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Objetivos: Descrever um caso de linfoma plasmablástico de cavidade oral em paciente portadora do vírus da imunodeficiência humana (HIV). Material e métodos: Os dados foram obtidos a partir de entrevista e revisão de prontuário, com autorização do paciente. Relato de caso: Sexo feminino, 65 anos, portadora do vírus da imunodeficiência humana em tratamento irregular na época do diagnóstico (apresentava carga viral de 27.678 cópias e CD4 183). Evoluiu com lesão em região de mucosa jugal/gengiva inferior à direita com evolução de aproximadamente quarenta dias, sendo realizada biópsia da lesão em 22/06/2023 com imuno-histoquímica: CD138, cadeia leve Lambda e EBER-1 (EBV) positivos e CD20 negativo, compatível com linfoma plasmablástico. Realizado PET (01/09/23) que evidenciou lesão expansiva nodular sólida no corpo da mandíbula direita medindo 50 × 47 mm (SUV 66), linfonodos cervicais bilaterais (maior SUV 44). Proposto protocolo EPOCH (etoposídeo, prednisona, vincristina, ciclofosfamida, doxorubicina). Paciente realizou primeiro ciclo do tratamento, com diminuição importante da lesão em cavidade oral. Evoluiu com enterite neutropênica, internada para realização de antibioticoterapia endovenosa, com abandono de tratamento posteriormente. Discussão: O linfoma plasmablástico (PBL) é um subtipo raro de linfoma difuso de grandes células B, com mediana de idade de apresentação aos 50 anos, mais comum no sexo masculino (5,7:1), acometendo mais frequentemente a cavidade oral. Pode apresentar-se com odontalgia ou abscesso dentário, embora possa acometer outros sítios como pele e trato gastrointestinal. Está associado a estados de imussupressão como HIV, transplante de órgãos sólidos, doença autoimune e idosos. Presume-se que o linfoma plasmablástico seja derivado de plasmablastos, que são células B ativadas, as quais foram submetidas a hipermutação somática e mudança de classe. Alguns marcadores prognósticos como sítio (cavidade oral tem melhor prognóstico, devido a sintomas mais precoces), associação ao EBV e controle do HIV sugerem melhor prognóstico. Já a presença do rearranjando do gene MYC, idade maior que 50 anos e fase avançada conferem pior prognóstico. Em relação ao tratamento, pode ser feito protocolo CHOP, porém quando associado ao HIV, tratamento mais intensivo como EPOCH é indicado. Estudos mostraram que a terapia antirretroviral altamente eficaz (HAART) tem impacto na sobrevida. Terapias com bortezomib (inibidor de proteassoma) e daratumumab (anti-CD38) em associação com os protocolos clássicos mostraram melhores resultados. Conclusão: Esse relato descreve o diagnóstico de linfoma plasmablástico em paciente com vírus da imunodeficiência humana, com acometimento de cavidade oral. Por se tratar de um linfoma raro, mais associado a estados de imunossupressão, é importante se atentar ao tipo de apresentação e sempre realizar biópsia para o diagnóstico. É uma doença grave, com sobrevida mediana variando de 6 a 32 meses.

Objetivos: Descrever um caso de linfoma T/NK extranodal subtipo nasal. Material e métodos: Os dados foram obtidos a partir de entrevista e revisão de prontuário, com autorização do paciente. Relato de caso: Sexo masculino, 58 anos, trabalhador rural, apresentou quadro de perda ponderal de 20 quilos em um ano; evoluiu com lesão ulcerada em cavidade nasal, com invasão periocular esquerda e em palato mole. Realizada biópsia de lesão intranasal à esquerda em 20/10/23 com imunohistoquímica: CD3, CD20, CD56, EBER-I (EBV) positivos e CD20 negativo, Ki-67 90% compatível com linfoma T/NK extranodal. Realizado PET-CT (11/10/23) evidenciou acometimento em face, orofaringe, laringe, pregas vocais, linfonodos cervicais e abdominais (Estadio IV-E). Proposto protocolo SMILE (dexametasona, metotrexato, ifosfamida, L-asparaginase e etoposideo). Nos exames pré-tratamento apresentou sorologia anti-HBc total e anti-HBs positivos (contato com hepatite B com soroconversão), com necessidade de profilaxia com entecavir. Paciente fez uso de diversos tratamentos com antibióticos devido infecção secundária em sítio tumoral, com melhora após administração de Meropenem e Linezolida; iniciado protocolo SMILE com primeiro ciclo em 29/10/23. Devido ao baixo aporte nutricional e impossibilidade de passagem de sonda nasoentérica pelas lesões, optado por realizar gastrostomia como via alternativa de alimentação. Paciente evoluiu com piora clínica progressiva, com necessidade terapia intensiva 10 dias após iniciar protocolo quimioterápico, escalonamento de antibioticoterapia para polimixina B, necessidade de suporte ventilatório invasivo e droga vasoativa. Paciente veio a óbito em novembro/23 em decorrência das complicações infecciosas. Discussão: O linfoma T/NK extranodal é um subtipo de Linfoma não-Hodgkin relacionado ao vírus Epstein Barr, raro, compreende menos de 2% dos linfomas T. Desenvolve-se a partir de células natural killer (NK) - mais comum-, ou células T citotóxicas. A maioria dos linfomas T/NK ocorre na cavidade nasal e são denominados do tipo nasal, mas podem ocorrer em qualquer local. O sistema de estadiamento Ann Arbor é o mais indicado, e quanto ao prognóstico, IPI, KPI e o PINK são os modelos prognósticos e/ou preditivos mais utilizados. Existem vários tipos de esquemas quimioterápicos para tratamento. Quando a doença ocorre de forma localizada, é frequentemente tratada com radioterapia, com uma sobrevida em 5 anos de 70% dos casos. Já a doença em fase avançada pode ser tratada com radioterapia e quimioterapia, com sobrevida inferior, de apenas 40% em 5 anos. No caso do paciente relatado, foi optado por realizar protocolo SMILE, devido ao estágio avançado. Também pode ser feito P-GEMOX (peg-asparaginase, gencitabina, oxaliplatina), DDGP (dexametasona, cisplatina, gencitabina e peg-asparaginase) e em casos de pacientes que não toleram terapia de alta intensidade, pode ser realizado AspaMetDex (peg-asparaginase, metotrexato, dexametasona). Conclusão: O linfoma T/NK é um subtipo raro de linfoma T, com prognóstico reservado para os casos avançados. Esse relato descreve um caso com apresentação comum. Por se tratar de um linfoma agressivo, é importante que o diagnóstico seja feito precocemente e o tratamento correto seja instituído o mais breve possível.

Introdução: Tricoleucemia é uma leucemia crônica de linfócitos B considerada rara que acomete principalmente homens de meia idade (média de 58 anos). Clinicamente, os pacientes podem apresentar esplenomegalia palpável, astenia relacionada a anemia, febre e infecções secundárias a neutropenia. É trazido um relato de caso de paciente que evoluiu com manifestações pouco prevalentes. Objetivos: Descrever caso raro de tricoleucemia com manifestações atípicas, enfatizando desafios diagnósticos e necessidade de terapias menos tóxicas. Material e métodos: Dados coletados por meio de revisão de prontuário. Relato de caso: Homem, 45 anos, hígido, foi encaminhado para investigação de dor em flanco esquerdo e anemia refratária a sulfato ferroso há 6 meses. Exame físico revelou baço palpável 2 cm do rebordo costal. Hemograma mostrou anemia macrocítica normocrômica (hemoglobina 7,6 g/dL; Volume Corpuscular Médio 104), predomínio de linfócitos, neutropenia (leucócitos totais 4.400/mm3, segmentados 1.006/mm3, eosinófilos 40/mm3, basófilos 10/mm3, linfócitos 2.904/mm3, monócitos 440/mm3) e trombocitopenia (plaquetas 79.000/mm3). Ultrassom abdominal com hepatoesplenomegalia (baço: 1.700 cm3) e linfonodomegalia interartocaval. Provas de hemólise negativas (reticulócitos 1,9%, desidrogenase lática 160 U/L, bilirrubina indireta 0,29 mg/dL), e exames de função hepática com elevação de enzimas canaliculares (fosfatase alcalina 205 U/L, gama glutamil transferase 114 U/L). Sorologias para HIV, hepatite B e C foram negativas e sem deficiência de vitamina B12 ou ácido fólico. Eletroforese de proteínas revelou pico monoclonal não mensurável. Lâmina de sangue periférico evidenciou linfocitose com prolongamentos sugestivos de hairy cell. Imunofenotipagem confirmou Tricoleucemia, com marcadores positivos para CD19, CD20, CD38 Lambda, CD11c, CD25, CD49d, CD79b, CD81, cyIgM, sIgM, CD103, CD123, CD200, CD305; e negativos para CD3, CD4, CD5, CD8, CD10, CD23, CD43, CD56, TCR gama-delta e Kappa. Biópsia de medula óssea revelou infiltração extensa por hairy cell (linfócitos com marcadores CD20 e anexina 1), com 95% de carga tumoral e fibrose grau 2. Tomografias evidenciaram linfonodomegalia difusa. O paciente recebeu um ciclo de 5 dias de cladribina, mas evoluiu com neutropenia grave refratária a filgrastim e foi internado devido a infecção pulmonar. Apesar do tratamento com antibióticos de amplo espectro, antifúngicos e esquema RIPE, o paciente faleceu após 2 meses por infecção. Discussão: O caso relatado teve manifestações incomuns como esplenomegalia sintomática e linfonodomegalia difusa, além da ausência de monocitopenia. Esse quadro atrasou o diagnóstico em 6 meses associado à natureza oligossintomática da doença. Análogos de nucleosídeos de purina são a primeira linha de tratamento, mas nem todos os pacientes necessitam de início imediato de quimioterapia. Apesar de apresentarem bons resultados, mielotoxicidade com neutropenia a longo prazo tornam os primeiros meses desafiadores. Neste caso, o quadro infeccioso associado ao longo período de neutropenia grave foi fatal. Conclusão: Apesar de ser uma leucemia crônica, a Tricoleucemia pode ter um desfecho desfavorável. O tratamento padrão tem alta toxicidade e não há consenso sobre fatores prognósticos ou momento ideal para iniciar a quimioterapia. A formulação de protocolos mais precisos e desenvolvimento de terapias menos tóxicas são essenciais para melhorar os resultados para esses pacientes.

Introdução: Ao longo das décadas, diversas mudanças em classificação e diagnóstico foram feitas a respeito das leucemias mieloides agudas (LMA). Desde a classificação da OMS de 2016, houve uma grande expansão da categorização desta condição em torno de alterações genéticas recorrentes, relação com mielodisplasia e com terapias prévias. Neste contexto, um dos subtipos anteriormente reconhecidos como eritroleucemia, descrito inicialmente por Giovanni Di Guglielmo em 1917, passou a ser classificado no grupo de LMA sem especificações. Ao mesmo tempo, emergiu o conceito de leucemia eritroide pura (LEP). A correta categorização dos subtipos de LMA é importante no contexto da biologia e fisiopatologia da doença, podendo ser traduzida em implicações prognósticas. Objetivo: Relatar caso de leucemia mieloide aguda relacionada à mielodisplasia com diferenciação eritroide e realização de contraponto à hipótese de leucemia eritroide. Material e métodos: Os dados foram obtidos a partir de entrevista e revisão de prontuário, com autorização da paciente. Relato do caso: Paciente do sexo feminino, 73 anos, iniciou quadro de astenia com evolução de 3 meses, associada a anemia e plaquetopenia. Encaminhada para investigação em serviço terciário de saúde. Ao mielograma, identificado 18% de células imaturas de tamanho e relação núcleo-citoplasmática intermediários com presença de microvacúolos citoplasmáticos. Imunofenotipagem de medula óssea consistente com presença de 23% de células mieloides imaturas de tamanho e complexidade interna intermediários com perfil imunofenotípico demonstrando o perfil CD45±, CD117++, cyMPO+, CD7-/+ (50%) heterogêneo, CD13-/+ (16,5%), CD33-/+, CD36++, CD71++, CD105+, compatível com leucemia mieloide aguda com diferenciação eritróide. O cariótipo apresentava alterações complexas, com presença de del5q, monossomia do 9 e do 18, além de poliploidia. Optado por tratamento com Citarabina Low Dose. Discussão: LMA relacionada à mielodisplasia é uma entidade caracterizada pela presença de mais de 20% de blastos em associação a alterações moleculares e/ou citogenéticas (presença de cariótipo complexo ou alterações genéticas recorrentes definidoras de classe) especificamente atreladas às neoplasias mielodisplásicas. A LEP, por sua vez, é definida nos critérios da OMS quando presentes mais de 80% de precursores eritroides na medula e mais de 30% de proeritroblastos. Corresponde a cerca de 1% de todos os casos de LMA. A sua prevalência parece ser maior em homens e na sétima década de vida. Caracteriza-se à imunofenotipagem pela positividade de CD36 e CD71. É esperada a negatividade de CD34 e HLA-DR, enquanto CD117 e E-caderina geralmente apresentam expressão positiva ou parcial. Morfologicamente, os blastos são tipicamente grandes e redondos, com nucléolos proeminentes e com citoplasma profundamente basofílico, na presença de vacuolização e carência de grânulos. São comuns alterações citogenéticas como as deleções do 5q, 7q e 17p e cariótipo complexo, bem como alterações bialélicas do TP53. Conclusão: Ao se analisar o caso, estabelece-se o diagnóstico de LMA relacionada à mielodisplasia com blastos com diferenciação eritroide, a qual é notada tanto pela imunofenotipagem, quanto pelo padrão morfológico visualizado ao mielograma, mas não havendo critérios para se considerar a hipótese de uma leucemia eritroide.

An experiment was conducted in the greenhouse to study growth, development, yield and water-use by Anahein pepper grown in a potting mixture supplemented with MiracleGro® (9:4:12) and milled alfalfa (3:1:2) as sources of nutrient. The study was comprised of 5 treatments, control (C), 3 gL-1 MiracleGro® (MG), 9 g alfalfa mill supplement (SA-1), 18 g (SA-2), and 27 g (SA-3), and replicated 6 times. Ten physiological and morphological parameters were used to evaluate growth, development and yield of the Anaheim pepper, and two parameters used to evaluate the water holding capacity of the potting mixture. The results indicate that the potting medium supplemented with alfalfa mill required significantly less water to support growth and development of the species. Also, growth, development and yield of Anaheim pepper was significantly higher in the organic supplements at SA-2 and SA-3.

Background. An important strategy in the transformation and scaling up of medical education is the inclusion and utilisation of decentralised training platforms (DTPs). Objective. In light of the dearth of research on the activities of medical students at DTPs, the purpose of this study was to determine how final-year medical students spent their time during the integrated primary care (IPC) rotation at a DTP. Methods. The study was conducted at Sefako Makgatho Health Sciences University (SMU), the University of KwaZulu-Natal (UKZN), the University of the Witwatersrand (Wits) and Walter Sisulu University (WSU). At each of the participating universities, a voluntary group of final-year medical students completed a log diary by entering all activities for a period of 1 week during the IPC rotation. The log diary contained five activity codes: clinical time teaching time, skill time, community time and free time, with each subdivided into additional categories. The data were analysed for students at each university separately, using frequencies and proportions. Results. A total of 60 students volunteered to complete the diaries: at WSU n=21; UKZN n=11; Wits n=18; and SMU n=10. At each university, students reported that they spent large amounts of time on clinical activities: WSU=46.0%; UKZN=33.8%; Wits=29.6%; and SMU=44.1%. They reported low amounts of time spent on community-based activities: WSU 0.8%; UKZN 7.6%; Wits 6.8%; and SMU 0.0%. Conclusion. Students reported that they spent a sizeable proportion of their time on clinical activities, while reported time spent on community-based activities was negligible. The transformation potential of DTPs will only be realised when students spend more time on community-based activities.

Background and Purpose: Slow-acting biogenic amines, such as dopamine, are known to modulate fast neurotransmitters e.g. glutamate. In the striatum, dopamine (DA) interacts with glutamate, influencing neural excitability and promoting synaptic plasticity. The exact mechanism of such interaction is not fully understood. This study investigates, in detail, how dopamine overactivity in dopamine transporter knockout (DAT -/- ) rats, alters the homeostasis of the striatal glutamate synapse from a molecular, behavioural and functional point of view., Experimental Approach: The expression, localisation, retention and electrophysiological properties of N-methyl-D-aspartate (NMDA) receptors as well as dendritic spine density and morphology were investigated in the striatum of DAT -/- rats, at baseline and after treatment with the non-competitive NMDA receptor antagonist memantine (30 mg kg -1 )., Key Results: Dopamine overactivity dramatically reorganises the striatal glutamate synapse, redistributing NMDA receptors in the synapse as typified by reduced synaptic availability and reduced expression of NMDA scaffolding proteins, as well as by increased GluN2B-containing NMDA receptors in the extra synapse. Such changes are accompanied by reduced spine density, suggesting dopamine-induced structural rearrangements. These results converge into a compromised plasticity, as shown by the impaired ability to promote long-term depression (LTD) in the striatum of DAT -/- rats. Notably, memantine counteracts hyperlocomotion, reverses spine alterations and abolishes the extrasynaptic movements of NMDA receptors in the striatum of DAT -/- rats, thus restoring functional LTD., Conclusion and Implications: A hyperdopaminergic condition seems to alter striatal homeostasis by increasing extrasynaptic NMDA receptors. These findings may be relevant to manipulate disorders characterised by elevated dopaminergic activity., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Introduction: Neurogenic lower urinary tract (NLUTD), bowel (NBD), and sexual dysfunction (SD) are commonly observed in patients with (pw) multiple sclerosis (MS) and diminish the patients' quality of life (QoL). This systematic review aim to evaluate and discuss the current algorithms for the management of these issues., Methods: A systematic review was conducted on the PubMed in June 2024. The primary search criterion was the presence of the term 'algorithm/s' or 'management/ing' in the title and/or abstract, followed by the MeSH term 'multiple sclerosis' and a combination of free-text keywords referring to NLUTD, NBD or SD., Results: Fifteen articles regarding NLUTD were considered eligible, only one regarding SD while none addressed NBD., Discussion: Numerous studies emphasize the profound impact of urinary and bowel symptoms on the QoL and morbidity in pwMS. Few algorithms addressing NLUTD are designed for first-line physicians and addresses the key priorities in MS care. Specific approaches to NBD management in pwMS are lacking. Screening for SD requires a structured assessment to deliver appropriate solutions., Conclusion: NLUTD, NBD, and SD are underdiagnosed and undertreated. The implementation of straightforward algorithms for first-line physicians could enhance the management of these common issues, improve the QoL, reduce costs, and ensure appropriate referral to specialists., Competing Interests: Declaration of competing interest The author declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Microglial cells, as the primary defense line in the central nervous system, play a crucial role in responding to various mechanical signals that can trigger their activation. Despite extensive research on the impact of chemical signaling on brain cells, the understanding of mechanical signaling in microglia remains limited. To bridge this gap, we subjected microglial cells to a singular mechanical stretch and compared their responses with those induced by lipopolysaccharide treatment, a well-established chemical activator. Here we show that stretching microglial cells leads to their activation, highlighting their significant mechanosensitivity. Stretched microglial cells exhibited distinct features, including elevated levels of Iba1 protein, a denser actin cytoskeleton, and increased persistence in migration. Unlike LPS-treated microglial cells, the secretory profile of chemokines and cytokines remained largely unchanged in response to stretching, except for TNF-α. Intriguingly, a single stretch injury resulted in more compacted chromatin and DNA damage, suggesting potential long-term genomic instabilities in stretched microglia. Using compartmentalized microfluidic chambers with neuronal networks, we observed that stretched microglial cells exhibited enhanced phagocytic and synaptic stripping activities. These findings collectively suggest that stretching events can unlock the immune potential of microglial cells, contributing to the maintenance of brain tissue homeostasis following mechanical injury., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Sylvain Gabriele reports financial support was provided by University of Mons. Anthony Proces reports financial support was provided by Fund for Scientific Research. Yeranddy A. Alpizar reports financial support was provided by Research Foundation Flanders. Frederic Saudou reports financial support was provided by European Research Council., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Alzheimer's disease (AD) is a neurodegenerative disorder lacking any curative treatment up to now. Indeed, actual medication given to the patients alleviates only symptoms. The cytosolic phospholipase A2 (cPLA 2 -IVA) appears as a pivotal player situated at the center of pathological pathways leading to AD and its inhibition could be a promising therapeutic approach., Objective: A cPLA 2 -IVA inhibiting peptide was identified in the present work, aiming to develop an original therapeutic strategy., Methods: We targeted the cPLA 2 -IVA using the phage display technology. The hit peptide PLP25 was first validated in vitro (arachidonic acid dosage [AA], cPLA 2 -IVA cellular translocation) before being tested in vivo . We evaluated spatial memory using the Barnes maze, amyloid deposits by MRI and immunohistochemistry (IHC), and other important biomarkers such as the cPLA 2 -IVA itself, the NMDA receptor, AβPP and tau by IHC after i.v. injection in APP/PS1 mice., Results: Showing a high affinity for the C2 domain of this enzyme, the peptide PLP25 exhibited an inhibitory effect on cPLA 2 -IVA activity by blocking its binding to its substrate, resulting in a decreased release of AA. Coupled to a vector peptide (LRPep2) in order to optimize brain access, we showed an improvement of cognitive abilities of APP/PS1 mice, which also exhibited a decreased number of amyloid plaques, a restored expression of cPLA 2 -IVA, and a favorable effect on NMDA receptor expression and tau protein phosphorylation., Conclusions: cPLA 2 -IVA inhibition through PLP25 peptide could be a promising therapeutic strategy for AD., Competing Interests: The authors have no conflict of interest to report., (© 2023 – The authors. Published by IOS Press.)

Background: The African Copperbelt is a site of intense artisanal and industrial mining and refining of copper and cobalt., Aim: We aimed to investigate factors that are possibly associated with erectile dysfunction (ED) in metal miners in the former Katanga province of the Democratic Republic of the Congo., Methods: In a cross-sectional study of 138 miners and 139 controls (bakers), we administered questionnaires to obtain sociodemographic and occupational data and to assess male sexual function (International Index of Erectile Function [IIEF]) and marital relation quality (Revised Dyadic Adjustment Scale). Furthermore, we measured trace metals in blood and urine, as well as testosterone and thyroid hormones in serum., Outcomes: Outcomes included the prevalence of questionnaire-derived ED and the relation of ED with individual characteristics, serum testosterone, and environmental factors., Results: Miners were on average 4 years older than bakers (mean ± SD, 37.5 ± 6.9 vs 33.3 ± 5.7 years). Miners had significantly lower scores than bakers on the IIEF (median [IQR], 66 [49-73] vs 73 [66-74]) and the 3 domains of the Revised Dyadic Adjustment Scale (consensus, satisfaction, cohesion). Free testosterone was significantly lower in miners than bakers (ng/dL; 8.11 [6.90-10.10] vs 10.52 [8.83-12.58]; P ˂ .001). In miners, sex hormone-binding globulin correlated positively with blood Pb and urinary Cd. In a multivariable analysis, mild to moderate ED or moderate ED (IIEF-erectile function score ≤18) was significantly associated with having a mining-related job (adjusted odds ratio [aOR], 2.6; 95% CI, 1.3-5.3), work seniority ˃5 years (aOR, 2.3; 95% CI, 1.1-4.6), alcohol consumption (aOR, 2.8; 95% CI, 1.2-6.7), and aphrodisiacs use (aOR, 4.2; 95% CI, 2.2-8.0). Mediation analysis showed that marital relationship partially mediated the relation between work seniority >5 years in mining and ED., Clinical Implications: The high prevalence of ED found in artisanal mine workers indicates that work-related factors should be considered as possibly contributing, directly or indirectly, to sexual dysfunction in men., Strengths and Limitations: Strengths include being the first epidemiologic study documenting ED with validated questionnaires and its possible determinants, including exposure to toxic metals, among young artisanal miners vs a suitable control group. Limitations are the cross-sectional design with convenience sampling and absence of objective confirmation of ED., Conclusion: As compared with controls, miners reported poorer sexual function and lower quality of their marital relationship, and they had lower free testosterone levels, which may be due to their high exposure to trace metals., Competing Interests: The authors declare that they have no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

Explainable Artificial Intelligence (xAI) is a rapidly growing field that focuses on making deep learning models interpretable and understandable to human decision-makers. In this study, we introduce xAAEnet, a novel xAI model applied to the assessment of Obstructive Sleep Apnea (OSA) severity. OSA is a prevalent sleep disorder that can lead to numerous medical conditions and is currently assessed using the Apnea-Hypopnea Index (AHI). However, AHI has been criticized for its inability to accurately estimate the effect of OSAs on related medical conditions. To address this issue, we propose a human-centric xAI approach that emphasizes similarity between apneic events as a whole and reduces subjectivity in diagnosis by examining how the model makes its decisions. Our model was trained and tested on a dataset of 60 patients' Polysomnographic (PSG) recordings. Our results demonstrate that the proposed model, xAAEnet, outperforms models with traditional architectures such as convolutional regressor, autoencoder (AE), and variational autoencoder (VAE). This study highlights the potential of xAI in providing an objective OSA severity scoring method.Clinical relevance- This study provides an objective OSA severity scoring technique which could improve the management of apneic patients in clinical practice.

The network formed by the brainstem, cerebellum, and hippocampus occupies a central position to achieve navigation. Multiple physiological functions are implicated in this complex behavior. Among these, control of the eye-head and body movements is crucial. The gaze-holding system realized by the brainstem oculomotor neural integrator (ONI) situated in the nucleus prepositus hypoglossi and fine-tuned by the contribution of different regions of the cerebellum assumes the stability of the image on the fovea. This function helps in the recognition of environmental targets and defining appropriate navigational pathways further elaborated by the entorhinal cortex and hippocampus. In this context, an enigmatic brainstem area situated in front of the ONI, the nucleus incertus (NIC), is implicated in the dynamics of brainstem-hippocampus theta oscillation and contains a group of neurons projecting to the cerebellum. These neurons are characterized by burst tonic behavior similar to the burst tonic neurons in the ONI that convey eye velocity-position signals to the cerebellar flocculus. Faced with these forgotten cerebellar projections of the NIC, the present perspective discusses the possibility that, in addition to the already described pathways linking the cerebellum and the hippocampus via the medial septum, these NIC signals related to the vestibulo-ocular reflex and gaze holding could participate in the hippocampal control of navigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Cheron, Ris and Cebolla.)

Background: Clinical practice guidelines promote bio-psychosocial management of patients suffering from low back pain (LBP). The objective of this study was to examine the current knowledge, attitudes and beliefs of physiotherapists about a guideline-adherent approach to LBP and to assess the ability of physiotherapists to recognise signs of a specific LBP in a clinical vignette., Methods: Physiotherapists were recruited to participate in an online study. They were asked to indicate whether they were familiar with evidence-based guidelines and then to fill in the Health Care Providers' Pain and Impairment Relationship Scale (HC-PAIRS), Back Pain Attitudes Questionnaire (Back-PAQ), Neurophysiology of Pain Questionnaire (NPQ), as well as questions related to two clinical vignettes., Results: In total, 527 physiotherapists participated in this study. Only 38% reported being familiar with guidelines for the management of LBP. Sixty-three percent of the physiotherapists gave guideline-inconsistent recommendations regarding work. Only half of the physiotherapists recognised the signs of a specific LBP., Conclusions: The high proportion of physiotherapists unfamiliar with guidelines and demonstrating attitudes and beliefs not in line with evidence-based management of LBP is concerning. It is crucial to develop efficient strategies to enhance knowledge of guidelines among physiotherapists and increase their implementation in clinical practice.

Brain Computer Interfaces (BCIs) consist of an interaction between humans and computers with a specific mean of communication, such as voice, gestures, or even brain signals that are usually recorded by an Electroencephalogram (EEG). To ensure an optimal interaction, the BCI algorithm typically involves the classification of the input signals into predefined task-specific categories. However, a recurrent problem is that the classifier can easily be biased by uncontrolled experimental conditions, namely covariates, that are unbalanced across the categories. This issue led to the current solution of forcing the balance of these covariates across the different categories which is time consuming and drastically decreases the dataset diversity. The purpose of this research is to evaluate the need for this forced balance in BCI experiments involving EEG data. A typical design of neural BCIs involves repeated experimental trials using visual stimuli to trigger the so-called Event-Related Potential (ERP). The classifier is expected to learn spatio-temporal patterns specific to categories rather than patterns related to uncontrolled stimulus properties, such as psycho-linguistic variables (e.g., phoneme number, familiarity, and age of acquisition) and image properties (e.g., contrast, compactness, and homogeneity). The challenges are then to know how biased the decision is, which features affect the classification the most, which part of the signal is impacted, and what is the probability to perform neural categorization per se . To address these problems, this research has two main objectives: (1) modeling and quantifying the covariate effects to identify spatio-temporal regions of the EEG allowing maximal classification performance while minimizing the biasing effect, and (2) evaluating the need to balance the covariates across categories when studying brain mechanisms. To solve the modeling problem, we propose using a linear parametric analysis applied to some observable and commonly studied covariates to them. The biasing effect is quantified by comparing the regions highly influenced by the covariates with the regions of high categorical contrast, i.e., parts of the ERP allowing a reliable classification. The need to balance the stimulus's inner properties across categories is evaluated by assessing the separability between category-related and covariate-related evoked responses. The procedure is applied to a visual priming experiment where the images represent items belonging to living or non-living entities. The observed covariates are the commonly controlled psycho-linguistic variables and some visual features of the images. As a result, we identified that the category of the stimulus mostly affects the late evoked response. The covariates, when not modeled, have a biasing effect on the classification, essentially in the early evoked response. This effect increases with the diversity of the dataset and the complexity of the algorithm used. As the effects of both psycho-linguistic variables and image features appear outside of the spatio-temporal regions of significant categorical contrast, the proper selection of the region of interest makes the classification reliable. Having proved that the covariate effects can be separated from the categorical effect, our framework can be further used to isolate the category-dependent evoked response from the rest of the EEG to study neural processes involved when seeing living vs. non-living entities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 La Fisca, Vandenbulcke, Wauthia, Miceli, Simoes Loureiro, Ris, Lefebvre, Gosselin and Pernet.)

Tetrahydroisoquinoline (THIQ) alkaloids and their derivatives have a structural similarity to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a well-known neurotoxin. THIQs seem to present a broad range of actions in the brain, critically dependent on their catechol moieties and metabolism. These properties make it reasonable to assume that an acute or chronic exposure to some THIQs might lead to neurodegenerative diseases including essential tremor (ET). We developed a method to search for precursor carbonyl compounds produced during the Maillard reaction in overcooked meats to study their reactivity with endogenous amines and identify the reaction products. Then, we predicted in silico their pharmacokinetic and toxicological properties toward the central nervous system. Finally, their possible neurological effects on a novel in vitro 3D neurosphere model were assessed. The obtained data indicate that meat is an alkaloid precursor, and we identified the alkaloid 1-benzyl-1,2,3,4-tetrahydroisoquinoline-6,7-diol (1-benz-6,7-diol THIQ) as the condensation product of phenylacetaldehyde with dopamine; in silico study of 1-benz-6,7-diol-THIQ reveals modulation of dopamine receptor D1 and D2; and in vitro study of 1-benz-6,7-diol-THIQ for cytotoxicity and oxidative stress induction does not show any difference after 24 h contact for all tested concentrations. To conclude, our in vitro data do not support an eventual neurotoxic effect for 1-benz-6,7-diol-THIQ.

Alzheimer's disease is histopathologically well defined by the presence of amyloid deposits and tau-related neurofibrillary tangles in crucial regions of the brain. Interest is growing in revealing and determining possible pathological markers also in the cerebellum as its involvement in cognitive functions is now well supported. Despite the central position of the Purkinje cell in the cerebellum, its electrophysiological behaviour in mouse models of Alzheimer's disease is scarce in the literature. Our first aim was here to focus on the electrophysiological behaviour of the cerebellum in awake mouse model of Alzheimer's disease (APPswe/PSEN1dE9) and the related performance on the water-maze test classically used in behavioural studies. We found prevalent signs of electrophysiological alterations in both Purkinje cells and deep cerebellar nuclei neurons which might explain the behavioural deficits reported during the water-maze test. The alterations of neurons firing were accompanied by a dual (~16 and ~228 Hz) local field potential's oscillation in the Purkinje cell layer of Alzheimer's disease mice which was concomitant to an important increase of both the simple and the complex spikes. In addition, β-amyloid deposits were present in the molecular layer of the cerebellum. These results highlight the importance of the output firing modification of the AD cerebellum that may indirectly impact the activity of its subcortical and cortical targets., (© 2022 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Extensive research has uncovered diverse forms of synaptic plasticity and an array of molecular signaling mechanisms that act as positive or negative regulators. Specifically, cyclic 3',5'-cyclic adenosine monophosphate (cAMP)-dependent signaling pathways are crucially implicated in long-lasting synaptic plasticity. In this study, we examine the role of Popeye domain-containing protein 1 (POPDC1) (or blood vessel epicardial substance (BVES)), a cAMP effector protein, in modulating hippocampal synaptic plasticity. Unlike other cAMP effectors, such as protein kinase A (PKA) and exchange factor directly activated by cAMP, POPDC1 is membrane-bound and the sequence of the cAMP-binding cassette differs from canonical cAMP-binding domains, suggesting that POPDC1 may have an unique role in cAMP-mediated signaling. Our results show that Popdc1 is widely expressed in various brain regions including the hippocampus. Acute hippocampal slices from Popdc1 knockout (KO) mice exhibit PKA-dependent enhancement in CA1 long-term potentiation (LTP) in response to weaker stimulation paradigms, which in slices from wild-type mice induce only transient LTP. Loss of POPDC1, while not affecting basal transmission or input-specificity of LTP, results in altered response during high-frequency stimulation. Popdc1 KO mice also show enhanced forskolin-induced potentiation. Overall, these findings reveal POPDC1 as a novel negative regulator of hippocampal synaptic plasticity and, together with recent evidence for its interaction with phosphodiesterases (PDEs), suggest that POPDC1 is involved in modulating activity-dependent local cAMP-PKA-PDE signaling., (© The Author(s) 2021. Published by Oxford University Press.)

Abstract: Prdm12 is a conserved epigenetic transcriptional regulator that displays restricted expression in nociceptors of the developing peripheral nervous system. In mice, Prdm12 is required for the development of the entire nociceptive lineage. In humans, PRDM12 mutations cause congenital insensitivity to pain, likely because of the loss of nociceptors. Prdm12 expression is maintained in mature nociceptors suggesting a yet-to-be explored functional role in adults. Using Prdm12 inducible conditional knockout mouse models, we report that in adult nociceptors Prdm12 is no longer required for cell survival but continues to play a role in the transcriptional control of a network of genes, many of them encoding ion channels and receptors. We found that disruption of Prdm12 alters the excitability of dorsal root ganglion neurons in culture. Phenotypically, we observed that mice lacking Prdm12 exhibit normal responses to thermal and mechanical nociceptive stimuli but a reduced response to capsaicin and hypersensitivity to formalin-induced inflammatory pain. Together, our data indicate that Prdm12 regulates pain-related behavior in a complex way by modulating gene expression in adult nociceptors and controlling their excitability. The results encourage further studies to assess the potential of Prdm12 as a target for analgesic development., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Worldwide, approximately 27 million people are affected by Alzheimer's disease (AD). AD pathophysiology is believed to be caused by the deposition of the β-amyloid peptide (Aβ). Aβ can reduce long-term potentiation (LTP), a form of synaptic plasticity that is closely associated with learning and memory and involves postsynaptic glutamate receptor phosphorylation and trafficking. Moreover, Aβ seems to be able to reduce glutamatergic transmission by increasing the endocytosis of NMDA receptors. Trace amines (TAs) are biogenic amines that are structurally similar to monoamine neurotransmitters. TAs bind to G protein-coupled receptors, called TAARs (trace amine-associated receptors); the best-studied member of this family, TAAR1, is distributed in the cortical and limbic structures of the CNS. It has been shown that the activation of TAAR1 can rescue glutamatergic hypofunction and that TAAR1 can modulate glutamate NMDA receptor-related functions in the frontal cortex. Several lines of evidence also suggest the pro-cognitive action of TAAR1 agonists in various behavioural experimental protocols. Thus, we studied, in vitro, the role of the TAAR1 agonist RO5256390 on basal cortical glutamatergic transmission and tested its effect on Aβ-induced dysfunction. Furthermore, we investigated, in vivo, the role of TAAR1 in cognitive dysfunction induced by Aβ infusion in Aβ-treated mice. In vitro data showed that Aβ 1-42 significantly decreased NMDA cell surface expression while the TAAR1 agonist RO5256390 promoted their membrane insertion in cortical cells. In vivo, RO5256390 showed a mild pro-cognitive effect, as demonstrated by the better performance in the Y maze test in mice treated with Aβ. Further studies are needed to better understand the interplay between TAAR1/Aβ and glutamatergic signalling, in order to evaluate the eventual beneficial effect in different experimental paradigms and animal models. Taken together, our data indicate that TAAR1 agonism may provide a novel therapeutic approach in the treatments of disorders involving Aβ-induced cognitive impairments, such as AD.

Among the different modalities to assess emotion, electroencephalogram (EEG), representing the electrical brain activity, achieved motivating results over the last decade. Emotion estimation from EEG could help in the diagnosis or rehabilitation of certain diseases. In this paper, we propose a dual model considering two different representations of EEG feature maps: 1) a sequential based representation of EEG band power, 2) an image-based representation of the feature vectors. We also propose an innovative method to combine the information based on a saliency analysis of the image-based model to promote joint learning of both model parts. The model has been evaluated on four publicly available datasets: SEED-IV, SEED, DEAP and MPED. The achieved results outperform results from state-of-the-art approaches for three of the proposed datasets with a lower standard deviation that reflects higher stability. For sake of reproducibility, the codes and models proposed in this paper are available at https://github.com/VDelv/Emotion-EEG.

Introduction: Low back pain (LBP) is ranked as the first musculoskeletal disorder considering years lived with disability worldwide. Despite numerous guidelines promoting a bio-psycho-social (BPS) approach in the management of patients with LBP, many health care professionals (HCPs) still manage LBP patients mainly from a biomedical point of view., Objective: The purpose of this pilot study was to evaluate the feasibility of implementing an interactive e-learning module on the management of LBP in HCPs., Methods: n total 22 HCPs evaluated the feasibility of the e-learning module with a questionnaire and open questions. Participants filled in the Back Pain Attitude Questionnaire (Back-PAQ) before and after completing the module to evaluate their attitudes and beliefs about LBP., Results: The module was structured and easy to complete (91%) and met the expectations of the participants (86%). A majority agreed that the module improved their knowledge (69%). Some participants (77%) identified specific topics that might be discussed in more detail in the module. HCPs knowledge, beliefs and attitudes about LBP significantly improved following module completion (t = -7.63, P < .001) with a very large effect size ( d s  = -1.63)., Conclusion: I The module seems promising to change knowledge, attitudes and beliefs of the participants. There is an urgent need to develop and investigate the effect of educational interventions to favor best practice in LBP management and this type of e-learning support could promote the transition from a biomedical to a bio-psycho-social management of LBP in HCPs.

The cystine/glutamate antiporter system x c - has been identified as the major source of extracellular glutamate in several brain regions as well as a modulator of neuroinflammation, and genetic deletion of its specific subunit xCT (xCT -/- ) is protective in mouse models for age-related neurological disorders. However, the previously observed oxidative shift in the plasma cystine/cysteine ratio of adult xCT -/- mice led to the hypothesis that system x c - deletion would negatively affect life- and healthspan. Still, till now the role of system x c - in physiological aging remains unexplored. We therefore studied the effect of xCT deletion on the aging process of mice, with a particular focus on the immune system, hippocampal function, and cognitive aging. We observed that male xCT -/- mice have an extended lifespan, despite an even more increased plasma cystine/cysteine ratio in aged compared to adult mice. This oxidative shift does not negatively impact the general health status of the mice. On the contrary, the age-related priming of the innate immune system, that manifested as increased LPS-induced cytokine levels and hypothermia in xCT +/+ mice, was attenuated in xCT -/- mice. While this was associated with only a very moderate shift towards a more anti-inflammatory state of the aged hippocampus, we observed changes in the hippocampal metabolome that were associated with a preserved hippocampal function and the retention of hippocampus-dependent memory in male aged xCT -/- mice. Targeting system x c - is thus not only a promising strategy to prevent cognitive decline, but also to promote healthy aging., (© 2022. The Author(s).)

Increasing evidence suggests that mechanics play a critical role in regulating brain function at different scales. Downstream integration of mechanical inputs into biochemical signals and genomic pathways causes observable and measurable effects on brain cell fate and can also lead to important pathological consequences. Despite recent advances, the mechanical forces that influence neuronal processes remain largely unexplored, and how endogenous mechanical forces are detected and transduced by brain cells into biochemical and genetic programs have received less attention. In this review, we described the composition of brain tissues and their pronounced microstructural heterogeneity. We discuss the individual role of neuronal and glial cell mechanics in brain homeostasis and diseases. We highlight how changes in the composition and mechanical properties of the extracellular matrix can modulate brain cell functions and describe key mechanisms of the mechanosensing process. We then consider the contribution of mechanobiology in the emergence of brain diseases by providing a critical review on traumatic brain injury, neurodegenerative diseases, and neuroblastoma. We show that a better understanding of the mechanobiology of brain tissues will require to manipulate the physico-chemical parameters of the cell microenvironment, and to develop three-dimensional models that can recapitulate the complexity and spatial diversity of brain tissues in a reproducible and predictable manner. Collectively, these emerging insights shed new light on the importance of mechanobiology and its implication in brain and nerve diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Procès, Luciano, Kalukula, Ris and Gabriele.)

Background: Cognitive models indicated that social anxiety disorder (SAD) would be caused and maintained by a biased attentional processing of threatening information. This study investigates whether socially anxious children may present impaired attentional engagement and disengagement from negative emotional faces, as well as their underlying event-related potential responses., Methods and Findings: Fifteen children with high levels of social anxiety (HSA; 9 boys; mean age = 9.99y; SD = 1.14) and twenty low socially anxious children (LSA; 16 boys; mean age = 10.47y; SD = 1.17) participated in a spatial cueing task in which they had to detect targets following neutral/disgusted faces in a valid or invalid location. No group effect was reported on reaction times [p>.05]. However, electrophysiological data showed lower P3a amplitude in HSA children compared with the LSA group when processing facial stimuli. They also reported larger N2 amplitudes for valid-disgusted targets and a larger P3a amplitude for the invalid-disgusted ones., Conclusion: In terms of electrophysiological data, our results validated, the hypothesis of attentional disengagement difficulties in SAD children. We also confirm the idea that high levels of social anxiety are associated with cognitive control impairments and have a greater impact on the processing efficiency than on the performance effectiveness., Competing Interests: The authors have declared that no competing interests exist.

Deformation, compression, or stretching of brain tissues cause diffuse axonal injury (DAI) and induce structural and functional alterations of astrocytes, the most abundant cell type in the brain. To gain further insight into the role of mechanically activated astrocytes on neuronal networks, this study was designed to investigate whether cytokines released by mechanically activated astrocytes can affect the growth and synaptic connections of cortical neuronal networks. Astrocytes were cultivated on elastic membranes and subjected to repetitive mechanical insults, whereas well-defined protein micropatterns were used to form standardized neuronal networks. GFAP staining showed that astrocytes were mechanically activated after two cycles of stretch and mesoscale discovery assays indicated that injured astrocytes released four major cytokines. To understand the role of these cytokines, neuronal networks were cultured with the supernatant of healthy or mechanically activated astrocytes, and the individual contribution of the proinflammatory cytokine tumor necrosis factor-α (TNF-α) was studied. We found that the supernatant of two-cycle stretched astrocytes decreased presynaptic terminals and indicated that TNF-α must be considered a key player of the synaptic loss. Furthermore, our results indicate that cytokines released by injured astrocytes significantly modulate the balance between TNFR1 and TNFR2 receptors by enhancing R2 receptors. We demonstrated that TNF-α is not involved in this process, suggesting a predominant role of other secreted cytokines. Together, these results contribute to a better understanding of the consequences of repetitive astrocyte deformations and highlight the role of inflammatory signaling pathways in synaptic plasticity and modulation of TNFR1 and TNFR2 receptors.

The astrocytic cystine/glutamate antiporter system x c - represents an important source of extracellular glutamate in the central nervous system, with potential impact on excitatory neurotransmission. Yet, its function and importance in brain physiology remain incompletely understood. Employing slice electrophysiology and mice with a genetic deletion of the specific subunit of system x c - , xCT (xCT -/- mice), we uncovered decreased neurotransmission at corticostriatal synapses. This effect was partly mitigated by replenishing extracellular glutamate levels, indicating a defect linked with decreased extracellular glutamate availability. We observed no changes in the morphology of striatal medium spiny neurons, the density of dendritic spines, or the density or ultrastructure of corticostriatal synapses, indicating that the observed functional defects are not due to morphological or structural abnormalities. By combining electron microscopy with glutamate immunogold labeling, we identified decreased intracellular glutamate density in presynaptic terminals, presynaptic mitochondria, and in dendritic spines of xCT -/- mice. A proteomic and kinomic screen of the striatum of xCT -/- mice revealed decreased expression of presynaptic proteins and abnormal kinase network signaling, that may contribute to the observed changes in postsynaptic responses. Finally, these corticostriatal deregulations resulted in a behavioral phenotype suggestive of autism spectrum disorder in the xCT -/- mice; in tests sensitive to corticostriatal functioning we recorded increased repetitive digging behavior and decreased sociability. To conclude, our findings show that system x c - plays a previously unrecognized role in regulating corticostriatal neurotransmission and influences social preference and repetitive behavior., (© 2020. The Author(s).)

Perceptual experience through the five modalities (i.e., vision, hearing, touch, taste, and smell) has demonstrated its key role in semantics. Researchers also highlighted the role of interoceptive information in the grounded representation of concepts. However, to this day, there is no available data across these modalities in the French language. Therefore, the aim of this study was to circumvent this caveat. Participants aged between 18 and 50 completed an online survey in which we recorded scores of perceptual strength (PS), interoceptive information, imageability, concreteness, conceptual familiarity, and age of acquisition of 270 words of the French language. We also analysed the relationships between perceptual modalities and psycholinguistic variables. Results showed that vast majority of concepts were visually-dominant. Correlation analyses revealed that the five PS variables were strongly correlated with imageability, concreteness, and conceptual familiarity and highlight that PS variables index one aspect of the semantic representations of a word. On the other hand, high interoceptive scores were highlighted only for the less imageable and less concrete words, emphasizing their importance for the grounding of abstract concepts. Future research could use these norms in the investigation of the role of perceptual experience in the representation of concepts and their impact on word processing., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Miceli, Wauthia, Lefebvre, Ris and Simoes Loureiro.)

Alzheimer's disease (AD) and related dementia is one of the growing threats to the sustainability of health and care systems in developed countries, and efforts to find therapies have had scant success. The main reasons for this are lack of efficient therapy, which is linked to too late discovery of the disease itself. With this in mind, biomarkers are recognised as an element which can bring a major contribution to research, helping elucidate the disease and the search for treatments. They are also playing an increasing role in early detection and timely diagnosis, which are considered the principal hopes of effective management in the absence of an effective drug. The current arsenal of biomarkers could already, if more widely deployed, provide an effective minimum service to patients and health systems. A concerted action by policy makers and stakeholders could drive progress in access to AD biomarker testing to provide an optimum service in the medium term. This paper discusses how to improve the use of and access to biomarker testing in the detection and diagnosis of AD and other diseases featuring dementia, and how EU healthcare systems could benefit. It outlines the challenges, lists the achievements to date, and highlights the actions needed to allow biomarker testing to deliver more fully on their potential in AD., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2020 by S. Karger AG, Basel.)

While magnesium deficiency is common and its effects well known on the nervous system, very few studies has been dedicated to the efficiency of magnesium replacement treatments on the central nervous system. In this study, the effects of oral administration of magnesium salts of acetyl-taurinate on the central manifestations of magnesium deficiency is described in rats submitted to low-magnesium diet and in a murine model of Alzheimer's disease. We tested the effect of ATA Mg ® , a salt combining magnesium and taurine, on the hippocampus, a critical component of cognition. 7-10-month-old rats were submitted to dietary magnesium deprivation for 64 days. The effect of magnesium deficiency was studied in ex vivo hippocampal slices. We showed that long-term potentiation of synaptic transmission in the hippocampus was significantly improved by the oral administration of ATA Mg ® at a dose of 50 mg/kg bw/day, which is comparable to the recommended dose in humans. 7-10-months-old transgenic APP/PS1 mice, a model of Alzheimer's disease, received ATA Mg ® during 24 days at a dose of 700 mg/kg bw/day which is the dose used in previous studies demonstrating the positive effect of magnesium supplementation. We showed that long-term potentiation was significantly improved in the treated mice. Moreover, the expression of NR2B subunit of NMDA receptors, known to be involved in synaptic plasticity, was significantly increased in the hippocampus. These results demonstrate the ability of ATA Mg ® to improve the symptoms related to chronic magnesium deficiency at the level of the hippocampus suggesting its bioavailability and effectiveness in reaching the central nervous system.

Objective: To investigate the occurrence of olfactory and gustatory dysfunctions in patients with laboratory-confirmed COVID-19 infection., Methods: Patients with laboratory-confirmed COVID-19 infection were recruited from 12 European hospitals. The following epidemiological and clinical outcomes have been studied: age, sex, ethnicity, comorbidities, and general and otolaryngological symptoms. Patients completed olfactory and gustatory questionnaires based on the smell and taste component of the National Health and Nutrition Examination Survey, and the short version of the Questionnaire of Olfactory Disorders-Negative Statements (sQOD-NS)., Results: A total of 417 mild-to-moderate COVID-19 patients completed the study (263 females). The most prevalent general symptoms consisted of cough, myalgia, and loss of appetite. Face pain and nasal obstruction were the most disease-related otolaryngological symptoms. 85.6% and 88.0% of patients reported olfactory and gustatory dysfunctions, respectively. There was a significant association between both disorders (p < 0.001). Olfactory dysfunction (OD) appeared before the other symptoms in 11.8% of cases. The sQO-NS scores were significantly lower in patients with anosmia compared with normosmic or hyposmic individuals (p = 0.001). Among the 18.2% of patients without nasal obstruction or rhinorrhea, 79.7% were hyposmic or anosmic. The early olfactory recovery rate was 44.0%. Females were significantly more affected by olfactory and gustatory dysfunctions than males (p = 0.001)., Conclusion: Olfactory and gustatory disorders are prevalent symptoms in European COVID-19 patients, who may not have nasal symptoms. The sudden anosmia or ageusia need to be recognized by the international scientific community as important symptoms of the COVID-19 infection.

The development of a program to integrate an organization's values and culture, Watson's Caring Theory, and personal motivators resulted in transforming nursing theory into practice and a noted improvement in the patient experience. This article will teach the reader how this was accomplished.

Mechanisms driving cognitive improvements following nuclear receptor activation are poorly understood. The peroxisome proliferator-activated nuclear receptor alpha (PPARα) forms heterodimers with the nuclear retinoid X receptor (RXR). We report that PPARα mediates the improvement of hippocampal synaptic plasticity upon RXR activation in a transgenic mouse model with cognitive deficits. This improvement results from an increase in GluA1 subunit expression of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, eliciting an AMPA response at the excitatory synapses. Associated with a two times higher PPARα expression in males than in females, we show that male, but not female, PPARα null mutants display impaired hippocampal long-term potentiation. Moreover, PPARα knockdown in the hippocampus of cognition-impaired mice compromises the beneficial effects of RXR activation on synaptic plasticity only in males. Furthermore, selective PPARα activation with pemafibrate improves synaptic plasticity in male cognition-impaired mice, but not in females. We conclude that striking sex differences in hippocampal synaptic plasticity are observed in mice, related to differences in PPARα expression levels., (© 2019 Pierrot et al.)

Nowadays, nanoparticles (NPs) of titanium dioxide (TiO 2 ) are abundantly produced. TiO 2 NPs are present in various food products, in paints, cosmetics, sunscreens and toothpastes. However, the toxicity of TiO 2 NPs on the central nervous system has been poorly investigated until now. The aim of this study was to evaluate the toxicity of TiO 2 NPs on the central nervous system in vitro and in vivo . In cell cultures derived from embryonic cortical brain of rats, a significant decrease in neuroblasts was observed after 24 to 96 h of incubation with TiO 2 NPs (5 to 20 μg/ml). This phenomenon resulted from an inhibition of neuroblast proliferation and a concomitant increase in apoptosis. In the same time, a gliosis, characterized by an increase in proliferation of astrocytes and the hypertrophy of microglial cells, occurred. The phagocytosis of TiO 2 NPs by microgliocytes was also observed. In vivo , after intraperitoneal injection, the TiO 2 NPs reached the brain through the blood brain barrier and the nanoparticles promoted various histological injuries such as cellular lysis, neuronal apoptosis, and inflammation. A reduction of astrocyte population was observed in some brain area such as plexiform zone, cerebellum and subependymal area. An oxidative stress was also detected by immunohistochemistry in neurons of hippocampus, cerebellum and in subependymal area. In conclusion, our study demonstrated clearly the toxic impact of TiO 2 NPs on rat brain and neuronal cells and pointed about not yet referenced toxicity impacts of TiO2 such as the reduction of neuroblast proliferation both in vitro and in vivo .

The development of the cerebral cortex is a tightly regulated process that relies on exquisitely coordinated actions of intrinsic and extrinsic cues. Here, we show that the communication between forebrain meninges and apical neural progenitor cells (aNPC) is essential to cortical development, and that the basal compartment of aNPC is key to this communication process. We found that Celsr1, a cadherin of the adhesion G protein coupled receptor family, controls branching of aNPC basal processes abutting the meninges and thereby regulates retinoic acid (RA)-dependent neurogenesis. Loss-of-function of Celsr1 results in a decreased number of endfeet, modifies RA-dependent transcriptional activity and biases aNPC commitment toward self-renewal at the expense of basal progenitor and neuron production. The mutant cortex has a reduced number of neurons, and Celsr1 mutant mice exhibit microcephaly and behavioral abnormalities. Our results uncover an important role for Celsr1 protein and for the basal compartment of neural progenitor cells in fate decision during the development of the cerebral cortex.

Contextual memory is an intricate process involving synaptic plasticity and network rearrangement. Both are governed by many molecular processes including phosphorylation and modulation of protein expression. However, little is known about the molecules involved in it. Here, we exploited the advantages of a quantitative proteomic approach to identify a great number of molecules in the rat dentate gyrus after a contextual fear conditioning session. Our results allowed us to highlight protein expression patterns, not only related to neuroplasticity, but also to myelin structure, such as myelin basic protein and myelin proteolipid protein showing a decrease in expression. Validation of the modification in protein expression reveals a dynamic profile during the 48 h following the fear conditioning session. The expression of proteins involved in neurite outgrowth, such as BASP-1 and calcineurin B1, and in synaptic structure and function, VAMP2 and RAB3C, was increased in the dentate gyrus of rats submitted to fear conditioning compared to controls. We showed that the increase in BASP-1 protein was specific to fear conditioning learning as it was not present in immediate-shock rats, neither in rats exposed to a novel environment without being shocked. As myelin is known to stabilise synaptic network, the decrease in myelin proteins suggests a neuroglia interactive process taking place in the dentate gyrus in the 24 h following contextual fear learning, which has never been demonstrated before. These results therefore open the way to the study of new plasticity mechanisms underlying learning and memory., (© 2017 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background: Hippocampal organotypic slices are used to improve the understanding of synaptic plasticity mechanisms because they allow longer term studies compared to acute slices. However, it is more delicate to keep cultures alive in the recording system outside  in vitro conditions. Experiments from the organotypic cultures are common but the handling of slices is rarely described in the literature, even though tissue preservation is crucial. Instruments are sometimes required to extract the slices from the culture inserts but this approach is delicate and can lead to damage, given how strongly the slices are attached to the insert., Methods: A new configuration is proposed to secure the transfer of slices from the incubator to the recording chamber through an adaptor piece that can be designed for any model of chamber and/or insert. The adaptor is a Plexiglas ring in which a culture insert containing the slice can be easily introduced and stabilized. This system allows slices to be placed in the interface for electrophysiological investigations without having to detach them from the insert. That way, no damage is caused and the recording system can safely hold the slices, maintaining them close to culture conditions., Results: In addition to the description of the adaptation system, slices were characterized. Their viability was validated and microglial expression was observed. According to the experimental conditions, neuroprotective ramified microgliocytes are present. Dendritic spines studies were also performed to determine neuronal network maturity in culture. Moreover, SKF 83822 hydrobromide and three trains of 100 pulses at 100 Hz with a 10-min inter-train interval are suggested to induce long-term potentiation and to record an increase of fEPSP amplitude and slope., Conclusion: This paper provides detailed information on the preparation and characterization of hippocampal organotypic slices, a new recording configuration more suitable for cultures, and a long-term potentiation protocol combining SKF and trains.

In vitro and in vivo studies suggest that the astrocytic adrenergic signalling enhances glycogenolysis which provides energy to be transported to nearby cells and in the form of lactate. This energy source is important for motor and cognitive functioning. While it is suspected that the β2-adrenergic receptor on astrocytes might contribute to this energy balance, it has not yet been shown conclusively in vivo. Inducible astrocyte specific β2-adrenergic receptor knock-out mice were generated by crossing homozygous β2-adrenergic receptor floxed mice (Adrb2flox) and mice with heterozygous tamoxifen-inducible Cre recombinase-expression driven by the astrocyte specific L-glutamate/L-aspartate transporter promoter (GLAST-CreERT2). Assessments using the modified SHIRPA (SmithKline/Harwell/Imperial College/Royal Hospital/Phenotype Assessment) test battery, swimming ability test, and accelerating rotarod test, performed at 1, 2 and 4 weeks, 6 and 12 months after tamoxifen (or vehicle) administration did not reveal any differences in physical health or motor functions between the knock-out mice and controls. However deficits were found in the cognitive ability of aged, but not young adult mice, reflected in impaired learning in the Morris Water Maze. Similarly, long-term potentiation (LTP) was impaired in hippocampal brain slices of aged knock-out mice maintained in low glucose media. Using microdialysis in cerebellar white matter we found no significant differences in extracellular lactate or glucose between the young adult knock-out mice and controls, although trends were detected. Our results suggest that β2-adrenergic receptor expression on astrocytes in mice may be important for maintaining cognitive health at advanced age, but is dispensable for motor function., Competing Interests: The authors have declared that no competing interests exist.

Tau protein is mainly intracellular. However, several studies have demonstrated that full-length Tau can be released into the interstitial fluid of the brain. The physiological or pathological function of this extracellular Tau remains unknown. Moreover, as evidence suggests, extracellular Tau aggregates can be internalized by neurons, seeding Tau aggregation. However, much less is known about small species of Tau. In this study, we hypothesized that the status of phosphorylation could alter the internalization of recombinant Tau in Neuro2A and cortical cells. Our preliminary results revealed that the highly phosphorylated form of Tau entered the cells ten times more easily than a low phosphorylated one. This suggests that hyperphosphorylated Tau protein could spread between neurons in pathological conditions such as Alzheimer's disease., Competing Interests: The authors declare no conflict of interest.

The ability to construct easily in vitro networks of primary neurons organized with imposed topologies is required for neural tissue engineering as well as for the development of neuronal interfaces with desirable characteristics. However, accumulating evidence suggests that the mechanical properties of the culture matrix can modulate important neuronal functions such as growth, extension, branching and activity. Here we designed robust and reproducible laminin-polylysine grid micropatterns on cell culture substrates that have similar biochemical properties but a 100-fold difference in Young's modulus to investigate the role of the matrix rigidity on the formation and activity of cortical neuronal networks. We found that cell bodies of primary cortical neurons gradually accumulate in circular islands, whereas axonal extensions spread on linear tracks to connect circular islands. Our findings indicate that migration of cortical neurons is enhanced on soft substrates, leading to a faster formation of neuronal networks. Furthermore, the pre-synaptic density was two times higher on stiff substrates and consistently the number of action potentials and miniature synaptic currents was enhanced on stiff substrates. Taken together, our results provide compelling evidence to indicate that matrix stiffness is a key parameter to modulate the growth dynamics, synaptic density and electrophysiological activity of cortical neuronal networks, thus providing useful information on scaffold design for neural tissue engineering., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Prion-like seeding and propagation of Tau-pathology have been demonstrated experimentally and may underlie the stereotyped progression of neurodegenerative Tauopathies. However, the involvement of templated misfolding of Tau in neuronal network dysfunction and behavioral outcomes remains to be explored in detail. Here we analyzed the repercussions of prion-like spreading of Tau-pathology via neuronal connections on neuronal network function in TauP301S transgenic mice. Spontaneous and GABA(A)R-antagonist-induced neuronal network activity were affected following templated Tau-misfolding using synthetic preformed Tau fibrils in cultured primary neurons. Electrophysiological analysis in organotypic hippocampal slices of Tau transgenic mice demonstrated impaired synaptic transmission and impaired long-term potentiation following Tau-seed induced Tau-aggregation. Intracerebral injection of Tau-seeds in TauP301S mice, caused prion-like spreading of Tau-pathology through functionally connected neuroanatomical pathways. Electrophysiological analysis revealed impaired synaptic plasticity in hippocampal CA1 region 6 months after Tau-seeding in entorhinal cortex (EC). Furthermore, templated Tau aggregation impaired cognitive function, measured in the object recognition test 6 months post-seeding. In contrast, Tau-seeding in basal ganglia and subsequent spreading through functionally connected neuronal networks involved in motor control, resulted in motoric deficits reflected in clasping and impaired inverted grid hanging, not significantly affected following Tau-seeding in EC. Immunostaining, biochemical and electron microscopic analysis in the different models suggested early pathological forms of Tau, including Tau-oligomers, rather than fully mature neurofibrillary tangles (NFTs) as culprits of neuronal dysfunction. We here demonstrate for the first time using in vitro, ex vivo and in vivo models, that prion-like spreading of Tau-misfolding by Tau seeds, along unique neuronal connections, causes neuronal network dysfunction and associated behavioral dysfunction. Our data highlight the potential relevance of this mechanism in the symptomatic progression in Tauopathies. We furthermore demonstrate that the initial site of Tau-seeding thereby determines the behavioral outcome, potentially underlying the observed heterogeneity in (familial) Tauopathies, including in TauP301 mutants.