A neuropatia hansênica e a neuropatia hereditária com suscetibilidade à pressão (Hereditary Neuropathy with liability to Pressure Palsies - HNPP) são mononeuropatias múltiplas em que os estudos da condução nervosa (ECN) mostram geralmente alentecimento focal em topografias muito semelhantes. Na ausência de uma história familiar de HNPP e das manifestações na pele típicas da hanseníase, o diagnóstico diferencial entre elas pode ser muito difícil. Procurando identificar características que ajudassem a distinguir essas doenças, revisamos e catalogamos os dados da história clínica e dos ECN de 39 pacientes com HNPP e 78 pacientes com neuropatia hansênica. A manifestação inicial mais frequente na hanseníase foi o déficit sensitivo (43 pacientes-55.1%) e na HNPP foi a fraqueza muscular localizada indolor (24 pacientes-61%). Fraqueza muscular foi significativamente superior na HNPP e déficit sensitivo foi significativamente superior na hanseníase (p<0.001). A evolução clínica foi estável ou progressiva até o tratamento em todos os pacientes com hanseníase e na HNPP dez pacientes (25.6%) tiveram um curso progressivo e 29 (74.4%) uma evolução com flutuações. O padrão predominante ao exame neurológico foi a mononeuropatia múltipla: 66 pacientes (84.6%) na hanseníase e 26 pacientes (66.7%) na HNPP. Espessamento neural foi mais frequente na hanseníase (p=0,001) e déficit sensitivo intradérmico foi observado somente na hanseníase (p<0,001). Episódio prévio ou atual de paralisia aguda de nervo foi referido somente na HNPP (p<0,001). O padrão dos ECN prevalente foi a neuropatia sensitivo-motora assimétrica com alentecimento focal da condução (NSMAAF): 44 pacientes (56.4%) na hanseníase e 31 pacientes (94.0%) na HNPP. Os parâmetros clínicos mais úteis em distinguir as duas doenças foram: a perda sensitiva intradérmica com comprometimento precoce das fibras finas e ocorrência de reação hansênica na hanseníase; o envolvimento motor inicial predominante, episódios de paralisia aguda de nervo e a evolução com flutuações na HNPP. Se o paciente a ser avaliado apresentar mononeuropatia múltipla com alentecimentos focais da velocidade de condução, os seguintes achados neurofisiológicos sugerem hanseníase: a não detecção de potenciais sensitivos ou motores, a redução da amplitude dos potenciais de ação sensitivos dos nervos sural, fibular superficial e radial superficial (< 8,8 ?V), a redução da amplitude do potencial de ação muscular composto dos nervos ulnar e tibial posterior, a redução da velocidade de condução do potencial de ação muscular composto do nervo ulnar motor no segmento do antebraço (< 43 m/s) e a presença de dispersão temporal frequente; enquanto os seguintes achados sugerem HNPP: aumento desproporcional da latência distal do nervo mediano motor e a presença de bloqueio de condução. / The Hansen\'s disease neuropathy (HDN) and the Hereditary Neuropathy with liability to Pressure Palsies (HNPP) are multiple mononeuropathies whose nerve conduction studies (NCS) usually show focal slowing at very similar topographies. In the absence of a family history of HNPP and the typical skin manifestations of HD, the differential diagnosis between them may be very difficult. In order to identify characteristics that may distinguish these diseases, we reviewed the data of 39 patients with HNPP and of 78 patients with HDN. The most frequent presenting sign was a sensory deficit in 43 patients (55.1%) in the HDN and a localized painless muscular weakness in 24 patients (61%) in the HNPP. Muscle weakness was significantly higher in HNPP and sensory deficit was significantly higher in leprosy (p<0.001). The disease was stable or progressive until treatment in all patients with HDN and among HNPP ten patients (25.6%) had a progressive course and 29 (74.4%) an intermittent evolution. Neural thickening was more frequent in leprosy (p=0.001) and intradermal sensory deficit was observed only in leprosy (p<0.001). Previous or current episode of acute nerve palsy was reported only in HNPP (p<0.001). The predominant pattern on neurological examination was the multiple mononeuropathy: 66 patients (84.6%) in the HDN and 26 patients (66.7%) in the HNPP. The most prevalent pattern of NCS was an asymmetric sensorimotor neuropathy with focal slowing (ASMNFS): 44 patients (56.4%) in HDN and 31 patients (94.0%) in HNPP. The most helpful clinical parameters in distinguishing these diseases were the presence of leprosy reaction and the intradermal sensory loss with predominant early involvement of small nerve fibers in HDN; the initial predominant motor involvement, episodes of acute nerve palsies and the intermittent evolution in HNPP. If the patient evaluation show a pattern of multiple mononeuropathy with focal slowing, the following neurophysiological findings suggest HDN: no detection of sensory or motor potentials, amplitude reduction of the sural, superficial fibular and superficial radial (<8.8 ?V) nerves, amplitude reduction of the motor ulnar and posterior tibial nerves, reduction of the conduction velocity of the motor ulnar nerve at the forearm segment (<43 m/s) and the presence of frequent temporal dispersion; while the following findings suggest HNPP: a disproportionate increase in the motor distal latency of the median nerve and the presence of conduction block.

Les neuropathies périphériques héréditaires (NP) sont caractérisées par des phénotypes très divers et une hétérogénéité génétique importante. La maladie de Charcot-Marie-Tooth (CMT) représente la majeure partie des neuropathies périphériques sensitivo-motrices. D’autres symptômes peuvent être associés, telle que la surdité. A l’heure actuelle, aucune estimation précise de la surdité n’existe dans cette population et la pathogénicité est incertaine. L’objectif de cette thèse était de mieux comprendre la physiopathologie de la surdité chez les patients atteints de neuropathies périphériques. Pour cela plusieurs approches complémentaires ont été mises en œuvre : 1) Approche clinique sur une cohorte française de patients atteints à la fois de neuropathie périphérique et de surdité et tests de génétique moléculaire avec séquençage NGS (Panels NP, surdités et/ou exomes) ; 2) Approche biochimique sur des prélèvements de nerfs cochléaires murins et humains ; 3) Approche bioinformatique afin d’identifier des réseaux de protéines impliquées dans l’apparition de surdité liée à une neuropathie périphérique. Grâce à ce travail, nous avons pu caractériser les phénotypes variés des patients atteints de NP génétique et surdité, et ainsi constater que la surdité peut être endo, rétro ou endo et rétrocochléaire. Trente-six gènes ont été rapportés comme associées à NP et surdité. Le génotype de nos patients NP+Surdité a pu être établi dans 60% des cas, avec la découverte de sept nouveaux variants pathogènes dans cinq gènes différents. Nos travaux suggèrent également que PMP22, le gène le plus retrouvé dans les CMT, n’est probablement pas ou peu impliqué dans l’apparition de la surdité des patients NP. Chez deux de nos patients présentant un variant pathogène de PMP22, un deuxième gène impliqué a été trouvé avec respectivement COCH et MYH14. Des corrélations génotypes-phénotypes ont pu être mises en évidence avec les gènes ABHD12, SH3TC2, NEFL et PRPS1. Deuxièmement, l’étude préliminaire immunohistochimique sur des nerfs auditifs de rats sauvages a permis de mettre en évidence l’expression de pmp22, mpz, nefl et trpv4 au niveau du nerf cochléaire et de pister une différence d’expression chez les rats CMTpmp22/+. L’étude chez l’humain n’a pas été concluante. Dernièrement, la recherche in silico de voies communes aux différents gènes décrits comme impliqués dans NP+surdité a permis de confirmer le lien direct entre PMP22 et MPZ. Des liens indirects entre plusieurs autres protéines ont été pistés. Cette thèse montre également que la surdité est très certainement sous-diagnostiquée dans cette population de NP génétique. Nous proposons donc un suivi audiométrique systématique des patients atteints de NP héréditaire, et une évaluation neurologique pour les enfants diagnostiqués pour surdité. / Hereditary Peripheral Neuropathies (PN) are characterized by various phenotypes and great genetic heterogeneity. Charcot-Marie-Tooth disease (CMT) accounts for most sensori-motor peripheral neuropathies. Besides, other symptoms can be associated, such as deafness. No precise estimation of deafness within this population exist and its pathogenicity is uncertain. The aim of this PhD was to better understand the physiopathology of deafness in patients suffering from PN. Various complementary approaches were used; 1) a clinical approach on a French cohort of patients suffering from both PN and hearing loss and molecular genetic tests with NGS sequencing (PN, deafness panels, and/or exomes), 2) a biochemical approach on murine and human cochlear nerve samples and 3) a bioinformatic approach to identify protein hubs implicated in the onset of PN-associated deafness.This has enabled us to characterize the various phenotypes of patients suffering from both hereditary PN and deafness, and then notice that deafness can be endo-, retro- or endo- and retrocochlear. Thirty-six genes were reported to be associated with both PN and hearing impairment. Sixty percent of our patients were genotyped, highlighting seven novel pathogenic variants in five different genes. Our research also suggests that PMP22, the most frequent gene in CMT, is probably not or poorly implicated in deafness onset in PN patients. In two of our patients with PMP22 pathogenic variants, a second involved gene was found with COCH and MYH14 respectively. Genotype-phenotype correlations were found out with the ABHD12, SH3TC2, NEFL and PRPS1 genes. Secondly, the preliminary immunohistochemical study on wild-type rats auditory nerves highlighted the expression of pmp22, mpz, nefl and trpv4 on the cochlear nerve and tracked a different expression in CMTpmp22/+ rats. However, the study on humans was not conclusive. Recently, in silico research of pathways common to the different genes described to be involved in both PN and deafness, has found the direct link between PMP22 and MPZ. Indirect links between several other proteins have been tracked.This thesis also shows that hearing impairment is most probably under-diagnosed in this population of genetic PN sufferers. We suggest regular audiologic follow-up for PN patients and neurological assessment for deaf children.

Introdução: A infecção crônica pelo vírus da hepatite C (HCV) é considerada uma doença sistêmica com numerosas manifestações extra-hepáticas. Comprometimento do sistema nervoso periférico e alterações neuropsiquiátricas são relatadas em algumas séries, com certa heterogeneidade entre elas. Embora alterações cognitivas tenham sido descritas, alguns estudos não comprovaram esta associação. Poucos estudos sobre o tema foram realizados no Brasil. Objetivo: estudar alterações do sistema nervoso periférico e alterações neuropsiquiátricas nos pacientes com infecção pelo HCV e verificar se têm relação com genótipo viral, grau de fibrose hepática e presença de autoanticorpos. Método: 76 pacientes adultos (40 mulheres) com 18 anos ou mais de idade portadores de infecção crônica por HCV, virgens de tratamento, sem sinais de encefalopatia hepática franca, não portadores do vírus da Hepatite B (HBV), vírus da imunodeficiência adquirida (HIV) ou sífilis foram avaliados no período de agosto de 2009 a fevereiro de 2016 e comparados com grupo controle composto por 76 indivíduos não portadores de HCV, HBV, HIV ou sífilis (43 mulheres) com distribuição semelhante quanto ao gênero, faixas etárias e graus de escolaridade. Pacientes e controles foram submetidos a avaliação clínica, avaliação cognitiva breve [Miniexame do Estado Mental (MEEM), teste do desenho do relógio (TDR), teste de fluência verbal (FV) semântica, teste dos dígitos em ordem direta e indireta (WAIS-III)] e avaliação do humor, ansiedade e desesperança (Inventário de Beck). Os pacientes com hepatite C foram submetidos a extensa bateria de exames laboratoriais, determinação do genótipo, dosagem de insulina, gamaglobulinas, crioglobulinas (CGs), fator reumatoide (FR), frações do complemento e pesquisa de autoanticorpos. Resultados de biópsias hepáticas realizadas em menos de 18 meses da avaliação inicial no estudo foram considerados para análise. Além de exames para inclusão no estudo, os controles foram submetidos a avaliação laboratorial. O programa SPSS 20 (Statistical Package for the Social Sciences) foi utilizado para análise estatística. Resultados: Neuropatias periféricas (NP) foram encontradas em 29 pacientes (38,1%) e 14 controles (18,3%) [p=0,007]. Dos pacientes portadores de HCV com NP, 12 (41,4%) apresentavam mononeuropatias (MN) ou mononeuropatias múltiplas (MNM), 7 (24,1%) polineuropatias (PNP) sensitivas ou sensitivomotoras, 5 (17,2%) PNP com MN ou MNM sobrepostas, 4 (13,8%) radiculopatias e 1 (3,4%) neuropatia motora pura (1/29). Dos 14 portadores de NP no grupo controle, 8 (57,1%) apresentavam neuropatia uni ou bilateral do nervo mediano, 4 (28,6%) radiculopatias e 3 (21,4%) PNP. Parestesias/dores neuropáticas nos membros sem sinais objetivos de NP foram relatadas por 26,3% dos pacientes e por 7,9% dos controles (p < 0,0001). Não houve diferença significativa na prevalência de diabetes melito (DM) entre pacientes e controles (6,6% vs 9,2%). Dezessete pacientes (22,4%) tinham intolerância à glicose. CGs foram detectadas no soro de 9,2% (6/65) dos pacientes e foram positivas no soro de 13,8% dos pacientes portadores de HCV com NP. Teor aumentado de gamaglobulinas séricas foi encontrado em 46,2% (30/64) dos pacientes, positividade do FR em 26,7% (16/60), níveis baixos de C4 em 19,3% (16/60), anticorpos (AC) antimúsculo liso em 26,2% (18/65), AC antitireoperoxidade em 22,9% (8/35) e AC anticardiolipinas IgM em 20,7% (12/58). Houve diferença estatística significativa entre pacientes com hepatite C com e sem NP em relação à presença de AC anti-SSA/RO e antitirosina fosfatase (p=0,028 e p=0,038, respectivamente). Nos pacientes com hepatite C, NP se correlacionou com idade (p < 0,05), grau de fibrose à biópsia hepática (p < 0,05) e alteração do metabolismo da glicose (p < 0,05) e no grupo controle com o diagnóstico de DM (p < 0,01). Não foram verificadas diferenças estatísticas significativas entre pacientes e controles em relação aos escores totais no MEEM, FV semântica, TDR e testes dos dígitos em ordem direta e indireta. A memória de evocação mostrou diferença significativa entre os grupos (p=0,009). Mais pacientes que controles tinham escores <= 23 no MEEM (p=0,025). Resultados semelhantes foram obtidos na comparação entre sujeitos com escolaridade > 4 anos. Não foi verificada diferença estatística entre pacientes e controles em relação ao grau de depressão, ansiedade e desesperança. Os genótipos do HCV não se correlacionaram com nenhuma variável estudada. Conclusão: 38,1% dos pacientes e 18,3% dos controles apresentavam NP. MN ou MNM representaram 41,3%, as PNP 24,1% e as PNP com MN ou MNM sobrepostas 17,2%. Nos pacientes com hepatite C as NP mostraram correlação com AC anti-SSA/RO e antitirosina fosfatase. Foi verificada diferença significativa entre os grupos na memória de evocação e no número de sujeitos que obtiveram escores <= 23 no MEEM, mas não quanto aos sintomas de depressão, ansiedade e desesperança / Background: Chronic hepatitis C virus (HCV) infection is increasingly considered a systemic disease with numerous extrahepatic manifestations. Peripheral neuropathies (PN) and neuropsychiatric disorders are reported in some series of patients, with a certain heterogeneity between them. Although cognitive dysfunction has been described, some studies failed to prove this association. Few studies on the subject were conducted in Brazil. Objectives: identify disorders in peripheral nerve function and neuropsychiatric dysfunction in treatment-naïve patients with chronic HCV infection without overt hepatic encephalopathy and verify whether there is a relationship with viral genotype, liver fibrosis grade and presence of autoantibodies. Methods: a cohort of 76 adult patients with chronic HCV infection aged 18 years and older (40 women), treatment naïve, not coinfected with hepatitis B virus (HBV), acquired immunodeficiency virus (HIV) or syphilis was evaluated from August 2009 to February 2016 and compared with a control group of 76 individuals (43 women) with a negative screening for HCV, HBV, HIV or syphilis, with similar gender, age and educational level distribution. Patients and controls were clinically evaluated and submitted to a brief cognitive screening (Minimental State Examination (MMSE), clock drawing test (CDT), semantic verbal fluency test (VF) and digit span test (WAIS-III) in direct and inverse order and assessment of mood, anxiety and hopelessness through the Beck Inventory. Hepatitis C patients underwent extensive battery of laboratory tests, genotype determination, insulin dosage, and gammaglobulins, cryoglobulins (CGs), rheumatoid factor (RF), complement fractions, and autoantibody screening. Anatomopathological studies of the liver performed within less than 18 months of the initial study interview were considered for analysis. The Statistical Package for the Social Sciences was used to carry out appropriate tests. Results: PN was found in 29 patients with HCV infection (38.1%) and 14 controls (18.3%) [p = 0.007]. Of the HCV patients with PN, 12 (41.4%) presented MN or MNM, 7 (24.1%) sensory or sensoriomotor PNP, 5 (17.2%) PNP with MN or MNM overlap, 4 (13.8%) radiculopathies and 1 (3.4%) pure motor neuropathy. Of the 14 control subjects with PN, 8 (57,1%) had uni or bilateral medial nerve neuropathy, 4 (28.6%) radiculopathy and 3 (21.4%) PNP. Paresthesias / neuropathic limb pain without objective signs of PN were reported by 26.3% of patients and 7.9% of controls (p < 0.0001). There was no significant difference in the prevalence of diabetes mellitus (DM) between patients and controls (6,6% vs 9,2%). Glucose intolerance was found in 17 (22.4%) HCV patients. Serum CGs were detected in 9.2% (6/65) of the HCV patients and were positive in 13.8% of HCV patients with PN. High serum gamma globulins levels were found in 46.2% (30/64) of the patients, FR in 26.7% (16/60), low C4 levels in 19.3% (16/60), smooth muscle antibodies in 26.2% (18/65), anti-thyroperoxidase antibodies in 22.9% (8/35) and IgM anticardiolipin antibodies in 20.7% (12/58). Anti-SSA / RO and anti-tyrosine phosphatase antibodies were significantly different between HCV patients with and without PN (p = 0.028 and p = 0.038, respectively). PN in HCV patients was correlated with age (p < 0.05), grade of liver fibrosis (p < 0.05) and altered glucose metabolism (p < 0.05) and in the control group with DM (p < 0.01). No statistically significant differences between patients and controls were found in the total scores of MMSE, semantic VF, TDR and digit tests in direct and indirect order. Recall memory showed a significant difference between the groups (p = 0.009). More patients than controls had scores <= 23 in the MMSE (p = 0.025). Similar results were obtained in the comparison between subjects with > 4 years of schooling. No statistical difference was found between patients and controls regarding the degree of depression, anxiety and hopelessness. HCV genotypes did not correlate with any of the studied variables. Conclusion: 38.1% of the patients and 18.3% of the controls had NP. In HCV patients with PN, MN or MMN represented 41.3%, PNP 24.1% and PNP with MN or MMN superimposed 17.2%. Anti-SSA/RO and antityrosine phosphatase antibodies showed a significant difference between HCV patients with and without PN. There was a significant difference between the groups in recall memory and in the number of subjects who obtained scores <= 23 in the MMSE, but not in the symptoms of depression, anxiety and hopelessness

Submitted by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2018-09-24T15:40:23Z No. of bitstreams: 1 CAROLINE MARTINEZ.pdf: 15483260 bytes, checksum: 336be2ac82e6f35a3e3945f6a2b3b533 (MD5) / Approved for entry into archive by Marcos Anselmo (marcos.anselmo@unipampa.edu.br) on 2018-09-24T15:48:42Z (GMT) No. of bitstreams: 1 CAROLINE MARTINEZ.pdf: 15483260 bytes, checksum: 336be2ac82e6f35a3e3945f6a2b3b533 (MD5) / Made available in DSpace on 2018-09-24T15:48:42Z (GMT). No. of bitstreams: 1 CAROLINE MARTINEZ.pdf: 15483260 bytes, checksum: 336be2ac82e6f35a3e3945f6a2b3b533 (MD5) Previous issue date: 2017-12-13 / O Alumínio (Al) é o metal de maior exposição humana, no entanto os efeitos do metal em nível de exposição humana ainda são pouco conhecidos. Assim, o objetivo desse estudo foi investigar os efeitos da exposição ao Al por 60 dias em dose equivalente a exposição humana ao metal através da dieta sobre o Sistema Nervoso Central (SNC), Sistema Nervoso Periférico (SNP), sistema reprodutor masculino e sistema cardiovascular e, comparar com os efeitos de uma exposição alta ao metal com efeitos tóxicos conhecidos. Para isso, ratos Wistar com 3 meses de idade foram divididos em: 1) Grupo 1: baixas doses de Al, onde durante 60 dias os ratos receberam por água de beber: a) Controle – água ultrapura; b) Al na dose de 1,5 mg/kg de peso corporal e, c) Al na dose de 8,3 mg/kg de peso corporal e, 2) Grupo 2: alta dose de Al, onde durante 42 dias os ratos receberam por gavagem: a) Controle – água ultrapura; b) Al na dose de 100 mg/kg de peso corporal. O tratamento com Al mesmo em baixas doses prejudicou a memória de reconhecimento de objetos e promoveu o desenvolvimento de catalepsia nos ratos. Somado a isso, a exposição ao Al aumentou os níveis de espécies reativas de oxigênio (EROs) e de peroxidação lipídica, reduziu a capacidade antioxidante e inibiu a atividade da acetilcolinesterase no hipocampo dos animais. No SNP, o Al promoveu o desenvolvimento de alodínea mecânica, aumentou o estresse oxidativo sistêmico, induziu inflamação com recrutamento de macrófagos e, o metal foi capaz de depositar-se entre as fibras do nervo ciático. Já no sistema reprodutor masculino, a exposição ao Al reduziu a contagem espermática, a motilidade e a produção diária de espermatozides, aumentou a porcentagem de espermatozoides com anormalidades morfológicas, alterou a estrutura testicular, aumentou os níveis de estresse 14 oxidativo e a inflamação testicular, demonstrando que uma baixa concentração do metal nos testículos (3.35 μg/g) é o suficiente para comprometer a espermatogênese e a qualidade dos gametas masculinos. No sistema cardiovascular, o Al aumentou a pressão arterial sistólica, reduziu a resposta vasodilatadora a acetilcolina, aumentou a resposta vasoconstritora a fenilefrina, reduziu a modulação endotelial na resposta vasoconstritora, reduziu a biodisponibilidade de óxido nítrico, o envolvimento dos canais de potássio nas respostas vasculares e aumentou a produção de EROs principalmente via NAD(P)H oxidase e de prostanóides contráteis da via da COX-2. A exposição ao Al aumentou o estresse oxidativo em artérias aorta e mesentérica, reduziu a expressão de mRNA de eNOS e SOD1 e aumentou a expressão da isoforma da NAD(P)H oxidase 1, COX-2 e a expressão de TXA-2 R. Tomados em conjunto, nossos dados demonstram que a exposição subcrônica ao Al por 60 dias em baixa dose, que reflete a exposição humana ao metal através da dieta, alcança um limiar tóxico suficiente para promover efeitos adversos no SNC, SNP, sistema reprodutor masculino e sistema cardiovascular. Além disso, os efeitos de uma exposição em baixa dose são praticamente os mesmos de uma exposição alta ao metal. / Aluminum (Al) is the most important environmental and human contaminant. While a good deal of research has been conducted on the acute toxic effects of Al, little is known about the effects of longer-term exposure at human dietary Al levels. Therefore, the purpose of this study was to investigate the effects of 60-day Al exposure at low doses on Central Nervous System (CNS), Peripheral Nervous System (PNS), male reproductive system and cardiovascular system for comparison with a model of exposure known to produce toxicity in rats. Three-month-old male Wistar rats were divided into two major groups: 1) Grou 1, low aluminum levels - rats were treated orally by drinking water for 60 days as follows: a) Control – received ultrapure drinking water; b) Aluminum at 1.5 mg/kg b.w. and c) Aluminum at 8.3 mg/kg b.w. and 2) Group 2, high aluminum level - rats were treated through oral gavages for 42 days as follows: a) Control – received ultrapure water; b) Aluminum at 100 mg/kg b.w. Al treatment even at low doses promoted recognition memory impairment seen in object recognition memory testing and catalepsy behavior in rats. Moreover, Al increased hippocampal reactive oxygen species (ROS) and lipid peroxidation levels, reduced antioxidant capacity and decreased acetylcholinesterase activity. On PNS, Al promoted the development of mechanical allodynia, increased inflammation in the sciatic nerve, systemic oxidative stress and, is able to be retained in the sciatic nerve. Regarding the male reproductive system, Al decreased sperm count, daily sperm production, sperm motility, normal morphological sperm, impaired testis histology; increased oxidative stress in reproductive organs and inflammation in testis, showing that low concentrations of Al in testes (3.35 μg/g) are sufficient to impair 16 spermatogenesis and sperm quality. On cardiovascular system, Al increased systolic blood pressure, decreased acetylcholine-induced relaxation, increased response to phenylephrine, decreased endothelial modulation of vasoconstrictor responses, the bioavailability of nitric oxide, the involvement of potassium channels on vascular responses, as well as increased ROS production from NAD(P)H oxidase and contractile prostanoids mainly from COX-2 in both aorta and mesenteric resistance arteries (MRA). Al exposure increased vascular ROS production and lipid peroxidation as well as altered the antioxidant status in aorta and MRA. Al decreased vascular eNOS and SOD1 mRNA levels and increased the NAD(P)H oxidase 1, COX-2 and TXA-2 R mRNA levels. Taken together, our data demonstrate that 60-day subchronic exposure to low doses of Al from feed and added to the water, which reflect human dietary Al intake, reaches a threshold sufficient to promote adverse effects on SNC, PNS, male reproductive system and cardiovascular system. Moreover, these effects were almost the same as Al exposure at much higher levels.

Introdução: A Neuropatia Periférica Induzida pela Quimioterapia (NPIQ) é um efeito adverso comum e debilitante ocasionado pela infusão de agentes quimioterápicos neurotóxicos como os taxanos, as platinas, alcalóides da vinca, bortezomibe e talidomida. A administração destas medicações aumentam a sobrevida do paciente, porém, aproximadamente, 30% a 40% desenvolvem NPIQ, o que afeta negativamente o tratamento planejado e a qualidade de vida ao interferir nas atividades diárias do paciente. A NPIQ manifesta-se com sintomas sensitivos (parestesia, disestesia, dor entre outros), motores (fraqueza, alterações na marcha e no equilíbrio, dificuldade nas habilidades motoras finas e outros) e neurovegetativos (constipação, retenção urinária, disfunção sexual e alterações na pressão sanguínea). Até o momento não foi concebido um instrumento que avalie a dor neuropática na NPIQ e, além disso, não há instrumento validado com essa finalidade no Brasil. Objetivos: Realizar a tradução e adaptação transcultural do instrumento Chemotherapy-Induced Peripheral Neuropathy Assessment Tool (CIPNAT) para a língua portuguesa do Brasil e testar as propriedades psicométricas da versão adaptada em uma amostra de pacientes oncológicos, que apresentavam NPIQ. Métodos: Trata-se de um estudo metodológico com coleta de dados transversal. Para o processo de tradução e adaptação do instrumento, adotou-se o referencial teórico metodológico proposto por Beaton e colaboradores (2000). A coleta de dados ocorreu em dois hospitais referência no tratamento oncológico da cidade de São Paulo. Resultados: Obteve-se uma amostra de 245 participantes, sendo que, 135 (55,1%) apresentavam neoplasia maligna de intestino, 162 (66,1%) usavam um quimioterápico da classe análogos da platina, 125 (51%) manifestavam dormência nas mãos com gravidade média de 6,71 e angústia média de 7,0 (numa escala de 0-10), impactou negativamente nas Atividades de Vida Diária (AVD) como a prática de exercícios, o trabalho e atividades de lazer. Para testar a validade de construto convergente fez-se uma correlação de Spearmam da versão adaptada do CIPNAT com os instrumento NPSI e DN4 e, obteve-se uma moderada correlação. Não foi possível atingir a validade discriminante. A análise fatorial exploratória com rotação varimax identificou dois fatores, sendo estes, sintomas sensitivos e sintomas motores. Em relação a confiabilidade, alcançou-se um alfa de Cronbach de 0,87, considerado satisfatório. O teste-reteste demonstrou uma forte correlação entre a primeira e segunda avaliação pelo CIPNAT, sendo considerado estável. Conclusão: A análise psicométrica do CIPNAT foi adequada. Desta forma, estará disponível um instrumento válido e confiável que rastreia, caracteriza, avalia e mensura a NPIQ e seu impacto nas AVDs para que a enfermagem oncológica promova uma assistência segura e com qualidade / Background: Chemotherapy Induced Peripheral Neuropathy (CIPN) is a common and debilitating adverse effects caused by the infusion of neurotoxic chemotherapeutics such as taxanes, platines, vinca alkaloids, bortezomib and thalidomide. The administration of these medications increase patient survival, however, approximately 30% to 40% develop CIPN, which negatively affects the planned treatment and the quality of life by interfering with daily activities of the patient. The CIPN manifests itself with sensory symptoms (paresthesia, dysesthesia, pain and others), motors (weakness, changes in gait and balance, difficulty with fine motor skills and others) and neurovegetative (constipation, urinary retention, sexual dysfunction and changes in blood pressure). So far, it has not been a tool designed to evaluate the neuropathic pain in CIPN and furthermore, there is no validated instrument for this purpose in Brazil. Aims: To perform the translation and cultural adaptation of Chemotherapy- Induced Peripheral Neuropathy Assessment Tool instrument (CIPNAT) into Portuguese of Brazil and test the psychometric properties of the adapted version in a sample of cancer patients with CIPN. Methods: This is a methodological study with cross data collection. For the process of translation and adaptation of the instrument, it was adopted the methodological theoretical framework proposed by Beaton et al (2000). Data collection occurred in two referral hospitals in the oncological treatment of São Paulo. Results: There was obtained a sample of 245 participants, and that 135 (55.1%) had colorectal neoplasm, 162 (66.1%) used a platinum chemotherapeutic agent, 125 (51%) manifested numbness in the hands with medium gravity of 6.71 and average distress of 7.0 (on a scale of 0-10), impacted negatively on the activities of Daily Living (ADLs) such as exercise, work and leisure activities. To test the convergent validity has made a Spearman\' correlation of the adapted version of CIPNAT with NPSI and DN4 instrument and, was obtained a moderate correlation. Could not achieve the discriminant validity. Exploratory factor analysis with varimax rotation identified two factors, which are, sensory symptoms and motor symptoms. Regarding reliability, it was reached a Cronbach\'s alpha of 0.87, satisfactory. The test-retest showed a strong correlation between the first and second evaluation by CIPNAT and is considered stable. Conclusion: The psychometric analysis of CIPNAT was adequate. Thus, it will be available a valid and reliable instrument that tracks, features, evaluates and measures the CIPN and its impact on ADL for the oncology nursing promotes safe and quality care

Introdução: A Neuropatia Periférica Induzida pela Quimioterapia (NPIQ) é um efeito adverso comum e debilitante ocasionado pela infusão de agentes quimioterápicos neurotóxicos como os taxanos, as platinas, alcalóides da vinca, bortezomibe e talidomida. A administração destas medicações aumentam a sobrevida do paciente, porém, aproximadamente, 30% a 40% desenvolvem NPIQ, o que afeta negativamente o tratamento planejado e a qualidade de vida ao interferir nas atividades diárias do paciente. A NPIQ manifesta-se com sintomas sensitivos (parestesia, disestesia, dor entre outros), motores (fraqueza, alterações na marcha e no equilíbrio, dificuldade nas habilidades motoras finas e outros) e neurovegetativos (constipação, retenção urinária, disfunção sexual e alterações na pressão sanguínea). Até o momento não foi concebido um instrumento que avalie a dor neuropática na NPIQ e, além disso, não há instrumento validado com essa finalidade no Brasil. Objetivos: Realizar a tradução e adaptação transcultural do instrumento Chemotherapy-Induced Peripheral Neuropathy Assessment Tool (CIPNAT) para a língua portuguesa do Brasil e testar as propriedades psicométricas da versão adaptada em uma amostra de pacientes oncológicos, que apresentavam NPIQ. Métodos: Trata-se de um estudo metodológico com coleta de dados transversal. Para o processo de tradução e adaptação do instrumento, adotou-se o referencial teórico metodológico proposto por Beaton e colaboradores (2000). A coleta de dados ocorreu em dois hospitais referência no tratamento oncológico da cidade de São Paulo. Resultados: Obteve-se uma amostra de 245 participantes, sendo que, 135 (55,1%) apresentavam neoplasia maligna de intestino, 162 (66,1%) usavam um quimioterápico da classe análogos da platina, 125 (51%) manifestavam dormência nas mãos com gravidade média de 6,71 e angústia média de 7,0 (numa escala de 0-10), impactou negativamente nas Atividades de Vida Diária (AVD) como a prática de exercícios, o trabalho e atividades de lazer. Para testar a validade de construto convergente fez-se uma correlação de Spearmam da versão adaptada do CIPNAT com os instrumento NPSI e DN4 e, obteve-se uma moderada correlação. Não foi possível atingir a validade discriminante. A análise fatorial exploratória com rotação varimax identificou dois fatores, sendo estes, sintomas sensitivos e sintomas motores. Em relação a confiabilidade, alcançou-se um alfa de Cronbach de 0,87, considerado satisfatório. O teste-reteste demonstrou uma forte correlação entre a primeira e segunda avaliação pelo CIPNAT, sendo considerado estável. Conclusão: A análise psicométrica do CIPNAT foi adequada. Desta forma, estará disponível um instrumento válido e confiável que rastreia, caracteriza, avalia e mensura a NPIQ e seu impacto nas AVDs para que a enfermagem oncológica promova uma assistência segura e com qualidade / Background: Chemotherapy Induced Peripheral Neuropathy (CIPN) is a common and debilitating adverse effects caused by the infusion of neurotoxic chemotherapeutics such as taxanes, platines, vinca alkaloids, bortezomib and thalidomide. The administration of these medications increase patient survival, however, approximately 30% to 40% develop CIPN, which negatively affects the planned treatment and the quality of life by interfering with daily activities of the patient. The CIPN manifests itself with sensory symptoms (paresthesia, dysesthesia, pain and others), motors (weakness, changes in gait and balance, difficulty with fine motor skills and others) and neurovegetative (constipation, urinary retention, sexual dysfunction and changes in blood pressure). So far, it has not been a tool designed to evaluate the neuropathic pain in CIPN and furthermore, there is no validated instrument for this purpose in Brazil. Aims: To perform the translation and cultural adaptation of Chemotherapy- Induced Peripheral Neuropathy Assessment Tool instrument (CIPNAT) into Portuguese of Brazil and test the psychometric properties of the adapted version in a sample of cancer patients with CIPN. Methods: This is a methodological study with cross data collection. For the process of translation and adaptation of the instrument, it was adopted the methodological theoretical framework proposed by Beaton et al (2000). Data collection occurred in two referral hospitals in the oncological treatment of São Paulo. Results: There was obtained a sample of 245 participants, and that 135 (55.1%) had colorectal neoplasm, 162 (66.1%) used a platinum chemotherapeutic agent, 125 (51%) manifested numbness in the hands with medium gravity of 6.71 and average distress of 7.0 (on a scale of 0-10), impacted negatively on the activities of Daily Living (ADLs) such as exercise, work and leisure activities. To test the convergent validity has made a Spearman\' correlation of the adapted version of CIPNAT with NPSI and DN4 instrument and, was obtained a moderate correlation. Could not achieve the discriminant validity. Exploratory factor analysis with varimax rotation identified two factors, which are, sensory symptoms and motor symptoms. Regarding reliability, it was reached a Cronbach\'s alpha of 0.87, satisfactory. The test-retest showed a strong correlation between the first and second evaluation by CIPNAT and is considered stable. Conclusion: The psychometric analysis of CIPNAT was adequate. Thus, it will be available a valid and reliable instrument that tracks, features, evaluates and measures the CIPN and its impact on ADL for the oncology nursing promotes safe and quality care

Introduction : La chimiothérapie cytotoxique constitue une modalité thérapeutique de nombreux cancers. L’amélioration de la durée de survie des patients a fait apparaître des complications de ces traitements notamment sur le nerf périphérique. Il s’agit d’une complication fréquente et potentiellement sévère qui peut avoir un impact durable. Pourtant, bien que les chimiothérapies neurotoxiques soient connues, il n’existe pas de données précises permettant de prédire la tolérance individuelle. La détection précoce des polyneuropathies chimio-induites (PNCI) est donc capitale pour évaluer les facteurs favorisants. L’utilisation du TNSc (Total Neuropathy Score clinical version) et le Sudoscan® peut notamment permettre la détection de ces PNCI. En effet, le TNSc (Total Neuropathy Score clinical version), un score composite évaluant les petites et grosses fibres nerveuses. Celui-ci a été validé pour déterminer la sévérité de la PNCI. Selon le traitement, l’atteinte concerne les grosses fibres myélinisées ou les fibres fines amyéliniques (FFA). L’examen des grosses fibres est bien standardisé au moyen de l’EMG. Cependant il n’en est pas de même pour le diagnostic d’atteinte des FFA. Le Sudoscan® mesure la conductance cutanée (mesure chronoampérométrique) après une exposition à un courant continu inférieur à 100µA/6V permet d’apprécier la fonction sudomotrice. Des études dans le diabète ont montré que la fonction sudomotrice est directement liée à l’état des FFA, car ces fibres contrôlent les glandes sudoripares. Le Sudoscan® pourrait donc être utilisé pour la détection de PNCI.Objectifs i) Evaluer l’incidence des PNCI par le TNSc selon la dose et évaluer l’atteinte des FFA chez des patients au cours de traitement par Sels de platines ou Taxanes ou Alcaloïdes de pervenche; ii) étudier l’évolution dans le temps des PNCI par le TNSc et par Sudoscan® au cours de la chimiothérapie et à distance de son arrêt; iii) caractériser des facteurs de risque de PNCI; iv) comparer les TNSc et mesures chronoampérométriques selon les traitements reçus v) évaluer l’intérêt des conductances par rapport au TNSc.Résultats Une attention particulière a été portée aux patients sous Oxaliplatine (n=65) et Taxanes (n=28). Nous avons retrouvé une augmentation du TNSc chez tous les patients sous chimiothérapie neurotoxique. Pendant le suivi, 57% des patients sous Oxaliplatine et 58% des patients sous Taxanes atteignaient un TNSc correspondant à une neuropathie clinique. Aucune différence du TNSc entre les patients symptomatiques et asymptomatiques n’a été observée à distance de traitement par Oxaliplatine (≥4mois). De même, on ne retrouvait pas de différences du TNSc entre les patients symptomatiques et asymptomatiques à distance de traitement par Taxanes. D’autre part, l’étude des conductances n’a pas révélé d’évolution en fonction de la dose reçue pour les patients sous Oxaliplatine. En revanche, chez les patients sous Taxanes on retrouvait des différences significatives des conductances en fonction des doses reçues. La mesure la plus basse des pieds pendant le suivi est observée en moyenne 23 jours avant que le TNSc le plus élevé ne soit atteint (p=0,03). On ne retrouve pas de différences des conductances pendant le suivi entres les patients symptomatiques et asymptomatiques à distance de traitement par Oxaliplatine. Toutefois, les patients symptomatiques à distance de traitement par Taxanes avaient des conductances des pieds plus basses que les patients asymptomatiques à distance (p=0.004). Le TNSc est plus élevé selon la dose reçue chez les patients diabétiques que chez les patients non diabétiques. Les conductances des mains et des pieds des patients diabétiques étaient significativement plus basses (p=0.003) chez les patients diabétiques que chez les patients non diabétiques.Conclusion Ces résultats suggèrent que les mesures chronoampérométriques permettent de détecter et quantifier l’atteinte des FFA chez les patients recevant des Taxanes. / Introduction : Cytotoxic chemotherapy is a treatment modality for many cancers. The improved survival time of patients showed some complications of these cytotoxic treatments including chemotherapy-induced peripheral neuropathy (CIPN). This is a common and potentially severe complication that can have a lasting impact on the quality of life. Although neurotoxic chemotherapies are known, there is no accurate data to predict individual tolerance. Early detection of CIPN is therefore essential to assess the contributing factors. To this end, the use of the TNSc (Total Neuropathy Score clinical view) and the Sudoscan® can improve the detection CIPN.Indeed, the TNSc (Total Neuropathy Score clinical view), a composite score assessing small and large nerve fibers, has been validated to evaluate the severity of CIPN. The nerve impairment concerns the large myelinated fibers or small fibers, depending on the treatment. The objective assessment of large fibers is standardized by means of the EMG (Electromyography), but it is not the same for the diagnosis of the small fibers impairment.On the other hand, the Sudoscan® measures skin conductance (chronoamperometric measurement) after exposure to a direct current of less than 100μA and 6V, and can assess the sudomotor function. Interestingly, studies in diabetes have shown that sudomotor function is directly related to the status of the small fibers that control the sweat glands. The Sudoscan® could thus be used for the detection of CIPN.Objectives: i) to evaluate the impact, depending on the dose received of chemotherapy, of CIPN by TNSc and assess the impairment of small fibers in patients during treatment with Platinum compounds or Taxanes or vinca alkaloids; ii) to study the evolution of the peripheral neurologic impairment by TNSC and skin conductance measurements during chemotherapy and after the end of the treatment; iii) to characterize risk factors for CIPN; iv) to assess the usefulness of conductance measurements compared to TNSc.Results: Particular attention has been given to patients treated with Oxaliplatin (n= 65) and Taxanes (n= 28), known to damage small fibers. We found an increased TNSc in all patients receiving neurotoxic chemotherapy. During follow-up, 57% of patients receiving Oxaliplatin and 58% of patients receiving Taxanes reach a TNSc corresponding to a clinical neuropathy. However, there was no difference of TNSc during the follow-up between symptomatic and asymptomatic patients, 4 months after the end of the treatment by Oxaliplatin. Similarly, we did not find differences of TNSc during the follow-up between symptomatic and asymptomatic patients, 4 months after the end of the treatment by Taxanes.Regarding conductance values, we didn’t observe changes depending on the dose received for patients treated by Oxaliplatin. However, in patients receiving Taxanes we found significant differences, based on the cumulative dose, for the hands and feet. Indeed, the lowest measure of the feet during the tracking is observed within an average of 23 days before the TNSc reached its highest value (p = 0.03). We didn’t find differences in conductance values during follow-up among symptomatic and asymptomatic patients 4 months after the end of their treatment. However, 4 months after the end of the chemotherapy, symptomatic patients treated with Taxanes had feet conductance values lower than asymptomatic patients (p= 0.004). The TNSc was higher in diabetic patients than in non-diabetic patients depending on the dose received during the follow-up. During the follow-up, the conductance values of the hands and feet were significantly lower (p= 0.003) for these patients than in nondiabetic ones.Conclusion: These results suggest that the chronoamperometric measurements can be useful in the detection and quantification of small fibers impairment in patients receiving Taxanes.

This thesis addresses chemotherapy-induced peripheral neuropathy (CIPN)- a form of pain sensation and a prevalent dose-limiting side-effect of several chemotherapy agents such as vincristine, paclitaxel, and oxaliplatin. These agents are used for treating various cancers such as leukemia, brain tumor, lung cancer. Peripheral neuropathy is a numbing, tingling, and burning sensation felt in the palms and feet, which occurs due to damage to neurons (nerve cells). Prolonged CIPN can impact the quality of life of cancer patients. Occasionally, severe CIPN can result in termination of chemotherapy treatment altogether. Currently, there are no established strategies for treating CIPN due to a lack of understanding of its mechanisms. Moreover, different patients react differently to the same treatment; a subgroup of patient population may never experience CIPN, while another may experience severe CIPN for the same dose. In addition, there are no established strategies for predicting CIPN either. This thesis addresses both prediction and mechanisms of CIPN.<br><br>The following paragraphs reflect the organization of this thesis. Each paragraph introduces a research problem, the approaches taken to investigate it, and states the key results.<br><br>First, a metabolomics-based approach was used to investigate CIPN prediction. Blood samples of pediatric leukemic cancer patients who underwent treatment with a chemotherapy agent - vincristine were provided. These blood samples were analyzed at different treatment time points using mass spectrometry to obtain the metabolite profiles. Machine learning was then employed to identify specific metabolites that can predict overall susceptibility to peripheral neuropathy in those patients at specific treatment time points. Subsequently, selected metabolites were used to train machine learning models to predict neuropathy susceptibility. Finally, the models were deployed into an open-source interactive tool- <i>VIPNp</i>- that can be used by researchers to predict CIPN in new pediatric leukemic cancer patients.<br><br>Second, the focus was shifted to the pathophysiology of pain and the pain-sensing neuron; specifically: (i) investigating pain sensation mutations and the dynamics of the pain-sensing neuron, and (ii) exploring chemotherapy-induced peripheral neuropathy mechanisms. <br><br>While pain is a common experience, genetic mutations in individuals can alter their experience of pain, if any at all (certain mutations yield individuals insensitive to pain). Despite its ubiquity, we do not have a complete understanding of the onset and/or mechanisms of pain sensation. Pain sensation can be broadly classified into three types: (i) nociceptive, (ii) neuropathic, and (iii) inflammatory. Nociceptive pain arises due to a noxious external stimulus (e.g., upon touching a hot object). Neuropathic pain (which is felt as a side-effect of the aforementioned chemotherapy agents) is the numbing and tingling sensation due to nerve damage. Inflammatory pain occurs due to damage to internal tissues. Pain in any form can be characterized in terms of electrical signaling by the pain-sensing neuron. Signal transmission regarding pain occurs through generation of an electrical signal called the action potential- a peak in neuron membrane potential. Excessive firing of action potentials by a pain-sensing neuron indicates pain of a specific form and intensity. In order to investigate this electrical signaling, a mathematical modeling approach was employed. The neuron membrane was assumed to be an electrical circuit and the potential across the membrane was modeled in terms of the sodium and potassium ions flowing across it via voltage-gated sodium and potassium channels, respectively. Generation of a single action potential followed by a resting state corresponds to a normal state, whereas periodic firing of action potentials (an oscillatory state) corresponds to pain of some form and intensity <i>in vitro</i>. Therefore, an investigation into the switch from a resting state to an oscillatory state was proposed. A bifurcation theory approach (generally useful in exploring changes in qualitative behavior of a model) was used to explore possible bifurcations to explain this switch. Firstly, genetic mutations that can shift the pain sensation threshold in the pain-sensing neuron were explored. The detected bifurcation points were found to be sensitive to specific sodium channels’ model parameters, implying sodium channels’ sensitivity towards the pain sensation threshold. This was corroborated by experimental evidence in existing literature. Secondly, a theoretical analysis was performed to explore all possible bifurcations that can explain the dynamics of this pain-sensing neuron model. The mathematical modeling simulations revealed a mixture of small amplitude and large amplitude membrane potential oscillations (mixed-mode oscillations) for specific parameter values. The onset and disappearance of the oscillations were investigated. Model simulations further demonstrated that the mixed-mode oscillations solutions belonged to Farey sequences. Furthermore, regions of bistability- where stable steady state and periodic solutions coexisted- were explored. Additionally, chaotic behavior was observed for specific model parameters.<br><br>Finally, this thesis investigated the role of voltage-gated ion channels in inducing CIPN using the same mathematical model. Repetitive firing of action potentials in the absence of any external stimulus was used as an indicator of peripheral neuropathy. Bifurcation analysis revealed that specific sodium and potassium conductances can induce repetitive firing without any external stimulus. The findings were supplemented by recording the firing rate of a sensory neuron culture. Next, a chemotherapy agent - paclitaxel, was introduced in the model to investigate its potential effects on the firing behavior. It was seen that a medium dose of paclitaxel increased repetitive firing. This was supported by the firing rate recordings of the sensory neuron culture.<br><br>In summary, this thesis presents a prediction strategy for CIPN. Moreover, it presents a bifurcation theory-based framework that can be used to investigate pain sensation, in particular, genetic mutations related to pain sensation and chemotherapy-induced peripheral neuropathy. This framework can be used to find potential voltage-gated ion channels that can be targeted to control the pain sensation threshold in individuals, and can be extended to investigate various degeneracies in CIPN mechanisms to find therapeutic cures for it.

The purpose of this study was to determine if NO blood concentrations increased acutely following an 8-week course of pulsed infrared light therapy (PILT) which could be linked to an improvement in peripheral protective sensation (PPS) in patients who have profound chronic diabetic peripheral neuropathy. A total of 22 subjects with the diagnosis of type 1 (N = 2) or type 2 (N = 20) diabetes participated in the study. PILT was administered to one foot chosen at random with the other foot serving as a within-subject control (no treatment). Patients underwent 24 treatments (3 times/week, for 8 weeks) for 30 min per treatment. Venous blood samples were taken during the last 5 min of treatment from veins in the dorsum of the control and experimental feet and were later analyzed for NO concentration. Contrary to the popular supposition, PILT treatments actually resulted in a significantly (P < 0.05) decreased concentration of NO. Additionally, there were no significant differences between the treated and untreated feet. Since in individuals where PILT has significantly improved PPS, PILT did not stimulate an increased NO content in the blood, it appears that infrared light improves peripheral protective sensation in patients by a mechanism other than an increased NO production.

Pulsed infrared light therapy (PILT) has been shown to increase peripheral sensation in diabetic patients with diabetic peripheral neuropathy (DPN). However, most studies last for very short periods, with the subjects receiving only 6-20 treatments. The purpose of this study was to evaluate the effectiveness of an eight-week course of PILT in reversing long-standing, profound DPN in patients with type 1 and type 2 diabetes. Twenty-two subjects with a diagnosis of type 1 (n=2) or type 2 (n=20) diabetes participated in the study. PILT was administered to one foot chosen at random with the other foot serving as a within-subject control (no treatment). Patients underwent 24 treatments (3 times/week, for eight weeks) for 30 min per treatment. Changes in peripheral protective sensation (PPS) were measured using Semmes-Weinstein monofilaments (SWM) ranging from 3.7 to 6.48. PILT improved PPS even in patients with long-standing chronic neuropathies whose initial pre-study sensation was not measurable with a 200-g SWM. PILT significantly improves PPS. While the exact mechanism of action is not understood, infrared light may improve peripheral neuropathies by improving foot perfusion by stimulating nitric oxide production.