No description available.

The validity of corneal confocal microscopy (CCM) in assessing peripheral neuropathy has been studied extensively in several studies with a large cohort of subjects with diabetes and in a handful of studies with small sample sizes in subjects with other systemic conditions. The non-invasive nature of this technique as well as its high reproducibility, moderate to high sensitivity and specificity, and ease of use make it an ideal biomarker for diagnosing onset, severity and progression of peripheral neuropathy. This thesis aims to further investigate the potential of CCM by evaluating abnormalities in the corneal sub-basal nerve plexus, Langerhans Cells (LCs) and epithelial cells in neuropathy related to diabetes and cancer. This thesis has established that evaluating the sub-basal nerve plexus in the centre and at the inferior whorl increases the diagnostic performance of CCM. In addition to diagnosing clinical and subclinical neuropathy in children and adults with diabetes CCM can also identify sub-clinical nerve damage in patients with upper gastrointestinal cancer and assess the effects of chemotherapy. CCM also identifies differences in small fibre pathology between diabetic patients with and without painful neuropathy. Although there was an increased prevalence and severity of dry eye and LCs' density, this was not related to an abnormality of corneal nerves in diabetic patients with no or mild neuropathy. Epithelial cell morphology was not associated with corneal nerve damage and did not alter in patients with Type 1 diabetes. In conclusion, CCM has been shown to be an ideal marker for quantifying early small fibre pathology and assessing peripheral neuropathies.

nÃo hà / Oxaliplatina (OXL) à a 3 geraÃÃo de agentes platinos com amplo espectro de atividade antitumoral. Exibe potente atividade citotÃxica, incluindo cÃncer colorretal, ovariano e pulmonar. Dentre os efeitos tÃxicos estÃo: laringoespasmo, nÃuseas, vÃmitos, fadiga e neuropatia perifÃrica, foco desse trabalho. Essa pesquisa objetivou desenvolver um modelo experimental para estudo da neuropatia sensitiva perifÃrica induzida por OXL em camundongos que sÃo animais geneticamente mais semelhantes ao ser humano, econÃmicos e dado a existÃncia de espÃcies diferentes para vÃrios fatores. O estudo foi aprovado pelo Comità de Ãtica em Pesquisa Animal da UFC (protocolo n 70/07). Camundongos Swiss machos (20-40g) foram tratados com OXL (1-4 mg/kg, EV) por 4 semanas paralelamente aos testes neuropÃticos utilizados para avaliar o desenvolvimento da neuropatia sensitiva e Rota Rod para verificar comprometimento motor. A hiperalgesia e alodÃnia tÃrmica foram avaliadas pelo teste de imersÃo da cauda (TIC) em Ãgua fria (4 ou 10ÂC) e em Ãgua aquecida (46 ou 42ÂC). O teste de hiperalgesia e alodÃnia mecÃnico (HPM; Von Frey) consistiu na estimulaÃÃo das patas traseiras com um sensor de forÃa (g) atà a sua retirada por um movimento de âflinchâ. Foi ainda verificado a aÃÃo analgÃsica da carbamezepina (CZP), oxcarbazepina (OZP), gabapentina (GABAP) e indometacina (INDO) no TIC Ãgua fria. Foi realizado a imunohistoquÃmica das patas traseiras dos animais em 24h e de 7 a 28 dias. Como resultados observou-se que no HPM houve uma diminuiÃÃo significativa (p<0,001) no limiar nociceptivo a partir do 14 dia atingindo o mÃximo na dose de 2mg/kg comparado ao grupo controle. No TIC 4ÂC houve uma diminuiÃÃo significativa (p<0,05) no limiar nociceptivo no 56 dia, no TIC alodÃnia pelo frio (10ÂC) foi observado uma diminuiÃÃo significativa (p<0,01) no limiar nociceptivo tambÃm no 56 dia, no TIC alodÃnia pelo quente (42ÂC) foi observado uma diminuiÃÃo significativa (p<0,05) no limiar nociceptivo a partir do 35 dia. Esses testes atingiram o mÃximo na dose de 1mg/kg comparados com o grupo controle e no TIC 46ÂC foi observado uma diminuiÃÃo significativa (p<0,01) no limiar nociceptivo a partir do 49 dia atingindo o mÃximo na dose de 1 e de 4mg/kg comparado ao grupo controle. No teste Rota Rod nenhuma variaÃÃo significativa foi observada em nenhum dos grupos, indicando a ausÃncia de comprometimento motor. O tratamento com CZP (0,3-30mg/kg), OZP (0,3-100mg/kg) e GABAP (6-54mg/kg) aumentou o limiar nociceptivo, indicando efeito analgÃsico e INDO (1-4mg/kg) nÃo demonstrou atividade analgÃsica nesse modelo. Na anÃlise da imunohistoquÃmica ficou comprovado que existe a participaÃÃo provÃvel de SP, CGRP e NMDA perifÃricos e nitrotirosina. Portanto, o uso de camundongos e do diferente mÃtodo de administraÃÃo da OXL (EV) pode ser utilizado em modelos futuros viabilizando o uso do fÃrmaco para tratamento do cÃncer, principalmente o colorretal, com todo o esquema terapÃutico, sem que a NSP interfira nas atividades de vida do paciente tratado. / Oxaliplatin (OXL) is a third-generation platinum-based chemotherapy with broad spectrum of anti-tumoral activity. Exhibt potent cytotoxic activity including against cancer colorectal, ovarian and lung cancer. Among the toxic effects are: laryngospasm, nauseas, vomiting, fatigue and peripheral neuropathy, focus of that work. That research planned to develop an experimental model for study of the peripheral neuropathy induced by OXL in mice that are animal genetically more similar to the human, economic and given the knockout species existence for several factors. The study was approved by the Committee of Ethics in Animal Research of the UFC (protocol n 70/07). Mice Swiss male (20-40g) were treated with OXL (1-4 mg/kg, EV) for 4 weeks in parallel to the neurophatic tests utilized for evaluate the development of the peripheral neuropathy and Route Rod for verify some motor compromise. To mechanical hyperalgesia and allodynia thermal were evaluated by the test of immersion of the tail (TIC) in cold water (4 or 10ÂC) and in water heated (46 or 42ÂC). The test of hyperalgesia and allodynia (HPM; Von Frey) consisted of the stimulation of the rear paws with a sensor of force (g) up to his retreat by a movement of "flinch". It was still verified the analgesic action of the carbamezepine (CZP), oxcarbazepine (OZP), gabapentin (GABAP) and indomethacin (INDO) in the TIC cold water. It was carried out to immunohistochemical of the hands paws of the animals in 24h and of 7 to 28 days. The results shows that in the HPM had a significant reduction (p<0,001) in the nociceptive threshold from the 14 day reaching the maximum one in the dose of 2mg/kg compared to the control group. In the TIC 4ÂC had a significant reduction (p<0,05) in the nociceptive threshold in the 56 day, in the TIC allodynia by the cold one (10ÂC) was observed a significant reduction (p<0,01) in the nociceptive threshold also in the 56 day, in the TIC allodynia by the hot one (42ÂC) was observed a significant reduction (p<0,05) in the nociceptive threshold from the 35 day. Those tests reached the maximum one in the dose of 1mg/kg compared with the control group and in the TIC 46ÂC was observed a significant reduction (p<0,01) in the nociceptive threshold from the 49 day reaching the maximum one in the doses of 1 and 4mg/kg compared to the control group. In the test Route Rod no significant variation was observed in no of the groups, indicating the absence of motor compromise. The handling with CZP (0,3-30mg/kg), OZP (0,3-100mg/kg) and GABAP (6-54mg/kg) increased the nociceptive threshold, indicating analgesic effect and INDO (1-4mg/kg) did not show analgesic activity in that model. In the analysis of the immunohistochemical was verified that exists the probable participation of SP, CGRP and NMDA peripheral and nitrotyrosine. Therefore, the use of mice and of the different approach of administration of the OXL (EV) can be utilized in future models making feasible the use of the drug for handling of the cancer, mainly the colorectal, with all the therapeutic plan without that to NSP interfere in the activities of the treated patient.

No description available.

Key words: Peripheral neuropathy, HIV/AIDS, Progressive resisted exercise, Performance oriented mobility, Quality of life. Background: Distal symmetrical poly-neuropathy (DSP) has emerged as one of the major neurological complication associated with HIV/AIDS and antiretroviral therapy. People with DSP commonly have problems with pain, mobility, altered gait and balance all which affect their quality of life. While therapeutic strengthening exercise has been reported to attenuate these impairments in other co-morbid conditions like diabetes mellitus and in HIV/AIDS, there is no evidence available on the effects of exercise on DSP in people living with HIV/AIDS (PLWHA).The purpose of this study was to determine the effects of progressive resisted exercises (PRE) on performance oriented mobility and health related quality of life in (PLWHA) related DSP. Objectives of this study were to determine the effects of PRE on gait, balance and pain levels and establish if there is a relationship between performance-oriented mobility and health-related quality of life in PLWHA related DSP. Methods: In order to fulfil the objectives, an assessor-blinded randomized controlled trial was conducted over two studies, with a combined sample of 160 participants sourced from two family care clinics at two central hospitals and ten anti-retroviral therapy dispensing municipal clinics in Harare, Zimbabwe. While the experimental group with 80 participants had an intervention program of PRE sessions of one hour for the lower limbs, done twice per week over 12 weeks, the control group of 80 participants was given advice to walk unsupervised at home. Loss to follow up in this study was at 60% (n=97) and the data was analysed using an intention to treat analysis approach. Results: Participants of an average age of 42.2 years (SD=8.5) constituted of 70.6% (n=113) female participants. Combination antiretroviral therapy containing stavudine, was used by 59% (n=94) of the participants and 59% (n=94) of the participants had moderate to severe neuropathy. Proximal muscles exhibited weakness (hamstring muscles strength = 3.43 kg force (SD=1.5)) when compared to leg muscles (gastrocnemius muscles strength = 12.8 kg force (SD=2.0)). Gait and balance scores did not show differences in effect between the intervention and the control group (95%CI 0.00-0.02, p = 0.8). Similarly there were no differences of effect for muscle strength (95%CI 0.00-0.08, p=0.13-0.8) and pain (95%CI 0.0-0.06, p>0.13). However the effect on quality of life changes were significantly different between the two groups (95%CI 0.00-0.12 p= 0.04). Quality of life was positively associated with gait, odds ratio 1.01 (95%CI 1.00 – 1.04), moderately associated with balance odds ratio 0.68, (95%CI 0.52 – 0.93) negatively associated with pain odds ratio 0.98 (95%CI 0.97 – 0.99). Conclusion: This research study established that progressive resisted exercises have positive effects on the health related quality of life in PLWHA related DSP. However this study did not show a difference of the effects of progressive resisted exercises on performance oriented mobility in PLWHA related DSP when compared to advice to exercise at home. The study findings may not be generalized to all individuals living with HIV/AIDS who have DSP as the participants were from a particular demographic setting. This project may be continued at the participating family care clinics as a roll on of the perceived benefits of exercise for people with HIV related DSP.

Made available in DSpace on 2014-06-11T19:33:26Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-08-05Bitstream added on 2014-06-13T19:23:20Z : No. of bitstreams: 1 camargo_mhb_dr_jabo.pdf: 420685 bytes, checksum: bb865aac367212839aba8ddd9ff5b0df (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / A leishmaniose visceral é uma antropozoonose, que vem aumentando no Brasil em número de casos e já sendo endêmica em vários estados. Os cães, considerados o principal reservatório doméstico, são de grande importância na manutenção do ciclo epidemiológico da leishmania visceral, já que a mesma é mais prevalente na população canina que na humana, e também podem servir como modelo experimental da doença. Partindo-se da hipótese de que a leishmaniose visceral causa uma neuropatia periférica em cães, o presente ensaio teve como objetivos analisar as alterações eletroneurográficas e histopatológicas dos nervos radial, ulnar, tibial e peroneal de cães naturalmente acometidos pela doença. Assim, 33 cães naturalmente acometidos por leishmaniose visceral, e quatro cães sem a doença foram submetidos a exames eletroneurográficos e retirada de fragmentos dos nervos para análise histopatológica. Os resultados obtidos neste trabalho permitiram concluir que cães com leishmaniose visceral podem apresentar velocidade de condução nervosa motora diminuída, caracterizando um quadro de neuropatia periférica; apresentar alterações histopatológicas indicativas de uma neuropatia periférica; e que as principais alterações histopatológicas nos nervos radial, ulnar, tibial e peroneal de cães com leishmaniose visceral foram aumento de tecido conjuntivo no endoneuro, variação no diâmetro de fibras nervosas, degeneração axonal, infiltrado inflamatório no perineuro e no tecido adiposo, desmielinização e aumento de tecido conjuntivo no perineuro. / Visceral leishmaniasis is an antropozoonosis, that is increasing in Brazil in number of cases and already being endemic in several states. The dogs, considered the main domestic reservoir, are of great importance in the maintenance of the epidemic cycle of the visceral leishmania, since the same is more prevalent in the canine population than in the human, and they can also serve as experimental model of the disease. Breaking of the hypothesis that the leishmaniasis visceral cause an outlying neuropathy in dogs, the present study aimed to analyze the alterations electroneurographics and histopathologics of the radial, ulnar, tibial and peroneal nerves of dogs attacked by the disease. Like this, 33 dogs naturally attacked by visceral leishmaniasis, and four dogs without the disease were submitted to eletroneurography and retreat of fragments of the nerves for analysis. The results obtained in this work allowed to end that dogs with visceral leishmaniasis can present reduced motor nerve conduction velocity, characterizing a neuropathy; to present histopathologics alterations indicative of an outlying neuropathy; and that the main alterations in the radial, ulnar, tibial and peroneal nerves of dogs with visceral leishmaniasis were increase of conjunctive tissue in the endoneurium, variation in the diameter of nervous fibers, degeneration axonal, infiltrated inflammatory in the perineurium and in the adipous tissue, desmielinization and increase of conjunctive tissue in the perineurium.

Chemotherapy-Induced Peripheral Neuropathy (NPIQ) is characterized by the toxic action of some medications used to treat cancer on the peripheral nerves. Approximately 48% of patients treated with multiple agents have some degree of NPIQ and the main symptoms involve: weakening or sensory loss, numbness, tingling, temperature sensitivity, allodynia, and hyperalgesia in a ‘stocking and glove’ format distribution. There is no definition of a pharmacological approach specific to NPIQ capable of showing relevant clinical benefit. However, in recent years a number of possible neuroprotective drugs have been investigated as an alternative for prevention or treatment of NPIQ. In this context, there are the antioxidant substances that have been used for centuries in preventive medicine and epidemiological studies support the idea that there is an inverse relationship between the levels of antioxidants in an organism and the development of neurodegenerative diseases. Different strategies to prevent and / or treat NPIQ have been developed in pre-clinical models with animals. However, when analyzing the methodologies used in this type of study, some methodological weaknesses arise and it becomes evident the need for a greater interaction between the methodologies developed for the experimental studies and the clinical studies. Thus, the objective of our study was to review the literature on the use of antioxidant substances for the treatment of peripheral neuropathy induced by chemotherapy in experimental models. A search of the SCOPUS, PUBMED and SCIENCE DIRECT databases was carried out in February and March 2016, which covered the works published since 2006. 25 articles were used to prepare the final version of the review. / A Neuropatia Periférica Induzida por Quimioterapia (NPIQ) é caracterizada pela ação tóxica de alguns medicamentos utilizados no tratamento do câncer sobre os nervos periféricos. Aproximadamente 48% dos pacientes tratados com múltiplos agentes têm algum grau de NPIQ e os principais sintomas envolvem: enfraquecimento ou perda sensorial, dormência, formigamento, sensibilidade à temperatura, alodinia e hiperalgesia, numa distribuição chamada de "bota e luva" (nas mãos e nos pés). Não há definição de uma abordagem farmacológica específica para a NPIQ capaz de mostrar benefício clínico relevante. Entretanto, nos últimos anos uma série de possíveis drogas neuroprotetoras tem sido investigada como alternativa de prevenção ou tratamento à NPIQ. Neste contexto, encontram-se as substâncias antioxidantes, que têm sido utilizadas há séculos na medicina preventiva e os estudos epidemiológicos sustentam a ideia de que existe uma relação inversa entre os níveis de antioxidantes em um organismo e o desenvolvimento de doenças neurodegenerativas. Diferentes estratégias para prevenir e/ou tratar a NPIQ vem sendo desenvolvidas em modelos pré-clínicos com animais. Entretanto, quando analisadas as metodologias empregadas neste tipo de estudo, algumas fragilidades metodológicas surgem e torna-se evidente a necessidade de uma maior interação entre as metodologias desenvolvidas para os estudos experimentais e os estudos clínicos. Desta forma, o objetivo do nosso trabalho foi realizar uma revisão da literatura sobre o uso de substâncias antioxidantes para o tratamento de neuropatia periférica induzida por quimioterapia, em modelos experimentais. Foi realizada uma busca nas bases de dados SCOPUS, PUBMED e SCIENCE DIRECT, nos meses de Fevereiro e Março de 2016, que abrangeu os trabalhos publicados a partir do ano de 2006. 25 artigos foram utilizados para elaboração da versão final da revisão. / Aracaju, SE

京都大学 / 0048 / 新制・課程博士 / 博士(農学) / 甲第21802号 / 農博第2315号 / 新制||農||1065(附属図書館) / 学位論文||H31||N5174(農学部図書室) / 京都大学大学院農学研究科応用生物科学専攻 / (主査)教授 久米 新一, 教授 松井 徹, 教授 廣岡 博之 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

n-Hexane and its metabolites are neurotoxic to animals and man. Studies have revealed a progressive neuropathy which affects the distal regions of motor and sensory peripheral nerves. This paper describes efforts to determine whether 2-hexanone or 2,5-hexanedione is more neurotoxic to rats when given in drinking water. Our results show that 2,5-hexanedione is more neurotoxic than 2-hexanone and that it first affects the distal axon. Concentrations of 20 mM produced no effects after 3 weeks but 40 mM increased distal latency after 2 weeks.

Indiana University-Purdue University Indianapolis (IUPUI) / The main focus of this study is to determine the impact of Set-Binding Factor 2 (SBF2) on human-derived neurons in the context of taxane-induced peripheral neuropathy. Taxane-induced peripheral neuropathy (TIPN) is a devastating survivorship issue for many cancer patients; SBF2 has been previously identified as a potential germline predictor that has been found to be significantly associated with severe TIPN in African American (AA) patients. The work described here provides ex vivo support for the use of SBF2 as a genotypic biomarker to identify a priori which patients are at a higher risk of manifesting severe TIPN. This study demonstrates that diminished expression of SBF2 exacerbated the effect of paclitaxel on viability and morphology and altered the functional response of a neuronal model exposed to paclitaxel treatment. Furthermore, transcriptomic work showed that reduced expression of SBF2 in a neuronal model treated with paclitaxel impacted the expression of genes that modulate stress-induced cell death and pain threshold. Altogether, these findings suggest that SBF2 plays a role in the development of TIPN. This work sheds light on the pathways potentially involving SBF2 that can be studied to further evaluate the function of this gene in neurons and its contribution to severe TIPN. Further functional approaches investigating these pathways will be pivotal in elucidating the underlying biological mechanism for this toxicity and identifying novel targeted therapeutic strategies to prevent or treat TIPN. / 2021-05-17