Synapse Dysfunctions in Multiple Sclerosis

Multiple sclerosis (MS) is a chronic neuroinflammatory disease of the central nervous system (CNS) affecting nearly three million humans worldwide. In MS, cells of an auto-reactive immune system invade the brain and cause neuroinflammation. Neuroinflammation triggers a complex, multi-faceted harmful process not only in the white matter but also in the grey matter of the brain. In the grey matter, neuroinflammation causes synapse dysfunctions. Synapse dysfunctions in MS occur early and independent from white matter demyelination and are likely correlates of cognitive and mental symptoms in MS. Disturbed synapse/glia interactions and elevated neuroinflammatory signals play a central role. Glutamatergic excitotoxic synapse damage emerges as a major mechanism. We review synapse/glia communication under normal conditions and summarize how this communication becomes malfunctional during neuroinflammation in MS. We discuss mechanisms of how disturbed glia/synapse communication can lead to synapse dysfunctions, signaling dysbalance, and neurodegeneration in MS

Early Changes in Exo- and Endocytosis in the EAE Mouse Model of Multiple Sclerosis Correlate with Decreased Synaptic Ribbon Size and Reduced Ribbon-Associated Vesicle Pools in Rod Photoreceptor Synapses

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that finally leads to demyelination. Demyelinating optic neuritis is a frequent symptom in MS. Recent studies also revealed synapse dysfunctions in MS patients and MS mouse models. We previously reported alterations of photoreceptor ribbon synapses in the experimental auto-immune encephalomyelitis (EAE) mouse model of MS. In the present study, we found that the previously observed decreased imunosignals of photoreceptor ribbons in early EAE resulted from a decrease in synaptic ribbon size, whereas the number/density of ribbons in photoreceptor synapses remained unchanged. Smaller photoreceptor ribbons are associated with fewer docked and ribbon-associated vesicles. At a functional level, depolarization-evoked exocytosis as monitored by optical recording was diminished even as early as on day 7 after EAE induction. Moreover compensatory, post-depolarization endocytosis was decreased. Decreased post-depolarization endocytosis in early EAE correlated with diminished synaptic enrichment of dynamin3. In contrast, basal endocytosis in photoreceptor synapses of resting non-depolarized retinal slices was increased in early EAE. Increased basal endocytosis correlated with increased de-phosphorylation of dynamin1. Thus, multiple endocytic pathways in photoreceptor synapse are differentially affected in early EAE and likely contribute to the observed synapse pathology in early EAE

Myelodysplastic syndromes: Aspects of current medical care and economic considerations in Germany

Myelodysplastic syndromes (MDS) are a heterogeneous group of diseases mainly affecting older people. The use of an increasing number of therapeutic options depends on a systematic risk stratification of the patients. A high percentage of MDS patients need blood transfusions as supportive care, which influence quality of life and cause a great part of the costs generated by MDS therapy. In this article which is based on a workshop about the burden of MDS held in October 2006 in Munich, MDS is discussed with regard to different aspects: current therapies, transfusion medicine, geriatrics, quality of life, and health economic aspects

EF hand-mediated Ca2+- and cGMP-signaling in photoreceptor synaptic terminals

Photoreceptors, the light-sensitive receptor neurons of the retina, receive and transmit a plethora of visual informations from the surrounding world. Photoreceptors capture light and convert this energy into electrical signals that are conveyed to the inner retina. For synaptic communication with the inner retina, photoreceptors make large active zones that are marked by synaptic ribbons. These unique synapses support continuous vesicle exocytosis that is modulated by light-induced, graded changes of membrane potential. Synaptic transmission can be adjusted in an activity-dependent manner, and at the synaptic ribbons, Ca2+- and cGMP-dependent processes appear to play a central role. EF-hand-containing proteins mediate many of these Ca2+- and cGMP-dependent functions. Since continuous signaling of photoreceptors appears to be prone to malfunction, disturbances of Ca2+- and cGMP-mediated signaling in photoreceptors can lead to visual defects, retinal degeneration (rd), and even blindness. This review summarizes aspects of signal transmission at the photoreceptor presynaptic terminals that involve EF-hand-containing Ca2+-binding proteins

The physical, psychological, and social day-to-day experience of women living with endometriosis compared to healthy age-matched controls — a mixed-methods study

Background: Endometriosis is characterized by lesions of endometrial tissue outside the uterus. Chronic pain is considered as main symptom, but challenges can relate to various physical, mental, and social aspects of the women's lives. The aim of our study was to gain a holistic understanding of the everyday reality of women with endometriosis compared to healthy controls. Methods: The total sample comprised 12 hormone-free endometriosis patients (EP) and 11 age-matched healthy women (HC). A mixed-methods design was used comprising semi-structured interviews, standardized questionnaires and a comprehensive diary to assess pain ratings and various mental and physical symptoms over the course of a menstrual cycle. Interviews were recorded, transcribed, and evaluated according to phenomenological analysis using the MAXQDA software. Results: Interviews showed that living with endometriosis was associated with an impairment in everyday life. Physical strains, especially pain, high levels of psychological distress, and social limitations have been reported. Living with endometriosis affected the patients' personality and they “no longer felt like themselves.” Physical and psychological symptoms were reported to interfere with social interaction and participation. Evaluation of the standardized questionnaires revealed significant impairments in EP compared to HC in regard to anxiety and depression scores (both p < 0.001; Hospital Anxiety and Depression Scale), mental and physical quality of life (both p < 0.001; Short-Form Health Survey-12), stress ratings (p < 0.001; Patient Health Questionnaire-15) and functional well-being (p < 0.001; Functional Well-being-7). The highest levels of mean pelvic pain and dyschezia were observed in EP during menstruation, but mean pain ratings and dyschezia were increased in EPs compared to HP during the whole cycle. EP reported mental symptoms (e.g., depressed mood or anxiety) mainly during menstruation, while HC did not show any mental symptoms during the cycle. In addition, physical symptoms were elevated during the entire cycle in EPs (all p < 0.01). Discussion: The mixed-methods approach enabled to interpret the interviews, the standardized questionnaires, and the symptom diary in a broader context of everyday life. The symptoms do not appear to act independently, but rather influence each other. This leads to a complex interplay of physical, mental, and social impairments, with pain often being the starting point

Assessment of lunch served in the Workers’ Food Program, Brazil

OBJETIVO: Face à expansão do Programa de Alimentação do Trabalhador no País e sua atualização na normatização dos aspectos nutricionais, foi avaliado o consumo alimentar de trabalhadores participantes do programa, por meio da análise nutricional do almoço servido e do estado nutricional da população atendida. MÉTODOS: Realizou-se estudo transversal com amostra representativa dos trabalhadores participantes do Programa de Alimentação do Trabalhador no Distrito Federal (n=1.044) que almoçam em 52 Unidades de Alimentação e Nutrição. Foram avaliadas variáveis socioeconômicas e sociodemográficas, medidas antropométricas para o cálculo do Índice de Massa Corporal e o consumo alimentar obtido pelo método da pesagem e pela observação direta da montagem dos pratos. RESULTADOS: Observou-se que 43% da população estudada apresentam excesso de peso, sendo 33,7% com sobrepeso e 9,3% com obesidade, com maiores percentuais no sexo masculino. A mediana do valor energético do almoço foi de 515 Kcal para as mulheres e de 736 Kcal para os homens. O consumo mediano de fibras foi de 6,0 g para o sexo feminino e de 8,3 g para o sexo masculino, e o consumo mediano de colesterol foi acima de 90 mg nos indivíduos com excesso de peso. CONCLUSÕES: Os resultados indicam risco nutricional nessa população, tradicionalmente considerada sadia, devendo a mesma ser alvo de estratégias com foco na promoção da saúde, salientado-se, assim, a atribuição de educador do nutricionista. ___________________________________________________________________________________________________________________ ABSTRACTOBJECTIVE: In the light of the Workers' Food Program (WFP) growth and its recent review of nutritional parameters regulations, the study aimed at evaluating food intake in WFP through dietary assessment of lunch served in the program and workers' nutritional status. METHODS: A cross-sectional study was carried out in a representative sample of workers in Brasília, Federal District, Brazil. A total of 1,044 subjects who had lunch at 52 food and nutrition units were evaluated. Social-economic and demographic data were collected as well as anthropometric measures for calculating the Body Mass Index. Food intake was assessed by dish weight and direct observation of dish composition. RESULTS: Of all subjects, 43% had excess weight, 33.7% were overweight and 9.3% were obese. Males were most affected. Median lunch energy intake was 515 kcal in women and 736 kcal in men. Median dietary fiber intake was 6.0 g among women and 8.3 g among men, and median cholesterol intake was over 90 mg among subjects with excess weight. CONCLUSIONS: The results indicate that the study population who is often seen as healthy is at nutritional risk. Workers in WFP should be targeted for health promotion strategies using especially nutritionists' skills as educators

Sex, income and level of education associated with physical activity level among workers

OBJETIVO: Analisar fatores socioeconômicos e demográfi cos associados ao nível de atividade física de trabalhadores. MÉTODOS: Estudo transversal realizado no Distrito Federal, de 2000 a 2001, com amostra representativa de trabalhadores de ambos os sexos, vinculados ao Programa de Alimentação do Trabalhador, envolvendo 1.044 trabalhadores. Utilizou-se a regressão logística binária para determinação dos possíveis fatores de risco associados ao nível de atividade física e selecionados pelo processo de “backward elimination”. Efeitos interativos das variáveis foram verifi cados no modelo fi nal por meio da razão de chances, para nível de atividade física >1,4. RESULTADOS: O modelo fi nal incluiu o sexo, a renda e a escolaridade. Indivíduos do sexo masculino que cursaram apenas o primeiro grau e ganhavam menos de quatro salários mínimos eram os que tinham mais chances de apresentar nível de atividade física >1,4. A estimativa das razões de chances indicou que os homens tinham cinco vezes mais chances de apresentar nível de atividade física >1,4, níveis inferiores aos das mulheres. Indivíduos que cursaram apenas o primeiro grau e com renda igual ou inferior a quatro salários mínimos tinham duas vezes mais chances de nível de atividade física ≥1,4 do que indivíduos com renda superior a quatro salários mínimos e curso superior ou pós-graduação. CONCLUSÕES: Os resultados indicam que os fatores associados ao nível de atividade física de trabalhadores são: sexo masculino, escolaridade primeiro grau e renda menor que quatro salários mínimos.OBJECTIVE: To analyze socioeconomic and demographic factors associated with physical activity level among workers. METHODS: Cross-sectional study conducted in Brazil’s Federal District, from 2000 to 2001, with a representative sample of 1,044 workers from both sexes, who are covered by the Programa de Alimentação do Trabalhador (Workers’ Food Program). Binary logistic regression was used to determine possible risk factors associated with physical activity level and selected by the backward elimination process. Interactive effects of the variables were verifi ed in the fi nal model by means of the odds ratio for physical activity level >1.4. RESULTS: The fi nal model included sex, income and level of education. Male individuals who only fi nished elementary school and earned less than four Brazilian minimum wages per month were the most likely to show physical activity level ≥1.4. The odds ratio estimate indicated that men were fi ve times more likely to show physical activity level ≥1.4 than women. Individuals who only fi nished elementary school and had an income equal to or below four minimum wages were two times more likely to show physical activity level ≥1.4 than individuals who earned more than four minimum wages and had a university degree or higher. CONCLUSIONS: Results indicate that the factors associated with physical activity level among workers are the following: male, elementary school level, and income below four Brazilian minimum wages per month

Detection of Cerebrospinal Fluid Neurofilament Light Chain as a Marker for Alpha-Synucleinopathies

Alpha-synucleinopathies, such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), are a class of neurodegenerative diseases. A diagnosis may be challenging because clinical symptoms partially overlap, and there is currently no reliable diagnostic test available. Therefore, we aimed to identify a suitable marker protein in cerebrospinal fluid (CSF) to distinguish either between different types of alpha-synucleinopathies or between alpha-synucleinopathies and controls. In this study, the regulation of different marker protein candidates, such as alpha-synuclein (a-Syn), neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and total tau (tau) in different types of alpha-synucleinopathies, had been analyzed by using an ultrasensitive test system called single-molecule array (SIMOA). Interestingly, we observed that CSF-NfL was significantly elevated in patients with DLB and MSA compared to patients with PD or control donors. To differentiate between groups, receiver operating characteristic (ROC) curve analysis resulted in a very good diagnostic accuracy as indicated by the area under the curve (AUC) values of 0.87-0.92 for CSF-NfL. Furthermore, we observed that GFAP and tau were slightly increased either in DLB or MSA, while a-Syn levels remained unregulated. Our study suggests NfL as a promising marker to discriminate between different types of alpha-synucleinopathies or between DLB/MSA and controls

Disturbed Presynaptic Ca2+ Signaling in Photoreceptors in the EAE Mouse Model of Multiple Sclerosis

Multiple sclerosis (MS) is a demyelinating disease caused by an auto-reactive immune system. Recent studies also demonstrated synapse dysfunctions in MS patients and MS mouse models. We previously observed decreased synaptic vesicle exocytosis in photoreceptor synapses in the EAE mouse model of MS at an early, preclinical stage. In the present study, we analyzed whether synaptic defects are associated with altered presynaptic Ca2+ signaling. Using high-resolution immunolabeling, we found a reduced signal intensity of Cav-channels and RIM2 at active zones in early, preclinical EAE. In line with these morphological alterations, depolarization-evoked increases of presynaptic Ca2+ were significantly smaller. In contrast, basal presynaptic Ca2+ was elevated. We observed a decreased expression of Na+/K+-ATPase and plasma membrane Ca2+ ATPase 2 (PMCA2), but not PMCA1, in photoreceptor terminals of EAE mice that could contribute to elevated basal Ca2+. Thus, complex Ca2+ signaling alterations contribute to synaptic dysfunctions in photoreceptors in early EAE

Ciliary Proteins Repurposed by the Synaptic Ribbon: Trafficking Myristoylated Proteins at Rod Photoreceptor Synapses

The Unc119 protein mediates transport of myristoylated proteins to the photoreceptor outer segment, a specialized primary cilium. This transport activity is regulated by the GTPase Arl3 as well as by Arl13b and Rp2 that control Arl3 activation/inactivation. Interestingly, Unc119 is also enriched in photoreceptor synapses and can bind to RIBEYE, the main component of synaptic ribbons. In the present study, we analyzed whether the known regulatory proteins, that control the Unc119- dependent myristoylated protein transport at the primary cilium, are also present at the photoreceptor synaptic ribbon complex by using high-resolution immunofluorescence and immunogold electron microscopy. We found Arl3 and Arl13b to be enriched at the synaptic ribbon whereas Rp2 was predominantly found on vesicles distributed within the entire terminal. These findings indicate that the synaptic ribbon could be involved in the discharge of Unc119-bound lipid-modified proteins. In agreement with this hypothesis, we found Nphp3 (Nephrocystin-3), a myristoylated, Unc119- dependent cargo protein enriched at the basal portion of the ribbon in close vicinity to the active zone. Mutations in Nphp3 are known to be associated with Senior–Løken Syndrome 3 (SLS3). Visual impairment and blindness in SLS3 might thus not only result from ciliary dysfunctions but also from malfunctions of the photoreceptor synapse