An organic suckler cattle farming system in the Massif Central: analysis of technical and economic results.

in the Massif Central. An organic suckler cattle farm network was set up in order to establish technical and economic references. In 2004, 22 farms were monitored (13 of which had been monitored since 2001). All of these farms are located in economically-depressed areas. One hundred percent of the fodder area is under grassland. Annual crops (cereals and a cereal/pulse mix) take up 13% of the farm area and are used as livestock feed. The stocking rate (1 Livestock Unit/ha of fodder area) is 20% lower on organic farms than on conventional farms. Organic farms use 33% less concentrates per LU, and the meat production/LU is 16% lower than for conventional farms. The poorly structured organic beef market forces organic farmers to sell most of their animals (mainly store animals, since fattened animals represent only 43% of the animals sold) on the conventional market without getting premium prices. Since only fattened animals are sold on the organic market at a premium price, the average selling price (€/kg live-weight) of all the animals sold is only 12% higher for organically-bred than for conventionally-bred animals. However, because of lower operational costs (-35% for herd and fodder area costs), the bovine gross margin/LU is 3% higher for OF than for conventionally-bred animals. The lower stocking rate leads to a lower gross product per hectare of farm area. Since this result is balanced by a very low level of operational costs (no chemical inputs), the economic efficiency of the OF system is higher than that of the conventional system. The farm income per worker is the same in both systems. The search for feed self-sufficiency at the farm scale is a crucial element in farm economics, but it is only possible on mixed-crop livestock farms where cropping is possible with adapted crop rotation. The grassland farms, which are the least self-sufficient and have to purchase all the concentrates needed, must sell all their animals on the organic market to get the premium price that will then enable them to buy the inputs not produced on the farm

Commitment to a healthy lifestyle for students in grades 5-11

The article analyzes the state of health and the presence of bad habits in schoolchildren with the help of a questionnaire. The analysis of the obtained data is carried out, conclusions are drawn, and also provided the consequences of not respecting a healthy lifestyle.Изучена приверженность к здоровому образу жизни учащихся 5-11 классов Муниципального автономного общеобразовательного учреждения средней общеобразовательной школы № 29, состояние здоровья и наличие вредных привычек у школьников при помощи анкетирования. Проведен анализ полученных данных, сделаны выводы, а также предоставлены возможные последствия при не соблюдении здорового образа жизни

Limited Utility of Structural MRI to Identify the Epileptogenic Zone in Young Children With Tuberous Sclerosis

BACKGROUND AND PURPOSE: The success of epilepsy surgery in children with tuberous sclerosis complex (TSC) hinges on identification of the epileptogenic zone (EZ). We studied structural MRI markers of epileptogenic lesions in young children with TSC. METHODS: We included 26 children with TSC who underwent epilepsy surgery before the age of 3 years at five sites, with 12 months or more follow-up. Two neuroradiologists, blinded to surgical outcome data, reviewed 10 candidate lesions on preoperative MRI for characteristics of the tuber (large affected area, calcification, cyst-like properties) and of focal cortical dysplasia (FCD) features (cortical malformation, gray-white matter junction blurring, transmantle sign). They selected lesions suspect for the EZ based on structural MRI, and reselected after unblinding to seizure onset location on electroencephalography (EEG). RESULTS: None of the tuber characteristics and FCD features were distinctive for the EZ, indicated by resected lesions in seizure-free children. With structural MRI alone, the EZ was identified out of 10 lesions in 31%, and with addition of EEG data, this increased to 48%. However, rates of identification of resected lesions in non-seizure-free children were similar. Across 251 lesions, interrater agreement was moderate for large size (κ = .60), and fair (κ = .24) for all other features. CONCLUSIONS: In young children with TSC, the utility of structural MRI features is limited in the identification of the epileptogenic tuber, but improves when combined with EEG data

Inherited variants in CHD3 show variable expressivity in Snijders Blok-Campeau syndrome

Purpose Common diagnostic next-generation sequencing strategies are not optimized to identify inherited variants in genes associated with dominant neurodevelopmental disorders as causal when the transmitting parent is clinically unaffected, leaving a significant number of cases with neurodevelopmental disorders undiagnosed. Methods We characterized 21 families with inherited heterozygous missense or protein-truncating variants in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome. Results Computational facial and Human Phenotype Ontology–based comparisons showed that the phenotype of probands with inherited CHD3 variants overlaps with the phenotype previously associated with de novo CHD3 variants, whereas heterozygote parents are mildly or not affected, suggesting variable expressivity. In addition, similarly reduced expression levels of CHD3 protein in cells of an affected proband and of healthy family members with a CHD3 protein-truncating variant suggested that compensation of expression from the wild-type allele is unlikely to be an underlying mechanism. Notably, most inherited CHD3 variants were maternally transmitted. Conclusion Our results point to a significant role of inherited variation in Snijders Blok-Campeau syndrome, a finding that is critical for correct variant interpretation and genetic counseling and warrants further investigation toward understanding the broader contributions of such variation to the landscape of human disease

MYT1L mutations cause intellectual disability and variable obesity by dysregulating gene expression and development of the neuroendocrine hypothalamus.

Deletions at chromosome 2p25.3 are associated with a syndrome consisting of intellectual disability and obesity. The smallest region of overlap for deletions at 2p25.3 contains PXDN and MYT1L. MYT1L is expressed only within the brain in humans. We hypothesized that single nucleotide variants (SNVs) in MYT1L would cause a phenotype resembling deletion at 2p25.3. To examine this we sought MYT1L SNVs in exome sequencing data from 4, 296 parent-child trios. Further variants were identified through a genematcher-facilitated collaboration. We report 9 patients with MYT1L SNVs (4 loss of function and 5 missense). The phenotype of SNV carriers overlapped with that of 2p25.3 deletion carriers. To identify the transcriptomic consequences of MYT1L loss of function we used CRISPR-Cas9 to create a knockout cell line. Gene Ontology analysis in knockout cells demonstrated altered expression of genes that regulate gene expression and that are localized to the nucleus. These differentially expressed genes were enriched for OMIM disease ontology terms "mental retardation". To study the developmental effects of MYT1L loss of function we created a zebrafish knockdown using morpholinos. Knockdown zebrafish manifested loss of oxytocin expression in the preoptic neuroendocrine area. This study demonstrates that MYT1L variants are associated with syndromic obesity in humans. The mechanism is related to dysregulated expression of neurodevelopmental genes and altered development of the neuroendocrine hypothalamus.This article is freely available online via Open Access. Click on the Additional Link above to access the full-text via the publisher's site

Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations. Methods: Chairs and working group cochairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference on July 25 and 26 in Dallas, TX, USA. Before the meeting, working group cochairs worked with group members via e-mail and telephone to (1) review TSC literature since the 2013 publication, (2) confirm or amend prior recommendations, and (3) provide new recommendations as required. Results: Only two changes were made to clinical diagnostic criteria reported in 2013: “multiple cortical tubers and/or radial migration lines” replaced the more general term “cortical dysplasias,” and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed, including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for electroencephalographic abnormalities, enhanced surveillance and management of TSC-associated neuropsychiatric disorders, and new medication approvals. Conclusions: Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families

De novo mutations in MED13, a component of the Mediator complex, are associated with a novel neurodevelopmental disorder

Genetics of disease, diagnosis and treatmen

Add-on cannabidiol treatment for drug-resistant seizures in tuberous sclerosis complex

Importance Efficacy of cannabidiol has been demonstrated in seizures associated with Lennox-Gastaut and Dravet syndromes but appears not yet to have been established in conditions with primarily focal seizures, such as tuberous sclerosis complex (TSC).Objective To evaluate efficacy and safety of 25-mg/kg/day and 50-mg/kg/day cannabidiol dosages vs placebo against seizures associated with TSC.Design, Setting, and Participants This double-blind, placebo-controlled randomized clinical trial (GWPCARE6) enrolled patients between April 6, 2016, and October 4, 2018; follow-up was completed on February 15, 2019. The trial was conducted at 46 sites in Australia, Poland, Spain, the Netherlands, United Kingdom, and United States. Eligible patients (aged 1-65 years) were those with a clinical diagnosis of TSC and medication-resistant epilepsy who had had at least 8 TSC-associated seizures during the 4-week baseline period, with at least 1 seizure occurring in at least 3 of the 4 weeks, and were currently taking at least 1 antiepileptic medication.Interventions Patients received oral cannabidiol at 25 mg/kg/day (CBD25) or 50 mg/kg/day (CBD50) or a matched placebo for 16 weeks.Main Outcomes and Measures The prespecified primary outcome was the change from baseline in number of TSC-associated seizures for cannabidiol vs placebo during the treatment period.Results Of 255 patients screened for eligibility, 31 were excluded and 224 were randomized. Of the 224 included patients (median [range] age, 11.4 [1.1-56.8] years; 93 female patients [41.5%]), 75 were randomized to CBD25, 73 to CBD50, and 76 to placebo, with 201 completing treatment. The percentage reduction from baseline in the type of seizures considered the primary end point was 48.6% (95% CI, 40.4%-55.8%) for the CBD25 group, 47.5% (95% CI, 39.0%-54.8%) for the CBD50 group, and 26.5% (95% CI, 14.9%-36.5%) for the placebo group; the percentage reduction from placebo was 30.1% (95% CI, 13.9%-43.3%; P < .001) for the CBD25 group and 28.5% (95% CI, 11.9%-42.0%; nominal P = .002) for the CBD50 group. The most common adverse events were diarrhea (placebo group, 19 [25%]; CBD25 group, 23 [31%]; CBD50 group, 41 [56%]) and somnolence (placebo group, 7 [9%]; CBD25 group, 10 [13%]; CBD50 group, 19 [26%]), which occurred more frequently with cannabidiol than placebo. Eight patients in CBD25 group, 10 in CBD50 group, and 2 in the placebo group discontinued treatment because of adverse events. Twenty-eight patients taking cannabidiol (18.9%) had elevated liver transaminase levels vs none taking placebo.Conclusions and Relevance Cannabidiol significantly reduced TSC-associated seizures compared with placebo. The 25-mg/kg/day dosage had a better safety profile than the 50-mg/kg/day dosage

ARF1 -related disorder: Phenotypic and molecular spectrum

Purpose ARF1 was previously implicated in periventricular nodular heterotopia (PVNH) in only five individuals and systematic clinical characterisation was not available. The aim of this study is to provide a comprehensive description of the phenotypic and genotypic spectrum of ARF1-related neurodevelopmental disorder. Methods We collected detailed phenotypes of an international cohort of individuals (n=17) with ARF1 variants assembled through the GeneMatcher platform. Missense variants were structurally modelled, and the impact of several were functionally validated. Results De novo variants (10 missense, 1 frameshift, 1 splice altering resulting in 9 residues insertion) in ARF1 were identified among 17 unrelated individuals. Detailed phenotypes included intellectual disability (ID), microcephaly, seizures and PVNH. No specific facial characteristics were consistent across all cases, however microretrognathia was common. Various hearing and visual defects were recurrent, and interestingly, some inflammatory features were reported. MRI of the brain frequently showed abnormalities consistent with a neuronal migration disorder. Conclusion We confirm the role of ARF1 in an autosomal dominant syndrome with a phenotypic spectrum including severe ID, microcephaly, seizures and PVNH due to impaired neuronal migration