Disruption of cellular proteostasis by H1N1 influenza A virus causes α-synuclein aggregation.

Neurodegenerative diseases feature specific misfolded or misassembled proteins associated with neurotoxicity. The precise mechanisms by which protein aggregates first arise in the majority of sporadic cases have remained unclear. Likely, a first critical mass of misfolded proteins starts a vicious cycle of a prion-like expansion. We hypothesize that viruses, having evolved to hijack the host cellular machinery for catalyzing their replication, lead to profound disturbances of cellular proteostasis, resulting in such a critical mass of protein aggregates. Here, we investigated the effect of influenza virus (H1N1) strains on proteostasis of proteins associated with neurodegenerative diseases in Lund human mesencephalic dopaminergic cells in vitro and infection of Rag knockout mice in vivo. We demonstrate that acute H1N1 infection leads to the formation of α-synuclein and Disrupted-in-Schizophrenia 1 (DISC1) aggregates, but not of tau or TDP-43 aggregates, indicating a selective effect on proteostasis. Oseltamivir phosphate, an antiinfluenza drug, prevented H1N1-induced α-synuclein aggregation. As a cell pathobiological mechanism, we identified H1N1-induced blocking of autophagosome formation and inhibition of autophagic flux. In addition, α-synuclein aggregates appeared in infected cell populations connected to the olfactory bulbs following intranasal instillation of H1N1 in Rag knockout mice. We propose that H1N1 virus replication in neuronal cells can induce seeds of aggregated α-synuclein or DISC1 that may be able to initiate further detrimental downstream events and should thus be considered a risk factor in the pathogenesis of synucleinopathies or a subset of mental disorders. More generally, aberrant proteostasis induced by viruses may be an underappreciated factor in initiating protein misfolding.

Stigma about mental disease in Portuguese medical students: a cross-sectional study.

BACKGROUND: The stigma about mental diseases is common in the population and also in medical students, where it may condition their future practice and the way they deal with these patients. AIM: To evaluate and characterize the stigma on mental diseases in Portuguese sixth-year medical students, based on a clinical scenario of a classmate suffering from a mental disorder. METHODS: Observational cross-sectional study, involving sixth-year students of all Portuguese medical schools. We applied an online self-response questionnaire, using the Portuguese version of the Attribution Questionnaire AQ-9, and a vignette of a classmate colleague, presenting mental illness symptoms. Stigma scores were calculated. We used logistic regression to estimate the effect of social determinants on stigma pattern, and we analysed the correlation between 9 variables evaluated by the AQ-9 and total stigma. RESULTS: A total of 501 participants were included for analysis (69.5% females, median age of 24 years old). Medical students were available to help in the proposed clinical scenario (6.93/9.00; 95%CI:6.77-7.10), if necessary using coercion for treatment (3.85; 95%CI:3.63-4.07), because they felt pity (6.86; 95%CI:6.67-7.06) and they perceived some kind of dangerousness (4.06; 95%CI:3.84-4.28). Stigma was lower in students having a personal history of mental illness (OR:0.498; 95%CI:0.324-0.767; p = 0.002) and in those with positive familial history (OR: 0.691; 95%CI:0.485-0.986; p = 0.041). CONCLUSION: Our results show the importance of implementing anti-stigma education, to improve medical students' attitudes towards peers living with mental diseases.

Stress among Portuguese Medical Students: A National Cross-Sectional Study.

Introduction: The medical course is extremely stimulating but also demanding, and it can interfere with students' mental health. Stress leads to lower life quality, academic performance, and ultimately to a lower quality of patient care delivered. Objective: To analyse stress levels of sixth-year medical students who attend Portuguese colleges. Methodology. This observational cross-sectional study involved Portuguese medical students attending the sixth year of all Portuguese faculties. We applied an online self-response questionnaire, including the 10 items Perceived Stress Scale (PSS) to assess stress levels and sociodemographic variables. Logistic regression was used to estimate the weight of the studied determinants on stress levels. Results: A total of 501 participants were included for analysis (69.5% females), with a median age of 24 years old. We found significant levels of stress in 49.9% (95% CI: 45.5-54.3%), with 20.8% of total students presenting extremely high levels, irrespective of age, gender, and faculty. Stress was higher when students presented bad sleeping and eating habits, lack of ability to manage time, dissatisfaction with social life and academic experience, and low family support. Also, these students are more worried about their future and present a higher degree of concern about their graduation test performance. Conclusion: This study found high stress levels among Portuguese medical students, associated with social determinants and the intrinsic complexity of the course. This is worrying, and it elucidates the importance of coping strategies to make students deal with stress and be healthier, currently and in the future.

Risk of recurrence after a first unprovoked seizure in children.

OBJECTIVES: This study aimed to evaluate the first episode of unprovoked epileptic seizure in children and assess recurrence risk factors. METHODS: This was a retrospective observational study, based on the analysis of medical records of patients admitted between 2003 and 2014, with first epileptic seizure, at the pediatric service of a secondary hospital. The data were analyzed using the SPSS 20.0 program. RESULTS: Of the 103 patients, 52.4% were boys. The median age at the first seizure was 59 (1-211) months. About 93% of children were submitted to an electroencephalogram at the first episode and 47% underwent neuroimaging assessment. Treatment with an antiepileptic drug was started in 46% of patients. The recurrence rate was 38% and of these, 80% had the second seizure within six months after the first event. Of the assessed risk factors, there was a statistically significant association between seizure during sleep and recurrence (p=0.004), and between remote symptomatic etiology seizure and occurrence of new seizure (p=0.02). The presence of electroencephalogram abnormalities was also associated with the occurrence of new seizures (p=0.021). No association was found between age, duration of the seizure, and family history of epilepsy with increased risk of recurrence. CONCLUSIONS: Most children with a first unprovoked epileptic seizure had no recurrences. The risk of recurrence was higher in patients with seizure occurring during sleep or remote symptomatic ones and those with abnormal electroencephalogram results.

Risk of recurrence after a first unprovoked seizure in children / Risco de recorrência após uma primeira crise epilética não provocada em idade pediátrica

Abstract Objectives: This study aimed to evaluate the first episode of unprovoked epileptic seizure in children and assess recurrence risk factors. Methods: This was a retrospective observational study, based on the analysis of medical records of patients admitted between 2003 and 2014, with first epileptic seizure, at the pediatric service of a secondary hospital. The data were analyzed using the SPSS 20.0 program. Results: Of the 103 patients, 52.4% were boys. The median age at the first seizure was 59 (1-211) months. About 93% of children were submitted to an electroencephalogram at the first episode and 47% underwent neuroimaging assessment. Treatment with an antiepileptic drug was started in 46% of patients. The recurrence rate was 38% and of these, 80% had the second seizure within six months after the first event. Of the assessed risk factors, there was a statistically significant association between seizure during sleep and recurrence (p = 0.004), and between remote symptomatic etiology seizure and occurrence of new seizure (p = 0.02). The presence of electroencephalogram abnormalities was also associated with the occurrence of new seizures (p = 0.021). No association was found between age, duration of the seizure, and family history of epilepsy with increased risk of recurrence. Conclusions: Most children with a first unprovoked epileptic seizure had no recurrences. The risk of recurrence was higher in patients with seizure occurring during sleep or remote symptomatic ones and those with abnormal electroencephalogram results.

Resumo Objetivos: Este trabalho teve como objetivos estudar o primeiro episódio de crise epilética não provocada em idade pediátrica e avaliar os fatores de risco de recorrência. Métodos: Estudo observacional retrospectivo, baseado na análise dos processos clínicos dos pacientes internados entre 2003 e 2014, num serviço de pediatria de um hospital de nível 2, com primeira crise epilética. Os dados foram trabalhados com o programa SPSS Statistics 20.0. Resultados: Dos 103 pacientes, 52,4% eram meninos. A mediana da idade da primeira crise foi de 59 (um-211) meses. Fizeram eletroencefalograma no primeiro episódio 93% das crianças e 47% neuroimagem. O tratamento com fármaco antiepilético foi instituído em 46% dos pacientes. A taxa de recorrência foi 38% e, desses, 80% tiveram a segunda crise nos seis meses seguintes após o primeiro evento. Dos fatores de risco estudados verificou-se uma relação estatisticamente significativa entre a crise durante o sono e a recorrência (p = 0,004), assim como entre as crises de etiologia sintomática remota e a ocorrência de novas crises (p = 0,02). A presença de anormalidades no eletroencefalograma também esteve associada à ocorrência de novas crises (p = 0,021). Não se encontrou relação entre idade, duração da crise e história familiar de epilepsia com risco aumentado de recorrência. Conclusões: A maioria das crianças com uma primeira crise epilética não provocada não teve recorrências. O risco de recorrência foi superior nos pacientes com crise durante o sono ou crise sintomática remota e naqueles com eletroencefalograma alterado.