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    ABSTRACT: Receptor-type protein tyrosine phosphatases (RPTPs) have been implicated as direct or indirect regulators of neurotrophin receptors (Trks). It remains less clear if and how such RPTPs might regulate Trk proteins in vivo during development. Here we present a comparative expression profile of RPTP genes and Trk genes during early stages of murine, dorsal root ganglion maturation. We find little if any specific, temporal mRNA co-regulation between individual RPTP and Ntrk genes between E12.5-E14.5. Moreover, a double fluorescent in-situ hybridization and immunofluorescence study of seven Rptp genes with Ntrks revealed widespread co-expression of RPTPs in individual neurons, but no tight correlation with Trk expression profiles. No Rptp is expressed in 100% of Ntrk1-expressing neurons, whereas at least 6 RPTPs are expressed in 100% of Ntrk2- and Ntrk3-expressing neurons. An exception is Ptpro, which showed very selective expression. Short hairpin RNA suppression of Ptprf, Ptprs or Ptpro in primary, E13.5 DRG neurons did not alter Trk signaling. We therefore propose that Trk signaling may not be simply dependent on rate-limiting regulation by individual RPTP subtypes during sensory neuron development. Instead, Trk signaling has the potential to be buffered by concurrent inputs from several RPTPs in individual neurons.
    International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 01/2014;
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    ABSTRACT: IMPORTANCE In Duchenne muscular dystrophy (DMD), the reading frame of an out-of-frame DMD deletion can be repaired by antisense oligonucleotide (AO)-mediated exon skipping. This creates a shorter dystrophin protein, similar to those expressed in the milder Becker muscular dystrophy (BMD). The skipping of some exons may be more efficacious than others. Patients with exon 44 or 45 skippable deletions (AOs in clinical development) have a less predictable phenotype than those skippable for exon 51, a group in advanced clinical trials. A way to predict the potential of AOs is the study of patients with BMD who have deletions that naturally mimic those that would be achieved by exon skipping. OBJECTIVE To quantify dystrophin messenger RNA (mRNA) and protein expression in patients with DMD deletions treatable by, or mimicking, exon 44 or 45 skipping. DESIGN, SETTING, AND PARTICIPANTS Retrospective study of nondystrophic controls (n = 2), patients with DMD (n = 5), patients with intermediate muscular dystrophy (n = 3), and patients with BMD (n = 13) at 4 university-based academic centers and pediatric hospitals. Biochemical analysis of existing muscle biopsies was correlated with the severity of the skeletal muscle phenotype. MAIN OUTCOMES AND MEASURES Dystrophin mRNA and protein expression. RESULTS Patients with DMD who have out-of-frame deletions skippable for exon 44 or 45 had an elevated number of revertant and trace dystrophin expression (approximately 19% of control, using quantitative immunohistochemistry) with 4 of 9 patients presenting with an intermediate muscular dystrophy phenotype (3 patients) or a BMD-like phenotype (1 patient). Corresponding in-frame deletions presented with predominantly mild BMD phenotypes and lower dystrophin levels (approximately 42% of control) than patients with BMD modeling exon 51 skipping (approximately 80% of control). All 12 patients with in-frame deletions had a stable transcript compared with 2 of 9 patients with out-of-frame deletions (who had intermediate muscular dystrophy and BMD phenotypes). CONCLUSIONS AND RELEVANCE Exon 44 or 45 skipping will likely yield lower levels of dystrophin than exon 51 skipping, although the resulting protein is functional enough to often maintain a mild BMD phenotype. Dystrophin transcript stability is an important indicator of dystrophin expression, and transcript instability in DMD compared with BMD should be explored as a potential biomarker of response to AOs. This study is beneficial for the planning, execution, and analysis of clinical trials for exon 44 and 45 skipping.
    JAMA neurology. 11/2013;
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    ABSTRACT: Background Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous ciliopathy disorder affecting cilia and sperm motility. A range of ultrastructural defects of the axoneme underlie the disease, which is characterised by chronic respiratory symptoms and obstructive lung disease, infertility and body axis laterality defects. We applied a next-generation sequencing approach to identify the gene responsible for this phenotype in two consanguineous families. Methods and results Data from whole-exome sequencing in a consanguineous Turkish family, and whole-genome sequencing in the obligate carrier parents of a consanguineous Pakistani family was combined to identify homozygous loss-of-function mutations in ARMC4, segregating in all five affected individuals from both families. Both families carried nonsense mutations within the highly conserved armadillo repeat region of ARMC4: c.2675C>A; pSer892* and c.1972G>T; p.Glu658*. A deficiency of ARMC4 protein was seen in patient's respiratory cilia accompanied by loss of the distal outer dynein arm motors responsible for generating ciliary beating, giving rise to cilia immotility. ARMC4 gene expression is upregulated during ciliogenesis, and we found a predicted interaction with the outer dynein arm protein DNAI2, mutations in which also cause PCD. Conclusions We report the first use of whole-genome sequencing to identify gene mutations causing PCD. Loss-of-function mutations in ARMC4 cause PCD with situs inversus and cilia immotility, associated with a loss of the distal outer (but not inner) dynein arms. This addition of ARMC4 to the list of genes associated with ciliary outer dynein arm defects expands our understanding of the complexities of PCD genetics. Primary ciliary dyskinesia (PCD; MIM244400) is a heterogeneous genetic disorder arising from ultra-structural defects that cause abnormal function of motile cilia and sperm flagella. 1 The disease has an autosomal recessive mode of inheritance and affects one in every 15 000–30 000 births. Motile cilia are hair-like organelles found on the epithelial surface of the respiratory airway tract, the brain
    Journal of Medical Genetics 11/2013;
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    ABSTRACT: To investigate the association between autistic traits and emotion recognition in a large community sample of children using facial and social motion cues, additionally stratifying by gender. A general population sample of 3,666 children from the Avon Longitudinal Study of Parents and Children (ALSPAC) were assessed on their ability to correctly recognize emotions using the faces subtest of the Diagnostic Analysis of Non-Verbal Accuracy, and the Emotional Triangles Task, a novel test assessing recognition of emotion from social motion cues. Children with autistic-like social communication difficulties, as assessed by the Social Communication Disorders Checklist, were compared with children without such difficulties. Autistic-like social communication difficulties were associated with poorer recognition of emotion from social motion cues in both genders, but were associated with poorer facial emotion recognition in boys only (odds ratio = 1.9, 95% CI = 1.4, 2.6, p = .0001). This finding must be considered in light of lower power to detect differences in girls. In this community sample of children, greater deficits in social communication skills are associated with poorer discrimination of emotions, implying there may be an underlying continuum of liability to the association between these characteristics. As a similar degree of association was observed in both genders on a novel test of social motion cues, the relatively good performance of girls on the more familiar task of facial emotion discrimination may be due to compensatory mechanisms. Our study might indicate the existence of a cognitive process by which girls with underlying autistic traits can compensate for their covert deficits in emotion recognition, although this would require further investigation.
    Journal of the American Academy of Child and Adolescent Psychiatry 11/2013; 52(11):1148-1157.e2.
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    ABSTRACT: There is a recognised need to strengthen capacity in the nutrition in emergencies sector and for greater clarity on the role of emergency nutritionists and the skills they require. Competency frameworks are an important tool for human resource development and have been developed for several other humanitarian sectors. We therefore developed a technical competency framework for practitioners in nutrition in emergencies. Existing competency frameworks were reviewed and interviews conducted to explore methods used in developing competency frameworks for other sectors. Competencies were identified through interviews with field experts, feedback from course trainees, academic course content and job specifications. Competencies were then categorised and behavioural indicators developed for each. The draft framework was then reviewed by members of the Global Nutrition Cluster and modified in an iterative process. Global. Not applicable. A wide range of competencies were identified as essential for nutritionists working in emergencies, covering technical skills and general core competencies. The proposed framework contains twenty competency areas with 161 behavioural indicators categorised into three levels, corresponding to the requirements of progressively more senior roles. Many of the competencies are common across development and emergency nutrition. The proposed technical competency framework should prove to be a valuable tool in creating standards within the sector and promoting effective capacity strengthening and professionalisation. Continued research is needed to validate the framework, optimise methods for assessment, develop approaches to integrate it within the sector and measure its impact on performance.
    Public Health Nutrition 10/2013;
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    International Journal of Epidemiology 10/2013; 42(5):1223-7.
  • Diabetes care 10/2013; 36(10):e175-6.
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    ABSTRACT: Many human diseases are multifactorial, involving multiple genetic and environmental factors impacting on one or more biological pathways. Much of the environmental effect is believed to be mediated through epigenetic changes. Although many genome-wide genetic and epigenetic association studies have been conducted for different diseases and traits, it is still far from clear to what extent the genomic loci and biological pathways identified in the genetic and epigenetic studies are shared. There is also a lack of statistical tools to assess these important aspects of disease mechanisms. In the present study, we describe a protocol for the integrated analysis of genome-wide genetic and epigenetic data based on permutation of a sum statistic for the combined effects in a locus or pathway. The method was then applied to published type 1 diabetes (T1D) genome-wide- and epigenome-wide-association studies data to identify genomic loci and biological pathways that are associated with T1D genetically and epigenetically. Through combined analysis, novel loci and pathways were also identified, which could add to our understanding of disease mechanisms of T1D as well as complex diseases in general.
    Epigenetics: official journal of the DNA Methylation Society 09/2013; 8(11).
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    ABSTRACT: To describe the clinical presentation and sequelae, including salt-wasting crises of newly-diagnosed congenital adrenal hyperplasia (CAH) in children aged over 1 year in a contemporary population without screening. To appraise the potential benefit of newborn screening for late-presenting CAH. Active national surveillance undertaken in Great Britain prospectively from 2007-2009 through the British Paediatric Surveillance Unit. England, Wales and Scotland. Children first presenting aged 1-15 years with clinical features of CAH and elevated 17-hydroxyprogesterone. Fifty-eight children (26 [45%] boys) aged 1-15 years were reported; 50 (86%) had 21-hydroxylase deficiency. Diagnosis was precipitated by secondary sexual characteristics (n=38 [66%]; median age 5.8 [IQR] 4.8, 7.6) years, genital virilisation (8 girls; 3.2 [IQR 1.3, 7.3] years) or an affected sibling (n=8; 10.0 [IQR 7.4, 13.3] years). At least 33 (57%) children had advanced bone age and 13 (30%) were obese (body mass index ≥95th centile). No child had experienced a salt-wasting crisis. In Great Britain, 30 children aged 1-15 years present annually for the first time with CAH. Older children frequently manifest prematurely advanced epiphyseal and pubertal maturation and genital virilisation, which are often irreversible and likely to have long-lasting consequences for adult health and wellbeing. Almost one-third of affected children are obese before commencing steroid therapy. Newborn screening offers the potential to avoid serious clinical manifestations in older children with unrecognised CAH; however, it may also detect some children who would otherwise remain asymptomatic and for whom the benefit from treatment is uncertain.
    Archives of Disease in Childhood 09/2013;
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    ABSTRACT: Reorganization of eloquent cortex enables rescue of language functions in patients who sustain brain injury. Individuals with left-sided, early-onset focal epilepsy often show atypical (i.e. bilateral or right-sided) language dominance. Surprisingly, many patients fail to show such interhemispheric shift of language despite having major epileptogenic lesions in close proximity to eloquent cortex. Although a number of epilepsy-related factors may promote interhemispheric plasticity, it has remained unexplored if neuroanatomical asymmetries linked to human language dominance modify the likelihood of atypical lateralization. Here we examined the asymmetry of the planum temporale, one of the most striking asymmetries in the human brain, in relation to language lateralization in children with left-sided focal epilepsy. Language functional magnetic resonance imaging was performed in 51 children with focal epilepsy and left-sided lesions and 36 healthy control subjects. We examined the association of language laterality with a range of potential clinical predictors and the asymmetry of the length of the planum temporale. Using voxel-based methods, we sought to determine the effect of lesion location (in the affected left hemisphere) and grey matter density (in the unaffected right hemisphere) on language laterality. Atypical language lateralization was observed in 19 patients (38%) and in four controls (11%). Language laterality was increasingly right-sided in patients who showed atypical handedness, a left perisylvian ictal electroencephalographic focus, and a lesion in left anterior superior temporal or inferior frontal regions. Most striking was the relationship between rightward asymmetry of the planum temporale and atypical language (R = 0.70, P < 0.0001); patients with a longer planum temporale in the right (unaffected) hemisphere were more likely to have atypical language dominance. Voxel-based regression analysis confirmed that increased grey matter density in the right temporo-parietal junction was correlated with right hemisphere lateralization of language. The length of the planum temporale in the right hemisphere was the main predictor of language lateralization in the epilepsy group, accounting for 48% of variance, with handedness accounting for only a further 5%. There was no correlation between language lateralization and planum temporale asymmetry in the control group. We conclude that asymmetry of the planum temporale may be unrelated to language lateralization in healthy individuals, but the size of the right, contra-lesional planum temporale region may reflect a 'reserve capacity' for interhemispheric language reorganization in the presence of a seizure focus and lesions within left perisylvian regions.
    Brain 09/2013;
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