TNF-α protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation

Abstract Background Chronic neuroinflammation is a hallmark of several neurological disorders associated with cognitive loss. Activated microglia and secreted factors such as tumor necrosis factor (TNF)-α are key mediators of neuroinflammation and may contribute to neuronal dysfunction. Our study was aimed to evaluate the therapeutic potential of a novel analog of thalidomide, 3,6'-dithiothalidomide (DT), an agent with anti-TNF-α activity, in a model of chronic neuroinflammation. Methods Lipopolysaccharide or artificial cerebrospinal fluid was infused into the fourth ventricle of three-month-old rats for 28 days. Starting on day 29, animals received daily intraperitoneal injections of DT (56 mg/kg/day) or vehicle for 14 days. Thereafter, cognitive function was assessed by novel object recognition, novel place recognition and Morris water maze, and animals were euthanized 25 min following water maze probe test evaluation. Results Chronic LPS-infusion was characterized by increased gene expression of the proinflammatory cytokines TNF-α and IL-1β in the hippocampus. Treatment with DT normalized TNF-α levels back to control levels but not IL-1β. Treatment with DT attenuated the expression of TLR2, TLR4, IRAK1 and Hmgb1, all genes involved in the TLR-mediated signaling pathway associated with classical microglia activation. However DT did not impact the numbers of MHC Class II immunoreactive cells. Chronic neuroinflammation impaired novel place recognition, spatial learning and memory function; but it did not impact novel object recognition. Importantly, treatment with DT restored cognitive function in LPS-infused animals and normalized the fraction of hippocampal neurons expressing the plasticity-related immediate-early gene Arc. Conclusion Our data demonstrate that the TNF-α synthesis inhibitor DT can significantly reverse hippocampus-dependent cognitive deficits induced by chronic neuroinflammation. These results suggest that TNF-α is a critical mediator of chronic neuroinflammation-induced neuronal dysfunction and cognitive impairment and targeting its synthesis could provide an effective therapeutic approach to several human neurodegenerative diseases

Patients with Alzheimer’s disease dementia show partially preserved parietal ‘hubs’ modeled from resting-state alpha electroencephalographic rhythms

Introduction: Graph theory models a network by its nodes (the fundamental unit by which graphs are formed) and connections. ‘Degree’ hubs reflect node centrality (the connection rate), while ‘connector’ hubs are those linked to several clusters of nodes (mainly long-range connections). Methods: Here, we compared hubs modeled from measures of interdependencies of between-electrode resting-state eyes-closed electroencephalography (rsEEG) rhythms in normal elderly (Nold) and Alzheimer’s disease dementia (ADD) participants. At least 5 min of rsEEG was recorded and analyzed. As ADD is considered a ‘network disease’ and is typically associated with abnormal rsEEG delta (<4 Hz) and alpha rhythms (8–12 Hz) over associative posterior areas, we tested the hypothesis of abnormal posterior hubs from measures of interdependencies of rsEEG rhythms from delta to gamma bands (2–40 Hz) using eLORETA bivariate and multivariate-directional techniques in ADD participants versus Nold participants. Three different definitions of ‘connector’ hub were used. Results: Convergent results showed that in both the Nold and ADD groups there were significant parietal ‘degree’ and ‘connector’ hubs derived from alpha rhythms. These hubs had a prominent outward ‘directionality’ in the two groups, but that ‘directionality’ was lower in ADD participants than in Nold participants. Discussion: In conclusion, independent methodologies and hub definitions suggest that ADD patients may be characterized by low outward ‘directionality’ of partially preserved parietal ‘degree’ and ‘connector’ hubs derived from rsEEG alpha rhythms

Análise dos casos de citomegalovírus, toxoplasmose e rubéola em gestantes em um hospital de referência em João Pessoa, Paraíba, no período de agosto a novembro de 2015

Introduction: Infectious diseases are common during pregnancy and can be transmitted from mother to fetus. Objective: The present study investigated socio-economic and demographic factors associated with cytomegalovirus, toxoplasmosis and rubella, in pregnant women in the reference hospital for high-risk pregnancy, Candida Vargas Institute, located in Joao Pessoa, Paraiba. Method: A descriptive observational study was conducted, using cross-sectional design, by the application of questionnaires and evaluation of the tests, from August to November 2015. Results: By the descriptive data’s analysis, it was verified that from the 242 pregnant women included in the study, 39.50% were 20 to 29 years old, 70.00% had a family income under a salary under the minimum wage; 90.00% lived in the urban area and 34.70% were primiparas. From the pregnant women with serological data on the pregnancy’s record, IgM seroreactivity was 88.90% for cytomegalovirus, 67.70% and 70.80% for toxoplasmosis and rubella, respectively. Conclusions: Thus, the found cases of susceptible and acutely ill pregnant women evidences the need of to institute guidelines for prevention, control and treatment of those diseases in order to avoid vertical transmission as much as their deleterious effects in newborns.Introdução: As doenças infecciosas são frequentes durante o período gestacional e podem ser transmitidas da mãe para o feto. Objetivo: O presente estudo investigou fatores socioeconômicos e demográficos associados à citomegalovírus, toxoplasmose e rubéola, em gestantes atendidas no hospital de referência na gestação de alto risco, Instituto Cândida Vargas, localizado em João Pessoa, Paraíba. Método: Realizou-se um estudo observacional descritivo, com delineamento transversal, a partir da aplicação de questionários e avaliação dos exames, no período de agosto a novembro de 2015. Resultados: A partir da análise descritiva dos dados, verificou-se que das 242 gestantes incluídas no estudo, 39,50% tinham 20 a 29 anos, 70,00% possuíam renda familiar inferior a um salário, 90,00% residiam na zona urbana, 34,70% estavam na primeira gestação. Das gestantes com registros de dados sorológicos no cartão da gestante, a sororeatividade para IgG foi 88,90% para citomegalovírus, 67,70% e 70,80% para toxoplasmose e rubéola, respectivamente. Conclusões: Assim, tem-se que os casos encontrados de gestantes suscetíveis e com doenças agudas demonstram a necessidade de instituir medidas de orientação para a prevenção, controle e tratamento, de modo a evitar a transmissão vertical e os efeitos deletérios destas doenças nos recém-nascidos

&quot;Delirium Day&quot;: A nationwide point prevalence study of delirium in older hospitalized patients using an easy standardized diagnostic tool

Background: To date, delirium prevalence in adult acute hospital populations has been estimated generally from pooled findings of single-center studies and/or among specific patient populations. Furthermore, the number of participants in these studies has not exceeded a few hundred. To overcome these limitations, we have determined, in a multicenter study, the prevalence of delirium over a single day among a large population of patients admitted to acute and rehabilitation hospital wards in Italy. Methods: This is a point prevalence study (called "Delirium Day") including 1867 older patients (aged 65 years or more) across 108 acute and 12 rehabilitation wards in Italian hospitals. Delirium was assessed on the same day in all patients using the 4AT, a validated and briefly administered tool which does not require training. We also collected data regarding motoric subtypes of delirium, functional and nutritional status, dementia, comorbidity, medications, feeding tubes, peripheral venous and urinary catheters, and physical restraints. Results: The mean sample age was 82.0 ± 7.5 years (58 % female). Overall, 429 patients (22.9 %) had delirium. Hypoactive was the commonest subtype (132/344 patients, 38.5 %), followed by mixed, hyperactive, and nonmotoric delirium. The prevalence was highest in Neurology (28.5 %) and Geriatrics (24.7 %), lowest in Rehabilitation (14.0 %), and intermediate in Orthopedic (20.6 %) and Internal Medicine wards (21.4 %). In a multivariable logistic regression, age (odds ratio [OR] 1.03, 95 % confidence interval [CI] 1.01-1.05), Activities of Daily Living dependence (OR 1.19, 95 % CI 1.12-1.27), dementia (OR 3.25, 95 % CI 2.41-4.38), malnutrition (OR 2.01, 95 % CI 1.29-3.14), and use of antipsychotics (OR 2.03, 95 % CI 1.45-2.82), feeding tubes (OR 2.51, 95 % CI 1.11-5.66), peripheral venous catheters (OR 1.41, 95 % CI 1.06-1.87), urinary catheters (OR 1.73, 95 % CI 1.30-2.29), and physical restraints (OR 1.84, 95 % CI 1.40-2.40) were associated with delirium. Admission to Neurology wards was also associated with delirium (OR 2.00, 95 % CI 1.29-3.14), while admission to other settings was not. Conclusions: Delirium occurred in more than one out of five patients in acute and rehabilitation hospital wards. Prevalence was highest in Neurology and lowest in Rehabilitation divisions. The "Delirium Day" project might become a useful method to assess delirium across hospital settings and a benchmarking platform for future surveys

Atypical patterns i n serological d iagnosis of Epstein-Barr virus infection, 2015-2022

Os testes laboratoriais de pesquisa de anticorpos específicos para o vírus Epstein-Barr são uma das ferramentas usadas para a rápida e correta identificação da infeção causada por este vírus. No entanto, existem perfis serológicos atípicos que dificultam a obtenção de um diagnóstico. Assim, o objetivo deste estudo foi determinar a frequ ência dos perfis serológicos atípicos e caracterizar a sua distribuição em indivíduos cuja pesquisa de anticorpos foi realizada no Instituto Nacional de Saúde Doutor Ricardo Jorge. Foi realizada uma análise retrospetiva de 1346 indivíduos residentes em Portugal, com per fil serológico completo para o diagnóstico laboratorial da infeção pelo vírus Epstein-Barr, obtido entre 2015 e 2022. Dos indivíduos incluídos no estudo, 192 (14,2%) apresentaram um perfil serológico atípico. O perfil serológico atípico mais frequente foi a presença de anticorpos IgG VCA/EA isolados (8,3%; 112/1346), seguido da pre sença simultânea de anticorpos IgM VCA, IgG VCA/EA e IgG EBNA-1 (3,6%; 48/1346), depois o perfil de anticorpos IgG EBNA-1 isolados (1,6%; 22/1346) e, por último, o perfil de anticorpos IgM VCA iso lados (0,7%; 10/1346). No geral, a frequência dos perfis serológi cos atípicos obtida neste estudo está de acordo com a literatura. Em comparação com outro estudo realizado em Portugal, os perfis de anticorpos IgG EBNA-1 isolados e anticorpos IgM VCA isolados apre sentaram uma frequência ligeiramente superior. O presente estudo demonstra a importância dos perfis atípicos no diagnóstico seroló gico da infeção pelo vírus Epstein-Barr e a necessidade de efetuar testes serológicos e moleculares adicionais, que variam de acordo com a especificidade de cada perfil atípico.Specific antibody tests are used to determine different stages of Epstein-Barr virus infection. However, the detection of atypical sero logical patterns may pose a diagnostic challenge. This study aims to determine the frequency and distribution of atypical patterns in individuals tested at the Portuguese National Institute of Health. We reviewed 1346 individuals with serological patterns obtained between 2015 and 2022, from individuals living in Portugal. Of those included in this study, 192 (14.2%) showed an atypical pattern. Iso lated VCA IgG was the most frequent (8.3%, 112/1346), followed by the simultaneous presence of antibodies VCA IgM, VCA/EA IgG, and EBNA-1 IgG (3.6%, 48/1346), isolated EBNA-1 IgG (1.6%, 22/1346), and finally isolated VCA IgM (0.7%, 10/1346). The frequency of atypi cal serological patterns obtained in this study was similar to those obtained in other studies. When comparing to another study conduc ted in Portugal, we found slightly higher percentages of the atypi cal serological patterns: isolated EBNA-1 IgG, and isolated VCA IgM. This study highlights the importance of atypical serological patterns in Epstein-Barr virus diagnosis, and the need to perform additional serologic and molecular tests to better interpret them.info:eu-repo/semantics/publishedVersio

Clinical outcome measures in dementia with Lewy bodies trials: critique and recommendations.

The selection of appropriate outcome measures is fundamental to the design of any successful clinical trial. Although dementia with Lewy bodies (DLB) is one of the most common neurodegenerative conditions, assessment of therapeutic benefit in clinical trials often relies on tools developed for other conditions, such as Alzheimer's or Parkinson's disease. These may not be sufficiently valid or sensitive to treatment changes in DLB, decreasing their utility. In this review, we discuss the limitations and strengths of selected available tools used to measure DLB-associated outcomes in clinical trials and highlight the potential roles for more specific objective measures. We emphasize that the existing outcome measures require validation in the DLB population and that DLB-specific outcomes need to be developed. Finally, we highlight how the selection of outcome measures may vary between symptomatic and disease-modifying therapy trials

O impacto das distorções na taxa de câmbio na análise social de projetos.

Monografia (graduação)—Universidade de Brasília, Departamento de Economia, 2014.O presente trabalho aborda o tema da taxa de cambio social e sua importância na analise social de projetos. Através de uma revisão da literatura econômica, buscou-se mostrar a relevância e a atualidade da analise econômica de projetos e, mais especificamente, o risco que se incorre ao se negligenciar a taxa de cambio social como fator de correção do custo de insumos importados. A intenção deste trabalho e, então, retomar a discussão sobre este tema que foi bastante intenso durante a década de 70. Para isto, escolhemos, dentre os diversos métodos de calculo da taxa de cambio social, apresentar o da taxa de cambio de equilíbrio. Este método, no entanto, se desdobra em uma vasta gama de procedimentos de calculo, os quais sao apresentados neste trabalho. Dentre estes, escolhemos, então, o a da paridade de poder de compra para encontrar a taxa de cambio social do Brasil. Em seguida, comparamos o valor do real encontrado com o calculado pelo índice BigMac, para assim eliminar as distorções encontradas na PPP causadas pelo uso do índice de preço ao consumidor de cada pais como indicador da inflação internacional, uma que estes sao calculados com base em cestas de bens e serviços caracteristicadas de cada regiao e nao com base em uma cesta homogênea. De fato, a taxa de cambio encontrada pelo índice BigMac apresenta uma distorcao, com relacao a taxa de cambio oficial, menor que a encontrada pela PPP, mais ainda bastanta significativa. Para, então, mostrar o quanto essas distorções podem afetar a analise econômica de um projeto, usamos tanto um valor arbitrário como o da PPP como fator de correção dos preços dos insumos importados de um projeto fictício. Comparando os resultados, vemos que a escolha de como interpretar a taxa de cambio tem forte impacto no resultado da analise de viabilidade social de um projeto. Esse pensamento, no entato, pode ser estendido para alem da teoria da analise de projetos. Dada a interdependencia entre a politica cambial e politicas como a de comercio exterior, política industrial, e a importancia da taxa de cambio para o desenvolvimento economico como um todo, o estudo da taxa de cambio social nos permite pensar o quanto esta deveria balizar a politica cambial brasileira para, assim, potencializar seus resultados.The present work presents the subject of exchange rate and its relevance in social analysis of projects . Through a review of the economic literature, it was sought to show the relevance of this type of analysis and the risk associated when neglecting the social exchange rate as a factor to correct the value of imported inpust of a project. It's objective is then to bring back the discussion, relevant in the 1970's, about the social exchande rate. To do that, we chose, among a large spectrum of methods to find the social exchange rate, to present the one caled equilibrium exchange rate. This method, non the less, unfolds in a great amount of different procedures, which is shown in this paper. Among those, we chose to calculate brazilian's social exchange rate throught purchasing power parity. Then we compared what was found with the BigMac index so to eliminate distortions caused by using consumer price indexes based in a number good and services specif to wich country, instead of based in a single and homogeneous number of products. In fact, the social exchange rate found throught BigMac's index presents a smaller distortion with the oficial exchange rate when compared with the one found with PPP. This distorcion, non the less, is significant. To show then how much this can afect a economic analyses of a project, we used an arbitrare value and the PPP as a correction factor for imported imput's prices of a fictional project. Comparing the results, we see that the choise of how to interprete the social exchange rate has a strong effect in the result of the project's viability analyses. This conclusion, however, can be extended beyond the theorie of project's social analyses. Given the interdependence of politics and the relevance of exchange rate and economic development as a whole, the study os social exchange rate allow us to think how much it sould guide our exchange rate policy as to leverage it's results

Clinical outcome measures in dementia with Lewy bodies trials: critique and recommendations

The selection of appropriate outcome measures is fundamental to the design of any successful clinical trial. Although dementia with Lewy bodies (DLB) is one of the most common neurodegenerative conditions, assessment of therapeutic benefit in clinical trials often relies on tools developed for other conditions, such as Alzheimer's or Parkinson's disease. These may not be sufficiently valid or sensitive to treatment changes in DLB, decreasing their utility. In this review, we discuss the limitations and strengths of selected available tools used to measure DLB-associated outcomes in clinical trials and highlight the potential roles for more specific objective measures. We emphasize that the existing outcome measures require validation in the DLB population and that DLB-specific outcomes need to be developed. Finally, we highlight how the selection of outcome measures may vary between symptomatic and disease-modifying therapy trials

Alteraciones neurológicas en pacientes cirróticos con Encefalopatía Hepática Mínima. Implicación de la inflamación y el estrés oxidativo

La encefalopatía hepática (EH) es un síndrome neuropsiquiátrico complejo secundario a una cirrosis hepática, mostrando una incidencia importante (33-50%). Existe una fase subclínica llamada Encefalopatía Hepática Mínima (EHM) en la cual el paciente no muestra síntomas evidentes de EH pero sí que tiene alteraciones cognitivas y motoras y son pacientes con un potencial riesgo de ingreso hospitalario, debido al deterioro cognitivo. Para el diagnóstico de la EHM se utiliza como ‘gold standard’ una batería de tests psicométricos llamada PHES (Psycometric Hepatic Encephalopathy Score). Se sabe que uno de los principales factores que contribuyen al desarrollo de la EHM son el amonio y la inflamación. El objetivo principal de esta tesis es, por un lado utilizar tests psicométricos que permitan un estudio más fino de cada alteración neurológica específica que la que realiza el PHES y, realizar un estudio sobre la presencia de estrés oxidativo/nitrosativo en la EHM y la implicación de éste y de la inflamación en el deterioro cognitivo. Para ello se han evaluado diferentes alteraciones cognitivas (atención selectiva, atención selectiva/sostenida, memoria de trabajo, velocidad de procesamiento mental, concentración) y motoras (coordinación bimanual y visuomotora) mediante tests específicos para cada una de éstas y, diferentes parámetros en sangre indicadores de estrés oxidativo e inflamación, correlacionándose entre sí con el fin de determinar la posible implicación del estrés oxidativo e inflamción en el deterioro cognitivo en la encefalopatía hepática mínima.Hepatic encephalopathy (HE) is a complex neuropsychiatric syndrome secondary to liver cirrhosis, showing a significant incidence (33-50%). There is a subclinical stage called Minimal Hepatic Encephalopathy (MHE) in which the patient shows no obvious symptoms of HE but does shows cognitive and motor impairment and a potential risk of hospitalization due to cognitive impairment. The method of diagnosis of MHE used as a 'gold standard' consists in a battery of psychometric tests called PHES (Psycometric Hepatic Encephalopathy Score). It is known that one of the main factors contributing to the development of MHE are hyperammonia and inflammation. The main objective of this thesis is use psychometric tests that allow a more sensible study of each specific neurological disorder that PHES and a study on the presence of oxidative/nitrosative stress in MHE and study involvement of this and inflammation in cognitive impairment. This has been evaluated different cognitive disorders (selective attention, selective attention/sustained, working memory, mental processing speed, concentration) and motor (bimanual and visuomotor coordination) through specific tests for each of these alterations and different blood parameters indicators of oxidative stress and inflammation, correlated with each other in order to determine the possible involvement of oxidative stress and inflammation in cognitive impairment in minimal hepatic encephalopathy