A Novel null homozygous mutation confirms <i>CACNA2D2</i> as a gene mutated in epileptic encephalopathy

Contribution to epileptic encephalopathy (EE) of mutations in CACNA2D2, encoding α2δ-2 subunit of Voltage Dependent Calcium Channels, is unclear. To date only one CACNA2D2 mutation altering channel functionality has been identified in a single family. In the same family, a rare CELSR3 polymorphism also segregated with disease. Involvement of CACNA2D2 in EE is therefore not confirmed, while that of CELSR3 is questionable. In a patient with epilepsy, dyskinesia, cerebellar atrophy, psychomotor delay and dysmorphic features, offspring to consanguineous parents, we performed whole exome sequencing (WES) for homozygosity mapping and mutation detection. WES identified extended autozygosity on chromosome 3, containing two novel homozygous candidate mutations: c.1295delA (p.Asn432fs) in CACNA2D2 and c.G6407A (p.Gly2136Asp) in CELSR3. Gene prioritization pointed to CACNA2D2 as the most prominent candidate gene. The WES finding in CACNA2D2 resulted to be statistically significant (p = 0.032), unlike that in CELSR3. CACNA2D2 homozygous c.1295delA essentially abolished α2δ-2 expression. In summary, we identified a novel null CACNA2D2 mutation associated to a clinical phenotype strikingly similar to the Cacna2d2 null mouse model. Molecular and statistical analyses together argued in favor of a causal contribution of CACNA2D2 mutations to EE, while suggested that finding in CELSR3, although potentially damaging, is likely incidental

Relationship between Sensory Alterations and Repetitive Behaviours in Children with Autism Spectrum Disorders: A Parents' Questionnaire Based Study

The relationship between sensory profile and repetitive behaviours in autism spectrum disorder (ASD) has long been known. However, there is no consensus on the type of relationship that exists between them. This monocentric retrospective-prospective observational study aimed (a) to detect a clinical correlation between the severity of repetitive behaviours and the alterations of sensory profile in a sample of 50 children diagnosed with ASD; (b) to evaluate how different patterns of stereotypies and sensory alterations correlate with each other and with the main clinical-instrumental variables in the same sample. We enrolled 29 children in the retrospective phase of the study and 21 in the prospective phase. The Repetitive Behaviour Scale-Revised (RBS-R) and the Short Sensory Profile (SSP) were administered to the caregivers, and clinical-instrumental data were collected. SSP and RBS-R total scores directly correlated with a high significance rate. Among the subscales, the strongest correlations involved "Visual/Auditory Sensitivity", related to "Stereotyped Behaviour" and "Sameness Behaviour". "Under-Responsive/Seeks Sensation" related to "Stereotyped Behaviour". Sex and intellectual disability significantly influenced both the stereotypies and the sensory alterations of the examined population. In conclusion, this study provides new insights into the relationship between sensory alterations and repetitive behaviours in ASD children by using direct medical observation and parent observation

Pandemic (H1N1) 2009 and HIV Co-infection

We report a case of pandemic (H1N1) 2009 infection in a man with serologic evidence of HIV-1 infection. The clinical course was complicated by lung and brain involvement (respiratory failure and lethargy), severe leukopenia, and thrombocytopenia, but complications resolved after treatment with oseltamivi

CAUSAS E CONSEQUÊNCIAS DA INADIMPLÊNCIA: UMA ANÁLISE SOB DIFERENTES DIMENSÕES

O objetivo deste trabalho consistiu em analisar e diferenciar as principais causas e consequências da inadimplência sob diferentes dimensões. As análises do estudo foram realizadas por meio de levantamento bibliográfico. Entre as causas da inadimplência, foi preciso fazer uma diferenciação deste fenômeno entre o setor público e o privado, visto que há um conjunto de causas que trazem um grau de complexidade ao se tratar dessa questão. Na área privada, as causas da inadimplência têm praticamente as mesmas origens, destacando-se fatores conjunturais, sócio-políticos, institucionais, ligados ao serviço, falta de atualização das informações cadastrais, consumismo, falta de planejamento, restrições orçamentárias e falta de conhecimentos financeiros. Na área pública, a inadimplência dos impostos também está relacionada à fatores conjunturais, ações dos governos, problemas relacionados cobrança e incentivo da inadimplência. Em relação aos fatores conjunturais tem-se a carga tributária excessiva, legislações tributárias inadequadas e punições existentes mínimas. Referente ao consequências da inadimplência houve a distinção entre três agentes impactados. Dentre estes cita-se a perspectiva do indivíduo, das instituições e da sociedade. Na perspectiva pessoal nota-se que a inadimplência traz implicações negativas tanto financeiras, quanto sociais ou psicológicas. Em relação às instituições as principais consequências da inadimplência, é que essas, muitas vezes, têm que recorrer a empréstimos bancários, aumentando seu custo operacional, ou mesmo atrasar o pagamento de suas obrigações tributárias e fiscais. Por último, com relação a sociedade a inadimplência pode causar redução no nível de emprego e salários, problemas de saúde, maximização do número de suicídios e elevação da violência

Increased expression of interleukin-22 in patients with giant cell arteritis

GCA is characterized by arterial remodelling driven by inflammation. IL-22 is an attractive cytokine which acts at the crosstalk between immune and stromal cells. We hypothesized that IL-22 might be induced in GCA and might be involved in disease pathogenesis

GESTÃO AMBIENTAL E SUSTENTABILIDADE: ANÁLISE DAS PRÁTICAS SUSTENTÁVEIS DA UNIVERSIDADE FEDERAL DE SANTA MARIA

Ao longo dos anos, o Brasil, passou por reformas administrativas, e com isso, novas ferramentas e práticas de gestão foram introduzidas nas organizações públicas a fim de melhorar a eficiência e reduzir custos, como é o caso das práticas sustentáveis. Nesse sentido, o presente estudo tem por objetivo analisar as práticas de gestão ambiental e sustentabilidade adotadas pela Universidade Federal de Santa Maria – UFSM com base nos Relatórios de Gestão (RG), no período 2014-2016. Quanto aos procedimentos metodológicos, realizou-se um estudo de natureza qualitativa, do tipo descritivo por meio de análise documental e de conteúdo. Foram analisados os aspectos de gestão ambiental e sustentabilidade nos Relatórios de Gestão da Universidade Federal de Santa Maria (UFSM), no período 2014-2016. Os resultados apontaram que, apesar da Instituição não participar da Agenda Ambiental da Administração Pública (A3P), a UFSM realiza a separação e a destinação de resíduos recicláveis a associações e/ou cooperativas de catadores. Além disso, possui um Plano de Gestão Logística Sustentável (PLS) e as contratações e compras seguem as orientações de decretos e normas voltados para compras públicas sustentáveis e logísticas reversa

Nerve Growth Factor Biodelivery: A Limiting Step in Moving Toward Extensive Clinical Application?

Nerve growth factor (NGF) was the first-discovered member of the neurotrophin family, a class of bioactive molecules which exerts powerful biological effects on the CNS and other peripheral tissues, not only during development, but also during adulthood. While these molecules have long been regarded as potential drugs to combat acute and chronic neurodegenerative processes, as evidenced by the extensive data on their neuroprotective properties, their clinical application has been hindered by their unexpected side effects, as well as by difficulties in defining appropriate dosing and administration strategies. This paper reviews aspects related to the endogenous production of NGF in healthy and pathological conditions, along with conventional and biomaterial-assisted delivery strategies, in an attempt to clarify the impediments to the clinical application of this powerful molecule

Higher Frequencies of Lymphocytes Expressing the Natural Killer Group 2D Receptor in Patients With Behçet Disease

Behçet disease (BD) is an inflammatory systemic disease with a fluctuating course, which can affect the skin, eyes, central nervous system, musculoskeletal, gastrointestinal, and vascular systems. No laboratory tests are currently available for the diagnosis of BD and monitoring disease activity. Moreover there is a lack of knowledge on BD pathogenesis. This study focused on circulating Natural Killer (NK), NKT and T cells evaluated as CD3neg CD56pos, CD3pos CD56pos, and CD3pos CD56neg. Peripheral blood mononuclear cells (PBMCs) were collected from 38 BD patients and 20 healthy controls (HC). The frequencies of NK, NKT, and T cells expressing CD16, CD69, NKG2D, Nkp30, Nkp46, and NKG2A were assessed by flow cytometry. Cytotoxic potential of NK cells was evaluated by flow cytometry as the percentage of cells expressing the degranulation marker CD107a after incubation with K562 cells. The levels of 27 cytokines were determined in plasma with a multiplex bead-based assay. Higher percentages of NK, NKT, and T cells expressing NKG2D were detected in PBMCs of BD patients than HC. ROC curve analysis showed that the evaluation of NKG2Dpos NK, NKT, and T cell percentages discriminated between BD patients and HC. Moreover, there was a positive correlation between the BD Current Activity Form (BDCAF) scores and the frequencies of NKG2Dpos NK and NKT cells. A higher frequency of NK cells expressing CD107a was induced in PBMCs from BD patients than HC after incubation with K562 cells. Concentrations of IL-5, IL-6, IL-10, IL-13, IP-10, and MIP-1β were higher in plasma of BD patients than HC. Monitoring the frequencies of NKG2Dpos lymphocytes could help the clinicians in BD patients management. In addition, the increased expression of NKG2D in BD patients is likely involved in disease pathogenesis

Candidate biomarkers from the integration of methylation and gene expression in discordant autistic sibling pairs

While the genetics of autism spectrum disorders (ASD) has been intensively studied, resulting in the identification of over 100 putative risk genes, the epigenetics of ASD has received less attention, and results have been inconsistent across studies. We aimed to investigate the contribution of DNA methylation (DNAm) to the risk of ASD and identify candidate biomarkers arising from the interaction of epigenetic mechanisms with genotype, gene expression, and cellular proportions. We performed DNAm differential analysis using whole blood samples from 75 discordant sibling pairs of the Italian Autism Network collection and estimated their cellular composition. We studied the correlation between DNAm and gene expression accounting for the potential effects of different genotypes on DNAm. We showed that the proportion of NK cells was significantly reduced in ASD siblings suggesting an imbalance in their immune system. We identified differentially methylated regions (DMRs) involved in neurogenesis and synaptic organization. Among candidate loci for ASD, we detected a DMR mapping to CLEC11A (neighboring SHANK1) where DNAm and gene expression were significantly and negatively correlated, independently from genotype effects. As reported in previous studies, we confirmed the involvement of immune functions in the pathophysiology of ASD. Notwithstanding the complexity of the disorder, suitable biomarkers such as CLEC11A and its neighbor SHANK1 can be discovered using integrative analyses even with peripheral tissues