Behavioral or neuropsychiatric symptoms of Alzheimer's disease: from psychopathology to pharmacological management / Sintomas comportamentais ou neuropsiquiátricos da doença de Alzheimer: psicopatologia e abordagem terapêutica

Abstract Neuropsychiatric or behavioral symptoms of dementia encompass a series of disorders, such as anxiety, depression, apathy, psychosis, and agitation, all commonly present in individuals living with dementia. While they are not required for the diagnosis of Alzheimer's disease (AD), they are ubiquitously present in all stages of the disease, contributing to negative clinical outcomes, including cognitive decline, functional disability, and caregiver burden. Neuropsychiatric symptoms have been conceptualized not only as risk factors but as clinical markers of decline along the AD spectrum. The concept of "mild behavioral impairment", the behavioral correlate of mild cognitive impairment, has been proposed within this framework. The first steps in the management of behavioral symptoms in AD involve defining the target and investigating potential causes and/or aggravating factors. Once these factors are addressed, non-pharmacological approaches are preferred as first-line interventions. Following the optimization of anticholinesterase treatments, specific pharmacological approaches (e.g., antidepressants, antipsychotics) can be considered weighing potential side effects.

Resumo Sintomas neuropsiquiátricos ou comportamentais de demência envolvem uma série de condições, como ansiedade, depressão, apatia, psicose e agitação, frequentemente observadas em indivíduos com demência. Embora esses sintomas não sejam necessários para o diagnóstico da doença de Alzheimer, estão presentes em todas as fases ou estágios da doença, contribuindo negativamente para o declínio cognitivo, comprometimento funcional e sobrecarga do cuidador. Os sintomas neuropsiquiátricos têm sido conceituados não apenas como fatores de risco, mas também como marcadores clínicos de progressão da doença de Alzheimer. O construto "comprometimento comportamental leve", correlato comportamental do comprometimento cognitive leve, tem sido proposto nesse contexto. Os primeiros passos na abordagem dos sintomas comportamentais da doença de Alzheimer envolvem definir os alvos-terapêuticos e investigar potenciais causas ou fatores agravantes. Após intervir nesses fatores, abordagens não farmacológicas constituem a primeira linha de intervenção. Depois da otimização do tratamento anticolinesterásico, terapias farmacológicas específicas (por exemplo, antidepressivos, antipsicóticos) podem ser consideradas, levando-se em conta potencias efeitos colaterais.

Evaluation of New Potential Inflammatory Markers in Patients with Nonvalvular Atrial Fibrillation.

Atrial fibrillation (AF), the most common arrhythmia in clinical practice, is associated with an increase in mortality and morbidity due to its high potential to cause stroke and systemic thromboembolism. Inflammatory mechanisms may play a role in the pathogenesis of AF and its maintenance. We aimed to evaluate a range of inflammatory markers as potentially involved in the pathophysiology of individuals with nonvalvular AF (NVAF). A total of 105 subjects were enrolled and divided into two groups: patients with NVAF (n = 55, mean age 72 ± 8 years) and a control group of individuals in sinus rhythm (n = 50, mean age 71 ± 8 years). Inflammatory-related mediators were quantified in plasma samples by using Cytometric Bead Array and Multiplex immunoassay. Subjects with NVAF presented significantly elevated values of interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF), interferon-gamma, growth differentiation factor-15, myeloperoxidase, as well as IL-4, interferon-gamma-induced protein (IP-10), monokine induced by interferon-gamma, neutrophil gelatinase-associated lipocalin, and serum amyloid A in comparison with controls. However, after multivariate regression analysis adjusting for confounding factors, only IL-6, IL-10, TNF, and IP-10 remained significantly associated with AF. We provided a basis for the study of inflammatory markers whose association with AF has not been addressed before, such as IP-10, in addition to supporting evidence about molecules that had previously been associated with the disease. We expect to contribute to the discovery of markers that can be implemented in clinical practice hereafter.

Cognitive evaluation in Parkinson's disease: applying the Movement Disorder Society recommendations in a population with a low level of formal education / Avaliação cognitiva na doença de Parkinson: aplicando as recomendações da Movement Disorder Society em uma população de baixa escolaridade

Abstract Background The diagnosis of cognitive disorders in Parkinson disease (PD) can be very challenging. Aiming at establishing uniform and reliable diagnostic procedures, the International Parkinson's Disease and Movement Disorder Society (MDS) commissioned task forces to delineate diagnostic criteria for mild cognitive impairment (MCI) and dementia in PD. Objectives To investigate the applicability of the MDS recommendations for cognitive evaluation in a Brazilian sample of patients with PD with low levels of formal education. Methods A total of 41 patients with PD were subjected to a comprehensive neuropsychological evaluation based on tests proposed by the MDS, which included the Mini-Mental State Examination, the Mattis Dementia Rating Scale (MDRS), the Trail Making Test (TMT) parts A and B, in addition to language and memory skills assessment. Neuropsychiatric and daily functioning features were also evaluated. Spearman correlation analyses were used to evaluate the association between the scores obtained in the cognitive scales and demographic/clinical variables. Results Although none of the participants had a formal diagnosis of dementia, 50% presented some degree of cognitive impairment when considering the results of the MDRS. Of note, a noticeable number of patients was not able to complete the full neuropsychological assessment. The TMT part B was the most difficult task, being completed by only 22 participants (54%). As expected, the greater the educational level, the better the performance on the cognitive tests. Better motor function was also associated with better scores in cognition. Conclusions Adopting strict inclusion/exclusion criteria and a comprehensive clinical evaluation, we found remarkable limitations for the MDS recommendations when individuals with low educational levels are considered. A revision of the current guidelines is necessary considering differences among populations, especially related to formal education.

Resumo Antecedentes O diagnóstico de distúrbios cognitivos na doença de Parkinson (DP) pode ser muito desafiador. Com o objetivo de estabelecer procedimentos diagnósticos uniformes e confiáveis, a Sociedade Internacional da Doença de Parkinson e Distúrbios do Movimento (MDS, na sigla em inglês) encomendou forças-tarefa para delinear critérios diagnósticos para comprometimento cognitivo leve (CCL) e demência na DP. Objetivos Investigar a aplicabilidade das recomendações da MDS para avaliação cognitiva em uma amostra brasileira de pacientes com DP de baixa escolaridade. Métodos Um total de 41 pacientes com DP foram submetidos a uma avaliação neuropsicológica abrangente com base nos testes propostos pela MDS, que incluiu o Miniexame do Estado Mental, a Escala de Avaliação de Demência de Mattis (MDRS, na sigla em inglês), o teste de trilhas (TMT, na sigla em inglês) partes A e B, além da avaliação das habilidades de linguagem e memória. Características neuropsiquiátricas e de funcionamento diário também foram avaliadas. Análises de correlação de Spearman foram utilizadas para avaliar a associação entre os escores obtidos nas escalas cognitivas e variáveis demográficas/clínicas. Resultados Apesar de nenhum dos participantes ter diagnóstico formal de demência, 50% apresentaram algum grau de comprometimento cognitivo ao levar em consideração os resultados da MDRS. Vale ressaltar que um número notável de pacientes não conseguiu completar a avaliação neuropsicológica completa. A parte B do TMT foi a tarefa mais difícil, sendo realizada por apenas 22 participantes (54%). Como esperado, quanto maior o nível educacional, melhor o desempenho nos testes cognitivos. Melhor função motora também foi associada a melhores escores em cognição. Conclusões Adotando critérios rígidos de inclusão/exclusão e uma avaliação clínica abrangente, encontramos limitações marcantes para as recomendações da MDS quando considerados indivíduos com baixa escolaridade. É necessária uma revisão das diretrizes atuais considerando as diferenças entre as populações, principalmente relacionadas ao nível educacional.

Traumatic brain injury in Brazil: an epidemiological study and systematic review of the literature / Traumatismo cranioencefálico no Brasil: um estudo epidemiológico e uma revisão sistemática da literatura

ABSTRACT Background: Traumatic brain injury (TBI) is a serious public health problem worldwide. Although TBI is common in developing countries, there are few epidemiological studies. Objective: To investigate the sociodemographic and clinical features of patients with TBI at the Hospital João XXIII, a public reference center for trauma in Belo Horizonte, Brazil, and to systematically review the available literature on TBI in Brazil. Methods: Clinical and sociodemographic data were collected from electronic medical records for the entire month of July 2016. The literature on epidemiology of TBI in Brazil was systematically reviewed using MeSH/DeCS descriptors in the PubMed and Lilacs databases. Results: Most patients admitted with TBI were male and under 60 years of age. Mild TBI was the most prevalent form and the most common cause of TBI was falls. A Glasgow Coma Scale score below 12, neuroimaging changes on computer tomography, and presence of any medical conditions were significantly associated with longer hospital stay. Brazilian studies showed that TBI affected mainly men and young adults. In addition, mild TBI was the most common TBI severity reported and the most common causes were motor vehicle accidents and falls. Conclusions: Overall, the profile of TBI in this center reflects the data from other Brazilian studies.

RESUMO Antecedentes: O traumatismo cranioencefálico (TCE) representa, mundialmente, um problema sério de saúde pública. Apesar de o TCE ser prevalente em países em desenvolvimento, estudos epidemiológicos permanecem escassos. Objetivo: Investigar as características sociodemográficas e clínicas de pacientes acometidos por TCE no Hospital João XXIII - centro de referência em trauma situado em Belo Horizonte, Brasil - e revisar sistematicamente toda a literatura disponível sobre o TCE no Brasil. Métodos: Os dados clínicos e sociodemográficos foram coletados apenas para o mês de julho, 2016, por meio de prontuários eletrônicos. A literatura sobre a epidemiologia do TCE no Brasil foi sistematicamente revisada usando descritores Medical Subject Headings (MeSH)/Descritores em Ciências da Saúde (DeCS) nos bancos de dados PubMed e Literatura Latino-Americana e do Caribe em Ciências da Saúde (Lilacs). Resultados: Os pacientes acometidos por TCE eram em sua maioria homens com menos de 60 anos. O TCE leve foi a gravidade mais prevalente entre os casos. O TCE foi causado principalmente por quedas. Escores menores que 12 na escala de Coma de Glasgow mais alterações de neuroimagem em tomografia computadorizada e a presença de qualquer comorbidade médica estão significativamente associados à maior estadia hospitalar. Estudos brasileiros demonstraram que o TCE acomete principalmente homens e adultos jovens. Além disso, o TCE leve foi a gravidade mais comum reportada, e os mecanismos de TCE mais comuns foram acidentes automobilísticos e quedas. Conclusões: O perfil de pacientes acometidos por TCE no centro de referência em questão reflete os dados de outros estudos brasileiros.

IL-6 levels are associated with clinical status in patients with Myasthenia Gravis / Os níveis de IL-6 estão associados com o status clínico de pacientes com Miastenia Gravis

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease marked by fluctuating course of muscle weakness. OBJECTIVES: The current study was designed to evaluate plasma levels of cytokines (IL-2, IL-4, IL-6, IL-10, TNF, IFN-γ, and IL17A) in patients with MG and controls and to investigate whether cytokines levels are associated with clinical parameters. This study was conducted at the Neuromuscular Diseases Outpatient Clinic, Hospital das Clínicas, Universidade Federal de Minas Gerais (UFMG), Brazil. METHODS: Peripheral blood was drawn, and plasma levels of cytokines were measured by cytometric bead array (CBA) in 80 treated patients with MG and 50 controls. The MG Composite (MGC) was used to evaluate muscle weakness and severity of typical motor symptoms of MG. RESULTS: Patients with MG undergoing treatment exhibit lower levels of all evaluated cytokines compared to controls. There was a negative correlation between IL-6 levels and the MG Composite score, indicating that higher levels of IL-6 were associated with better control of the disease. CONCLUSION: This exploratory study suggests that IL-6 is associated with MG clinical status, as assessed by the MGC.

INTRODUÇÃO: A Miastenia Gravis (MG) é uma doença autoimune caracterizada por fraqueza muscular flutuante. OBJETIVOS: avaliar os níveis plasmáticos de citocinas (IL-2, IL-4, IL-6, IL-10, TNF, IFN-γ, e IL-17A) em pacientes com MG e controles e investigar se essas citocinas estão associadas com parâmetros clínicos. Este estudo foi conduzido no ambulatório de doenças neuromusculares do Hospital das Clínicas, Universidade Federal de Minas Gerais (UFMG), Brasil. MÉTODOS: Foi coletado sangue periféricos e os níveis plasmáticos das citocinas foram medidos por citometria em 80 pacientes com MG tratados e em 50 controles. O MG composite (MGC) foi utilizado para avaliar a fraqueza muscular e a gravidade dos sintomas motores típicos da MG. RESULTADOS: Os pacientes com MG em tratamento apresentaram menores níveis de todas as citocinas avaliadas comparados ao controle. Houve uma correlação negativa entre os níveis de IL-6 e o MGC, indicando que altos níveis de IL-6 estão associados com melhor controle da doença. CONCLUSÃO: este estudo exploratório sugere que a IL-6 está associada com o status clínico da MG, quando avaliado pelo MGC.

Tumor necrosis factor superfamily molecules are increased in behavioral variant frontotemporal dementia and correlate with cortical atrophy: An exploratory investigation.

Frontotemporal dementia (FTD) is the second most frequent cause of young-onset dementia. Even though immune-mediated and neuroinflammatory factors have been recognized as potential pathophysiological mechanisms, the role of specific immune molecules, such as the tumor necrosis factor (TNF) superfamily, remains elusive. The aim of this study was to investigate TNF Superfamily Molecules (TNF, TNF-related weak inducer of apoptosis [TWEAK], soluble TNF receptor type 1 [sTNFRI] and soluble TNF receptor type 2 [sTNFRII]) in patients with behavioral variant FTD (bvFTD) and controls, and to explore potential associations with clinical parameters and brain atrophy. This study included two groups of participants matched for age, sex and schooling years: patients with probable bvFTD (n = 17, mean age = 64.9 years, 6 women/11 men) and healthy controls (HC, n = 17; mean age = 63.9 years, 10 women/7 men). All participants underwent comprehensive cognitive assessment and structural brain imaging with 3 T magnetic resonance imaging. Plasma levels of TNF, TWEAK, sTNFRI and sTNFRII were determined by ELISA. We conducted voxel-based morphometry analyses to investigate correlations between grey matter (GM) atrophy and plasma levels of TNF, TWEAK, sTNFRI and sTNFRII within bvFTD group. Compared to HC, bvFTD patients had lower cognitive scores and marked frontotemporal atrophy. Patients with bvFTD had significantly higher plasma levels of TNF (p < 0.0001), sTNFRI (p < 0.001), and sTNFRII (p < 0.0001), and similar levels of TWEAK in comparison with controls. The levels of sTNFRII were positively correlated with GM atrophy involving temporal poles, precuneus and cerebellum in bvFTD patients, while the levels of TWEAK positively correlated with right superior temporal gyrus. Our results implicate TNF superfamily in the pathophysiology of FTD.

Circulating levels of adipokines are altered in patients with temporal lobe epilepsy.

OBJECTIVE: A persistent low-grade inflammatory state has been described in patients with temporal lobe epilepsy (TLE) in the interictal period. Adipokines are cytokines produced by the adipose tissue that can influence inflammatory response. The purpose of this study was to evaluate the plasma levels of adipokines in patients with TLE in comparison with controls. In addition, we sought to investigate whether the levels of adipokines were associated with clinical parameters in TLE. METHODS: Forty patients with TLE and 40 controls were enrolled in this study. All participants were subjected to clinical assessment that included the Mini International Neuropsychiatric Interview (MINI) and the Hamilton Depression Rating Scale (HAM-D). Peripheral blood was drawn, and plasma levels of adipokines (adiponectin, leptin, and resistin) were measured by enzyme-linked immunoassay (ELISA). RESULTS: People with TLE presented higher leptin and lower adiponectin and resistin levels in comparison with controls. The levels of these adipokines correlated negatively with illness length but not with other clinical parameters. In a binary logistic regression model, higher leptin and lower adiponectin levels remained as significant predictors of TLE diagnosis. CONCLUSIONS: These results corroborate the view that TLE is a multisystemic condition associated with low-grade inflammation.

Predictors of cognitive performance in bipolar disorder: The role of educational degree and inflammatory markers.

BACKGROUND: The aim of this article was to evaluate the cognitive status of remitted patients with bipolar disorder (BD) using Mini-Mental State Examination (MMSE), Frontal Assessment Battery, and Brief Assessment of Cognition in Affective Disorders (BAC-A). The BAC-A is a comprehensive test battery addressing the cognitive domains compromised in BD. We also aimed to analyze potential clinical and immune predictors of cognitive performance in BD. METHODS: Remitted patients with BD (M ±â€¯S.E: 43.80 ±â€¯10.87 years) and age-matched controls (M ±â€¯S.E: 43.52 ±â€¯11.72) were administered clinical questionnaires and cognitive tests. Inflammatory plasma levels (IL-2, IL-4, IL-6, IL-10, IFN-γ, TNFα, IL-17A, sTNFR1, and sTNFR2) were measured using an enzyme-linked immunosorbent assay. We generated a global cognitive performance index based on BAC-A scores. Multivariate analyses compared cognitive and immune measures across groups. A regression analysis was performed to examine the relationship between global cognitive performance, clinical and immune parameters in BD. RESULTS: Remitted patients with BD performed poorly on tasks of affective processing, verbal memory, working verbal memory, and executive functioning. Patients with BD presented higher plasma levels sTNFR1, TNFα, IFN, IL2, IL4, IL6, IL10, and IL17compared with controls. Education and MMSE were found to be positively correlated with global cognitive performance. IL6 plasma levels were negatively correlated with global cognitive performance. CONCLUSION: The major determinants of poor cognitive performance in BD were education and IL6 plasma levels.

Neuroinflamação na esclerose lateral amiotrófica / Neuroinflammation in amyotrophic lateral sclerosis

A esclerose lateral amiotrófica (ELA) esporádica é uma doença neurodegenerativa que acomete o neurônio motor. Sua etiologia ainda não foi totalmente esclarecida e é considerada multifatorial. O objetivo desse trabalho é fazer uma revisão narrativa sobre os mecanismos fisiopatológicos da ELA esporádica, com foco no papel da neuroinflamação, além de descrever estudos envolvendo a pesquisa de biomarcadores de diagnóstico e prognóstico. O processo de neuroinflamação na ELA é considerado secundário às alterações que levam à morte neuronal, podendo influenciar na taxa de progressão da doença. Existem diversos estudos sobre o perfil dos fatores inflamatórios na ELA, por vezes com resultados contraditórios, reforçando a dificuldade de análise desses fatores num organismo dinâmico. Ainda assim, no contexto da ELA, o estudo de possíveis biomarcadores diagnósticos e/ou prognósticos é válido e de grande interesse, pois permitiria um avanço nos ensaios clínicos que buscam novos tratamentos, bem como na condução e planejamento de cada caso.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects the motor neuron. Its etiology has not been fully clarified and is considered multifactorial. The aim of this sudy is to perform a narrative review on the pathophysiological mechanisms of sporadic ALS, focusing on the role of neuroinflammation. It will also discuss studies investigating diagnostic and prognostic biomarkers. Neuroinflammation in ALS is considered to be a secondary event, triggered by neuronal death, and it may influence disease progression. There are several studies on inflammatory factors in ALS, some with contradictory findings, reinforcing the difficulty of assessing these factors in a dynamic organism. Even so, in ALS context, the study of possible diagnostic and/or prognostic biomarkers is valid and of great interest. This may allow the advance of clinical trials that investigate new treatments, as well as the management of individual cases.

Circulating levels of neurotrophic factors are unchanged in patients with Parkinson's disease / Os níveis circulantes de fatores neurotróficos não estão alterados em pacientes com doença de Parkinson

ABSTRACT There is great evidence linking neurotrophic factor (NF) dysfunction with Parkinson's disease (PD) pathophysiology. This study was conducted to evaluate plasma levels of NFs and their possible associations with clinical symptoms in PD. For this purpose, 40 PD patients and 25 controls were subjected to a clinical evaluation and peripheral blood draw. Plasma levels of brain-derived neurotrophic factor (BDNF), pro-BDNF, neurotrophin 3, neurotrophin 4, nerve growth, glial cell line-derived neurotrophic factor and ciliary neurotrophic factor were measured by enzyme-linked immunosorbent assay. There was no significant difference between PD patients and controls regarding the plasma levels of the evaluated NFs. In addition, NF levels were not associated with disease duration, degree of motor or functional impairment, cognitive performance or severity of depressive symptoms. In conclusion, although NFs may play relevant roles in the pathophysiology of PD, the circulating levels of these molecules are not necessarily changed in patients with PD.

RESUMO Há evidências de que alteracões nas ações exercidas por fatores neurotróficos (FNs) estejam associadas à fisiopatologia da doença de Parkinson (DP). O presente estudo foi conduzido para avaliar os níveis plasmáticos de FNs e suas possíveis associações com sintomas clínicos na DP. Para este fim, 40 pacientes com DP e 25 controles foram submetidos à avaliação clínica e coleta de sangue periférico. Os níveis plasmáticos do fator neurotrófico derivado do cérebro (BDNF), pro-BDNF, neurotrofina 3, neurotrofina 4, fator de crescimento do nervo, fator neurotrófico derivado da glia e fator neurotrófico ciliar foram avaliados por ensaio de imunoadsorção enzimática. Não houve diferença significativa entre pacientes com DP e controles quanto aos níveis plasmáticos dos FNs avaliados. Além disso, não encontramos associação entre os níveis dos FNs e duração da doença, grau de comprometimento motor ou funcional, desempenho cognitivo e gravidade dos sintomas depressivos. Em conclusão, embora os FNs possam desempenhar papéis relevantes na fisiopatologia da DP, os níveis circulantes dessas moléculas não estão necessariamente alterados em pacientes com DP.

Muscle strength and psychiatric symptoms influence health-related quality of life in patients with myasthenia gravis.

Myasthenia gravis (MG) is a neuromuscular autoimmune disease characterized by skeletal muscle weakness which can impact motor function and, furthermore, produce negative impact on the health-related quality of life (HRQOL). OBJECTIVE: To evaluate the predictors for HRQOL in patients with MG. METHODS: Eighty patients were evaluated with the MG Foundation of America classification and the MG Composite scale. HRQOL was estimated by the MGQOL15, while anxious and depressive symptoms were evaluated with the Hospital Anxiety and Depression Scale (HAD). RESULTS: The mean age of patients was 41.9 years with mean illness duration of 13.5 years. Almost half of the patients (43.75%) had significant anxiety and more than a quarter (27.50%) had depressive symptoms. Factors that influenced the HRQOL in MG were skeletal muscle weakness and anxiety and depressive symptoms (p < .001 in logistic regression model). CONCLUSION: Anxiety and depressive symptoms, besides motor symptoms, influence HRQOL in MG. Mental health must be a clinical focus in addition to the treatment of somatic symptoms during the course of MG.

Toxoplasma gondii infection and chronic schizophrenia: is there any association?

ABSTRACT Background: Toxoplasma gondii (T. gondii) infection has been identified as a risk factor for schizophrenia. Objectives: Herein, we sought to evaluate the association between T. gondii infection and clinical symptoms and quality of life in patients with schizophrenia. Methods: We conducted a cross-sectional study with 48 patients with chronic schizophrenia and 40 controls. Peripheral blood was drawn, and IgM and IgG anti-T. gondii antibodies were evaluated by Enzyme-Linked Immunosorbent Assay (ELISA). Depressive, positive and negative symptoms were assessed, respectively, by the Calgary Depression Scale (CDS) and the Positive and Negative Syndrome Scale (PANSS). Cognitive performance was assessed in patients by the Brazilian version of the Schizophrenia Cognition Rating Scale (SCoRS-BR). Quality of life was assessed by the Brazilian version of the Quality of Life in Schizophrenia scale (QLS-BR). Results: The prevalence and titers of T. gondii IgM and IgG antibodies did not differ between patients and controls. The positive serology for T. gondii IgG antibodies was not associated with illness symptoms, cognitive performance, depressive symptoms or quality of life. Discussion: Our findings suggest that toxoplasmosis infection is not associated with severity of symptoms, quality of life, cognitive or depressive symptoms in schizophrenia patients.

Body composition and adipokines plasma levels in patients with myasthenia gravis treated with high cumulative glucocorticoid dose.

This study aimed to evaluate changes in body composition, i.e. overweight, obesity, fat accumulation and low lean body mass and plasma levels of adipokines in patients with MG. The study enrolled 80 patients with MG, and 62 controls. Body fat mass and body lean mass was analyzed by dual-energy X-ray absorptiometry technique (DXA). Plasma levels of leptin were analyzed by Luminex® and adiponectin and resistin were analyzed by ELISA. The mean age of patients with MG was 41.9years, with 13.5years of length of illness, and mean cumulative dose of glucocorticoids 38,123mg. Our results showed that the frequency of obesity is higher in MG patients than in controls, and patients with MG presented higher body fat mass, android body adiposity and total body fat than controls. MG patients presented lower levels of resistin and higher levels of leptin in comparison with controls. There were no differences in the plasma levels of adiponectin. Higher total body fat and lower body lean mass were associated with increased severity of MG symptoms. This result points to the relevance of estimation of body composition in planning long-term care of MG patients.

Urinary cytokine profiles according to the site of blockade of the renin-angiotensin system in nephrectomized rats.

INTRODUCTION: It is still unknown how the pharmacological inhibition of the Renin Angiotensin System (RAS) impacts the levels of inflammation and fibrosis biomarkers. OBJECTIVE: This study sought to evaluate the effect of enalapril, candesartan and aliskiren on urinary levels of cytokines in a model of chronic kidney disease (CKD). METHODS: Male Wistar rats were submitted to surgical removal of ¾ of renal parenchyma to induce CKD (¾ nephrectomy), or subjected to sham surgery (control). Animals were then randomized into five groups: Sham surgery receiving vehicle; ¾ Nephrectomy receiving vehicle; ¾ Nephrectomy receiving enalapril (10 mg/kg); ¾ Nephrectomy receiving candesartan (10 mg/kg) and ¾ Nephrectomy receiving aliskiren (10 mg/kg). Urine output, water intake, mean arterial pressure (MAP) and urinary concentrations of creatinine, urea, albuminuria, Na+, K+, interleukin (IL) -1ß, IL-6, IL-10 and transforming growth factor beta (TGF-ß) were measured. RESULTS: Nephrectomy significantly impaired renal function, increased MAP and altered the levels of all evaluated cytokines in urine. Enalapril, candesartan and aliskiren improved renal function and decreased MAP and IL-6 when compared to vehicle-treated nephrectomized group. Candesartan and aliskiren decreased IL-1ß, while only candesartan reduced TGF-ß and only aliskiren increased IL-10. CONCLUSION: Enalapril, candesartan and aliskiren presented similar effects on improving renal function and reducing MAP and urinary levels of IL-6 in rats with CKD. On the other hand, cytokine profile differed according to the treatment, suggesting that differential mechanisms were triggered in response to the site of RAS blockade.

Plasma Levels of Tumor Necrosis Factor Superfamily Molecules Are Increased in Bipolar Disorder.

OBJECTIVE: Patients with bipolar disorder (BD) exhibit peripheral low-grade inflammation. The aim of the current study was to investigate the involvement of hitherto unexplored components of the tumor necrosis factor (TNF) superfamily in BD. METHODS: Eighty patients with type I BD and 50 healthy controls matched for age and gender were enrolled in this study. All subjects were assessed with the Mini-Plus to evaluate psychiatric comorbidities; the Young Mania Rating Scale and the Hamilton Depression Rating Scale to evaluate manic and depressive symptoms severity, respectively. TNF superfamily molecules (TNF, TNF-related weak inducer of apoptosis [TWEAK], TNF-related apoptosis-inducing ligand [TRAIL], soluble TNF receptor type 1 [sTNFR1], and soluble TNF receptor type 2 [sTNFR2]) levels were measured by ELISA. RESULTS: Patients with BD, regardless of mood state, presented increased plasma levels of sTNFR1 and TWEAK in comparison with controls. CONCLUSION: These findings corroborate the view that TNF superfamily may play a role in BD pathophysiology.

Urinary cytokine profiles according to the site of blockade of the renin-angiotensin system in nephrectomized rats / Perfil de citocinas urinárias de acordo com o local de bloqueio do sistema renina angiotensina em ratos nefrectomizados

Abstract Introduction: It is still unknown how the pharmacological inhibition of the Renin Angiotensin System (RAS) impacts the levels of inflammation and fibrosis biomarkers. Objective: This study sought to evaluate the effect of enalapril, candesartan and aliskiren on urinary levels of cytokines in a model of chronic kidney disease (CKD). Methods: Male Wistar rats were submitted to surgical removal of ¾ of renal parenchyma to induce CKD (¾ nephrectomy), or subjected to sham surgery (control). Animals were then randomized into five groups: Sham surgery receiving vehicle; ¾ Nephrectomy receiving vehicle; ¾ Nephrectomy receiving enalapril (10 mg/kg); ¾ Nephrectomy receiving candesartan (10 mg/kg) and ¾ Nephrectomy receiving aliskiren (10 mg/kg). Urine output, water intake, mean arterial pressure (MAP) and urinary concentrations of creatinine, urea, albuminuria, Na+, K+, interleukin (IL) -1β, IL-6, IL-10 and transforming growth factor beta (TGF-β) were measured. Results: Nephrectomy significantly impaired renal function, increased MAP and altered the levels of all evaluated cytokines in urine. Enalapril, candesartan and aliskiren improved renal function and decreased MAP and IL-6 when compared to vehicle-treated nephrectomized group. Candesartan and aliskiren decreased IL-1β, while only candesartan reduced TGF-β and only aliskiren increased IL-10. Conclusion: Enalapril, candesartan and aliskiren presented similar effects on improving renal function and reducing MAP and urinary levels of IL-6 in rats with CKD. On the other hand, cytokine profile differed according to the treatment, suggesting that differential mechanisms were triggered in response to the site of RAS blockade.

Resumo Introdução: Ainda não se sabe como a inibição farmacológica do Sistema Renina Angiotensina (SRA) afeta os níveis de biomarcadores de inflamação e fibrose. Objetivo: Este estudo pretendeu avaliar o efeito de enalapril, candesartan e alisquireno sobre os níveis urinários de citocinas em um modelo de doença renal crônica (DRC). Métodos: Ratos Wistar machos foram submetidos à remoção cirúrgica de ¾ do parênquima renal para induzir DRC (nefrectomia), ou submetidos à cirurgia fictícia (controle). Animais foram então randomizados em cinco grupos: Cirurgia fictícia recebendo veículo; Nefrectomia recebendo veículo; Nefrectomia recebendo enalapril (10 mg/kg); Nefrectomia recebendo candesartan (10 mg/kg) e Nefrectomia recebendo alisquireno (10 mg/kg). Débito urinário, ingesta hídrica, pressão arterial media (PAM) e concentrações urinárias de creatinina, ureia, albumina, Na+, K+, interleucina (IL) -1β, IL-6, IL-10 e fator de transformação e crescimento beta (TGF-β) foram medidas. Resultados: A nefrectomia comprometeu significativamente a função renal, aumentou a PAM e alterou os níveis de todas as citocinas avaliadas na urina. Enalapril, candesartan e alisquireno melhoraram a função renal e diminuíram a PAM e a IL-6 quando comparado aos grupo de animais nefrectomizados tratados com veículo. Candesartan e alisquireno reduziram IL-1β, enquanto somente candesartan diminuiu o TGF-β e somente alisquireno aumentou a IL-10. Conclusão: Enalapril, candesartan e alisquireno apresentaram efeitos similares em relação à melhora da função renal e redução da PAM e dos níveis urinários de IL-6 em ratos com DRC. Por outro lado, o perfil de citocinas diferiu de acordo com o tratamento, sugerindo que diferentes mecanismos sejam desencadeados em resposta ao local de bloqueio do SRA.

Negative impact of high cumulative glucocorticoid dose on bone metabolism of patients with myasthenia gravis.

This current study aimed to evaluate the frequency of low bone mass, osteopenia, and osteoporosis in patients with myasthenia gravis (MG) and to investigate the possible association between bone mineral density (BMD) and plasma levels of bone metabolism markers. Eighty patients with MG and 62 controls BMD were measured in the right femoral neck and lumbar spine by dual-energy X-ray absorptiometry. Plasma concentrations of osteocalcin, osteopontin, osteoprotegerin, tumor necrosis factor (TNF-α), interleukin (IL)-1ß, IL-6, dickkopf (DKK-1), sclerostin, insulin, leptin, adrenocorticotropic hormone, parathyroid hormone, and fibroblast growth factor (FGF-23) were analyzed by Luminex®. The mean age of patients was 41.9 years, with 13.5 years of length of illness, and a mean cumulative dose of glucocorticoids 38,123 mg. Patients had significant reduction in BMD of the lumbar, the femoral neck, and in the whole body when compared with controls. Fourteen percent MG patients had osteoporosis at the lumbar spine and 2.5% at the femoral neck. In comparison with controls, patients with MG presented lower levels of osteocalcin, adrenocorticotropic hormone, parathyroid hormone, sclerostin, TNF-α, and DKK-1 and higher levels of FGF-23, leptin, and IL-6. There was a significant negative correlation between cumulative glucocorticoid dose and serum calcium, lumbar spine T-score, femoral neck BMD, T-score, and Z-score. After multivariate analysis, higher TNF-α levels increased the likelihood of presenting low bone mass by 2.62. MG patients under corticotherapy presented low BMD and altered levels of bone markers.

Serum levels of neurotrophic factors in active toxoplasmic retinochoroiditis

Abstract Toxoplasmic retinochoroiditis (TR) is the most common identifiable cause of posterior uveitis in Brazil. Response to treatment and clinical presentation may vary significantly. We assessed serum levels of brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), neurotrophin (NT)-3, and NT-4/5 in patients with active TR, before and after TR treatment. Methods: Twenty patients with active lesion and 15 healthy controls were enrolled in the study. Serum concentration of neurotrophic factors was determined by enzyme-linked immunosorbent assay. Results: BDNF levels were significantly higher in patients before treatment when compared with controls (p = 0.0015). There was no significant difference in pro-BDNF, NGF, GDNF, NT-3, and NT-4/5 levels between TR patients and controls. Treatment did not affect the levels of these factors. Conclusion: BDNF may be released in the context of the active TR inflammatory response.

The Anti-Inflammatory Potential of ACE2/Angiotensin-(1-7)/Mas Receptor Axis: Evidence from Basic and Clinical Research.

BACKGROUND: The renin angiotensin system (RAS) plays an important role in inflammation and fibrosis. The classical axis of the RAS, formed by angiotensin converting en-zyme (ACE), angiotensin II (Ang II) and angiotensin receptor type 1 (AT1), activates several cell functions and molecular signaling pathways related to tissue injury, inflammation and fibrosis. In sharp contrast, the RAS axis composed by angiotensin converting enzyme 2 (ACE2), angiotensin-(1-7) and Mas receptor exerts opposite effects in relation to inflammatory response and tissue fibrosis. OBJECTIVE: In this review, we have the aim to summarize recent findings on the anti-inflammatory and anti-fibrogenic role of ACE2/Ang-(1-7)/Mas axis in the context of basic research, experimental human dis-eases and clinical studies. RESULTS: Several studies showed that ACE2/Angiotensin-(1-7)/Mas axis reduces cytokine release and inhibits signaling pathways of tissue fibrosis in experimental models of human diseases including atherosclerosis, cerebral ischemia, obesity, chronic kidney disease, liver diseases and asthma. On the other hand, very few data was provided by clinical studies. CONCLUSION: Experimental studies clearly support the anti-inflammatory and anti-fibrotic effects of ACE2/ Ang-(1-7)/Mas axis. Clinical studies, especially phase III and IV trials, will be necessary to establish the therapeutic role of ACE2/Ang-(1-7)/Mas axis in controlling inflammation in different human diseases.

Characterization of an experimental model of progressive renal disease in rats.

PURPOSE:: To characterize an experimental model of progressive renal disease induced by different degrees of nephrectomy in rats. METHODS:: Eighty male Wistar rats were divided into four experimental groups (n=20/group): sham surgery (control group), progressive degrees of nephrectomy leading to mild uremia (group 1), moderate uremia (group 2) and severe uremia (group 3). Ten animals of each group were followed for two or four weeks. At the end, blood and 24-hour urine samples were collected to determine renal function parameters. Urine output and water and food intake were daily monitored. RESULTS:: In rats of group 1, serum levels of creatinine and urea and microalbuminuria were increased, while reduced creatinine clearance (p<0.05, compared with control group), without changing blood pressure. Animals of group 2 had more accentuated alterations: increases in urinary output, blood pressure, serum concentrations of urea, creatinine, sodium, potassium, and in microalbuminuria, and reduction of creatinine clearance (p<0.05). Group 3 exhibited even more increased serum concentrations of urea, creatinine, sodium and potassium, blood pressure and microalbuminuria, and decreased creatinine clearance (p<0.05) in comparison with control group and unilateral nephrectomy. CONCLUSION:: Progressive nephrectomy in rats seems to be useful to study the physiopathology of chronic kidney disease and its mechanisms of progression.