Submitted by jose de souza andrade neto andrade (neto.jsa@hotmail.com) on 2018-01-09T15:51:07Z No. of bitstreams: 1 José Andrade Neto - Doutorado em Anestesiologia.pdf: 670032 bytes, checksum: b5c727b9c523ebb565c09234ac9ba901 (MD5) / Approved for entry into archive by Luciana Pizzani null (luciana@btu.unesp.br) on 2018-01-10T12:53:05Z (GMT) No. of bitstreams: 1 andrade neto_js_doc_int.pdf: 670032 bytes, checksum: b5c727b9c523ebb565c09234ac9ba901 (MD5) / Made available in DSpace on 2018-01-10T12:53:05Z (GMT). No. of bitstreams: 1 andrade neto_js_doc_int.pdf: 670032 bytes, checksum: b5c727b9c523ebb565c09234ac9ba901 (MD5) Previous issue date: 2017-10-16 / Introdução: a lesão renal aguda (LRA) é prevalente em pacientes hospitalizados e responsável por alta morbimortalidade. No entanto, ainda não há um marcador precoce e acurado para seu diagnóstico. Pacientes idosos estão em risco de desenvolver LRA no pós-operatório de grandes cirurgias. Objetivos: avaliar o biomarcador cistatina C plasmática como preditor precoce de LRA no período pós-operatório de cirurgia para correção de fratura de fêmur em idosos. Método: cinquenta e nove pacientes idosos submetidos à cirurgia de correção de fratura de fêmur foram estudados prospectivamente por 48 horas do pós-operatório. Amostras de sangue foram coletadas para análise de cistatina C plasmática nos seguintes tempos: logo ao término da cirurgia, no período de 4 e 24 horas depois. Amostras da creatinina foram coletadas na admissão hospitalar, ao término da cirurgia, 4, 24 e 48 horas no pós-operatório. Para a determinação do diagnóstico e estadiamento de LRA foi utilizado o critério KDIGO (Kidney Disease Improve Global Outcomes Acute Kidney Injury Workgroup). Foi analisada a precocidade e acurácia, esta última por meio da área sob a curva receiver operating characteristic (AUC ROC), da molécula de cistatina C plasmática para diagnóstico de LRA (KDIGO ≥1). Resultados: vinte e um pacientes (35,5%) apresentaram LRA. A cistatina C plasmática foi um marcador precoce de LRA elevando-se 4 horas após o fim da cirurgia (p < 0,003). Obteve uma AUC ROC em 4 horas de 0,750 (IC 95% de 0,610 a 0,860) e de 0,778 (IC 95% de 0,640 a 0,870) em 24 horas do pós-operatório. Conclusão: a molécula de cistatina C plasmática é um marcador precoce e com boa acurácia (apresentou AUC ROC > 0,70) para LRA, além de possuir elevado valor preditivo negativo para o ponto de corte de 0,92mg/L após 4 horas do término da cirurgia.

The thesis focuses on the investigation of the role of tick salivary components in the course of Lyme disease in mice. It includes studies on the saliva-facilitated transmission of Borrelia burgdorferi in vivo and the effect of tick cysteine protease inhibitors (cystatins) both on murine immune cells and the transmission of B. burgdorferi spirochetes in mice. The thesis also reveals practical applications of salivary cystatins for the development of anti-tick vaccine and the application of the pharmacological action of a tick salivary cystatin for the therapy of the disease symptoms in a mouse model of experimental asthma.

Tenofovir (TDF), um antirretroviral análogo nucleotídeo inibidor da transcriptase reversa, indicado para o tratamento da infecção pelo vírus da Hepatite B em indivíduos HBeAg reagentes, não cirróticos, tem sido implicado na ocorrência de Injúria renal aguda (IRA) e lesão do túbulo proximal renal (TPR), com características semelhantes à Síndrome de Fanconi, caracterizada por glicosúria, bicarbonatúria, fosfatúria, uricosúria e proteinúria de baixo peso molecular. Outros trabalhos sugerem que os pacientes em uso de TDF sofram toxicidade aos glomérulos, com uma pequena, porém significante redução da taxa de filtração glomerular. O tempo de uso da droga para que ocorra lesão renal é desconhecido. Entretanto, a maioria dos estudos de investigação de nefrotoxicidade do TDF foi realizada em pacientes portadores de infecção pelo HIV. Especula-se que a nefrotoxicidade desta droga possa ser exacerbada ou reduzida pelo uso de outras medicações, frequentemente usadas por pacientes com HIV, que competem com o transporte tubular ou com sua metabolização, aumentando o seu nível sérico. O objetivo geral deste trabalho é avaliar prospectivamente a incidência de lesão renal pelo uso de TDF em pacientes portadores de hepatite B. Os objetivos específicos deste trabalho são: (1) avaliar incidência de lesão do TPR através da avaliação da excreção urinária de ácido úrico, fósforo e da proteína de baixo peso molecular neutrophil gelatinase associated lipocalin (NGAL); (2) avaliar a incidência de redução aguda da taxa de filtração glomerular (LRA) ou redução crônica da mesma. Métodos: Foram incluídos 24 pacientes portadores de Hepatite B que tiveram indicação de iniciar o uso de TDF com idade superior a 18 anos ou inferior a 75 anos. Neste estudo prospectivo, foi realizado a coleta de dados clínicos (idade, gênero, etnia, tempo de doença, antecedentes pessoais, medicações concomitantes, fator de risco para contaminação do VHB, história familiar de infecção VHB) e a avaliação laboratorial foi feita através da coleta de sangue e urina feitas antes do início do uso do TDF e, posteriormente à sua introdução, semestralmente durante 2 anos. Ao final do seguimento foi avaliada a incidência de lesão renal pelo uso de TDF, através das seguintes dosagens: glicemia, fosfatemia, gasometria, creatinina e Cistatina C séricas, microalbuminúria, proteinúria, proteinúria de baixo peso molecular (NGAL), clearance de creatinina, fosfatúria, uricosúria e urina rotina. Foi feita análise estatística comparativa entre os pacientes que usaram o TDF pré tratamento e pós tratamento para detectar lesão do TPR ou redução da taxa de filtração glomerular ao longo do tempo. Resultados: Não foi identificado aumento significativo da creatinina no decorrer do estudo (p = 0,09; R = 2,4%), entretanto, foi observada uma queda significativa nos valores do clearance de creatinina em 24 horas (p < 0,01; R = 15,8%). Não foi observada tendência de queda da filtração glomerular através das fórmulas MDRD simplificada (p = 0,11), CKD-EPI (p=0,14), CKD-EPI cystatin C (p = 0,23). Em relação à cistatina C sérica também não foi observada sua elevação no decorrer do tempo (p=0,15; R = 2,4%). Não foi observado, utilizando-se modelo de regressão linear, aumento na excreção urinária de albumina no decorrer do estudo (p = 0,97; R = 0,00%), mas houve aumento significativo na proteinúria de 24h (p < 0,01). Foi observada também, redução da uricosúria com o passar do tempo (p = 0,01; R = 6,7%) e houve correlação positiva entre o clearance de creatinina dosado em urina de 24 horas e a excreção de ácido úrico em urina de 24 horas (p=0,01; r = + 0,60). A fração de excreção de fósforo (urina de 24h): não foi observada alteração no decorrer do tempo (p = 0,83; R = 0,5%), porém houve correlação negativa com entre o clearance de creatinina dosado em urina de 24 horas e a fração de excreção de fósforo (FePO4) dosada em urina de 24 horas (p = 0,05; r = - 0,25). A detecção de NGAL na urina foi feita pelo índice UNGAL/Ucreat e não foi observado aumento significativo de sua excreção no decorrer do tempo (p = 0,40, r = 0,8%). Conclusão: em conclusão no presente estudo observou-se desenvolvimento de lesão renal aguda em 10% dos pacientes em uso de tenofovir e redução significativa da filtração glomerular. A fosfatúria e proteinúria observados sugerem que a lesão tenha sido decorrente de tubulopatia proximal e os marcadores mais específicos de lesão renal, cistatina C e NGAL, não foram superiores aos biomarcadores disponíveis na prática clínica na detecção destas alterações. / Tenofovir (TDF) a nucleotide analog reverse transcriptase inhibitor antiretroviral indicated for the treatment of infection with the hepatitis B virus in reagents HBeAg individuals, non-cirrhotic patients, has been implicated in the occurrence of acute kidney Injury (AKI) and the proximal tubule injury kidney (TPR), with similar to Fanconi syndrome characterized by glucosuria, bicarbonatúria, phosphaturia, proteinuria, uricosuria and low molecular weight characteristics. Other studies suggest that patients using TDF toxicity suffer the glomeruli, with a small but significant reduction in glomerular filtration rate. The time of drug use for kidney damage that occurs is unknown. However, most of the research studies of nephrotoxicity TDF was performed in patients with HIV infection. It is speculated that the nephrotoxicity of this drug may be exacerbated or reduced by the use of other medications, often used by patients with HIV, which compete with the tubular transport or metabolism, increasing its serum level. The overall objective of this study is to prospectively evaluate the incidence of renal injury by the use of TDF in patients with hepatitis B. The specific objectives of this work are: (1) assess the incidence of injury TPR by assessment of urinary excretion of uric acid, phosphorus and protein of low molecular weight neutrophil gelatinase associated lipocalin (NGAL); (2) assess the incidence of acute reduction in glomerular filtration rate (IRA) or chronic reduction. Methods: 24 patients with hepatitis B who were advised to initiate the use of TDF over the age of 18 years or below 75 years were included. In this prospective study, the collection of clinical data (age, gender, ethnicity, duration of disease, personal history, concomitant medications, risk factor for HBV infection, family history of HBV infection) and laboratory evaluation was done by collect blood and urine samples taken before initiation of the use of TDF and after its introduction, semiannually for 2 years. At final follow-up the incidence of renal injury by the use of TDF was assessed through the following dosages: glucose, phosphatemia, gases, creatinine and serum cystatin C, microalbuminuria, proteinuria, low molecular weight proteinuria (NGAL), clearance creatinine, phosphaturia, uricosuria and urine routine. The comparative statistical analysis of patients using TDF pre-treatment and post treatment to detect the TPR injury or reduced glomerular filtration rate over time. Results: There was not significant increase in creatinine identified during the study (p = 0.09; R = 2.4%), however, a significant decrease was observed in the values of creatinine clearance at 24 hours (p <0.01; R = 15.8%). No downward trend was observed in glomerular filtration through the simplified MDRD formulas (p = 0.11), CKD-EPI (p = 0.14), CKD-EPI cystatin C (p = 0.23). Regarding the serum cystatin C its elevation was not observed over time (p = 0.15, R = 2.4%). Increased urinary albumin excretion during the study was not observed using a linear regression model (p = 0.97, R = 0.00%), but there was significant increase in 24-hour proteinuria (p <0, 01). And there was a positive correlation between creatinine clearance at 24 hour urine and the excretion of uric acid in 24 hour urine (p = 0.01, R = + 0.60), uricosuria reduction over time was also observed (p = 0.01, R = 6.7%). No change was observed over time in the fractional excretion of phosphorus (24 h urine), (p = 0.83; R = 0.5%), but there was a negative correlation between creatinine clearance urine dosed at 24 hours and fractional excretion of phosphorus (FePO4) measured in 24 hour urine (p = 0.05, r = - 0.25). The detection of NGAL in the urine was taken by UNGAL / Ucreat index and was not observed significant increase in excretion over time (p = 0.40, r = 0.8%). Conclusion: In conclusion at the present study we observed the development of acute kidney injury in 10% of patients using tenofovir and a significant reduction in glomerular filtration. The phosphaturia and proteinuria observed suggest that the injury has been caused by proximal tubulopathy and more specific markers of renal injury as cystatin C and NGAL were not greater than the available biomarkers in clinical practice for their detection.

Orientador: Norma Sueli Pinheiro Módolo / Resumo: Introdução: a lesão renal aguda (LRA) é prevalente em pacientes hospitalizados e responsável por alta morbimortalidade. No entanto, ainda não há um marcador precoce e acurado para seu diagnóstico. Pacientes idosos estão em risco de desenvolver LRA no pós-operatório de grandes cirurgias. Objetivos: avaliar o biomarcador cistatina C plasmática como preditor precoce de LRA no período pós-operatório de cirurgia para correção de fratura de fêmur em idosos. Método: cinquenta e nove pacientes idosos submetidos à cirurgia de correção de fratura de fêmur foram estudados prospectivamente por 48 horas do pós-operatório. Amostras de sangue foram coletadas para análise de cistatina C plasmática nos seguintes tempos: logo ao término da cirurgia, no período de 4 e 24 horas depois. Amostras da creatinina foram coletadas na admissão hospitalar, ao término da cirurgia, 4, 24 e 48 horas no pós-operatório. Para a determinação do diagnóstico e estadiamento de LRA foi utilizado o critério KDIGO (Kidney Disease Improve Global Outcomes Acute Kidney Injury Workgroup). Foi analisada a precocidade e acurácia, esta última por meio da área sob a curva receiver operating characteristic (AUC ROC), da molécula de cistatina C plasmática para diagnóstico de LRA (KDIGO ≥1). Resultados: vinte e um pacientes (35,5%) apresentaram LRA. A cistatina C plasmática foi um marcador precoce de LRA elevando-se 4 horas após o fim da cirurgia (p < 0,003). Obteve uma AUC ROC em 4 horas de 0,750 (IC 95% de 0,610 a 0,860) e de... (Resumo completo, clicar acesso eletrônico abaixo) / Doutor

A doença de Unverricht-Lundborg (DUL) é considerada uma doença rara, autossômica recessiva, sendo também denominada de Epilepsia Mioclônica Progressiva do tipo1 (emp1), causada por mutações no gene codificador (CSTB) da proteína cistatina B. A cistatina B é uma proteína essencial para a regulação dos processos fisiológicos do ser humano, e sua expressão reduzida parece ser a causa primária da EMP1. A doença em geral se inicia entre os seis e dezesseis anos, manifestando-se tanto como crises mioclônicas como por crises tônicoclônicas generalizadas. Trata-se de uma doença grave e limitante, cujo diagnóstico preciso é extremamente importante para as condutas apropriadas, incluindo aconselhamento genético. Este estudo tem como objetivo o estudo molecular e caracterização da expansão instável de repetição dodecamérica (CCCCGCCCCGCG) da região promotora 5\' não traduzida do gene CSTB entre pacientes com suspeita de EMP1 na população brasileira. No presente estudo, selecionamos 64 pacientes entre eles 54 casos índices do Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto (HCFMRP-USP) com suspeita de EMP1. Os restantes 10 casos eram parentes dos casos índices. Os 54 pacientes foram seguidos no setor de Epilepsia com diagnostico clinico e eletrofisiológico de EMP1, e foram encaminhados para o setor de Neurogenética para diagnostico molecular. Destes 54 casos índices, apenas 5 foram diagnosticados através da biologia molecular com expansão dodecamera acima de 30 repetições, sugestivo de DUL. Espera-se, com este estudo, identificar a população de pacientes com EPM1 que tenham mutação no gene CSTB e com os resultados de este projeto possibilitar assim um melhor entendimento da etiopatogenia e proporcionar um diagnóstico preciso dos casos de DUL. / Unverricht-Lundborg disease (ULD) is considered a rare autosomal recessive disease, also known as Progressive Myoclonic Epilepsy Type 1 (EMP1), caused by mutations in the CSTB gene, which provides instructions for making a protein called Cystatin B. Such protein is essential for regulating a person\'s physiological processes, and its reduced expression seems to be the first cause of EMP1. Affected individuals usually begin showing signs and symptoms of the disorder between the ages of 6 and 16, which manifests both as myoclonus or as generalized tonic-clonic crises. It is a grave and limiting condition whose precise diagnosis is extremely important for appropriate conducts, including genetic counseling. This study has as a goal the molecular evaluation and characterization of the unstable expansion of the decametric repetition (CCCCGCCCCGCG) from the non-translated CSTB\'s 5\' gene promoter region among Brazilian patients with suspected EMP1. In this study, 64 patients were selected, among them 54 key figures from Hospital das Clínicas of Faculdade de Medicina de Ribeirão Preto (HCFMRP-USP) with suspected EMP1. The other 10 figures were related to the key figures. The 54 patients were followed in the Epilepsy sector with EMP1 clinical and electrophysiological diagnostics and were forwarded to the neurogenetics sector for a molecular diagnostic. From such 54 key figures, only 5 were diagnosed through molecular biology with decametric expansion above 30 repetitions, suggestive of ULD. This study is aimed to identify the EPM1 patients with CSTB genetic mutation and hopefully the results of this identification will enable a better understanding of the etiopathogeny and provide with a exact diagnosis of ULD cases.

[Truncated abstract] An elevated total plasma homocysteine concentration (tHcy) is associated with an increased risk of myocardial infarction and ischemic stroke. Folic acid, vitamin B6 and B12 supplements significantly reduce tHcy even in people who are not overtly vitamin deficient. If homocysteine is a causal risk factor for atherothrombotic events, treatment with B-vitamins might prove a simple and cost-effective means to reduce cardiovascular risk. However, it remains unclear whether elevated tHcy causes atherosclerosis or is simply a risk marker. To prove that homocysteine is a modifiable risk factor for cardiovascular disease it is necessary to show that lowering tHcy reduces vascular risk. The aim of this study was to determine whether long-term homocysteine-lowering with B-vitamins would improve vascular structure and function in people with a history of stroke. This study was a cross-sectional sub-study of the Vitamins TO Prevent Stroke trial (VITATOPS), a multi-centre, randomised, double-blind, placebo-controlled clinical trial designed to test the efficacy and safety of B-vitamins (folic acid 2mg, vitamin B6 25mg and vitamin B12 0.5mg) in the prevention of vascular events in patients with a recent history of stroke or transient ischemic attack. 173 VITATOPS participants were recruited for the current study. Age, sex, stroke type, medications, cardiovascular risk factors and smoking history were recorded and blood pressure, height, weight, waist and hip girth were measured in all subjects at least two years after randomisation. ... After a mean treatment period of 3.9 ± 0.9 years, the subjects randomised to vitamin treatment had significantly lower tHcy than the subjects randomised to placebo (7.9mol/L, 95%CI 7.5, 8.4 versus 11.8mol/L, 95%CI 10.9, 12.8; p<0.001). There were no significant differences between groups in CIMT (0.84 ± 0.17mm vitamins versus 0.83 ± 0.18mm placebo; p=0.74) or FMD (median of 4.0%, IQR 0.9, 7.2, vitamins versus 3.0%, IQR 0.6, 6.6 placebo; p=0.48). Pooled estimates from the meta-analyses showed that B-vitamin treatment reduces CIMT by 0.10mm (95%CI –0.20, -0.01mm) and increases FMD by 1.4%, (95%CI 0.7, 2.2), although these estimates may have been influenced by positive publication bias. The improvement in FMD was significant in studies of less than eight weeks duration but not in studies with longer treatment periods. The association between tHcy and CIMT and FMD was eliminated by adjustment for renal function and long-term B-vitamin treatment did not alter the strong linear relationship between tHcy and cystatin C. Lowering tHcy did not alter arterial wall inflammation assessed by 18FDG-PET, although small subject numbers meant we were unable to exclude a minor treatment effect. Long-term homocysteine-lowering with B-vitamin treatment did not improve CIMT or FMD or reduce arterial wall inflammation in people with a history of stroke. The relationship between tHcy and these markers of vascular risk was eliminated by adjustment for renal function. Our data are consistent with the hypothesis that elevated tHcy is a risk marker for cardiovascular disease rather than a modifiable causal risk factor.

L’amertume fait partie intégrante de notre alimentation. Elle est par exemple fortement représentée dans certaines boissons (ex: café) ou dans certains légumes tels les crucifères. Néanmoins, la perception de l’amertume varie entre les individus et certains aliments considérés comme bénéfiques pour la santé peuvent être rejetés en raison de leur goût amer. Des facteurs génétiques (ex : polymorphisme génétique des récepteurs du goût amer) ou environnementaux (ex : âge, prise de médicaments) expliquent en partie les variations interindividuelles dans la perception de l’amertume. Cependant, d’autres facteurs péri-récepteurs pourraient intervenir, notamment la composition salivaire. Afin d’investiguer dans un premier temps le lien existant entre le protéome salivaire propre à un individu et sa sensibilité à l’amertume, le seuil de détection du goût amer de la caféine a été mesuré sur 29 hommes sains. Leur salive au repos a été étudiée par électrophorèse mono- et bidimensionnelle. L’analyse par électrophorèse bidimensionnelle de la salive au repos des 6 sujets les plus sensibles et 6 les sujets les moins sensibles à la caféine a permis la détection de 255 spots, dont 26 étaient significativement différents entre hyper- et hyposensibles. L’identification de ces 26 spots a révélé la surexpression de fragments d’alpha amylase, de fragments d’albumine sérique, et de sous-unités alpha de l’immunoglobuline A ainsi que la sous-expression de cystatine SN chez les hypersensibles. Ce dernier résultat a été confirmé par Western Blot. Ceci a permis de formuler une hypothèse sur le rôle de la protéolyse en bouche sur la sensibilité à l’amertume. Dans un deuxième temps et afin d’étudier l’effet des molécules amères sur la composition salivaire, une étude in vitro a été menée sur la lignée cellulaire de glandes salivaires humaines HSG différenciées en acini ou non. Après une mise au point des conditions de différenciation (culture dite en 3D), la cystatine SN a été détectée dans les cellules HSG par Western blot après traitement des cellules à la caféine, à la quinine, et à l’urée. Après traitement à la caféine à 5, 50 ou 100µM, une quantification par ELISA a mis en évidence que la cystatine SN était toujours plus abondante dans les cellules HSG différenciées que dans les cellules non-différenciées. Spécifiquement dans les cellules différenciées, l’exposition à la caféine induisait une sur-expression de cystatine SN, la teneur maximale en cystatine SN étant observée avec la caféine à 50 µM. La présence de cystatine SN a également été détectée dans les milieux de culture / Bitterness is present in every day beverages (e.g. coffee) and foods (e.g. vegetables such as cruciferous plants). However, bitterness is perceived differently among individuals and some foods considered as healthy may be rejected due to their bitter taste. Several genetic (eg. genetic polymorphism of bitter taste receptors) or environmental (eg. age, medications) factors partly explain the interindividual variability in bitterness perception. However, other peri-receptor factors may intervene, in particular salivary composition. First, in order to investigate the link between salivary proteome and sensitivity to bitterness, the detection threshold to the bitter taste of caffeine was measured in 29 male healthy subjects. Their resting saliva was studied by one- and two-dimensional electrophoresis. Two-dimensional electrophoresis revealed that 26 out of 255 spots were significantly different between the 6 hypersensitive and 6 hyposensitive subjects to the bitter taste of caffeine. Identification of the 26 spots revealed an overexpression of amylase-, serum albumin-, and immunoglobulin A fragments, and an underexpression of cystatin SN in hypersensitive subjects. The latter finding was confirmed by Western blotting. These results have led to formulate an hypothesis on the role of in-mouth proteolysis in bitterness perception. Second, in order to study the effect of bitter molecules on salivary composition, an in vitro study was performed on undifferentiated and differentiated human salivary cell line HSG. After setting the experimental conditions for HSG cell differentiation (culture in 3D conditions), cystatin SN was detected in HSG cells by Western blot after treatment with caffeine, quinine, and urea. After cell exposure with caffeine at 5, 50 and 100 µM, quantification by ELISA demonstrated that cystatin SN was always more abundant in differentiated vs undifferentiated HSG cells. Specifically in differentiated cells, caffeine exposure resulted in over-expression of cystatin SN, 50µM inducing the highest effect. Cystatin SN was also detected in culture media of the HSG cells

Les glandes salivaires sont des glandes mixtes : la salive (produit exocrine) estimpliquée dans le maintien de l’homéostasie buccale alors que les secrétions endocrines (ex :facteurs de croissance) ont un rôle physiologique (gamétogénèse, ostéogenèse,hypertension…) Chez les mammifères, elles affichent un dimorphisme sexuel qui laisseentrevoir une sensibilité éventuelle à des xeno-hormones.Ce mémoire présente l’action de la génistéine (phyto-oestrogène) et/ou de la vinclozoline(anti-androgène) sur la glande submandibulaire (SM) de rat lors d’une exposition précoce viala mère (gestation-lactation) et lors d’une exposition pendant la période de croissance (dusevrage à l’âge adulte). Les glandes SM, prélevées au stade immature et jeune adulte, ont faitl’objet d’une analyse histologique et d’une étude de marqueurs moléculaire des fonctionsendocrines et exocrines associées aux processus gustatifs. L’exposition précoce ralenti ledéveloppement de la glande SM et augmente sélectivement la préférence au sucré des malesimmatures mais pas des adultes ; l’analyse moléculaire révèle une action sélective sur lesfonctions exocrines corrélée à celle sur les préférences, ainsi qu’une action sur les fonctionsendocrines (facteurs de croissances) qui s’inverse avec l’âge. L’exposition à partir du sevrageperturbe seulement les mâles qui présentent des altérations des structures sécrétrices coupléesà des modifications d’expression des récepteurs hormonaux et facteurs de croissance, maisaussi au taux sérique de l’EGF.Cette étude identifie la glande submandibulaire comme cible de perturbateurs endocriniens etpose la question des conséquences physiologiques à terme / The salivary glands are mixed glands: saliva (exocrine product) is involved inmaintaining oral homeostasis whereas endocrine secretions (eg growth factors) have aphysiological role (gametogenesis, osteogenesis, hypertension ..). In mammals, they displaysexual dimorphism suggesting a possible susceptibility to xeno-hormones.This manuscript presents the action of genistein (phytoestrogen) and/or vinclozolin (antiandrogenic)on the submandibular gland (SM) rats when performing an early exposure via themother (pregnancy, lactation) or an exposure during the growth period (from weaning toadulthood). The SM glands, collected at immature and young adult ages, have been analyzedaccording histological aspect and expression of molecular markers of endocrine and exocrinefunctions associated with gustatory process. The early exposure disrupted the development ofthe SM gland and selectively increases the sweet preference in immature males but not inadults; molecular analysis reveals a selective action on exocrine functions related to the sweetpreferences and also an action on endocrine functions (growth factors) which reverses withage. Exposure from weaning disrupts only the male salivary glands with alterations insecretory structures coupled with changes in expression of both, sex-hormone receptors andgrowth factors, but also in serum EGF.This study identifies the submandibular gland as a target for endocrine disruptors and raisesthe question of the further physiological consequences

Introduction: L’approche endovasculaire pour la réparation d’anévrysmes aortiques s’associe à une utilisation importante de produit de contraste, qui peut causer une néphropathie induite par le produit de contraste (NIC) en postopératoire. L’hydratation intraveineuse peut réduire l’incidence de NIC, mais quel produit utiliser reste incertain. Nous avons évalué le bicarbonate de sodium, comparé au NaCl 0,9%, pour réduire l’incidence de NIC. Méthode: Nous avons mené une étude prospective, randomisée et contrôlée à double insu chez 34 patients subissant une chirurgie endovasculaire pour anévrysme aortique. Les patients des deux groupes (17 patients par groupe) ont reçu du bicarbonate de sodium ou du NaCl 0,9% à raison de 3 mL/kg/h pour une heure avant l’intervention puis 1 mL/kg/h jusqu’à 6 h après la fin de la chirurgie. Tous les patients ont reçu du N-acétylcystéine. L’objectif principal était l’incidence de NIC, définie comme une élévation de plus de 25% de la créatinine sérique 48 h suivant l’exposition au produit de contraste. Des biomarqueurs précoces de lésion rénale ont été mesurés. Résultats: Une NIC s’est développée chez 1 patient (5,88%) appartenant au groupe bicarbonate, comparé à aucun patient (0%) dans le groupe NaCl 0,9% (P = 0,31). Les biomarqueurs de lésion rénale étaient significativement augmentés dans les deux groupes après l’exposition au produit de contraste. Conclusions: Nous avons démontré un faible taux d’insuffisance rénale suivant une chirurgie endovasculaire aortique, que l’hydratation soit effectuée avec du bicarbonate ou du NaCl 0,9%, malgré une élévation des biomarqueurs de lésion rénale. / Background: The endovascular approach for the repair of aortic aneurysm involves the administration of large quantities of contrast media, which can cause contrast-induced nephropathy (CIN) in the post operative period. The only proven strategy to prevent CIN is intravenous hydration, but what type of infusion to use is not clear. We evaluated the efficacy of sodium bicarbonate, compared with NaCl 0.9%, to reduce the incidence of postoperative renal failure. Methods: We conducted a prospective, controlled, double-blind, randomized study in patients presenting for endovascular aortic aneurysm surgery. Patients in group A (n = 17) received sodium bicarbonate 3 mL/kg/h for 1 h before the procedure and then 1 mL/kg/h until 6 h after surgery, whereas patients in group B (n= 17) received the same amount of NaCl 0.9%. All patients received N-acetylcysteine. The primary end point was CIN, defined by serum creatinine greater than 25 % above baseline 48 h post operatively. Biomarkers of renal injury were measured. Results: CIN developed in one patient in the bicarbonate group (5,88%), compared with no patient in the NaCl 0,9% group (0%) (difference 5.88%;95% CI -5.3% to 17.06%, P = 0.31). Interleukin-18, N-acetyl-β-D-glucosaminidase and Kidney Injury Molecule-1 increased significantly in both groups after exposure to contrast media. Conclusions: We demonstrated a low rate of renal failure following endovascular aortic surgery using contrast media, regardless of whether bicarbonate or NaCl 0.9% was used for hydration, despite significant elevation in biomarkers of renal injury.

Introduction: L’approche endovasculaire pour la réparation d’anévrysmes aortiques s’associe à une utilisation importante de produit de contraste, qui peut causer une néphropathie induite par le produit de contraste (NIC) en postopératoire. L’hydratation intraveineuse peut réduire l’incidence de NIC, mais quel produit utiliser reste incertain. Nous avons évalué le bicarbonate de sodium, comparé au NaCl 0,9%, pour réduire l’incidence de NIC. Méthode: Nous avons mené une étude prospective, randomisée et contrôlée à double insu chez 34 patients subissant une chirurgie endovasculaire pour anévrysme aortique. Les patients des deux groupes (17 patients par groupe) ont reçu du bicarbonate de sodium ou du NaCl 0,9% à raison de 3 mL/kg/h pour une heure avant l’intervention puis 1 mL/kg/h jusqu’à 6 h après la fin de la chirurgie. Tous les patients ont reçu du N-acétylcystéine. L’objectif principal était l’incidence de NIC, définie comme une élévation de plus de 25% de la créatinine sérique 48 h suivant l’exposition au produit de contraste. Des biomarqueurs précoces de lésion rénale ont été mesurés. Résultats: Une NIC s’est développée chez 1 patient (5,88%) appartenant au groupe bicarbonate, comparé à aucun patient (0%) dans le groupe NaCl 0,9% (P = 0,31). Les biomarqueurs de lésion rénale étaient significativement augmentés dans les deux groupes après l’exposition au produit de contraste. Conclusions: Nous avons démontré un faible taux d’insuffisance rénale suivant une chirurgie endovasculaire aortique, que l’hydratation soit effectuée avec du bicarbonate ou du NaCl 0,9%, malgré une élévation des biomarqueurs de lésion rénale. / Background: The endovascular approach for the repair of aortic aneurysm involves the administration of large quantities of contrast media, which can cause contrast-induced nephropathy (CIN) in the post operative period. The only proven strategy to prevent CIN is intravenous hydration, but what type of infusion to use is not clear. We evaluated the efficacy of sodium bicarbonate, compared with NaCl 0.9%, to reduce the incidence of postoperative renal failure. Methods: We conducted a prospective, controlled, double-blind, randomized study in patients presenting for endovascular aortic aneurysm surgery. Patients in group A (n = 17) received sodium bicarbonate 3 mL/kg/h for 1 h before the procedure and then 1 mL/kg/h until 6 h after surgery, whereas patients in group B (n= 17) received the same amount of NaCl 0.9%. All patients received N-acetylcysteine. The primary end point was CIN, defined by serum creatinine greater than 25 % above baseline 48 h post operatively. Biomarkers of renal injury were measured. Results: CIN developed in one patient in the bicarbonate group (5,88%), compared with no patient in the NaCl 0,9% group (0%) (difference 5.88%;95% CI -5.3% to 17.06%, P = 0.31). Interleukin-18, N-acetyl-β-D-glucosaminidase and Kidney Injury Molecule-1 increased significantly in both groups after exposure to contrast media. Conclusions: We demonstrated a low rate of renal failure following endovascular aortic surgery using contrast media, regardless of whether bicarbonate or NaCl 0.9% was used for hydration, despite significant elevation in biomarkers of renal injury.