Inborn errors of metabolism represent a heterogenous group of rare conditions, most having an incidence of less than 1 in 100,000 births. Because of their low prevalence, they are on the margin of attention of general research and even more so of large pharmaceutical companies. Study of rare diseases is the only way to design therapeutic options in order to improve quality of life of affected patients. Present Thesis particularly focuses on disturbances in mitochondrial energy metabolism. The main goals were the characterization of mitochondrial biogenesis within foetal development, as well as in childhood and adulthood. Another aim was to define clinical, biochemical and molecular aspects of mitochondrial optic neuropathies in childhood and adulthood. This work supported the earlier observations that gestational week 22 is the edge of viability, which has to be taken into account in upcoming discussions about guidelines on resuscitation of preterm neonates. Secondly, over last four years, we managed to examine and describe large cohort of patients with optic neuropathies based on a mitochondrial dysfunction. We have managed to characterize the biochemical and molecular-genetic background in more than 200 patients, and both selected cases (LHON/MELAS overlap syndrome) and cohort studies (MELAS,...

My thesis introduces the topic of nociceptive signalisation and processes involved in the formation and spreading of neuropathic pain. This study focuses on the mechanisms of nociceptive synaptic transmission mechanisms in the level of spinal dorsal horn and its modulation by paclitaxel, a chemotherapeutic drug inducing neuropathic changes. The attention is put especially on the possibility of glial activity participation in paclitaxel side effects. This idea stems from the existing hypothesis of the functional connection between TLR4 and TRPV1 receptor activity. TRPV1 is well known for its participation in chemical, thermal and nociceptive sensory transmission. Minocycline antibiotic is considered as an inhibitor of microglial activation therefore it was used for blocking neuroinflammation. The experimental part is comparing an impact of substances applied to the model of tachyphylaxis used for monitoring of nociceptive transmission changes according to decreasing activity of TRPV1 receptors. Electrophysiological recording of miniature excitatory postsynaptic currents from neurons in the Rexed laminae I. and II. of spinal dorsal horn was used. The results of my measurements show that minocycline is able to suppress acute effects of paclitaxel application in vitro if the spinal slice is incubated...

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.

京都大学 / 0048 / 新制・課程博士 / 博士(人間健康科学) / 甲第21306号 / 人健博第62号 / 新制||人健||5(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 黒木 裕士, 教授 恒藤 暁, 教授 坂井 義治 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

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Background: To investigate whether vaccination against SARS-CoV-2 is associated with the onset of retinal vascular occlusive disease (RVOD). Methods: In this multicentre study, data from patients with central and branch retinal vein occlusion (CRVO and BRVO), central and branch retinal artery occlusion (CRAO and BRAO), and anterior ischaemic optic neuropathy (AION) were retrospectively collected during a 2-month index period (1 June–31 July 2021) according to a defined protocol. The relation to any previous vaccination was documented for the consecutive case series. Numbers of RVOD and COVID-19 vaccination were investigated in a case-by-case analysis. A case– control study using age- and sex-matched controls from the general population (study participants from the Gutenberg Health Study) and an adjusted conditional logistic regression analysis was conducted. Results: Four hundred and twenty-one subjects presenting during the index period (61 days) were enrolled: one hundred and twenty-one patients with CRVO, seventy-five with BRVO, fifty-six with CRAO, sixty-five with BRAO, and one hundred and four with AION. Three hundred and thirty-two (78.9%) patients had been vaccinated before the onset of RVOD. The vaccines given were BNT162b2/BioNTech/Pfizer (n = 221), followed by ChadOx1/AstraZeneca (n = 57), mRNA- 1273/Moderna (n = 21), and Ad26.COV2.S/Johnson & Johnson (n = 11; unknown n = 22). Our case–control analysis integrating population-based data from the GHS yielded no evidence of an increased risk after COVID-19 vaccination (OR = 0.93; 95% CI: 0.60–1.45, p = 0.75) in connection with a vaccination within a 4-week window. Conclusions: To date, there has been no evidence of any association between SARS-CoV-2 vaccination and a higher RVOD risk.

Au Canada, nous remarquons une prédominance du diabète de type 2 au sein des communautés autochtones. Une approche ethnobotanique est utilisée en collaboration avec la Nation Crie de Eeyou Istchee afin de déterminer quels traitements à base de plantes peuvent être utilisés pour contrer les différentes conditions qui, collectivement, forment le diabète. Les pharmacopées de deux communautés cries, soit celles de Waskaganish et de Nemaska, ont été établies puis comparées à celles de étudiées antérieurement : communautés Whapmagoostui et Mistissini. Malgré les différences géographiques de ces groupes, leurs utilisations sont majoritairement semblables, avec pour seule exception le contraste entre les communautés de Nemaska et de Whapmagoostui. De plus, nous avons complété l’évaluation du taux cytoprotecteur des aiguilles, de l’écorce et des cônes de l’épinette noire (Picea mariana). Les extraits provenant de tous les organes des plantes démontrent une protection qui dépend de la concentration. La réponse spécifique d’organes peut varier selon l’habitat; ainsi, les plantes poussant dans les tourbières ou dans les forêts, sur le littoral ou à des terres l’intérieur démontrent des différences quant à leur efficacité. Bref, l’écorce démontre une relation dose-effet plus forte dans la forêt littorale, tandis que les aiguilles n’indiquent pas de changements significatifs selon leur environnement de croissance. La bioactivité observée démontre une corrélation avec le contenu phénolique et non avec l’activité de l’agent antioxydant. Ces résultats contribuent à péciser les activités antidiabétiques des plantes de la forêt boréale canadienne, telles qu’identifiées au niveau cellulaire par les guérisseurs Cries. / In Canada there is an overwhelming prevalence of type II diabetes in First Nations communities. Here an ethnobotanical approach has been used in cooperation with the Cree Nation of Eeyou Istchee to focus on finding plant based treatments for the conditions which collectively make up the symptoms of diabetes. The pharmacopoeias of two Cree communities (Waskaganish and Nemaska) are elucidated then compared with previously studied populations (Whapmagoostui and Mistissini). Despite differences in north-south east-west geography, plant ranking and use matrices were similar with the exception of Nemaska/Whapmagoostui. We have also completed the evaluation of Black spruce (Picea mariana) needle, bark and cone cytoprotectivity. Extracts from all organs exhibited concentration-dependent protection. Organ-specific response was habitat and growth environment dependent with plants grown either in bog or forest habitats in coastal or inland environments exhibiting differences in efficacy. Observed bioactivity correlated with total phenolic content but not with antioxidant activity. Together, these results contributed to the understanding of antidiabetic activity of Canadian boreal forest plants identified by the Cree of Eeyou Istchee healers at the cellular level.

A proteína quinase dependente de RNA (PKR) é uma molécula sentinela ativada em situações de estresse celular, incluindo infecções virais. A ativação de PKR por meio de sua fosforilação aciona cascatas de sinalização intracelular envolvidas em respostas inflamatórias e inibição da síntese protéica. Dados prévios do nosso laboratório sugerem que PKR está envolvida na hiperalgesia térmica de origem inflamatória. No presente estudo, foi investigado o papel da PKR na hiperalgesia térmica induzida pelo vírus da herpes simples tipo 1 (HSV1), durante as fases herpética e pós-herpética, combinando métodos comportamentais, genéticos, farmacológicos e moleculares. Camundongos C57bl/6, PKR+/+ e PKR-/- machos foram inoculados com HSV1. Os grupos controle foram inoculados com HSV1 inativo. Alodínia mecânica e hiperalgesia térmica foram monitoradas antes da inoculação do vírus e 8, 14, 21 e 28 dias após a inoculação. A curva dose e temporesposta e o teste da capsaicina foram realizados no 8º e 21º dias após a inoculação do vírus. Também nos períodos herpético e pós-herpético, foi investigado o perfil de expressão de proteínas envolvidas nas vias de sinalização de PKR (PKR, eIF2?, PACT, IKK e PP2A?), assim como o efeito da inibição de PKR pelo monitoramento da fosforilação de PKR, IKK?/?, P38, JNK, ERK1,2 e STAT3, e expressão de CaMKII? e TRPV1 nos GRD (L3-L6) ipsilateralmente à pata inoculada. Alodínia mecânica e hiperalgesia térmica ficaram evidentes até 28 dias após a inoculação. Camundongos PKR-/- desenvolveram alodínia mecânica, mas não hiperalgesia térmica, quando comparados com animais PKR+/+. A inibição sistêmica de PKR reverteu a hiperalgesia térmica de modo tempo- e dose-dependente e preveniu o comportamento nocifensivo induzido por capsaicina, enquanto PKR-/- apresentaram resposta nocifensiva praticamente ausente em ambas as fases herpética e pósherpética. Houve aumento da expressão de PP2A? e da fosforilação de PKR, IKK?/? e eIF2?, durante os períodos herpético e pós-herpético, e de PACT na fase pósherpética. A inibição de PKR promoveu o aumento da fosforilação de P38 em ambas as fases, e redução da fosforilação de PLC?1 acompanhada do retorno da fosforilação de Akt e STAT3 ao nível do grupo controle e o aumento da expressão de Ca-MKII? na fase herpética. Já na fase pós-herpética, reduziu a fosforilação de JNK e Akt e a expressão de Ca-MKII?, retornou a fosforilação de ERK1,2, PLC?1 e STAT3 ao nível do grupo controle e aumentou a expressão de TRPV1. Nossos resultados indicam que a atividade de PKR desempenha papel essencial na hiperalgesia térmica induzida por infecção pelo HSV1 / Double stranded RNA-activated protein kinase (PKR) is a sentinel molecule activated by cellular stress conditions, including viral infections. PKR activation by phosphorylation triggers cascades involved in inflammatory response and protein synthesis suppression. Our previous data suggest that PKR is involved in the inflammatory thermal hyperalgesia. Here we investigated the role played by PKR on thermal hyperalgesia induced by herpes simplex virus type-1 (HSV-1), during herpetic and post-herpetic phases, by combining behavioral, genetic, pharmacological, and molecular methods. Adult male C57bl/6, PKR+/+ and PKR-/- mice were inoculated with HSV-1. Control groups were inoculated with inactive (mock) HSV1. Mechanical allodynia and thermal hyperalgesia were monitored before virus inoculation and 8, 14, 21, and 28 days post-inoculation. The dose- and timeresponse curve and the capsaicin test were performed at 8th and 21st days post virus inoculation. Also in the herpetic and post-herpetic periods, was investigated the expression profile of proteins involved in the PKR signaling pathways (PKR, eIF2?, PACT, IKK and PP2A?), and the effect of PKR inhibition by monitoring PKR, IKK?/?, P38, JNK, ERK1,2, and STAT3 phosphorylation, and Ca-MKII? and TRPV1 expression in the dorsal root ganglia (L3-L6) ipsilaterally to the inoculated paw. Mechanical allodynia and thermal hyperalgesia became evident until 28 days postinnoculation. PKR-/- mice developed mechanical allodynia but not thermal hyperalgesia, when compared with PKR+/+ mice. Systemic PKR inhibition reversed thermal hyperalgesia in a dose and time-dependent manner, and prevented the capsaicin-induced nocifensive behavior, whereas PKR-/- showed no nocifensive behavior almost absent in both herpetic and post-herpetic phases. There was increased expression of PP2A? and the phosphorylation of PKR, IKK?/?, and eIF2?, during herpetic and post-herpetic periods, and PACT in the post-herpetic phase. PKR inhibition increased P38 phosphorylation in both phases, and reduction of PLC?1 phosphorylation together with the return of the Akt and STAT3 phosphorylation to the control group level, and enhanced Ca-MKII? expression in the herpetic phase. At the post-herpetic phase, suppressed JNK and Akt, and Ca-MKII? expression returned ERK1,2, PLC?1 and STAT3 phosphorylation to control group level and increased TRPV1 expression. The data indicate that PKR activity plays an essential role in the HSV-1 infection-induced thermal hyperalgesia

Made available in DSpace on 2015-09-25T12:23:16Z (GMT). No. of bitstreams: 1 ValeriaRibeiroNogueiraBarbosa.pdf: 2894050 bytes, checksum: 2496af522e31ec83452db4d278903717 (MD5) Previous issue date: 2003-09-29 / Carpal Tunnel Syndrome (CTS) represents the most common entrapment neuropathy, better defined and more studied in the human being. The diagnosis is commonly presumed in patients with painful syndrome in the upper limbs, whose symptoms aggravate at night. The gold-standard for the diagnosis is the occurring of alterations in the sensitive and muscled conduction of the median nerve. Despite the CTS being well clinically characterized, when it is typical, a lot of painful factors in the upper limbs are not caused by CTS, and these patients neuralgic exam may vary from normal to serious alterations. This paper has as objectives: 1. To evaluate the profile of the painful symptoms that may presumably occur in patients with idiopatic CTS or without CTS; 2. to evaluate the profile of the neuralgic exam in patients with idiopatic CTS. Between April and December of 2002, 35 patients with idiopatic CTS (34 women and one man) with diagnosis confirmed by the clinical and electrophysiological exam were examined. They were paired according to their age and sex with 35 citzens of the general population (34 women and one man, aged between 34 and 72, average 51, +/- 9,7 years old). The frequency of paintful syndromes distribution in the two groups studied was analysed by the square test. The age average in both groups of patients was compared by the t-Student test. There was not statistical difference concerning the ages. In the group with CTS the complaints of pain were prevalent in the neck (45,7%), Phalen`s test (68,5%), and fist compression (74,3%) are common, being the last two ones prevalent ( &#945; = 0,05). The severity of the CTS was evaluated by the eletrophysiological exam. Most of the CTS cases are of light degree and occur bilaterally. Just seven patients have unilateral CTS. Concluding: 1- One must cogitate the CTS diagnosis in every case of pain of obscure origin in the lower limbs, being the location either proximal or distal; 2- Just one of patients with CTS had, clearly, signs of cervical radicular injury. One cannot establish etiological relation between these two conditions. What is told about the existence of double-crush syndrome as a nosological entity; 3- In the neurogical exam, the alteration in the sensibility to pain was the most observed sign. The discriminatitive sensibility test seems not to have value to support the CTS diagnosis; 4- the Phalen and the carpal compression tests are more useful to the CTS diagnosis than the Tinel sign, for they are more prevalent. / A Síndrome do Túnel do Carpo (STC) representa a neuropatia compressiva mais comum, melhor definida e mais estudada no ser humano. O diagnóstico é comumente presumido em pacientes com síndrome dolorosa nos membros superiores, cujos sintomas se agravam à noite. O padrão-ouro para o diagnóstico é a ocorrência de alterações na condução sensitiva e motora do nervo mediano. Apesar da STC ser bem caracterizada clinicamente, quando é típica, muitos quadros dolorosos nos membros superiores não são causados por STC, e o exame neurológico desses pacientes pode variar de normal a alterações graves. Este trabalho tem como objetivos: 1- avaliar o perfil dos sintomas dolorosos que presumivelmente possam ocorrer em pacientes com STC idiopático e sem STC; 2- avaliar o perfil do exame neurológico em pacientes com STC idiopático. Entre abril e dezembro de 2002, 35 pacientes com STC idiopático (34 mulheres e um homem, idades entre 34 e 72 anos, média 51, + 9,8 anos) com diagnóstico confirmado pelo exame clínico e eletrofisiológico foram examinados. Eles foram pareados por idade e sexo com 35 sujeitos da população geral (34 mulheres e um homem, idades entre 34 e 72 anos, média 51, + 9,7 anos). A freqüência de distribuição de síndromes dolorosas nos dois grupos estudados foi analisada pelo teste do qui-quadrado. A média de idade dos dois grupos de pacientes foi comparada pelo teste t de Student. Não houve diferença estatística quanto às idades. No grupo com STC as queixas de dor são prevalentes no pescoço (42,8%), membros superiores (36,8%) e mãos (82,8%). Nos sujeitos sem STC a localização do quadro doloroso predomina na cabeça (11,4%), região axial do corpo (37,1%) e membros inferiores (22,8%), (&#945; = 0,05). Entre os sujeitos com STC, 85,7% apresentam queixas de parestesias nos membros superiores e 74,2% destes apenas nas mãos. Os chamados testes provocativos: sinal de Tinel (45,7%), teste de Phalen (68,5%) e compressão do punho (74,3%) são comuns, sendo os dois últimos prevalentes (&#945; = 0,05). A gravidade da STC foi avaliada pelo exame eletrofisiológico. A maioria dos casos de STC são de grau leve e ocorrem bilateralmente. Apenas sete pacientes têm STC unilateral. Em conclusão: 1 - Deve-se cogitar o diagnóstico de STC em todos os casos de dor de origem obscura nos membros superiores, seja de localização proximal ou distal; 2 - apenas uma das pacientes com STC teve, claramente, sinais de lesão radicular cervical. Não se pôde estabelecer relação etiológica entre as duas condições. O que fala contra a existência de síndrome da dupla compressão como uma entidade nosológica; 3 no exame neurológico, a alteração da sensibilidade à dor foi o sinal mais observado. O teste da sensibilidade discriminativa parece não ter valor para suportar o diagnóstico de STC; 4 os testes de Phalen e da compressão carpal são mais úteis para o diagnóstico de STC do que o sinal de Tinel, pois são mais prevalentes.