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Background Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting toxicity with significant sequelae impacting prognosis and quality of life. The natural history and pathophysiological mechanisms of CIPN are unclear. Equally, the lack of systematic approach to diagnosis and assessments contribute to difficulty identifying at risk patients with implications on symptom burden. Effective management of CIPN is also difficult due to limited treatment options. To try and address this challenging clinical problem, this thesis aimed to adopt a translational approach to: 1) characterisation and early identification of the development of CIPN in cancer patients receiving neurotoxic chemotherapy and 2) explore topical treatment options in patients with chronic peripheral neuropathic pain. Methodology In the CIPN study, a mixed cohort of colorectal, gynaecological and lung cancer patients receiving neurotoxic chemotherapy (platinum agents and taxanes) were assessed prospectively, at baseline (prior to initiating chemotherapy), during cycles (every 3 weeks) and post-treatment (every 3 months) for up to 12 months (cumulative 261 assessments). Comprehensive longitudinal clinical characterisation consisted of the integration of quantitative sensory testing (QST), objective measure of function (grooved pegboard test), patient-reported outcomes and in vivo confocal microscopy to provide insight into the clinical course and potential psychophysical biomarkers of CIPN during and after chemotherapy. In the pilot intervention study, patients with chronic, complex cancer treatment related peripheral neuropathic pain received a single application of high concentration 8% capsaicin patch. Assessments conducted at baseline, 4 weeks and 12 weeks included patient-reported outcomes and QST with an exploratory application of in vivo confocal microscopy in a case. Results In the CIPN study, 33 patients when compared to 33 age and gender matched healthy controls displayed thermal hyperalgesia, sensorimotor impairment and increased resting heart rate prior to initiating neurotoxic chemotherapy. Characterisation of somato-sensory profile demonstrated dysfunction of the various types of primary afferent nerves (Aβ, Aδ and C). Assessing the change over time from baseline to during cycles and post-treatment follow up, revealed signs and symptoms as early as cycle 2 with an increase in the later cycles and 3 months post-treatment follow up. A greater burden was observed at 12 months in comparison to baseline. Significant changes were observed in QST parameters indicating both small and large fibre deficits. Interesting associations were observed for example with tactile deficits in the upper and lower limb and patient-reported outcomes. The repeated measures model provided an opportunity to distil the relationship between subjective and objective measures of CIPN. The subclinical findings at baseline however did not translate to obvious predictors of CIPN development. The exploratory use of in vivo confocal microscopy (45 healthy controls, 9 patients) demonstrated correlation with current assessment tools (QST). Analysis from the pilot intervention study of 20 patients revealed clinically significant improvement in pain in a subset at 4 and 12 weeks post-treatment. Conclusion Overall the combination of subjective and objective measures utilised in the prospective characterisation of this mixed cohort of cancer patients provided a useful paradigm for qualifying and quantifying the trajectory of CIPN related peripheral nerve damage and symptom burden with additional contribution from the novel in vivo confocal microscopy work. In capturing the varied spectrum of phenotypes, this approach may provide insight into the complexities of the underlying neurobiological mechanisms. The baseline subclinical sensory, motor and autonomic nerve dysfunction implicate a cancer-mediated process possibly contributing to CIPN. Although the preliminary investigation of baseline predictors of CIPN was inconclusive, thermal pain threshold warrant further investigation. These findings highlight the need to further address prediction and risk stratification in larger studies. The exploratory intervention study suggests that patients with chronic neuropathic pain may receive some benefit in pain severity, function and mood with effect continuing at 12 weeks post-treatment. This research warrants further investigation in larger cohorts.

Introduction. Painful diabetic peripheral neuropathy (DPN) is a common complication of diabetes that interferes with daily living and causes severe pain. Pharmacotherapy is the accepted treatment strategy, however, this strategy is associated with high cost, minimal reductions in pain, and adverse side effects. Thus, a critical need exists to develop alternative treatment strategies. Purpose. To determine if a 12-week whole-body vibration (WBV) intervention reduces pain in adults with DPN. Methods. Twenty-one adults with physician confirmed painful DPN volunteered to take part in a 26-week time series design study. Pain was assessed with the Brief Pain Inventory Short Form [BPI-sf] and a 0-10 numeric rating scale [NRS]. The BPI-sf contains two indices that respectively measure how pain interferes with daily living and severity. The intervention began after a 12-week control period. At week 13, participants were asked to stand on a WBV machine 3 d/week for 4, 3-min bouts at 30-50 Hz with 1-min rest intervals between bouts. Pain levels were reported using the NRS before and after each bout. Results. Comparing post- to pre-intervention, BPI-sf pain interference scores decreased from 5.61±1.40 to 2.39±1.82 (p≤0.001). BPI-sf pain severity scores decreased from 5.1±0.64 to 3.1±1.87 (p≤0.01). Analyses of the NRS scores indicate that pain decreased each week following WBV and that between weeks, pain continued to decrease. Conclusion. These findings demonstrate that whole-body vibration was effective at reducing pain in a sample of adults with painful DPN. / Graduation date: 2012

The peripheral nervous system can be seen as a huge network of neurons that prop-agates signals across the human body. In fact, as seen in [1] , "All the information streaming in the peripheral nervous system (PNS) is transmitted along axons byelectro-chemical signals called action potentials". The ordinary conduction of such nervous signals, or action potentials, can be prevented however due to nerve damage. In this context, the accurate passage of information to an intended destination or partwithin the organism is obstructed. Admittedly, it is understood that physiotherapy can be quite helpful in regaining correct functionality over a damaged part of the peripheral nervous system. Yet, it is still hard to visualize the nervous activity as it is achieved inside the human body. Simulating the nervous system would providea platform to visualize how the system works and how a damaged nerve can affect the PNS. Indeed, the purpose of this study is to simulate a virtual network that im-itates a general topology of the human peripheral nervous system e.g(simulate the nervous structure and behaviour of the human arm) that shows how the signals canbe routed to their correct destination and showcase how can the simulator created simulate biological nerve damage in its system.

Submitted by Edineia Teixeira (edineia.teixeira@unioeste.br) on 2018-02-23T19:34:28Z No. of bitstreams: 2 André_Santana2017.pdf: 2268024 bytes, checksum: d4eee1d456e910253f049c57a48abf85 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2018-02-23T19:34:28Z (GMT). No. of bitstreams: 2 André_Santana2017.pdf: 2268024 bytes, checksum: d4eee1d456e910253f049c57a48abf85 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2017-08-04 / Peripheral nerve damage causes a number of morphological changes, resulting in functional, nerve and muscle complications. There are several therapeutic measures applied in rehabilitation, such as physical exercise in the aquatic environment, which has been extensively studied in terms of functional improvement, although its regenerative potential needs more evidence. Also, it is important to search for substances with therapeutic potential and that can be used in association with physical exercise, in order to intensify recovery. The protein biopolymer, sericin, obtained from the cocoon of the silkworm (Bombyx mori), presents a series of important regenerative pharmacological effects, with cicatrizant action in the treatment of burns, improvement in the aerobic performance and the oxidation of fat at rest. In this sense, the objective of this study was to analyze the effect of sericin associated or not to physical swimming exercise on the muscular recovery of Wistar rats, submitted to sciatic nerve injury. The experiment was carried out in a sample composed of 40 animals, 10 ± 2 weeks old, randomly divided into five groups: Ct: control; Ls: injury; Being: injury + sericin; Nat: injury + swimming; Ser + Nat: injury + sericina + physical exercise. The animals were anesthetized and submitted to compression injury of the right sciatic nerve. Immediately after the nerve compression, a dose of 100 μL of hydrolyzed sericin was applied to the injured nerve in Ser and Ser + Nat animals. On the other hand, the animals of the Nat and Ser + Nat groups, 72 hours after the injury, were treated with resisted physical exercise of swimming, with overload of 10% of body weight, during three weeks, five days a week. The animals performed fifteen minutes of swimming in the first week, 20 minutes in the second and 25 minutes in the third week. During the treatment, the grip strength of the right pelvic limb of all animals was evaluated. At the end of the experimental period, the animals were anesthetized for dissection and collection of the plantar muscle, and the proximal part was processed and analyzed histomorphologically, and the distal for histoenzymological analysis. Regarding the functional data of muscular strength of grip, morphology and morphometry of the 8 neuromuscular junctions, no significant influence on the neuromuscular regeneration process was observed. The same occurred with the musculoskeletal properties, which did not suffer significant changes in the association of sericin and swimming. Although physical swimming exercise alone was efficient in maintaining the intramuscular conjunctiva, the association with sericin was not able to alter the plantar muscle phenotype, although experimental axonotmosis did so. / Lesões nervosas periféricas causam uma série de alterações morfológicas, resultando em complicações funcionais, nervosas e musculares. Várias são as medidas terapêuticas aplicadas na reabilitação, como, por exemplo, o exercício físico em meio aquático, que vem sendo amplamente estudado no que diz respoieto à melhora funcional, embora seu potencial regenerativo necessite de maiores comprovações. Ainda, é importante a busca de substâncias com potencial terapêutico e que possam ser utilizadas em associação ao exercício físico, de forma a intensificar a recuperação. O biopolímero protéico sericina, obtido do casulo do bicho-da-seda (Bombyx mori), apresenta uma série de efeitos farmacológicos regenerativos importantes, com ação cicatrizante no tratamento de queimaduras, melhora no desempenho aeróbico e na oxidação de gordura em repouso. Nesse sentido, o objetivo deste estudo foi analisar o efeito da sericina associada ou não ao exercício físico de natação sobre a recuperação muscular de ratos Wistar, submetidos à lesão nervosa isquiática. O experimento foi desenvolvido numa amostra composta por 40 animais, com 10±2 semanas de idade, separados aleatoriamente em cinco grupos: Ct: controle; Ls: lesão; Ser: lesão + sericina; Nat: lesão + natação; Ser+Nat: lesão + sericina + exercício físico. Os animais foram anestesiados e submetidos à lesão por compressão do nervo isquiático direito. Imediatamente após a compressão nervosa, nos animais dos grupos Ser e Ser+Nat, foram aplicadas uma dose de 100 μL de sericina hidrolisada sobre o nervo lesionado. Já os animais dos grupos Nat e Ser+Nat, 72 horas após a lesão, foram tratados com exercício físico resistido de natação, com sobrecarga de 10% da massa corporal, durante três semanas, cinco dias por semana. Os animais realizaram quinze minutos de natação na primeira semana, 20 minutos na segunda e 25 minutos na terceira semana. No decorrer do tratamento, avaliou-se a força de preensão do membro pélvico direito de todos os animais. Ao término do período experimental, os animais foram anestesiados para dissecação e coleta do músculo plantar, sendo que a parte proximal foi processada e analisada histomorfologicamente, e a distal para análise histoenzimológica. Com relação aos dados funcionais de força muscular de preensão, morfologia e morfometria das junções neuromusculares, não foi observado influência significativa sobre o processo de regeneração neuromuscular. O mesmo ocorreu com as propriedades músculo esqueléticas, que não sofreram alterações significativas na associação da sericina e da natação. Embora o exercício físico de natação sozinho tenha sido eficiente na manutenção do conjuntivo intramuscular, a associação com sericina não foi capaz de alterar o fenótipo do músculo plantar, embora a axonotmese experimental o tenha feito.

Submitted by Edineia Teixeira (edineia.teixeira@unioeste.br) on 2018-03-06T17:41:31Z No. of bitstreams: 2 Andre_Santana2017.pdf: 2268027 bytes, checksum: 9d06e9ab0f5b41d9bdfbfbafcbba9200 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2018-03-06T17:41:31Z (GMT). No. of bitstreams: 2 Andre_Santana2017.pdf: 2268027 bytes, checksum: 9d06e9ab0f5b41d9bdfbfbafcbba9200 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2017-08-04 / Peripheral nerve damage causes a number of morphological changes, resulting in functional, nerve and muscle complications. There are several therapeutic measures applied in rehabilitation, such as physical exercise in the aquatic environment, which has been extensively studied in terms of functional improvement, although its regenerative potential needs more evidence. Also, it is important to search for substances with therapeutic potential and that can be used in association with physical exercise, in order to intensify recovery. The protein biopolymer, sericin, obtained from the cocoon of the silkworm (Bombyx mori), presents a series of important regenerative pharmacological effects, with cicatrizant action in the treatment of burns, improvement in the aerobic performance and the oxidation of fat at rest. In this sense, the objective of this study was to analyze the effect of sericin associated or not to physical swimming exercise on the muscular recovery of Wistar rats, submitted to sciatic nerve injury. The experiment was carried out in a sample composed of 40 animals, 10 ± 2 weeks old, randomly divided into five groups: Ct: control; Ls: injury; Being: injury + sericin; Nat: injury + swimming; Ser + Nat: injury + sericina + physical exercise. The animals were anesthetized and submitted to compression injury of the right sciatic nerve. Immediately after the nerve compression, a dose of 100 μL of hydrolyzed sericin was applied to the injured nerve in Ser and Ser + Nat animals. On the other hand, the animals of the Nat and Ser + Nat groups, 72 hours after the injury, were treated with resisted physical exercise of swimming, with overload of 10% of body weight, during three weeks, five days a week. The animals performed fifteen minutes of swimming in the first week, 20 minutes in the second and 25 minutes in the third week. During the treatment, the grip strength of the right pelvic limb of all animals was evaluated. At the end of the experimental period, the animals were anesthetized for dissection and collection of the plantar muscle, and the proximal part was processed and analyzed histomorphologically, and the distal for histoenzymological analysis. Regarding the functional data of muscular strength of grip, morphology and morphometry of the 8 neuromuscular junctions, no significant influence on the neuromuscular regeneration process was observed. The same occurred with the musculoskeletal properties, which did not suffer significant changes in the association of sericin and swimming. Although physical swimming exercise alone was efficient in maintaining the intramuscular conjunctiva, the association with sericin was not able to alter the plantar muscle phenotype, although experimental axonotmosis did so / Lesões nervosas periféricas causam uma série de alterações morfológicas, resultando em complicações funcionais, nervosas e musculares. Várias são as medidas terapêuticas aplicadas na reabilitação, como, por exemplo, o exercício físico em meio aquático, que vem sendo amplamente estudado no que diz respoieto à melhora funcional, embora seu potencial regenerativo necessite de maiores comprovações. Ainda, é importante a busca de substâncias com potencial terapêutico e que possam ser utilizadas em associação ao exercício físico, de forma a intensificar a recuperação. O biopolímero protéico sericina, obtido do casulo do bicho-da-seda (Bombyx mori), apresenta uma série de efeitos farmacológicos regenerativos importantes, com ação cicatrizante no tratamento de queimaduras, melhora no desempenho aeróbico e na oxidação de gordura em repouso. Nesse sentido, o objetivo deste estudo foi analisar o efeito da sericina associada ou não ao exercício físico de natação sobre a recuperação muscular de ratos Wistar, submetidos à lesão nervosa isquiática. O experimento foi desenvolvido numa amostra composta por 40 animais, com 10±2 semanas de idade, separados aleatoriamente em cinco grupos: Ct: controle; Ls: lesão; Ser: lesão + sericina; Nat: lesão + natação; Ser+Nat: lesão + sericina + exercício físico. Os animais foram anestesiados e submetidos à lesão por compressão do nervo isquiático direito. Imediatamente após a compressão nervosa, nos animais dos grupos Ser e Ser+Nat, foram aplicadas uma dose de 100 μL de sericina hidrolisada sobre o nervo lesionado. Já os animais dos grupos Nat e Ser+Nat, 72 horas após a lesão, foram tratados com exercício físico resistido de natação, com sobrecarga de 10% da massa corporal, durante três semanas, cinco dias por semana. Os animais realizaram quinze minutos de natação na primeira semana, 20 minutos na segunda e 25 minutos na terceira semana. No decorrer do tratamento, avaliou-se a força de preensão do membro pélvico direito de todos os animais. Ao término do período experimental, os animais foram anestesiados para dissecação e coleta do músculo plantar, sendo que a parte proximal foi processada e analisada histomorfologicamente, e a distal para análise histoenzimológica. Com relação aos dados funcionais de força muscular de preensão, morfologia e morfometria das junções neuromusculares, não foi observado influência significativa sobre o processo de regeneração neuromuscular. O mesmo ocorreu com as propriedades músculo esqueléticas, que não sofreram alterações significativas na associação da sericina e da natação. Embora o exercício físico de natação sozinho tenha sido eficiente na manutenção do conjuntivo intramuscular, a associação com sericina não foi capaz de alterar o fenótipo do músculo plantar, embora a axonotmese experimental o tenha feito.

In patients with Parkinson’s disease (PD), the molecularly misfolded form of α-synuclein was recently identified in cutaneous autonomic nerve fibers which displayed increased accumulation even in early disease stages. However, the underlying mechanisms of synucleinopathic nerve damage and its implication for brain pathology in later life remain to be elucidated. To date, specific diagnostic tools to evaluate small fiber pathology and to discriminate neurodegenerative proteinopathies are rare. Recently, research has indicated that deposition of α-synuclein in cutaneous nerve fibers quantified via immunohistochemistry in superficial skin biopsies might be a valid marker of PD which could facilitate early diagnosis and monitoring of disease progression. However, lack of standardization of techniques to quantify neural α-synuclein deposition limits their utility in clinical practice. Additional challenges include the identification of potential distinct morphological patterns of intraneural α-synuclein deposition among synucleinopathies to facilitate diagnostic discrimination and determining the degree to which structural damage relates to dysfunction of nerve fibers targeted by α-synuclein. Answering these questions might improve our understanding of the pathophysiological role of small fiber neuropathy in Parkinson’s disease, help identify new treatment targets, and facilitate assessment of response to neuroprotective treatment.

In patients with Parkinson’s disease (PD), the molecularly misfolded form of α-synuclein was recently identified in cutaneous autonomic nerve fibers which displayed increased accumulation even in early disease stages. However, the underlying mechanisms of synucleinopathic nerve damage and its implication for brain pathology in later life remain to be elucidated. To date, specific diagnostic tools to evaluate small fiber pathology and to discriminate neurodegenerative proteinopathies are rare. Recently, research has indicated that deposition of α-synuclein in cutaneous nerve fibers quantified via immunohistochemistry in superficial skin biopsies might be a valid marker of PD which could facilitate early diagnosis and monitoring of disease progression. However, lack of standardization of techniques to quantify neural α-synuclein deposition limits their utility in clinical practice. Additional challenges include the identification of potential distinct morphological patterns of intraneural α-synuclein deposition among synucleinopathies to facilitate diagnostic discrimination and determining the degree to which structural damage relates to dysfunction of nerve fibers targeted by α-synuclein. Answering these questions might improve our understanding of the pathophysiological role of small fiber neuropathy in Parkinson’s disease, help identify new treatment targets, and facilitate assessment of response to neuroprotective treatment.