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INTRODUÇÃO: A diabetes mellitus tipo 2 (DM) é uma doença metabólica caracterizada pela presença de hiperglicemia crônica. Estudos prévios demonstraram que pacientes com pré-diabetes (PDM) têm uma história natural de progressão para DM. A neuropatia diabética é a complicação mais comum da DM e avanços recentes na neurofisiologia clínica trouxeram um refinamento das técnicas de avaliação. Entre estas estão à resposta cutânea simpática (SSR) e o teste sensorial quantitativo (QST). Biomarcadores como Enolase Neurônio-Específica (NSE) e a Proteína S100-Beta (S100B) vem sendo descritos por muitos autores como associados a danos em células do sistema nervoso. OBJETIVO: O objetivo deste estudo é avaliar parâmetros neurofisiológicos e compará-los com achados clínicos e bioquímicos (S100B e NSE) em pacientes com DM, PDM e controles saudáveis. MÉTODOS: Pacientes dos ambulatórios de Neurologia e Endocrinologia foram randomizados em um estudo transversal. Os participantes foram submetidos a uma bateria de testes clínicos e neurofisiológicos que englobaram condução nervosa, Onda-F, SSR e QST. Níveis séricos de NSE e S100B foram quantificados através de ensaio ELISA (Enzyme-linked immunosorbent assay). RESULTADOS: A avaliação clínica e os estudos de condução nervosa e Onda-F foram similares nos grupos estudados. Já os limiares QST calor (QSTc) e QST dor (QSTd) foram significativamente elevados nos pacientes PDM e DM com relação aos controles (P<0.05 para todas as comparações). No entanto, estes parâmetros não foram capazes de distinguir pacientes DM vs. PDM (P >0.1 para todas as comparações). O SSR foi capaz de diferenciar o grupo DM do controle (P <0,01) embora não tenha mostrado diferença entre os grupos PDM e controle (P = 0,6). Não houve diferença entre os níveis de S100B (P = 0.6) e NSE (P = 0.2) entre os grupos DM, PDM e controles. CONCLUSÃO: O QST e SSR são testes úteis para a avaliação de pacientes com diferentes graus de tolerância a glicose. Este estudo não encontrou diferenças entre os biomarcadores NSE e S100B em indivíduos com DM e PDM. / BACKGROUND: Type 2 diabetes mellitus (DM) is a metabolic disease characterized by the presence of chronic hyperglycemia. Previous studies demonstrated that patients with prediabetes states (PDM) have a natural history of progression to DM. Neuropathy is the most common and disabling complication of diabetes and recent advances in neurophysiology have enabled a refinement of neurophysiological diagnostic techniques such as sympathetic skin response (SSR) and quantitative sensory testing (QST). Biomarkers like Neuron-specific Enolase (NSE) and S100- Beta Protein (S100B) has been described for many authors as associated with damage at nervous system cells and are related with severity of injury as well as clinical outcomes. OBJECTIVE: The aim of this study is to evaluate neurophysiological findings and compare them with clinical and biochemical findings (S100B and NSE) in patients with DM, PDM and healthy controls. METHODS: Patients at the outpatient Neurology and Endocrinology service were randomized in a cross-sectional study. Participants underwent a battery of clinical and neurophysiological tests that encompassed nerve conduction studies, F-wave, SSR and QST. ELISA (enzyme-linked immunosorbent assay) were perform to quantify serum levels of NSE and S100B. RESULTS: There were no difference regarding clinical evaluation, nerve conduction studies and F-wave were between groups. The QST thresholds of warm (QSTw) and QST pain (QSTp) were significantly elevated in patients with PDM and DM compared to controls (P <0.05 for all comparisons). However, these parameters were not able to distinguish among DM and PDM (P > 0.1 for all comparisons). The SSR was able to differentiate DM from control group (P <0.01) but did not show difference between PDM and control groups (P = 0.6). There was no difference on levels of S100B (P = 0.6) and NSE (P = 0.2) between the DM, PDM and control groups. CONCLUSION: The QST and SSR are useful tests to evaluating patients with different degrees of glucose tolerance. This study found no differences between biomarkers NSE and S100B in subjects with DM and PDM.

INTRODUÇÃO: A diabetes mellitus tipo 2 (DM) é uma doença metabólica caracterizada pela presença de hiperglicemia crônica. Estudos prévios demonstraram que pacientes com pré-diabetes (PDM) têm uma história natural de progressão para DM. A neuropatia diabética é a complicação mais comum da DM e avanços recentes na neurofisiologia clínica trouxeram um refinamento das técnicas de avaliação. Entre estas estão à resposta cutânea simpática (SSR) e o teste sensorial quantitativo (QST). Biomarcadores como Enolase Neurônio-Específica (NSE) e a Proteína S100-Beta (S100B) vem sendo descritos por muitos autores como associados a danos em células do sistema nervoso. OBJETIVO: O objetivo deste estudo é avaliar parâmetros neurofisiológicos e compará-los com achados clínicos e bioquímicos (S100B e NSE) em pacientes com DM, PDM e controles saudáveis. MÉTODOS: Pacientes dos ambulatórios de Neurologia e Endocrinologia foram randomizados em um estudo transversal. Os participantes foram submetidos a uma bateria de testes clínicos e neurofisiológicos que englobaram condução nervosa, Onda-F, SSR e QST. Níveis séricos de NSE e S100B foram quantificados através de ensaio ELISA (Enzyme-linked immunosorbent assay). RESULTADOS: A avaliação clínica e os estudos de condução nervosa e Onda-F foram similares nos grupos estudados. Já os limiares QST calor (QSTc) e QST dor (QSTd) foram significativamente elevados nos pacientes PDM e DM com relação aos controles (P<0.05 para todas as comparações). No entanto, estes parâmetros não foram capazes de distinguir pacientes DM vs. PDM (P >0.1 para todas as comparações). O SSR foi capaz de diferenciar o grupo DM do controle (P <0,01) embora não tenha mostrado diferença entre os grupos PDM e controle (P = 0,6). Não houve diferença entre os níveis de S100B (P = 0.6) e NSE (P = 0.2) entre os grupos DM, PDM e controles. CONCLUSÃO: O QST e SSR são testes úteis para a avaliação de pacientes com diferentes graus de tolerância a glicose. Este estudo não encontrou diferenças entre os biomarcadores NSE e S100B em indivíduos com DM e PDM. / BACKGROUND: Type 2 diabetes mellitus (DM) is a metabolic disease characterized by the presence of chronic hyperglycemia. Previous studies demonstrated that patients with prediabetes states (PDM) have a natural history of progression to DM. Neuropathy is the most common and disabling complication of diabetes and recent advances in neurophysiology have enabled a refinement of neurophysiological diagnostic techniques such as sympathetic skin response (SSR) and quantitative sensory testing (QST). Biomarkers like Neuron-specific Enolase (NSE) and S100- Beta Protein (S100B) has been described for many authors as associated with damage at nervous system cells and are related with severity of injury as well as clinical outcomes. OBJECTIVE: The aim of this study is to evaluate neurophysiological findings and compare them with clinical and biochemical findings (S100B and NSE) in patients with DM, PDM and healthy controls. METHODS: Patients at the outpatient Neurology and Endocrinology service were randomized in a cross-sectional study. Participants underwent a battery of clinical and neurophysiological tests that encompassed nerve conduction studies, F-wave, SSR and QST. ELISA (enzyme-linked immunosorbent assay) were perform to quantify serum levels of NSE and S100B. RESULTS: There were no difference regarding clinical evaluation, nerve conduction studies and F-wave were between groups. The QST thresholds of warm (QSTw) and QST pain (QSTp) were significantly elevated in patients with PDM and DM compared to controls (P <0.05 for all comparisons). However, these parameters were not able to distinguish among DM and PDM (P > 0.1 for all comparisons). The SSR was able to differentiate DM from control group (P <0.01) but did not show difference between PDM and control groups (P = 0.6). There was no difference on levels of S100B (P = 0.6) and NSE (P = 0.2) between the DM, PDM and control groups. CONCLUSION: The QST and SSR are useful tests to evaluating patients with different degrees of glucose tolerance. This study found no differences between biomarkers NSE and S100B in subjects with DM and PDM.

Introdução: A fibromialgia (FM) é uma síndrome de dor crônica musculoesquelética difusa, cuja etiologia não está totalmente conhecida. A síndrome cursa com dor, alterações do humor e sintomas de ruptura do ritmo circadiano. Sabe-se que seu processo fisiopatogênico envolve um desbalanço entre os sistemas de modulação excitatório e inibitório da dor. A capacidade do sistema modulatório inibitório está enfraquecida, com hiperativação de neurônios e da neuroglia, constituindo um quadro de sensibilização central. Portanto, estudos adicionais são necessários para compreender a relação entre possíveis marcadores séricos da hiperativação neuronal, tais como o Brain Derived Neurotrophic Factor (BDNF) e a proteína S100 beta (S100B). Além disso, estudos que busquem opções terapêuticas com efeito em vias neurobiológicas alternativas, tais como a melatonina, uma indolamina com efeitos ressincronizador, analgésico, anti-inflamatório e em sistemas moduladores da dor, como o gabaérgico, opioidérgico e glutamatérgico. Objetivos: 1) Primário: Avaliar se os níveis séricos de BDNF e S100B teriam associação com a FM e se ambos os mediadores sorológicos poderiam ser associados com o limiar de dor à pressão. 2) Secundário: Testar o tratamento com melatonina isolada ou em combinação com amitriptilina é melhor que amitriptilina isolada para modificar o sistema modulatório da dor. Assim, para provar tais hipóteses, neste estudo foram quantificados a modulação condicionada da dor e níveis de BDNF sérico em pacientes que receberam tratamento com melatonina isolada ou associada com amitriptilina. Foi também testado se melatonina melhoraria os sintomas clínicos como dor, limiar de dor à pressão e qualidade do sono relacionado à FM. Métodos: Foram selecionadas pacientes com diagnóstico de FM de acordo com o American College of Rheumatology (ACR) 2010. No primeiro estudo, de desenho transversal, foram incluídas 56 mulheres com FM, com idades entre 18 e 65 anos. Foram avaliados o limiar de dor à pressão e dosagem sérica de BDNF e S100B. No segundo estudo, foram incluídas 63 pacientes com os mesmos critérios de inclusão descritos no estudo transversal. As pacientes foram randomizadas e receberam, ao deitar, amitriptilina (25mg) (n=21), melatonina (10mg) (n=21) ou melatonina (10 mg) + amitriptilina (25mg) (n=21), durante seis semanas. O sistema modulatório descendente da dor foi acessado pela modulação condicionada da dor, através da mensuração da escala numérica de dor (NPS(0-10)) durante aferição do limiar de dor ao calor. Resultados: O resultado do estudo transversal mostrou que BDNF e S100B séricos foram correlacionados. BDNF e S100B foram inversamente correlacionados com limiar de dor à pressão. BDNF sérico foi associado com limiar de dor à pressão, idade e transtorno obsessivo compulsivo, enquanto que S100B sérica foi apenas associada com limiar de dor à pressão. O ensaio clínico randomizado demonstrou que a melatonina aumentou a potência do sistema modulatório da dor inibitório e que a modulação condicionada da dor foi negativamente correlacionada com BDNF sérico. Conclusões: Os estudos desta tese demonstram que S100B e BDNF, ambos mediadores chave no processo de sensibilização central, foram inversamente correlacionados com o limiar de dor à pressão. BDNF sérico foi, ainda, inversamente correlacionado com a redução da dor. Portanto, a avaliação sérica de BDNF e S100B merece estudos adicionais para determinar seu potencial papel sinalizador no espectro da sensibilização central nessa doença. / Introduction: Fibromyalgia (FM) is a syndrome of chronic diffuse musculoskeletal pain whose etiology is not fully known. This syndrome causes pain, mood swings and symptoms of rupture of the circadian rhythm. Its pathophysiological process involves an imbalance between excitatory and inhibitory pain modulatory systems. The ability of inhibitory systems is weakened, providing a framework of central sensitization, with dysfunction in the descending pain modulatory system, hyper-activation of neurons and neuroglia. Therefore, additional studies are needed to understand the possible relationship between serum markers of neuronal hyperactivity, such as Brain Derived Neurotrophic Factor (BDNF) and S100B. Particularly, studies seeking therapeutic options with effect in neurobiological alternative pathways such as melatonin, a indolamine with resynchronization, analgesic, and anti-inflammatory effects and actions on the modulatory pain systems such as GABAergic, opiodergic and glutamatergic. Objectives: 1) Primary: Evaluate whether the serum levels of BDNF and S100B have association with FM and if both serological mediators could be associated with pressure pain threshold. 2) Secondary: To test the hypothesis that treatment with melatonin alone or in combination with amitriptyline is better than amitriptyline alone to modify the endogenous pain modulatory system. Thus, to prove these hypothesis, it was quantified the conditioned pain modulation and serum BDNF levels in FM patients receiving treatment with melatonin alone or in combination with amitriptyline. Also, it was tested whether melatonin would improve clinical symptoms such as pain, pressure pain threshold and quality of sleep related to FM. Methods: Patients with FM according to the American College of Rheumatology (ACR) 2010 were selected. In the first study, a cross-sectional design, 56 women aging 18-65 years old, with FM were included. It was evaluated the pressure pain threshold, and serum levels of BDNF and S100B. In the second study, 63 patients were included with the same inclusion criteria described in the cross-sectional study. Patients were randomized and received at bedtime amitriptyline (25 mg) (n = 21), melatonin (10 mg) (n = 21) or melatonin (10 mg) + amitriptyline (25 mg) (n = 21) for six weeks. The descending pain modulatory system was accessed by the conditioned pain modulation, measuring the numerical pain scale [NPS (0-10)] during the heat pain threshold. Results: On the cross-sectional study serum BDNF and S100B were correlated. Serum BDNF and S100B were correlated with the pressure pain threshold. Serum BDNF was associated with pressure pain threshold, age and obsessive compulsive disorder, while serum S100B was associated with pressure pain threshold, only. The randomized clinical trial showed that melatonin increased the efficacy of inhibitory pain modulatory system and the conditioned pain modulation was negatively correlated with serum BDNF. Conclusions: The studies of this thesis show that both key mediators of the central sensitization process, BDNF and S100B, were inversely correlated with the pressure pain threshold. They also showed that melatonin increased the inhibitory pain modutalory system. Furthermore, it emphasizes that serum BDNF was inversely correlated with pain reduction. Therefore, assessment of serum BDNF and S100B deserve further studies to determine their potential as a proxy for the central sensitization spectrum in FM.

INTRODUÇÃO: A diabetes mellitus tipo 2 (DM) é uma doença metabólica caracterizada pela presença de hiperglicemia crônica. Estudos prévios demonstraram que pacientes com pré-diabetes (PDM) têm uma história natural de progressão para DM. A neuropatia diabética é a complicação mais comum da DM e avanços recentes na neurofisiologia clínica trouxeram um refinamento das técnicas de avaliação. Entre estas estão à resposta cutânea simpática (SSR) e o teste sensorial quantitativo (QST). Biomarcadores como Enolase Neurônio-Específica (NSE) e a Proteína S100-Beta (S100B) vem sendo descritos por muitos autores como associados a danos em células do sistema nervoso. OBJETIVO: O objetivo deste estudo é avaliar parâmetros neurofisiológicos e compará-los com achados clínicos e bioquímicos (S100B e NSE) em pacientes com DM, PDM e controles saudáveis. MÉTODOS: Pacientes dos ambulatórios de Neurologia e Endocrinologia foram randomizados em um estudo transversal. Os participantes foram submetidos a uma bateria de testes clínicos e neurofisiológicos que englobaram condução nervosa, Onda-F, SSR e QST. Níveis séricos de NSE e S100B foram quantificados através de ensaio ELISA (Enzyme-linked immunosorbent assay). RESULTADOS: A avaliação clínica e os estudos de condução nervosa e Onda-F foram similares nos grupos estudados. Já os limiares QST calor (QSTc) e QST dor (QSTd) foram significativamente elevados nos pacientes PDM e DM com relação aos controles (P<0.05 para todas as comparações). No entanto, estes parâmetros não foram capazes de distinguir pacientes DM vs. PDM (P >0.1 para todas as comparações). O SSR foi capaz de diferenciar o grupo DM do controle (P <0,01) embora não tenha mostrado diferença entre os grupos PDM e controle (P = 0,6). Não houve diferença entre os níveis de S100B (P = 0.6) e NSE (P = 0.2) entre os grupos DM, PDM e controles. CONCLUSÃO: O QST e SSR são testes úteis para a avaliação de pacientes com diferentes graus de tolerância a glicose. Este estudo não encontrou diferenças entre os biomarcadores NSE e S100B em indivíduos com DM e PDM. / BACKGROUND: Type 2 diabetes mellitus (DM) is a metabolic disease characterized by the presence of chronic hyperglycemia. Previous studies demonstrated that patients with prediabetes states (PDM) have a natural history of progression to DM. Neuropathy is the most common and disabling complication of diabetes and recent advances in neurophysiology have enabled a refinement of neurophysiological diagnostic techniques such as sympathetic skin response (SSR) and quantitative sensory testing (QST). Biomarkers like Neuron-specific Enolase (NSE) and S100- Beta Protein (S100B) has been described for many authors as associated with damage at nervous system cells and are related with severity of injury as well as clinical outcomes. OBJECTIVE: The aim of this study is to evaluate neurophysiological findings and compare them with clinical and biochemical findings (S100B and NSE) in patients with DM, PDM and healthy controls. METHODS: Patients at the outpatient Neurology and Endocrinology service were randomized in a cross-sectional study. Participants underwent a battery of clinical and neurophysiological tests that encompassed nerve conduction studies, F-wave, SSR and QST. ELISA (enzyme-linked immunosorbent assay) were perform to quantify serum levels of NSE and S100B. RESULTS: There were no difference regarding clinical evaluation, nerve conduction studies and F-wave were between groups. The QST thresholds of warm (QSTw) and QST pain (QSTp) were significantly elevated in patients with PDM and DM compared to controls (P <0.05 for all comparisons). However, these parameters were not able to distinguish among DM and PDM (P > 0.1 for all comparisons). The SSR was able to differentiate DM from control group (P <0.01) but did not show difference between PDM and control groups (P = 0.6). There was no difference on levels of S100B (P = 0.6) and NSE (P = 0.2) between the DM, PDM and control groups. CONCLUSION: The QST and SSR are useful tests to evaluating patients with different degrees of glucose tolerance. This study found no differences between biomarkers NSE and S100B in subjects with DM and PDM.

Abstract There is a lack of reliable methods of evaluation of brain ischemic injury in patients undergoing cardiac surgery. The present study was, therefore, planned to evaluate whether serum S100β protein (I), brain cortical microdialysis (II), intracranial pressure (III) and electroencephalography (EEG) (IV) are predictive of postoperative death and brain ischemic injury in an experimental surviving porcine model of hypothermic circulatory arrest (HCA). One hundred and twenty eight (128) female, juvenile (8 to 10 weeks of age) pigs of native stock, weighing 21.0 to 38.2 kg, underwent cardio-pulmonary bypass prior to, and following, a 75-minute period of HCA at a brain temperature of 18°C. During the operation, hemodynamic, electrocardiograph and temperature monitoring was performed continuously. Furthermore, metabolic parameters were monitored at baseline, end of cooling, at intervals of two, four and eight hours after HCA and before extubation. Electroencephalographic recording was performed in all animals, serum S100β protein measurement in 18 animals, cortical microdialysis in 109 animals, and intracranial pressure monitoring in 58 animals. After the operation, assessment of behavior was made on a daily basis until death or elective sacrifice on the seventh postoperative day. All four studies showed that these parameters were predictive of postoperative outcome. Animals with severe histopathological injury had higher serum S100β protein levels at every time interval after HCA. Analysis of cortical brain microdialysis showed that the lactate/glucose ratio was significantly lower and the brain glucose concentration significantly higher among survivors during the early postoperative hours. Intracranial pressure increased significantly after 75 minutes of HCA, and this was associated with a significantly increased risk of postoperative death and brain infarction. A slower recovery of EEG burst percentage after HCA was significantly associated with the development of severe cerebral cortex, brain stem and cerebellum ischemic injury. In conclusion, serum S100β protein proved to be a reliable marker of brain ischemic injury as assessed on histopathological examination. Cerebral microdialysis is a useful method of cerebral monitoring during experimental HCA. Low brain glucose concentrations and high brain lactate/ glucose ratios after HCA are strong predictors of postoperative death. Increased intracranial pressure severely affected the postoperative outcome and may be a potential target for treatment. EEG burst percentage as a sum effect of anesthetic agent and ischemic brain damage is a useful tool for early prediction of severe brain damage after HCA. Among these monitoring methods, brain cortical microdialysis seems to be the most powerful one in predicting brain injury after experimental hypothermic circulatory arrest.

Introdução: A fibromialgia (FM) é uma síndrome de dor crônica musculoesquelética difusa, cuja etiologia não está totalmente conhecida. A síndrome cursa com dor, alterações do humor e sintomas de ruptura do ritmo circadiano. Sabe-se que seu processo fisiopatogênico envolve um desbalanço entre os sistemas de modulação excitatório e inibitório da dor. A capacidade do sistema modulatório inibitório está enfraquecida, com hiperativação de neurônios e da neuroglia, constituindo um quadro de sensibilização central. Portanto, estudos adicionais são necessários para compreender a relação entre possíveis marcadores séricos da hiperativação neuronal, tais como o Brain Derived Neurotrophic Factor (BDNF) e a proteína S100 beta (S100B). Além disso, estudos que busquem opções terapêuticas com efeito em vias neurobiológicas alternativas, tais como a melatonina, uma indolamina com efeitos ressincronizador, analgésico, anti-inflamatório e em sistemas moduladores da dor, como o gabaérgico, opioidérgico e glutamatérgico. Objetivos: 1) Primário: Avaliar se os níveis séricos de BDNF e S100B teriam associação com a FM e se ambos os mediadores sorológicos poderiam ser associados com o limiar de dor à pressão. 2) Secundário: Testar o tratamento com melatonina isolada ou em combinação com amitriptilina é melhor que amitriptilina isolada para modificar o sistema modulatório da dor. Assim, para provar tais hipóteses, neste estudo foram quantificados a modulação condicionada da dor e níveis de BDNF sérico em pacientes que receberam tratamento com melatonina isolada ou associada com amitriptilina. Foi também testado se melatonina melhoraria os sintomas clínicos como dor, limiar de dor à pressão e qualidade do sono relacionado à FM. Métodos: Foram selecionadas pacientes com diagnóstico de FM de acordo com o American College of Rheumatology (ACR) 2010. No primeiro estudo, de desenho transversal, foram incluídas 56 mulheres com FM, com idades entre 18 e 65 anos. Foram avaliados o limiar de dor à pressão e dosagem sérica de BDNF e S100B. No segundo estudo, foram incluídas 63 pacientes com os mesmos critérios de inclusão descritos no estudo transversal. As pacientes foram randomizadas e receberam, ao deitar, amitriptilina (25mg) (n=21), melatonina (10mg) (n=21) ou melatonina (10 mg) + amitriptilina (25mg) (n=21), durante seis semanas. O sistema modulatório descendente da dor foi acessado pela modulação condicionada da dor, através da mensuração da escala numérica de dor (NPS(0-10)) durante aferição do limiar de dor ao calor. Resultados: O resultado do estudo transversal mostrou que BDNF e S100B séricos foram correlacionados. BDNF e S100B foram inversamente correlacionados com limiar de dor à pressão. BDNF sérico foi associado com limiar de dor à pressão, idade e transtorno obsessivo compulsivo, enquanto que S100B sérica foi apenas associada com limiar de dor à pressão. O ensaio clínico randomizado demonstrou que a melatonina aumentou a potência do sistema modulatório da dor inibitório e que a modulação condicionada da dor foi negativamente correlacionada com BDNF sérico. Conclusões: Os estudos desta tese demonstram que S100B e BDNF, ambos mediadores chave no processo de sensibilização central, foram inversamente correlacionados com o limiar de dor à pressão. BDNF sérico foi, ainda, inversamente correlacionado com a redução da dor. Portanto, a avaliação sérica de BDNF e S100B merece estudos adicionais para determinar seu potencial papel sinalizador no espectro da sensibilização central nessa doença. / Introduction: Fibromyalgia (FM) is a syndrome of chronic diffuse musculoskeletal pain whose etiology is not fully known. This syndrome causes pain, mood swings and symptoms of rupture of the circadian rhythm. Its pathophysiological process involves an imbalance between excitatory and inhibitory pain modulatory systems. The ability of inhibitory systems is weakened, providing a framework of central sensitization, with dysfunction in the descending pain modulatory system, hyper-activation of neurons and neuroglia. Therefore, additional studies are needed to understand the possible relationship between serum markers of neuronal hyperactivity, such as Brain Derived Neurotrophic Factor (BDNF) and S100B. Particularly, studies seeking therapeutic options with effect in neurobiological alternative pathways such as melatonin, a indolamine with resynchronization, analgesic, and anti-inflammatory effects and actions on the modulatory pain systems such as GABAergic, opiodergic and glutamatergic. Objectives: 1) Primary: Evaluate whether the serum levels of BDNF and S100B have association with FM and if both serological mediators could be associated with pressure pain threshold. 2) Secondary: To test the hypothesis that treatment with melatonin alone or in combination with amitriptyline is better than amitriptyline alone to modify the endogenous pain modulatory system. Thus, to prove these hypothesis, it was quantified the conditioned pain modulation and serum BDNF levels in FM patients receiving treatment with melatonin alone or in combination with amitriptyline. Also, it was tested whether melatonin would improve clinical symptoms such as pain, pressure pain threshold and quality of sleep related to FM. Methods: Patients with FM according to the American College of Rheumatology (ACR) 2010 were selected. In the first study, a cross-sectional design, 56 women aging 18-65 years old, with FM were included. It was evaluated the pressure pain threshold, and serum levels of BDNF and S100B. In the second study, 63 patients were included with the same inclusion criteria described in the cross-sectional study. Patients were randomized and received at bedtime amitriptyline (25 mg) (n = 21), melatonin (10 mg) (n = 21) or melatonin (10 mg) + amitriptyline (25 mg) (n = 21) for six weeks. The descending pain modulatory system was accessed by the conditioned pain modulation, measuring the numerical pain scale [NPS (0-10)] during the heat pain threshold. Results: On the cross-sectional study serum BDNF and S100B were correlated. Serum BDNF and S100B were correlated with the pressure pain threshold. Serum BDNF was associated with pressure pain threshold, age and obsessive compulsive disorder, while serum S100B was associated with pressure pain threshold, only. The randomized clinical trial showed that melatonin increased the efficacy of inhibitory pain modulatory system and the conditioned pain modulation was negatively correlated with serum BDNF. Conclusions: The studies of this thesis show that both key mediators of the central sensitization process, BDNF and S100B, were inversely correlated with the pressure pain threshold. They also showed that melatonin increased the inhibitory pain modutalory system. Furthermore, it emphasizes that serum BDNF was inversely correlated with pain reduction. Therefore, assessment of serum BDNF and S100B deserve further studies to determine their potential as a proxy for the central sensitization spectrum in FM.

The doctoral dissertation: Searching for pathomechanisms of late-life minor depression – a combined MRI, biomarker and meta-analytic study was one of the first studies investigating the underlying pathophysiology of minor depression. The dissertation comprises a systematic review of the prevalence rates of minor depression, two meta-analyses of peripheral BDNF changes in major depressive disorder, as well as two original studies investigating serum BDNF, S100B and NSE levels and gray matter changes in minor depression. The limitations of studies and proposed improvements to the study design are discussed extensively.:1. INTRODUCTION 1.1 Motivation 1.1.1 Minor depression in the spectrum of psychiatric disorders 1.1.2 Minor depression is prevalent but unrecognized. 1.2 Theoretical background 1.2.1 Overview of depression hypotheses 1.2.2 Neurotrophic hypothesis of depressive disorders 1.2.3 Glial hypothesis of depressive disorders 1.2.4 Structural neuroimaging changes in major depression 1.3. Rationale and hypotheses of the empirical studies 1.3.1 Research questions 1.3.2 Research hypotheses 2. EMPIRICAL STUDIES 2.1 The prevalence of minor depression in the late life 2.2 The meta-analysis of BDNF changes in mood disorders 2.3 The meta-analysis of BDNF changes following ECT in depression 2.4 Serum biomarkers in minor depression 2.5 Structural brain imaging in minor depression 3. GENERAL DISCUSSION 3.1 Summary of results 3.2 Implications for research 3.3 Implications for clinical studies SUMMARY REFERENCES APPENDIX A: DECLARATION OF CONTRIBUTION APPENDIX B: STATEMENT OF AUTHORSHIP APPENDIX C: CURRICULUM VITAEAPPENDIX D: ACADEMIC CONTRIBUTIONS APPENDIX E: ACKNOWLEDGMENT

Tetrabromobisphenol-A (TBBPA) is the most widely used flame retardant. Flame retardants are sprayed on furniture, mattress beds, children’s pajamas, car seats, upholstery, carpets, and rugs in the United States. Chemical immune reactivity may play a role in the epidemic of autoimmune disease. The goal of this research is to investigate whether any correlation exists between immunological reactivity to TBBPA, a key chemical used in most flame retardants, and neurological autoimmune target sites that are associated with neurological autoimmune diseases with a diverse and specific list of antibodies that include myelin basic protein, myelin-associated glycoprotein, alpha-synuclein, aquaporin receptors, and S100B antibodies with human serum samples. The outcomes of this research can be used to support the development of safety regulations and for identifying potential health concerns for current mandatory flame-retardant legislation. Additionally, this research may support the decisions made in respect of those suffering from neurological autoimmune diseases, as to whether removing flame retardant chemicals is a factor for consideration.

Sharks often bioaccumulate mercury (Hg) concentrations in their muscle to levels that threaten the health of human consumers. However, few published studies have examined if the high Hg levels seen in shark muscle also occur in the shark brain, or if Hg accumulation affects shark neurophysiology. Therefore, this study examined if shark brains accumulate significant levels of Hg, if Hg accumulation occurs in certain subcomponents of the brain, and if Hg accumulation is associated with oxidative stress effects on the shark central nervous system, with special focus on the Atlantic sharpnose shark (Rhizoprionodon terraenovae). Sharks were collected along the U.S. Southeastern coast throughout most of the shark’s geographical range. Known biomarkers of Hg-induced neurological effects (markers of glial cell damage, S100b, and markers of oxidative stress) in the shark cerebrospinal fluid were examined. Brain Hg levels were correlated with muscle Hg levels, but were significantly lower and did not exceed most known thresholds for neurological effects, suggesting limited potential for such responses. Data on known biomarkers of Hg-induced neurological effects support this premise, because they were not correlated with brain Hg levels. Organic methylmercury did not compose of a high percentage of the total mercury in the brain, indicating demethylation of Hg is occurring in the brain. Higher Hg levels were measured in the forebrain of the shark in comparison with the midbrain and hindbrain, but levels in both were below threshold levels for effects. This study is the first to demonstrate the correlation and significant difference of Hg in the brain and muscle of sharks, and it identifies significantly higher Hg levels in the forebrain; making this study one of the most extensive analysis of Hg in a single shark species.