E-proteins orchestrate the progression of neural stem cell differentiation in the postnatal forebrain

Background Neural stem cell (NSC) differentiation is a complex multistep process that persists in specific regions of the postnatal forebrain and requires tight regulation throughout life. The transcriptional control of NSC proliferation and specification involves Class II (proneural) and Class V (Id1-4) basic helix-loop-helix (bHLH) proteins. In this study, we analyzed the pattern of expression of their dimerization partners, Class I bHLH proteins (E-proteins), and explored their putative role in orchestrating postnatal subventricular zone (SVZ) neurogenesis. Results Overexpression of a dominant-negative form of the E-protein E47 (dnE47) confirmed a crucial role for bHLH transcriptional networks in postnatal neurogenesis by dramatically blocking SVZ NSC differentiation. In situ hybridization was used in combination with RT-qPCR to measure and compare the level of expression of E-protein transcripts (E2-2, E2A, and HEB) in the neonatal and adult SVZ as well as in magnetic affinity cell sorted progenitor cells and neuroblasts. Our results evidence that E-protein transcripts, in particular E2-2 and E2A, are enriched in the postnatal SVZ with expression levels increasing as cells engage towards neuronal differentiation. To investigate the role of E-proteins in orchestrating lineage progression, both in vitro and in vivo gain-of-function and loss-of-function experiments were performed for individual E-proteins. Overexpression of E2-2 and E2A promoted SVZ neurogenesis by enhancing not only radial glial cell differentiation but also cell cycle exit of their progeny. Conversely, knock-down by shRNA electroporation resulted in opposite effects. Manipulation of E-proteins and/or Ascl1 in SVZ NSC cultures indicated that those effects were Ascl1 dependent, although they could not solely be attributed to an Ascl1-induced switch from promoting cell proliferation to triggering cell cycle arrest and differentiation. Conclusions In contrast to former concepts, suggesting ubiquitous expression and subsidiary function for E-proteins to foster postnatal neurogenesis, this work unveils E-proteins as being active players in the orchestration of postnatal SVZ neurogenesis.ISSN:1749-810

Cohort profile: the Swiss Cerebral Palsy Registry (Swiss-CP-Reg) cohort study.

BACKGROUND Cerebral Palsy (CP) is a group of permanent disorders of movement and posture that follow injuries to the developing brain. It results in motor dysfunction and a wide variety of comorbidities like epilepsy; pain; speech, hearing and vision disorders; cognitive dysfunction; and eating and digestive difficulties. Central data collection is essential to the study of the epidemiology, clinical presentations, care, and quality of life of patients affected by CP. CP specialists founded the Swiss Cerebral Palsy Registry (Swiss-CP-Reg) in 2017. This paper describes the design, structure, aims and achievements of Swiss-CP-Reg and presents its first results. METHODS Swiss-CP-Reg records patients of any age diagnosed with CP who are born, are treated, or live in Switzerland. It collects data from medical records and reports, from questionnaires answered by patients and their families, and from data linkage with routine statistics and other registries. The registry contains information on diagnosis, clinical presentation, comorbidities, therapies, personal information, family history, and quality of life. RESULTS From August 2017 to August 2021, 546 participants (55% male, mean age at registration 8 years [interquartile range IQR: 5-12]), were enrolled in Swiss-CP-Reg. Most had been born at term (56%), were less than two years old at diagnosis (73%, median 18 months, IQR: 9-25), and were diagnosed with spastic CP (76%). Most (59%) live with a mild motor impairment (Gross Motor Function Classification System [GMFCS] level I or II), 12% with a moderate motor impairment (GMFCS level III), and 29% with a severe motor impairment (GMFCS level IV or V). In a subset of 170 participants, we measured intelligence quotient (IQ) and saw lower IQs with increasing GMFCS level. Swiss-CP-Reg has a strong interest in research, with four nested projects running currently, and many more planned. CONCLUSIONS Swiss-CP-Reg collects and exchanges national data on people living with CP to answer clinically relevant questions. Its structure enables retrospective and prospective data collection and knowledge exchange between experts to optimise and standardise treatment and to improve the health and quality of life of those diagnosed with CP in Switzerland

Tendencias actuales de los derechos humanos y el derecho internacional humanitario en Colombia

Este libro presenta, desde diversas perspectivas y con un tratamiento interdisciplinario, problemáticas relacionadas con los derechos humanos y el Estado social de derecho, conflictos de sobrada actualidad en el país. Para su estructura, se eligieron tres ejes investigativos: primero, temas y debates del posconflicto, como los derechos de las víctimas y el marco jurídico del posacuerdo; segundo, debates sobre derechos humanos y género, como la no discriminación y la violencia, y tercero, aquellos temas que por la coyuntura social o política son dejados al margen, como redes sociales y privacidad, educación en derechos humanos y defensa del Estado. Es, entonces, un aporte indiscutible en el avance de la reflexión sobre los derechos fundamentales y el derecho de la guerra en nuestras latitudes y nuestro tiempo

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities

Cohort profile: the Swiss Cerebral Palsy Registry (Swiss-CP-Reg) cohort study

BACKGROUND: Cerebral Palsy (CP) is a group of permanent disorders of movement and posture that follow injuries to the developing brain. It results in motor dysfunction and a wide variety of comorbidities like epilepsy; pain; speech, hearing and vision disorders; cognitive dysfunction; and eating and digestive difficulties. Central data collection is essential to the study of the epidemiology, clinical presentations, care, and quality of life of patients affected by CP. CP specialists founded the Swiss Cerebral Palsy Registry (Swiss-CP-Reg) in 2017. This paper describes the design, structure, aims and achievements of Swiss-CP-Reg and presents its first results. METHODS: Swiss-CP-Reg records patients of any age diagnosed with CP who are born, are treated, or live in Switzerland. It collects data from medical records and reports, from questionnaires answered by patients and their families, and from data linkage with routine statistics and other registries. The registry contains information on diagnosis, clinical presentation, comorbidities, therapies, personal information, family history, and quality of life. RESULTS: From August 2017 to August 2021, 546 participants (55% male, mean age at registration 8 years [interquartile range IQR: 5–12]), were enrolled in Swiss-CP-Reg. Most had been born at term (56%), were less than two years old at diagnosis (73%, median 18 months, IQR: 9–25), and were diagnosed with spastic CP (76%). Most (59%) live with a mild motor impairment (Gross Motor Function Classification System [GMFCS] level I or II), 12% with a moderate motor impairment (GMFCS level III), and 29% with a severe motor impairment (GMFCS level IV or V). In a subset of 170 participants, we measured intelligence quotient (IQ) and saw lower IQs with increasing GMFCS level. Swiss-CP-Reg has a strong interest in research, with four nested projects running currently, and many more planned. CONCLUSIONS: Swiss-CP-Reg collects and exchanges national data on people living with CP to answer clinically relevant questions. Its structure enables retrospective and prospective data collection and knowledge exchange between experts to optimise and standardise treatment and to improve the health and quality of life of those diagnosed with CP in Switzerland. ClinicalTrials.gov identifier: NCT0499287

Health related quality of life and manual ability 5 years after neonatal ischemic stroke

AIM: To investigate health-related quality of life (HRQOL) and manual ability five years after neonatal arterial ischemic stroke (NAIS). METHODS: Data was prospectively obtained by the Swiss Neuropaediatric Stroke Registry between 2000 and 2010. Two years after NAIS, cognitive and motor outcomes was assessed using the Bayley Scales of Infant Development (BSID-II). After 5 years, HRQOL was assessed with the KIDSCREEN-27 and manual ability with the ABILHAND-Kids. Manual ability and HRQOL were compared between children with and without cerebral palsy (CP) and HRQOL was correlated with manual ability. RESULTS: Seventy-four patients were examined at the age of 2 years, at the age of 5 years 61 patients underwent a follow-up examination. Two years after NAIS, 29 children (39.1%) were diagnosed with CP. HRQOL 5 years after NAIS was comparable to normative values. Children with CP had a significantly lower HRQOL-index (p = 0.013) and lower scores in the subscale psychological well-being (p = 0.012) and social support & peers (p = 0.048). The ABILHAND-Kids measure was significantly lower in children with CP compared to children without CP (p < 0.001). Manual ability correlated significantly with HRQOL. CONCLUSION: Five years after NAIS, HRQOL is comparable to that of typically developing peers, but reduced in children with CP. Poorer manual ability is associated with lower HRQOL. Interventions improving hand function might influence HRQOL and should be considered early on

Impact of stroke volume on motor outcome in neonatal arterial ischemic stroke

BACKGROUND AND OBJECTIVES: Neonatal arterial ischemic stroke (NAIS) can lead to long-term neurological consequences such as cerebral palsy (CP). The aim of this study was to evaluate the predictive value of acute diffusion-weighted imaging (DWI) for CP by analyzing stroke volume next to brain structure involvement. METHODS: We included 37 term-born infants with NAIS prospectively registered in a nationwide pediatric stroke registry. DWI was performed between 0 and 8 days (mean 3 days) after stroke manifestation. Participants were neurologically assessed at the age of 2 years. We calculated the stroke volume (in mm3) and the ratio of the stroke volume to the volume of the entire brain (relative stroke volume). The predictive value of the relative stroke volume was analyzed and an optimal threshold for classification of children with high- and low-rates of CP was calculated. Predictive value of brain structure involvements and the prevalence of CP in combinations of different brain structures was also assessed. RESULTS: Sixteen children (43.2%) developed CP. Relative stroke volume significantly predicted CP (p < .001). Its optimal threshold for division into high- and low-rate of CP was 3.3%. The basal ganglia (OR 8.3, 95% CI 1.2-60.0) and basis pontis (OR 18.5, 95% CI 1.8-194.8) were independently associated with CP. CONCLUSION: In addition to determining the involvement of affected brain areas, the volumetric quantification of stroke volume allows accurate prediction of cerebral palsy in newborns with NAIS