioinformatic method is based on epigenomic and transcriptomic data, thus excluding features from DNA sequence. Such integrative approach applied on brain data allowed the discovery of two novel promoters and coding first exons in the human DLG2 gene, which were also found to be statistically associated with neurodevelopmental disorders and intellectual disability in particular. The application of the same methodology to the whole genome resulted in the discovery of other novel exons expressed in brain. Concerning the in-silico method itself, the research demanded a high number of functional and clinical datasets to properly support and validate our discoveries.This work describes a bioinformatic method for genome annotation, in the specific area of promoter and first exons. So far the method has been applied on brain data, and the extension to the whole body data would be a logical by-product. We will leverage distributed frameworks to tackle the even higher amount of data to analyse, a task that has already begun. Another interesting research direction that came up from this work is the temporal enrichment analysis of epigenomics data across different developmental stages, in which changes of epigenomic enrichment suggest time-specific and tissue-specific functional gene and gene isoforms regulation. / Doctorat en Sciences / info:eu-repo/semantics/nonPublished