Objectives: The incidence of type 2 diabetes mellitus (DM2) is on the rise worldwide. The primary objective was to determine the prevalence of nutrient inadequacy and excessiveness in persons with DM2 with and without diabetic peripheral neuropathy (DPN). Study Design: A validated semi-quantitative food frequency questionnaire was used to determine the prevalence of inadequacy of nutrients with an estimated average requirement; the mean intake of nutrients with an adequate intake; and the proportion of persons not meeting the recommendations for the acceptable macronutrient distribution range (AMDR). Results: Differences were observed in the prevalence of inadequacy of vitamin A and the proportion of persons not meeting the AMDR for total fat, linoleic acid and carbohydrate. Conclusion: The aforementioned nutrients may have a significant role in the progression/development of DPN and should be studied in further detail. We recommend a balanced diet and use of a multi-vitamin for persons with DM2.

In diabetes hyperglycemia and lack of insulin signaling are key factors in the induction of diabetic sensory neuropathy. The combination of these factors in diabetes may enhance oxidative stress and trigger distal nerve damage in the peripheral nervous system. The link between elevated reactive oxygen species (ROS) levels and nerve degeneration is not clear. We tested the hypothesis that elevation of 4-hydroxy-2-nonenal (4-HNE) induced by oxidative stress in diabetes impairs mitochondrial activity and axonal regeneration in dorsal root ganglion (DRG) neurons. Also, we investigated the association between mitochondrial dysfunction and altered mitochondrial proteome in the axons of streptozotocin–induced diabetic rats. Research design and methods. Cultured adult rat DRG sensory neurons were treated exogenously with 4-HNE, and cell survival, axonal morphology, and level of axon outgrowth assessed. Western blot and fluorescence imaging were used to determine changes in the levels of adducts of 4-HNE and abnormalities in the mitochondria. Proteomic analysis using stable isotope labeling with amino acids in cell culture (SILAC) determined expression of proteins in the mitochondria. Results. 4-HNE impaired axonal regeneration, mitochondrial activity and induced aberrant axonal structures along the axons, which mimicked axon pathology observed in nerve isolated from diabetic rats and replicated aspects of neurodegeneration observed in human diabetic neuropathy. Proteins associated with mitochondrial dysfunction, oxidative phosphorylation and biosynthesis were down regulated in diabetic samples. The axons of diabetic neurons exhibited oxidative stress and depolarized mitochondria. CNTF and resveratrol reversed abnormalities in the mitochondrial membrane potential induced by diabetes and treatment of neurons with 4-HNE. CONCLUSIONS. Elevation of 4-HNE levels in diabetes was associated with impaired mitochondrial function and might be an important link between increased ROS levels and nerve degeneration in diabetic neuropathy. Abnormal mitochondrial function correlated with a down-regulation of mitochondrial proteins, with components of the respiratory chain targeted in lumbar DRG in diabetes. The reduced activity of the respiratory chain was associated with diminished superoxide generation within the mitochondrial matrix and did not contribute to oxidative stress in axons of diabetic neurons.

There remains a high degree of scepticism about acupuncture since its theoretical basis has no clear reference in Western medical and scientific terms, making any associations between neurophysiology and specific acupuncture concepts difficult to determine. Using neuroimaging and engineering approaches to understand its physiological basis may engender greater acceptance of and improvement in the clinical application of acupuncture. Research into the efficacy of acupuncture has raised a number of difficult methodological issues, particularly in relation to the selection of appropriate controls. Separating specific effects from non-specific effects is complex because acupuncture is a physical, invasive, manual procedure involving time and ritual. Sham acupuncture results show only the difference between sham and real acupuncture not the real affect of acupuncture, and other controls may produce distinct subjective and objective effects. Point injection (the injection of a small amount of a substance at an acupoint), a recent innovation of traditional acupuncture, aims to enhance and prolong the stimulation effect in a standardised, reproducible manner. By providing precise, measurable acupoint stimulation applied incrementally in a specifically designed paradigm, an acupoint could act as its own control. This firstly requires injection to be validated against traditional needling. Aims 1. To develop an instrument for reproducible saline delivery at an acupoint. 2. To cross-validate saline acupoint injection (PI) with traditional needle acupuncture (TA). 3. To demonstrate central nervous system (CNS) effects of acupuncture both in health and chronic pain. Hypothesis The primary hypothesis is that stimulation of specific acupoints with linearly incremental saline injection produces differential effects within the CNS observable with functional magnetic resonance imaging (fMRI) allowing investigation of acupuncture in health and chronic pain. Novelty As neuroimaging has not yet clearly defined the brain structures that may be modulated by acupuncture, this project is exploratory in nature. It is expected that acupuncture effects can be robustly imaged with fMRI in healthy subjects and those suffering chronic pain. The demonstrated effects will result from the acupuncture process of progressive point stimulation by tissue distension rather than needle insertion or biological noise. It is proposed to examine the putative modulation of pain by acupuncture within the extensively mapped neuromatrix of cortical and subcortical regions, including the somatic, insula, and limbic cortices, and thalamus. Detailed information regarding differences in brain response between acupuncture in normal and diseased states will expand understanding of acupuncture as a clinical tool. The dilemma of sham stimulation or arbitrary controls will be addressed by confirming PI as a valid, reproducible stimulation method. Methods and Results A series of empirical experiments was designed and conducted to determine the effects of stimulation of different acupoints. 1. Chapters 1 and 3 outline the current understanding of acupuncture in the Western milieu and a review of the neuroimaging literature respectively. 2. In Chapter 2, the report of PI tested against TA in healthy volunteers to determine equivalence of physiological effect demonstrates no statistically significant differences between the methodologies. 3. Chapter 4 reports the design and validation of a task specific microprocessor controlled syringe driver. 4. Four differing acupoints were tested during an fMRI experiment described in Chapter 5; different activation areas were demonstrated across the acupoints providing early support for the hypothesis that different acupoints may have different effects. A subset of brain areas recognised within the pain neuromatrix was delineated, congruent spatially and directionally with those reported in pharmacological analgesia studies. 5. As outlined in Chapter 6, heart rate variability can be measured rapidly in a stressful environment to provide meaningful data on the response of the autonomic nervous system to acupuncture stimulation. 6. The hypothesis of different acupoints having different effects was tested in subjects suffering chronic pain by contrasting an accepted and a neutral acupoint, the results being reported in Chapter 7. Conclusion Despite a long history of clinical usage, appropriate scientific studies have not yet addressed the basic effectiveness and efficacy of acupuncture. This thesis presents a series of empirical studies designed to address a number of the questions arising in the literature and provides converging evidence of the manner in which different acupoints modulate the CNS, specifically within the pain neuromatrix.

There remains a high degree of scepticism about acupuncture since its theoretical basis has no clear reference in Western medical and scientific terms, making any associations between neurophysiology and specific acupuncture concepts difficult to determine. Using neuroimaging and engineering approaches to understand its physiological basis may engender greater acceptance of and improvement in the clinical application of acupuncture. Research into the efficacy of acupuncture has raised a number of difficult methodological issues, particularly in relation to the selection of appropriate controls. Separating specific effects from non-specific effects is complex because acupuncture is a physical, invasive, manual procedure involving time and ritual. Sham acupuncture results show only the difference between sham and real acupuncture not the real affect of acupuncture, and other controls may produce distinct subjective and objective effects. Point injection (the injection of a small amount of a substance at an acupoint), a recent innovation of traditional acupuncture, aims to enhance and prolong the stimulation effect in a standardised, reproducible manner. By providing precise, measurable acupoint stimulation applied incrementally in a specifically designed paradigm, an acupoint could act as its own control. This firstly requires injection to be validated against traditional needling. Aims 1. To develop an instrument for reproducible saline delivery at an acupoint. 2. To cross-validate saline acupoint injection (PI) with traditional needle acupuncture (TA). 3. To demonstrate central nervous system (CNS) effects of acupuncture both in health and chronic pain. Hypothesis The primary hypothesis is that stimulation of specific acupoints with linearly incremental saline injection produces differential effects within the CNS observable with functional magnetic resonance imaging (fMRI) allowing investigation of acupuncture in health and chronic pain. Novelty As neuroimaging has not yet clearly defined the brain structures that may be modulated by acupuncture, this project is exploratory in nature. It is expected that acupuncture effects can be robustly imaged with fMRI in healthy subjects and those suffering chronic pain. The demonstrated effects will result from the acupuncture process of progressive point stimulation by tissue distension rather than needle insertion or biological noise. It is proposed to examine the putative modulation of pain by acupuncture within the extensively mapped neuromatrix of cortical and subcortical regions, including the somatic, insula, and limbic cortices, and thalamus. Detailed information regarding differences in brain response between acupuncture in normal and diseased states will expand understanding of acupuncture as a clinical tool. The dilemma of sham stimulation or arbitrary controls will be addressed by confirming PI as a valid, reproducible stimulation method. Methods and Results A series of empirical experiments was designed and conducted to determine the effects of stimulation of different acupoints. 1. Chapters 1 and 3 outline the current understanding of acupuncture in the Western milieu and a review of the neuroimaging literature respectively. 2. In Chapter 2, the report of PI tested against TA in healthy volunteers to determine equivalence of physiological effect demonstrates no statistically significant differences between the methodologies. 3. Chapter 4 reports the design and validation of a task specific microprocessor controlled syringe driver. 4. Four differing acupoints were tested during an fMRI experiment described in Chapter 5; different activation areas were demonstrated across the acupoints providing early support for the hypothesis that different acupoints may have different effects. A subset of brain areas recognised within the pain neuromatrix was delineated, congruent spatially and directionally with those reported in pharmacological analgesia studies. 5. As outlined in Chapter 6, heart rate variability can be measured rapidly in a stressful environment to provide meaningful data on the response of the autonomic nervous system to acupuncture stimulation. 6. The hypothesis of different acupoints having different effects was tested in subjects suffering chronic pain by contrasting an accepted and a neutral acupoint, the results being reported in Chapter 7. Conclusion Despite a long history of clinical usage, appropriate scientific studies have not yet addressed the basic effectiveness and efficacy of acupuncture. This thesis presents a series of empirical studies designed to address a number of the questions arising in the literature and provides converging evidence of the manner in which different acupoints modulate the CNS, specifically within the pain neuromatrix.

Doctor of Philosophy / Abstract Neurodegenerative disorders are a diverse group of disorders that affect specific subsets of neurons. Motor neuron diseases, neurodegenerative disorders of motor neurons, are seen commonly as sporadic cases and less frequently as familial disease forms. The familial forms show genetic and phenotypic heterogeneity. Clinically motor neuron diseases may be seen as rapidly progressive disorders like amyotrophic lateral sclerosis, ALS or slowly progressive disorders like hereditary motor neuropathies, HMN. The only proven causes for motor neuron diseases are gene mutations that lead to motor neuron degeneration in familial disease forms. Only some of these genes have been identified and have contributed greatly to our understanding of the neurobiology of familial and sporadic disease forms. Identification of additional disease causing genes would help enhance our knowledge of the pathophysiological mechanisms underlying all forms of motor neuron disorders, which would lead to early diagnoses, effective prophylaxis and efficient therapies for these disorders. This study aimed to find gene mutations that cause rapid and slowly progressive familial motor neuron disorders in Australian families and to determine their relevance to sporadic forms of motor neuron disease. The familial forms of ALS show reduced disease penetrance, that is, not all gene mutation carriers manifest the disease. This study examines ALS penetrance in a group of Australian families. The most frequently observed mutations in ALS families are cytosolic superoxide dismutase/SOD1 gene mutations. In a collection of ALS families in our centre, families without the common SOD1 gene mutations were genotyped for other ALS genes and loci and studied using genetic linkage and haplotype analyses. Studies in a large Australian ALS family further confirmed genetic heterogeneity in non-SOD familial ALS, all known autosomal dominant ALS genes and chromosomal loci were excluded as cause of disease in this family. Such families can be studied further to identify additional disease genes and loci mapped in other ALS families. These families represent powerful resources for identification of additional ALS genes. Identifying the pathogenic genes in families with reduced disease penetrance may be more relevant to sporadic forms of disease. dHMN is a chronic neurodegenerative disorder predominantly affecting motor neurons. In a large Australian dHMN family, all the known dHMN genes and chromosomal loci were excluded as cause of disease. A genome wide microsatellite screen was performed in this family and genetic linkage was established to a novel 12.98 Mb locus on chromosome 7q34.2-q36. Candidate genes in this large interval will be screened based on their function and expression profile. Identification of a new dHMN locus provides the basis for future identification of a novel gene involved in motor neuron degeneration. Genes in dHMN have been shown to be pathogenic in ALS and Charcot Marie Tooth syndromes. The new locus for dHMN mapped in this project would lead to identification of a novel dHMN gene, which may elucidate the pathogenesis underlying a wide range of neurodegenerative disorders.

[Truncated abstract] Hereditary Motor and Sensory Neuropathy Lom (HMSNL) is a severe autosomal recessive peripheral neuropathy, the most common form of demyelinating Charcot-Marie-Tooth (CMT) disease in the Roma (Gypsy) population. The mutated gene, N-myc downstream-regulated gene 1 (NDRG1) on chromosome 8q24, is widely expressed and has been implicated in a wide range of processes and pathways. In this study we have aimed to assess the overall contribution of this gene to the pathogenesis of peripheral neuropathies, in cases where the most common causes of CMT disease havebeen excluded, as well as to gain clues about its function through the identification of its interactions with other proteins. Sequence analysis of NDRG1 in 104 patients with CMT disease and of diverse ethnicity identified one novel disease-causing mutation, IVS8-1G>A (g.2290787G>A), which affects the splice-acceptor site of IVS8 and results in the skipping of exon 9 . . . The results suggest a defect in Schwann cell lipid trafficking as a major pathogenetic mechanism in CMT4D. At the same time, database searches showed that the chromosomal location of NDRG1 coincides with a reported High-Density Lipoprotein-Cholesterol Quantitive Trait Locus (HDL-CQTL) in humans and in mice. A putative role of NDRG1 in the general mechanisms of HDL-mediated cholesterol transport was supported by biochemical studies of blood lipids, which revealed an association between the Gypsy founder mutation, R148X, and decreased HDL-C levels. These findings suggest that while peripheral neuropathy is the drastic result of NDRG1 deficiency, the primary role of the protein may be related to general mechanisms of lipid transport⁄metabolism.

by Zsolt Laszlo Kovacs. / Bibliography: p. 175-184. / Originally presented as the author's thesis, (Ph.D.) in the M.I.T. Dept. of Electrical Engineering and Computer Science, 1977. Partial support provided by the Funda? de Amparo a Pesquisa do Estado de S?Paulo, Brazil and by the National Science Foundation Grant no. NSF/ENG-7705200.

Objetivos/Hipótese: A Piridostigmina bloqueia a acetilcolinesterase, promove estimulação colinérgica e aumenta a variabilidade da freqüência cardíaca (VFC) em indivíduos saudáveis e com insuficiência cardíaca. Os efeitos sobre a modulação autonômica no diabetes mellitus tipo 2 (DM2) são desconhecidos. Nós testamos a hipótese de que a administração de piridostigmina aumenta a VFC em pacientes com DM2 e neuropatia autonômica cardiovascular (NAC). Métodos: Estudamos 34 pacientes com DM2 e NAC com idade entre 30 e 70 anos. Dezessete receberam 30 mg de piridostigmina via oral, de 8/8h por 24h (PI) e 17 receberam placebo (PL). A VFC foi avaliada pela média (RRMed) e desvio padrão dos intervalos RR (SDNN), pela raiz quadrada da média das diferenças sucessivas entre intervalos RR (RMSSD) e pelos índices do Mapa de Retorno Tridimensional P1, P2, P3 e MN. Resultados: Não houve diferenças significativas entre os grupos PI e PL quanto às características clínicas basais e à VFC sob efeito de piridostigmina e PL (RRMed - 748 ± 99 vs 733 ± 111ms; SDNN - 107 ± 26 vs 108 ± 36ms; RRMSD - 20,7 ± 12,7 vs 20,3 ± 10ms; P1 - 63 ± 11 vs 69 ± 14; P2 - 66 ±13 vs 63 ± 15; P3 - 86 ± 34 vs 80 ± 24 e MN - 392 ± 241 vs 369 ± 185). Conclusão: A piridostigmina não modifica a VFC em pacientes com DM2 e NAC. / Aims/Hypothesis: Pyridostigmine blocks acetylcholinesterase, promotes cholinergic stimulation and increases heart rate variability (HRV) in healthy individuals and with cardiac heart failure. The effects on the autonomic modulation in diabetes mellitus type 2 (DM2) are unknown. We have tested the hypothesis that the administration of pyridostigmine increases HRV in DM2 and CAN patients (CAN). Methods: We have studied 34 DM2 and CAN patients aged between 30 and 70 years old. Seventeen received 30mg of pyridostigmine via oral administration, every 8 hours during 24 hours (PY) and 17 received placebo (PL). HRV was assessed by the mean of all normal R-R intervals RR (mean RR) and the standard deviation of all normal R-R intervals (SDNN), by the root-mean-square of successive differences (RMSSD) and by the three-dimensional return map indices P1, P2, P3 and MN. Results: There were no significant differences between the PY and PL groups as to the baseline clinical characteristics and to HRV under the effect of pyridostigmine and PL (mean RR - 748 ± 99 vs 733 ± 111ms; SDNN - 107 ± 26 vs 108 ± 36ms; RRMSD - 20,7 ± 12,7 vs 20,3 ± 10ms; P1 - 63 ± 11 vs 69 ± 14; P2 - 66 ±13 vs 63 ± 15; P3 - 86 ± 34 vs 80 ± 24 e MN - 392 ± 241 vs 369 ± 185). Conclusion: Pyridostigmine does not modify HRV in DM2 and CAN patients.

Charles University Faculty of Pharmacy in Hradec Králové Department of Pharmacology and Toxicology Student: Simona Benčová Supervisors: Dr. Claire Demiot, Dr. Aurore Danigo Assoc. Prof. Přemysl Mladěnka, Ph.D Title of diploma thesis: Transcriptomic analysis of cutaneous inflammatory biomarkers in a mouse model of small fiber neuropathy. Peripheral neuropathy is an expanding public health problem conditioned by various diseases and associated with several adverse effects such as the occurrence of chronic pain or increased risk of pressure ulcers (PUs). The aim of this study is to explore, whether the inflammatory state of the skin is modified during peripheral neuropathy and in the course of the formation of a pressure ulcer. The transcriptomic analysis was performed with two different models of mice: PU model and uninjured model, to determine genes that differ in expression and in particular, those involved in inflammation. Small fiber neuropathy was induced in young mice by intraperitoneal injection of resiniferatoxin (50 µg/kg, i.p.) - transient receptor potential vanilloid 1 (TRPV1) agonist. PUs were induced by applying two magnetic plates on the dorsal skin. Gene expression was obtained based on RNA microarray and the results were subsequently verified by qPCR. The transcriptomic analysis of PU...

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Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil / O diabetes é uma doença de alta prevalência que, frequentemente, induz o comprometimento do sistema nervoso periférico. Na neuropatia diabética periférica, os sintomas mais encontrados são os sensitivos, no qual a dor neuropática, condição crônica caracterizada por alodinia e hiperalgesia, é a mais debilitante. Esta, prejudica a qualidade de vida do paciente, sendo muitas vezes não responsiva aos métodos farmacológicos convencionais de tratamento. Diante desse panorama, o desenvolvimento de novas abordagens terapêuticas que possuam ação efetiva neste tipo de dor é de grande relevância. O uso da terapia celular no tratamento de lesões do sistema nervoso tem demonstrado resultados promissores e o potencial terapêutico de células-tronco na neuropatia experimental tem sido proposto. Neste estudo, avaliou-se o efeito de células-tronco mesenquimais derivadas da medula óssea (CMsMO) na neuropatia diabética periférica estabelecida em modelo experimental de diabetes induzido por estreptozotocina (ETZ). Quatro semanas após a indução do modelo por ETZ (80 mg/kg; ip; 3 dias consecutivos), os animais receberam uma administração endovenosa de CMsMO (1 x 106) ou veículo. O tratamento com gabapentina (30 mg/kg; v.o. a cada 12 horas durante seis dias consecutivos) foi usado como padrão ouro. Os limiares nociceptivos térmico e mecânico foram avaliados durante todo o período experimental (90 dias), pelos métodos de hargreaves e von Frey. A avaliação da função motora foi realizada pelo teste de rota-rod. Em diferentes tempos e para todos os grupos experimentais, foram realizadas coletas de segmentos da medula espinal (L4-L5) para dosagem de citocinas por ELISA e segmentos do nervo isquiático foram também coletados para avaliação de alterações morfológicas por microscopia óptica e eletrônica de transmissão. Os dados comportamentais demonstraram que o tratamento com CMsMO reduziu a mecanoalodinia e a hipoalgesia térmica, levando os limiares nociceptivos de animais neuropáticos a níveis similares aos de animais não neuropáticos. Do mesmo modo, a administração de CMsMO normalizou a função motora dos animais neuropáticos. Dados de microscopia mostraram que animais neuropáticos apresentaram atrofia axonal, redução do número de fibras mielínicas e aparente redução do numero de fibras amielínicas no nervo isquiático. Animais neuropáticos tratados com CMsMO tiveram menor ocorrência de atrofia axonal e não apresentaram redução do numero de fibras mielínicas ou amielínicas, em relação aos neuropáticos tratados com salina. Além disso, animais neuropáticos tratados com CMsMO apresentaram menores níveis espinais de IL-1β e TNF-α, e maiores de IL-10 e TGF-β, em relação aos animais neuropáticos não tratados. Esse conjunto de resultados indica que CMsMO produzem efeito antinociceptivo duradouro na neuropatia diabética, seguido de modificações no padrão fisiopatológico da doença, o que aponta a terapia celular como uma interessante alternativa para o controle da neuropatia diabética periférica dolorosa. / Diabetes is a highly prevalent disease which frequently compromises the peripheral nervous system. In peripheral diabetic neuropathy, the most frequent symptoms are sensitive, in which the neuropathic pain, chronic condition characterized by allodynia and hyperalgesia, is the most debilitating. Neuropathic pain affects the quality of patients’ lives, and is often not responsive to pharmacological conventional treatment methods. Against this background, the development of new therapeutic approaches that have an effective action in this type of pain is of great importance. The use of cell therapy in the treatment of lesions in the nervous system has shown promising results and the therapeutic potential of stem cells in experimental neuropathy has been proposed. In this study, we evaluated the effect of mesenchymal stem cells derived from bone marrow (CMsMO) in peripheral diabetic neuropathy established in experimental model of streptozotocin (STZ) induced diabetes in mice. Four weeks after the induction of the model by administration of STZ (80 mg/kg, ip; 3 days) the animals received an CMsMO by intravenous administration (1x106) or vehicle. The treatment with gabapentin (30 mg/kg, orally every 12 hours for six days) was used as the gold standard. The thermal and mechanical nociceptive thresholds were assessed throughout the entire experimental period (90 days), using Hargreaves and von Frey methods, respectively. Motor function evaluation of was conducted using the rotarod test. At different times, were analyzes conducted in spinal cord segments (L4-L5) to determine cytokines profile by ELISA. Sciatic nerve segments were also collected for evaluation of morphological changes by optical and electron transmission microscopy. According to the behavioral data, the CMsMO treatment reduced the mecanoalodinia and the thermal hypoalgesia, leading nociceptive thresholds of neuropathic animals to levels similar to those of non-neuropathic animals. Similarly, CMsMO administration normalized motor function of neuropathic animals. Microscopy data demonstrated that neuropathic animals had axonal atrophy and an apparent decrease of the number of myelinated fibers as well a reduction in the number of unmyelinated fibers in the sciatic nerve, but neuropathic animals treated with CMsMO had a lower incidence of axonal atrophy, showed no decrease in the number of myelinated fibers and no apparent decrease in the amount of unmyelinated fibers in relation to neuropathics treated with saline. Furthermore, neuropathic animals treated with CMsMO presented lower levels of spinal IL-1β and higher levels of TNF-α, and IL-10 and TGF-β compared to neuropathic animals that received saline. These data indicate that CMsMO produces a lasting analgesic effect in diabetic neuropathy, followed by changes in the pathophysiological disease pattern, which indicates cell therapy as an interesting alternative for the control of painful peripheral diabetic neuropathy.