Immunoglobulin-mediated inhibition of amyloid fibril formation in vivo is a promising strategy for the treatment of protein misfolding diseases such as the amyloidoses. Here we focus on transthyretin amyloidoses, a group of protein conformation diseases caused by the misfolding of the serum protein transthyretin into fibrillar structures that deposit in specific organs and tissues—often with serious pathological consequences. Using a structure-guided immunological approach, we report a novel antibody that selectively recognizes monomeric, misfolded conformations of transthyretin in vitro. Raised to an epitope normally buried in the native form of transthyretin, this antibody was found to suppress transthyretin fibrillogenesis at substoichiometric concentrations in vitro. Overall, the selectivity and inhibitory nature of the antibody signals the potential use of conformation specific antibodies in the diagnosis and treatment of transthyretin amyloidoses, conditions which remain difficult to treat and are widely under/misdiagnosed at the current time.

Diabetes mellitus und seine Folgeerkrankungen haben aufgrund der hohen Prävalenz in der Bevölkerung eine starke medizinsche Relevanz. Dabei stellen die durch eine diabetische Neuropathie ausgelösten Schmerzen ein Herausforderung in der Schmerztherapie dar. Die Behandlung dieser Schmerzen mit TENS ist eine oft angewendete Therapieoption, welche jedoch in ihrer Wirksamkeit nicht ausreichend evidenzbasiert gesichert ist, da es methodenbedingt bei klinischen Studien zur Wirksamkeit der TENS-Therapie oft Zweifel an einer ausreichenden Verblindung gibt. Die vorliegende Studie untersuchte deshalb Mikro-TENS als Therapiealternative zur TENS-Behandlung im Rahmen einer einfach verblindeten, placebokontrollierten, klinischen Studie mit 41 Patienten. Die Placebokontrolle ist bei der Anwendung von Mikroreizstrom möglich, weil dieser unterhalb der Wahrnehmungsschwelle für sensible Nervenfasern liegt. Damit können die Patienten nicht zwischen MENS-Therapie und Placebo-Therapie unterscheiden. Die Diabetespatienten wurden über 4 Wochen in insgesamt 12 Sitzungen à 30 Minuten mit Mikro-TENS am distalen Fuß beidseits behandelt. Als Messgrößen dienten der PDI, der NPS, der ADS und die durchschnittliche Schmerzintensität auf einer numerischen Ratingskala von 0 bis 10. Diese Variablen wurden jeweils zu Beginn der Studie, direkt am letzten Behandlungstag und einen Monat nach der letzten Behandlung erhoben. Der PDI Score zeigte nach vierwöchiger Therapie eine durchschnittliche absolute Reduktion von 4,27 \\pm 4,17 in der Verum- und 3,79 \\pm 7,71 in der Placebogruppe. Eine mindestens 30 %ige Verbesserung des NPS- und PDI-Scores wurde als Ansprechen auf die Therapie gewertet. Insgesamt konnte bei circa 30 % der 40 Studienteilnehmer eine Therapieresponse festgestellt werden. Laut NPS sprachen nach vier Wochen Reizstromtherapie 6 von 22 Patienten in der Verumgruppe und 10 von 19 Patienten in der Placebogruppe auf die Therapie an. Die Unterschiede zwischen den Studiengruppen waren statistisch nicht signifikant. Letztlich konnte die Wirksamkeit von Mikroreizstromtherapie bei diabetischer Polyneuropathie nicht bestätigt werden. Mit einer größeren Fallzahl und damit größerer statistischer Power könnte möglicherweise ein geringer Unterschied im Therapieerfolg zwischen Placebo- und Verumbehandlung statistisch signifikant werden. Dieser Therapieeffekt wäre aber möglicherweise schmerztherapeutisch als nicht relevant einzuschätzen, da es sich mit 80 %iger Wahrscheinlichkeit (Power der vorliegenden Studie) um eine Reduktion von weniger als 15 Punkten im PDI handelt. Daher kann die Mikroreizstromtherapie zur symptomatischen Therapie bei schmerzhafter diabetischer Neuropathie (dPNP) nicht empfohlen werden. Auf die Wirksamkeit von TENS mit höheren Stromstärken zur Behandlung der dPNP kann anhand der vorliegenden Studie kein Rückschluß gezogen werden. Es profitieren dennoch circa 30 % der insgesamt 40 Studienteilnehmer von der Intervention. Da in der Schmerztherapie Ansprechraten auf eine Placebotherapie von 7 bis 49 % möglich sind, stellt TENS eine Möglichkeit dar, diesen Effekt zusätzlich mit relativ geringem Aufwand auszuschöpfen. Vorteile in der Therapie mit Reizstrom sind außerdem geringe Kosten, nahezu keine unerwünschten Nebenwirkungen und fast kein Vorliegen von Kontraindikationen. Damit ist diese zusätzliche Therapieoptionen der dPNP neben einer optimale Einstellung des Blutzuckers und einer medikamentösen Schmerztherapie nicht außer Acht zu lassen und die Wirksamkeit komplexer Therapieprogramme mit Langzeitreizstromtherapie sollte in weiteren kontrollierten klinischen Studien eruiert werden.

p. 1-68 / Submitted by Antonio Geraldo Couto Barreto (ppgms@ufba.br) on 2013-10-04T11:15:07Z No. of bitstreams: 1 TESE NEUROPATIA PERIFERICA NA DPI-GRACAS.pdf: 925860 bytes, checksum: accf87e5eb47a69b54a193d8b77c2a6b (MD5) / Approved for entry into archive by Patricia Barroso(pbarroso@ufba.br) on 2013-10-08T17:02:06Z (GMT) No. of bitstreams: 1 TESE NEUROPATIA PERIFERICA NA DPI-GRACAS.pdf: 925860 bytes, checksum: accf87e5eb47a69b54a193d8b77c2a6b (MD5) / Made available in DSpace on 2013-10-08T17:02:06Z (GMT). No. of bitstreams: 1 TESE NEUROPATIA PERIFERICA NA DPI-GRACAS.pdf: 925860 bytes, checksum: accf87e5eb47a69b54a193d8b77c2a6b (MD5) Previous issue date: 2013 / Palavras-chaves: 1.; 2.; 3.; 4.; 5..1.; 2.; 3.levodopa; 4., 5.homocysteine. / Indivíduos com doença de Parkinson idiopática (DPI) podem apresentar neuropatia periférica, o que pode agravar o desempenho motor. A causa da neuropatia periférica nesses pacientes é controversa. Objetivos- Identificar a prevalência de polineuropatia periférica (PNP) e os fatores que contribuem para seu surgimento na DPI. Métodos- Corte transversal com grupo controle. Foram avaliados 66 indivíduos: 36 com doença de Parkinson e 30 controles quanto à presença de polineuropatia pelos Escores de Toronto (ET), de Sintomas (ESN) e de Comprometimento Neuropáticos (ECN), e pela Eletroneuromiografia (EMG). Investigou-se a possível associação entre níveis séricos aumentados de homocisteína (HCI), hipovitaminose B12 (VB12), e diminuição de ácido fólico no soro, uso da levodopa, a gravidade da doença de Parkinson e a PNP. Resultados- O grupo Parkinson foi composto por 16M/20F [idade 69,4±6,8 anos] e os controles por 12M/18F[idade 70,5±6,1 anos]. A maioria dos participantes apresentou escores clínicos sugestivos de neuropatia, ET [controles 3,8±2,6; DPI 5,3±1,8, p=0,012], ECN [controles 3,0±2,3; DPI 4,2±1,7, p=0,026], alterações neuropáticas no estudo condução nervosa sensitiva e motora dos nervos sural e fibular ocorreu em 3% dos controles e em 8% dos pacientes com DPI. Embora a HCI tenha sido mais alta nos DPI, a diferença não foi significante [DPI 16,01±6,88 mmol/L; controles 14,68±5,77 mmol/L, p=0,403]; níveis baixos de VB12 foram mais frequentes nos controles 30% vs 19,4%, p=0,961. Não houve associação entre as dosagens bioquímicas (coef.associação= 0,30), nem entre o uso de levodopa (Phi= 0,533) e a PNP, que esteve associada a DPI (RC=2,64). Conclusão- Na nossa amostra, os escores neuropáticos foram mais altos entre os portadores de DPI e não esteve associado ao uso da levodopa nem a hiperhomocisteinemia e/ou deficiência da vitamina B12. / Salvador

Introdução: As polineuropatias periféricas (PNP) relacionadas ao diabetes têm sido descritas em associação com fatores causais como obesidade, hipertrigliceridemia, hipertensão arterial sistêmica (HAS) e síndrome metabólica (SM), alterações que frequentemente precedem o diabetes. Objetivo: Avaliar a prevalência da PNP em indivíduos obesos graus 2 e 3 com SM sem diabetes e buscar possíveis fatores associados. Métodos: Em um estudo transversal, realizado em indivíduos obesos graus 2 e 3 com SM e sem diagnóstico de diabetes, o Michigan Neuropathy Screening Instrument (MNSI) foi utilizado para avaliar a presença de PNP. Resultados: Um total de 46 de 218 pacientes obesos graus 2 e 3 com SM e sem diabetes tinham PNP. Das variáveis estudadas, HAS (p=0.003), pressão arterial média (PAM) (p<0.001), baixo HDL-colesterol (p=0.011), níveis séricos de HDL-colesterol (p=0.048), IMC (p=0.036) e circunferência da cintura (p=0.035) mostraram-se significativamente associados com PNP. Houve uma tendência para os níveis séricos de triglicerídeos (p=0.107) se associarem com a presença de PNP. Após regressão multivariada, HAS, baixo HDLcolesterol, IMC e circunferência da cintura mantiveram-se independentemente associados. Conclusão: Baixos níveis de HDL-colesterol, hipertensão e aumento do IMC e da circunferência da cintura estão associados com PNP definido pelo MNSI em pacientes com obesidade severa e SM mas sem diabetes. / Introduction: Peripheral polyneuropathy (PPN) related to diabetes has been reported in association with causal factors such as obesity, hypertriglyceridemia, systemic arterial hypertension (SAH) and metabolic syndrome (MS), changes which frequently precede diabetes. Objective: To evaluate the prevalence of PPN in subjects with grade 2 and 3 obesity with MS without diabetes and to investigate for possible associating factors. Methods: A cross-sectional study performed with grade 2 and 3 obese subjects with MS and without a diagnosis of diabetes using the Michigan Neuropathy Screening Instrument (MNSI) to assess the presence of PPN. Results: A total of 46 of 218 obese patients grade 2 and 3 with MS and without diabetes had PPN. From the variables studied, SAH (p=0.003), mean blood pressure (MBP) (p<0.001), low HDL-cholesterol (p=0.011), serum levels of HDL-cholesterol (p=0.048), BMI (p=0.036) and waist circumference (p=0.035) were significantly associated with PPN. There was a tendency for serum triglyceride levels (p=0.107) to associate with the presence of PPN. After multivariate regression, SAH, low HDL-cholesterol, BMI and waist circumference remained independently associated. Conclusion: Low levels of HDL-cholesterol, hypertension and increase of BMI and waist circumference are associated with PPN defined by the MNSI in patients with severe obesity and MS but without diabetes.

Introdução: A polineuromiopatia do doente crítico (PNMDC) é uma freqüente complicação neuromuscular adquirida na Unidade de Terapia Intensiva (UTI). O principal fator de risco está relacionado à sepse e à disfunção de múltiplos órgãos sendo que sua incidência pode variar entre 50 a 100%. A confirmação do diagnóstico é feita pela eletroneuromiografia, porém sugere-se que as características clínicas (fraqueza muscular, alterações sensoriais e de reflexos e dificuldade de desmame da ventilação mecânica) possam ser suficientes para o diagnóstico clínico. Objetivo: Identificar sinais clínicos que possam ser utilizados como marcadores para auxiliar no diagnóstico de PNMDC à beira do leito em pacientes sépticos. Resultados: Cinquenta pacientes foram avaliados e divididos em dois grupos conforme o resultado da eletroneuromiografia (PNMDC e não PNMDC). Os pacientes com PNMDC tinham idade maior e eram mais graves (APACHE IV e SAPS 3), permaneceram maior período hospitalizados e necessitaram de suporte ventilatório por mais tempo. Os pontos de corte: <40 para escore Medical Research Council (MRC); <7 kg para dinamometria em homens e <4 kg em mulheres; <34 cmH2O para pressão expiratória máxima e >-40 cmH2O para pressão inspiratória máxima conseguiram identificar com bons níveis de sensibilidade e de especificidade os pacientes com PNMDC. Conclusões: A força muscular esquelética pelo escore MRC, dinamometria e pressões respiratórias máximas é uma método simples que permite a identificação de PNMDC em uma avaliação clínica à beira do leito. / Introduction: Critical illness polyneuromyopathy (CIPNM) is a frequent acquired neuromuscular complication in the Intensive Care Units (ICU). The main risk factor is related to sepsis and multiple organs dysfunction and the incidence of this disorder can reach 50-100%. The diagnosis is made by electromyography, but it is suggested that the clinical features (muscle weakness, sensory and reflexes changes and difficulty in weaning patients from mechanical ventilation) may be sufficient for clinical diagnosis. Objective: To identify clinical signs that may be used as markers to help in the bedside diagnosis of CIPNM in septic patients. Results: Fifty patients were evaluated and divided into two groups according to the results of electromyography (CIPNM and non-CIPNM). The patients with CIPNM were older, showed more severe illness (Apache IV and Saps 3), remained hospitalized for longer period of time, and required longer period of ventilatory support than non-CIPNM. The cutoffs that could identify the patients with CIPNM with good levels of sensitivity and specificity were: Medical Research Council (MRC) score <40; dynamometry <7 kg for men and <4 kg for women, maximal expiratory pressure (MEP) <34 cmH2O and maximal inspiratory pressure (MIP) > -40 cmH2O . Conclusions: The assessment of skeletal muscle strength by MRC score, dynamometry and maximum respiratory pressure is a simple method that allows the diagnosis of CIPNM through a clinical examination at the bedside.

Introdução: A polineuromiopatia do doente crítico (PNMDC) é uma freqüente complicação neuromuscular adquirida na Unidade de Terapia Intensiva (UTI). O principal fator de risco está relacionado à sepse e à disfunção de múltiplos órgãos sendo que sua incidência pode variar entre 50 a 100%. A confirmação do diagnóstico é feita pela eletroneuromiografia, porém sugere-se que as características clínicas (fraqueza muscular, alterações sensoriais e de reflexos e dificuldade de desmame da ventilação mecânica) possam ser suficientes para o diagnóstico clínico. Objetivo: Identificar sinais clínicos que possam ser utilizados como marcadores para auxiliar no diagnóstico de PNMDC à beira do leito em pacientes sépticos. Resultados: Cinquenta pacientes foram avaliados e divididos em dois grupos conforme o resultado da eletroneuromiografia (PNMDC e não PNMDC). Os pacientes com PNMDC tinham idade maior e eram mais graves (APACHE IV e SAPS 3), permaneceram maior período hospitalizados e necessitaram de suporte ventilatório por mais tempo. Os pontos de corte: <40 para escore Medical Research Council (MRC); <7 kg para dinamometria em homens e <4 kg em mulheres; <34 cmH2O para pressão expiratória máxima e >-40 cmH2O para pressão inspiratória máxima conseguiram identificar com bons níveis de sensibilidade e de especificidade os pacientes com PNMDC. Conclusões: A força muscular esquelética pelo escore MRC, dinamometria e pressões respiratórias máximas é uma método simples que permite a identificação de PNMDC em uma avaliação clínica à beira do leito. / Introduction: Critical illness polyneuromyopathy (CIPNM) is a frequent acquired neuromuscular complication in the Intensive Care Units (ICU). The main risk factor is related to sepsis and multiple organs dysfunction and the incidence of this disorder can reach 50-100%. The diagnosis is made by electromyography, but it is suggested that the clinical features (muscle weakness, sensory and reflexes changes and difficulty in weaning patients from mechanical ventilation) may be sufficient for clinical diagnosis. Objective: To identify clinical signs that may be used as markers to help in the bedside diagnosis of CIPNM in septic patients. Results: Fifty patients were evaluated and divided into two groups according to the results of electromyography (CIPNM and non-CIPNM). The patients with CIPNM were older, showed more severe illness (Apache IV and Saps 3), remained hospitalized for longer period of time, and required longer period of ventilatory support than non-CIPNM. The cutoffs that could identify the patients with CIPNM with good levels of sensitivity and specificity were: Medical Research Council (MRC) score <40; dynamometry <7 kg for men and <4 kg for women, maximal expiratory pressure (MEP) <34 cmH2O and maximal inspiratory pressure (MIP) > -40 cmH2O . Conclusions: The assessment of skeletal muscle strength by MRC score, dynamometry and maximum respiratory pressure is a simple method that allows the diagnosis of CIPNM through a clinical examination at the bedside.

Introdução: As polineuropatias periféricas (PNP) relacionadas ao diabetes têm sido descritas em associação com fatores causais como obesidade, hipertrigliceridemia, hipertensão arterial sistêmica (HAS) e síndrome metabólica (SM), alterações que frequentemente precedem o diabetes. Objetivo: Avaliar a prevalência da PNP em indivíduos obesos graus 2 e 3 com SM sem diabetes e buscar possíveis fatores associados. Métodos: Em um estudo transversal, realizado em indivíduos obesos graus 2 e 3 com SM e sem diagnóstico de diabetes, o Michigan Neuropathy Screening Instrument (MNSI) foi utilizado para avaliar a presença de PNP. Resultados: Um total de 46 de 218 pacientes obesos graus 2 e 3 com SM e sem diabetes tinham PNP. Das variáveis estudadas, HAS (p=0.003), pressão arterial média (PAM) (p<0.001), baixo HDL-colesterol (p=0.011), níveis séricos de HDL-colesterol (p=0.048), IMC (p=0.036) e circunferência da cintura (p=0.035) mostraram-se significativamente associados com PNP. Houve uma tendência para os níveis séricos de triglicerídeos (p=0.107) se associarem com a presença de PNP. Após regressão multivariada, HAS, baixo HDLcolesterol, IMC e circunferência da cintura mantiveram-se independentemente associados. Conclusão: Baixos níveis de HDL-colesterol, hipertensão e aumento do IMC e da circunferência da cintura estão associados com PNP definido pelo MNSI em pacientes com obesidade severa e SM mas sem diabetes. / Introduction: Peripheral polyneuropathy (PPN) related to diabetes has been reported in association with causal factors such as obesity, hypertriglyceridemia, systemic arterial hypertension (SAH) and metabolic syndrome (MS), changes which frequently precede diabetes. Objective: To evaluate the prevalence of PPN in subjects with grade 2 and 3 obesity with MS without diabetes and to investigate for possible associating factors. Methods: A cross-sectional study performed with grade 2 and 3 obese subjects with MS and without a diagnosis of diabetes using the Michigan Neuropathy Screening Instrument (MNSI) to assess the presence of PPN. Results: A total of 46 of 218 obese patients grade 2 and 3 with MS and without diabetes had PPN. From the variables studied, SAH (p=0.003), mean blood pressure (MBP) (p<0.001), low HDL-cholesterol (p=0.011), serum levels of HDL-cholesterol (p=0.048), BMI (p=0.036) and waist circumference (p=0.035) were significantly associated with PPN. There was a tendency for serum triglyceride levels (p=0.107) to associate with the presence of PPN. After multivariate regression, SAH, low HDL-cholesterol, BMI and waist circumference remained independently associated. Conclusion: Low levels of HDL-cholesterol, hypertension and increase of BMI and waist circumference are associated with PPN defined by the MNSI in patients with severe obesity and MS but without diabetes.

Introdução: As polineuropatias periféricas (PNP) relacionadas ao diabetes têm sido descritas em associação com fatores causais como obesidade, hipertrigliceridemia, hipertensão arterial sistêmica (HAS) e síndrome metabólica (SM), alterações que frequentemente precedem o diabetes. Objetivo: Avaliar a prevalência da PNP em indivíduos obesos graus 2 e 3 com SM sem diabetes e buscar possíveis fatores associados. Métodos: Em um estudo transversal, realizado em indivíduos obesos graus 2 e 3 com SM e sem diagnóstico de diabetes, o Michigan Neuropathy Screening Instrument (MNSI) foi utilizado para avaliar a presença de PNP. Resultados: Um total de 46 de 218 pacientes obesos graus 2 e 3 com SM e sem diabetes tinham PNP. Das variáveis estudadas, HAS (p=0.003), pressão arterial média (PAM) (p<0.001), baixo HDL-colesterol (p=0.011), níveis séricos de HDL-colesterol (p=0.048), IMC (p=0.036) e circunferência da cintura (p=0.035) mostraram-se significativamente associados com PNP. Houve uma tendência para os níveis séricos de triglicerídeos (p=0.107) se associarem com a presença de PNP. Após regressão multivariada, HAS, baixo HDLcolesterol, IMC e circunferência da cintura mantiveram-se independentemente associados. Conclusão: Baixos níveis de HDL-colesterol, hipertensão e aumento do IMC e da circunferência da cintura estão associados com PNP definido pelo MNSI em pacientes com obesidade severa e SM mas sem diabetes. / Introduction: Peripheral polyneuropathy (PPN) related to diabetes has been reported in association with causal factors such as obesity, hypertriglyceridemia, systemic arterial hypertension (SAH) and metabolic syndrome (MS), changes which frequently precede diabetes. Objective: To evaluate the prevalence of PPN in subjects with grade 2 and 3 obesity with MS without diabetes and to investigate for possible associating factors. Methods: A cross-sectional study performed with grade 2 and 3 obese subjects with MS and without a diagnosis of diabetes using the Michigan Neuropathy Screening Instrument (MNSI) to assess the presence of PPN. Results: A total of 46 of 218 obese patients grade 2 and 3 with MS and without diabetes had PPN. From the variables studied, SAH (p=0.003), mean blood pressure (MBP) (p<0.001), low HDL-cholesterol (p=0.011), serum levels of HDL-cholesterol (p=0.048), BMI (p=0.036) and waist circumference (p=0.035) were significantly associated with PPN. There was a tendency for serum triglyceride levels (p=0.107) to associate with the presence of PPN. After multivariate regression, SAH, low HDL-cholesterol, BMI and waist circumference remained independently associated. Conclusion: Low levels of HDL-cholesterol, hypertension and increase of BMI and waist circumference are associated with PPN defined by the MNSI in patients with severe obesity and MS but without diabetes.

Chemotherapy Induced Peripheral Neuropathy (CIPN) is a common problem among cancer patients who receive a wide range of chemotherapy. This problem causes a decline in quality of life and increased disabilities. CIPN assessment instruments are either subjective, objective, or a combination of both. So far, there is no agreement on the best way for assessment. The goal of this study was to explore the relationships among subjective and objective CIPN assessment instruments. Specifically, this study aimed to 1) evaluate the relationship between the Total Neuropathy Score-reduced (mainly objective) and patients’ function, as measured by the interference scale of the Chemotherapy-Induced Peripheral Neuropathy Assessment Tool (subjective); and 2) evaluate the relationship between the Total Neuropathy Score-reduced and neuropathy symptom experience, as measured by the symptom experience scale of the Chemotherapy-Induced Peripheral Neuropathy Assessment Tool (Subjective). To achieve those aims, a secondary data analysis for 56 participants who participated in a study entitled: Group Acupuncture for Treatment of Neuropathy from Chemotherapy was done. After Pearson correlations were calculated, the study found that there is a positive, weak relationship between the TNSr and the symptom experience scale of the CIPNAT(r=0.34). A positive, week relationship was found between the TNSr and the interference with activity scale of the CIPNAT(r=0.28). These results suggest that objective and subjective assessment are not highly correlated, and likely measure different aspects of CIPN. A comprehensive assessment approach is needed for decision making in the clinical oncology setting.

Title: Evaluation of selected postural stability parameters of diabetic patients Objectives: The main objective of this thesis is to describe the level of postural stability using the selected parameters in diabetes mellitus type 2 and to try to find a relationship between the severity of disease. We also want to compare the level of postural stability for such an illness with respect to the values of selected parameters of the healthy population. Methods: It is a descriptive study. The theoretical part was the basis of the processing problems of diabetes mellitus, with a focus on neuropathy. After that we evaluate data of selected parameters of postural stability in diabetes mellitus type 2. The second part involves the experiment, which refers to the evaluation of this issue in terms of posturographic analysis. A group of 30 type 2 diabetic patients were divided according to their diabetologist disease severity into 4 groups. A control group of healthy subjects included a sample of 7 probands. The patient group was composed of 18 men and 12 women, whose average age was 62.63 ± 15.55 years, average weight 91.17 ± 19.97 kg, who were subjected to measurement using a pressure plate FootScan (RScan International, Belgium). Results: We managed to prove, that subjects with diabetic neuropathy have...