OLIVEIRA, Michelle Jacintha Cavalcante. Estudo da função túbulo-glomerular e inflamação renal em pacientes com leishmaniose visceral. 2014. 104 f. Tese (Doutorado em Ciências Médicas) - Universidade Federal do Ceará. Faculdade de Medicina, Fortaleza, 2014. / Submitted by denise santos (denise.santos@ufc.br) on 2013-01-21T12:15:42Z No. of bitstreams: 1 2010_dis_mjcoliveira.pdf: 1014007 bytes, checksum: ed5287e40e2bef46add81a80cdea76cd (MD5) / Approved for entry into archive by Erika Fernandes(erikaleitefernandes@gmail.com) on 2013-01-23T11:45:45Z (GMT) No. of bitstreams: 1 2010_dis_mjcoliveira.pdf: 1014007 bytes, checksum: ed5287e40e2bef46add81a80cdea76cd (MD5) / Made available in DSpace on 2013-01-23T11:45:45Z (GMT). No. of bitstreams: 1 2010_dis_mjcoliveira.pdf: 1014007 bytes, checksum: ed5287e40e2bef46add81a80cdea76cd (MD5) Previous issue date: 2010 / Background. The aim of this study is to investigate abnormalities in glomerular and tubular function in VL patients. Methods. This is a prospective study with 16 VL patients before treatment with pentavalent antimonium, in hospital monitoring, in Fortaleza, Ceará, Brazil. Urinary concentration and acidification tests were performed after a 12h period of water and food deprivation using desmopressin and calcium chloride (CaCl2). Glomerular filtration rate (GFR) Fractional excretion of sodium (FENa), transtubular potassium gradient (TTKG) and solute free water reabsorption (TcH2O) were calculated. Microalbuminúria and proteinúria were measured. The VL group pre-treatment was compared to a group of 13 healthy volunteers (control group) and 5 VL patients were revalued after treatment. Aquaporin 2 (AQP2), renal outer medullary K+ channels (ROMK) and pendrin were quantified trough exosomes search in urine. Monocyte chemotactic protein-1 (MCP-1) and malondialdehyde (MDA) were quantified in urine. Results. Urinary concentration deficit was found in all VL patients before (100%) and 4 in 5 cases (80%) after treatment. Urinary osmolality was significantly lower in VL patients pre-treatment compared to control group (516±113 vs. 743±189 mOsm/L, p<0,001, after 12h period water deprivation and desmopressin). There was no difference after treatment revaluation. Urinary acidification deficit was found in 9 cases before (56,22%) and 2 (40%) after treatment, considering urinary pH > 5.5 after CaCl2 test. GRF was similar between the groups. Proteinuria was significantly higher in VL patients pré-treatment (250,6±375,5 vs. 83,7±49,2 mg/24h, p=0,022) and presented important regression after revaluation (268,1±259,4 vs. 113,3±50,1, p=0,043). FENa was higher in VL group when compared to control group. The search for AQP2 (128±88 vs.100±40%, p=0,41), ROMK (122±42 vs. 100±27%, p=0,34) and pendrin (105±7,5 vs. 100±13% p=0,48) were not significant. Urinary MCP-1 showed significant difference between VL patients before treatment and control group (374±359 vs. 42±29 pg/mg-Cr, p=0.002) well as urinary MDA (5.4±2.6 vs. 2.0±0.8 μmol/mL). Conclusion. VL patients present persistent urinary concentration and acidification deficit in 90 days period after treatment and present inflammation and incipient renal damage although other classical markers such as creatinine are not cha / Introdução. O objetivo desse estudo é investigar as alterações túbulo-glomerulares e avaliar marcadores urinários nos pacientes com LV. Métodos. Foi realizado estudo prospectivo com 16 pacientes com LV antes do tratamento com antimonial pentavalente, em acompanhamento na cidade de Fortaleza, Ceará, Brasil. Testes de concentração e acidificação urinárias foram realizados. Foram calculadas taxa de filtração glomerular (TFG), fração de excreção de sódio (FENa), transporte transtubular de potássio (TTKG) e transporte de água livre de solutos (TCH2O). Avaliou-se a proteinúria. O grupo LV pré-tratamento foi comparado com 13 voluntários sadios (grupo controle) e cinco pacientes foram reavaliados no pós-tratamento. Os transportadores aquaporina 2 (AQP2), canal de K+ apical (ROMK) e pendrina foram quantificados pela pesquisa de exossomas na urina. A proteína quimiotática de monócitos (MCP-1) e o malondialdeído (MDA) foram quantificados na urina. Resultados. Déficit de concentração urinária foi encontrado em todos os pacientes antes (100%) e em cinco dos quatro casos reavaliados (80%) depois do tratamento. A osmolaridade urinária média foi significativamente menor nos pacientes LV pré-tratamento quando comparado ao controle (516±113 vs. 743±189 mOsm/L, p<0,001) e não houve diferença entre os pacientes reavaliados no pós-tratamento. Déficit de acidificação foi detectado em nove casos (56,2%) antes e 2 (40%) após o tratamento, considerando o pH urinário > 5,5 após sobrecarga de CaCl2. A proteinúria mostrou-se significantemente maior no grupo LV pré-tratamento (250,6±375,5 vs. 83,7±49,2 mg/24h, p=0,022) regredindo após o tratamento (268,1±259,4 vs. 113,3±50,1mg/24h, p=0,043). FENa foi mais elevada no grupo LV pré-tratamento. A pesquisa dos exossomas urinários AQP2 não mostrou diferença significativa em relação ao grupo controle (128±88 vs.100±40, p=0,41), assim como a do canal ROMK (122±42 vs. 100±27, p=0,34) e da pendrina (105±7,5 vs. 100±13% p=0,48). A dosagem de MCP-1 e MDA urinários foram mais elevadas nos pacientes pré-tratamento quando comparado aos controles (374±359 vs. 42±29 pg/mg-Cr, p=0.002 e 5.4±2.6 vs. 2.0±0.8 μmol/mL, respectivamente). Conclusão. Pacientes com LV apresentam déficit de concentração e acidificação urinárias antes e 90 dias após o tratamento e evidências de inflamação renal incipiente.

L’accident vasculaire cérébral (AVC) est l’une des principales causes de mortalité dans le monde. Sile taux de de mortalité associé à l’AVC a sensiblement diminué dans les dernières décennies, cela estprincipalement du à l’amélioration globale de l’état de santé de la population et non à la découverte d’untraitement thérapeutique contre l’AVC et de nombreux survivants garderont des séquelles. Dans ce contexte,l’influence de la nutrition qui pourrait jouer un rôle central dans la résistance à l’AVC reste très peu étudier.Pourtant de nombreuses études épidémiologiques confèrent des propriétés protectrices à certaines moléculesnaturelles comme les acides gras polyinsaturés oméga-3.Dans un modèle murin d’AVC, notre laboratoire ayant montré que la consommation d’un régimeenrichi en acide a-linolénique (ALA), l’oméga-3 végétal, réduisait le volume d’infarctus cérébral, mestravaux ont porté sur l’effet de la supplémentation nutritionnelle en ALA. J’ai montré que la supplémentationen ALA par voie orale ou intraveineuse favorise la récupération cognitive post-AVC. Ces bénéfices sontassociés à la préservation des neurones de l’hippocampe, une structure cérébrale impliquée dans la mémoire.Par la suite, je me suis intéressé à l’effet de l’ALA sur la réponse inflammatoire pos-AVC, une composantemajeure dans l’étendue des séquelles. J’ai pu ainsi caractériser le rôle neurotoxique de la chimiokine CCL2 etd’identifier la réduction de son expression post-AVC, comme un facteur clé de la protection cérébrale induitepar la supplémentation en ALA. De plus, une étude collaborative nous a permis de mettre en évidencel’implication de la voie de signalisation de cette chimiokine dans la perte de poids induite par uneinflammation du système nerveux central. Mes travaux soulignent l’importance de la supplémentation en ALA pour réduire les conséquences d’un AVC, en ciblant la réponse pro-inflammatoire post-ischémique, apportant une preuve supplémentaire del’intérêt de l’ALA contre l’une des priorités les plus urgentes de la médecine / Stroke is a worldwide major cause of mortality and morbidity without any therapeutic opportunities.While improvements in population health - in the control of major risk factors of stroke - over the pastdecades have contributed to reduced stroke mortality, numerous therapeutics applied acutely after stroke havefailed to improve long-term clinical outcomes. Weirdly, how nutrition may affect stroke damage and recoveryhas not yet been intensely investigated, which is surprising given its great influence as risk factor. Therefore,our lab is investigating an emerging view that is the health potential of a-linolenic acid (ALA is the omega-3contained in plant-derived edible products) in stroke.Our laboratory has previously shown that ALA injections or dietary supplementation reduces strokedamage by direct neuroprotection in rodent models of stroke. As successful translation of putative therapieswill depend on demonstration of efficacy on stroke-induced motor and cognitive deficits, my PhD work hasevaluated the value of ALA supplementation in stroke recovery. I demonstrated that oral and intravenoussupplementation of ALA improved cognitive recovery, which was associated to a better preservation ofhippocampus, a brain structure involved in memory. Looking for mechanistic insights, I also investigated theeffect of ALA supplementation by modification of the daily diet on post-stroke inflammatory response. Wefirst demonstrated a neurotoxic role of the chemokine CCL2 after stroke and identified its reduction, as a keyfactor in brain protection induced by ALA supplementation. In addition, I also contributed to a collaborativestudy deciphering the role of CCL2 in weight loss induced by inflammation of the central nervous system.To conclude, my PhD highlights the importance of ALA supplementation to reduce the consequencesof stroke, targeting post-ischemic pro-inflammatory response and prepare the ground of clinical trial onnutritional interventions that are yet to be evaluated

Prostatacancer är en vanlig form av cancer som blivit ett mänskligt såväl som medicinskt problem världen över, orsakerna är ännu inte kartlagda och man letar kontinuerligt efter adekvata biomarkörer. Cutibacterium acnes är en bakterie som ingår i vår normalflora som visat kontroversiella bevis på att kunna ha en inverkan på makrofagers produktion av cytokiner, så som CCL2, som i sin tur kan påverka progression av prostatacancer. Syftet med denna undersökning är att se om makrofager producerar förhöjda nivåer av CCL2 vid närvaro av C. acnes. Undersökningen utfördes genom användandet av immunoassay metoden ELISA för att detektera proteinnivåerna av CCL2 hos makrofager behandlade med typ I och typ II av C. acnes jämfört med obehandlade makrofager. Resultatet visade att det fanns en signifikant skillnad mellan de makrofager som var obehandlade och de som var behandlade med typ I av C. acnes men inte mellan de obehandlade och de som var behandlade med typ II av C. acnes över alla givare. Medelvärdena för de makrofager som var behandlade med någon typ av C. acnes var dock högre än hos de obehandlade för alla givare, trots att ingen signifikant skillnad uppvisades. Det behövs därmed mer forskning innan man kan se om CCL2 kan vara en adekvat biomarkör för prostatacancer men att närvaro av C. acnes typ I i makrofager kommer leda till en överproduktion av CCL2. / Prostate cancer is a common form of cancer worldwide; the reasons behind this disease are still largely unknown, and scientist are looking for informative biomarkers that are indicative of this disease. Cutibacterium acnes, a bacterium commonly found in human tissue, including prostate cancer tissue, has shown controversial evidence on its effects on macrophages and their consecutive production of cytokines such as CCL2, which potentially could contribute to cancer progression. The purpose of this paper is to examine if macrophages in contact with this bacterium will increase the production of CCL2. This was done by using the ELISA immunoassay method to detect the level and CCL2 production in macrophages treated with type I and type II forms of C. acnes and to compare this with untreated macrophages. The results showed that there was a significant difference between the untreated macrophages and those treated with type I of C. acnes but not between those untreated and those treated with type II of C. acnes across all donors. The average of CCL2 production was increased on those macrophages treated with any type of C. acnes compared to the untreated macrophages, even though no significant difference was shown statistically, on all donors. In conclusion the results show that it is evident that more research is needed to determine whether CCL2 are an adequate biomarker for prostate cancer but that infiltration of C. acnes type I in macrophages will contribute to an overproduction of the cytokine CCL2.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13454号 / 論医博第2247号 / 新制||医||1055(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 竹内 理, 教授 杉田 昌彦, 教授 生田 宏一 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23801号 / 医博第4847号 / 新制||医||1058(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 小林 恭, 教授 竹内 理, 教授 金子 新 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Modulation of nociceptive synaptic transmission in the spinal cord dorsal horn is a significant mechanism in the development and maintenance of different pathological pain states. Accumulating evidence indicates that the TRPV1 (transient receptor potential vanilloid 1) receptor and chemokine CCL2 (C-C motif ligand 2) may play a critical role in this process. The aim of this diploma thesis was to investigate the CCL2 induced modulation of nociceptive synaptic transmission in the dorsal horn of spinal cord and the role of the TRPV1 receptors. To investigate this aim patch-clamp recordings of spontaneous and miniature excitatory postsynaptic currents (sEPSC, mEPSC) from superficial dorsal horn neurons in acute rat lumbar spinal cord slices were used. After acute application of CCL2 on the slice preparation from naïve animals, a frequency increase of both sEPSC and mEPSC was present. This CCL2 induced increase in both sEPSC and mEPSC frequency was prevented by the TRPV1 receptor antagonist SB366791 application. No changes were observed in the amplitudes of sEPSC or mEPSC after application of the CCL2, SB366791, or co-application of CCL2 and SB366791. This suggests that the observed changes were mediated predominantly by presynaptic mechanisms. The preliminary results indicate that after chronic constriction...

Thesis (Ph. D.)--University of Washington, 2006. / Vita. Includes bibliographical references (leaves 71-91).

Submitted by Hiolanda Rêgo (hiolandarego@gmail.com) on 2016-12-21T14:48:29Z No. of bitstreams: 1 Tese_ICS_Eliane Pereira Menezes.pdf: 18598624 bytes, checksum: e2cc868d4bb1be2b815801b4f4db02b8 (MD5) / Made available in DSpace on 2016-12-21T14:48:29Z (GMT). No. of bitstreams: 1 Tese_ICS_Eliane Pereira Menezes.pdf: 18598624 bytes, checksum: e2cc868d4bb1be2b815801b4f4db02b8 (MD5) / Estudos mais recentes mostraram uma complexidade da resposta imune e diferentes tipos celulares estão envolvidos na imunoregulação de diversas doenças, incluindo a leishmaniose. Sendo assim, o tipo de resposta imune do hospedeiro infectado é determinado pelo padrão de citocinas produzidas pelos linfócitos T CD4+. A resposta imune Th1 é principalmente representada pela produção de INF-y, IL-2, TNF- e corresponde a denominada imunidade celular que auxilia a resposta efetora de outros linfócitos T CD4+, T CD8+ citotóxicos e macrófagos. A resposta imune Th2 está relacionada com a produção de IL-4, IL-5 e IL-10 e estimulação de linfócitos B na síntese de anticorpos IgG1, IgG4 e IgE, ativação de eosinófilos e mastócitos. As células T regulatórias suprimem ambos os tipos de resposta através de contato celular e pela produção de citocinas como IL-10 e TGF-b. Diversos estudos têm demonstrado uma influência genética em muitas doenças complexas, usando escaneamento de genoma e estudos de associação. Inicialmente diversos estudos mostraram associação entre doenças infecciosas, incluindo a leishmaniose e HLA. Posteriormente, a observação de polimorfismos genéticos em genes de citocinas, quimiocinas, receptores celulares, fatores de transcrição e diversos produtos que influenciam direta ou indiretamente a resposta imune, gerou diversos estudos associando esses polimorfismos com doenças. Por exemplo, um polimorfismo na posição -308, com mutação de G por A, no gene de TNF- , foi demonstrado que induzia a produção de níveis mais elevados dessa citocina e tem sido associado com várias doenças, incluindo leishmaniose cutânea (LC), mucosa (LM) e visceral (LV). No presente trabalho, avaliamos alguns polimorfismos funcionais em genes que codificam produtos relacionados à resposta imune com o objetivo de investigar se fatores genéticos relacionados com o controle da resposta imune influenciam o curso da infecção por Leishmania. Dois tipos de análises foram realizados: 1) Um estudo tipo caso-controle com objetivo de comparar as freqüências alélicas dos genes de IL- 6, linfotoxina- e MCP-1 em quatro grupos de 60 indivíduos cada: LM, LC, controle de vizinhança sem doença (“aparentemente normal”) (CN) e controle DTH+; 2) Um estudo baseado em família (FBAT) para confirmar as associações encontradas no estudo caso-controle. O estudo caso-controle demonstrou: 1) Alta freqüência do alelo C de IL-6 -174 G/C em LM quando comparado com LC e CN. A análise de FBAT confirmou a associação entre o alelo C e LM tanto no modelo aditivo (z=4.295, p=0.000017) como no modelo dominante (z=4.325, p=0.000015); 2) Uma freqüência alta do alelo G de linfotoxina- +252 G/A em LM quando comparado com LC, não sendo essa associação confirmada pelo estudo de famílias: 3) Uma freqüência alta do alelo G de CCL2/MCP-1 -2518 A/G em LM quando comparado com CN (OR=2.3; p=0.0078; 95% CI 1.3-4.1). O teste de FBAT confirmou a associação do alelo G de MCP-1 com LM no modelo recessivo (z=2.69, p=0.007). Esse estudo demonstrou uma associação entre os polimorfismos de genes que induzem a resposta inflamatória com a LM, sugerindo que eles podem influenciar o curso clínico da leishmaniose. Esta tese inclui 3 artigos originais e um capítulo de livro.