The shank active movement be able to cause an increase in venous return contribute to the improvement of the treatment of hemodialysis, increasing peripheral circulation and therefore increases the removal of toxins from the blood. The aim of this study was to evaluate the effect of shank active movement on the index of urea clearance ( Kt / V ) and the percentage removal of urea ( PRU ) , and check the effect on blood pressure and heart rate in renal patients during chronic hemodialysis. The sample comprised 44 patients, aged between 23 and 72 years and mean height of 167 ± 11 cm and body mass 66.7 ± 14.4 kg, divided into two groups: a control group and an exercise group. The shank active movement was performed in the sitting position and the patient performing movements of dorsiflexion and plantar flexion. The drive was carried out using an adjustable wooden support so that the patient would remain in correct and comfortable position to perform the exercise. The exercise protocol was four sets of 15 repetitions, following an increase of 5 repetitions per month until complete four sets of 30 repetitions, in intervals of 60 seconds between sets . The results of the comparison groups had no significant difference in Kt / V did not alter the PRU with the shank active movement , however had high blood pressure compared with controls ( p < 0.001 ) and heart rate ( p < 0.05). It is concluded that the active protocol - shank movement was not effective to improve the Kt / V and the PRU / A movimentação ativa tíbio-társica pode favorecer um aumento do retorno venoso, contribuindo para a melhora do tratamento da hemodiálise, incrementando a circulação periférica e, consequentemente, aumentando a remoção de toxinas do sangue. O objetivo deste estudo foi avaliar o efeito da movimentação ativa tíbio-társica sobre o índice de depuração de ureia (Kt/V) e o percentual de remoção de ureia (PRU), além de verificar o efeito disso na pressão arterial e frequência cardíaca de pacientes renais crônicos durante a hemodiálise. A amostra foi composta por 44 pacientes, com idades entre 23 e 72 anos e estatura média de 167 ± 11 cm e massa corporal de 66,7 ± 14,4 Kg, divididos em dois grupos: um grupo controle e o um grupo exercício. A movimentação ativa tíbio-társica foi realizada na posição sentada com o paciente realizando movimentos de dorsiflexão e flexão plantar. A movimentação foi realizada utilizando um suporte de madeira ajustável de forma que o paciente ficasse em posição correta e confortável para a realização do exercício. O protocolo de exercício foi de quatro séries de quinze repetições, seguindo uma progressão de cinco repetições por mês até que completássemos as quatro séries de trinta repetições, com intervalos de 60 segundos entre as séries. Os resultados encontrados, quando comparados os dos grupos, não apresentaram diferença significativa no Kt/V como também não se alterou o PRU com a movimentação ativa tíbio-társica; no entanto, apresentou-se elevação da pressão arterial comparado ao controle (p<0,001) e da frequência cardíaca (p<0,05). Conclui-se que o protocolo de movimentação ativa tíbio-társica não foi eficiente para melhorar o Kt/V e o PRU.

El proyecto se enfoca en brindar apoyo a personas que sufren de insuficiencia renal crónica terminal, a través de un centro especializado en el tratamiento integral del mismo. Brindando espacios de confort con una infraestructura moderna y agradable para el usuario. El objetivo del proyecto es lograr la satisfacción de las necesidades de salud de la población, brindando servicios de salud con calidad, equidad, eficiencia y efectividad, que sumados a la infraestructura ayudará a suplir la carencia de estos centros especializados. / The project focuses on supporting people who suffer from Terminal Chronic Renal Insufficiency; with a specialized integral treatment center that will provide comfort spaces and have a pleasant infrastructure for the user. The aim of the project is to achieve the satisfaction of the population through health needs, and providing high quality services, as well as equity, efficiency and effectiveness; the infrastructure will fill the lack of these specialized treatment centers. / Tesis

Indiana University-Purdue University Indianapolis (IUPUI) / FGF23 is the central regulator for phosphate homeostasis. Both FGF23 and phosphate dysregulation are highly related with the progression of chronic kidney disease (CKD), which is a global health problem. In previous studies, FGF23 was found to be produced in bone and targeting the kidneys to regulate phosphate reabsorption and excretion. In the FGF23 signaling axis, it binds a receptor complex (αKlotho and FGFRs) in the distal convoluted tubules (DCT) and causes its biological effects in the proximal tubules (PT). The mechanism of how the signals passing on from DCT to PT is not clear. In my research, experiments were focused on the FGF23 signaling pathway within the kidney to study the communication steps between tubular cells. HBEGF treatment was given to FGF23 signaling impaired mouse models resulting in significant change of genes regulated by FGF23, indicating that HBEGF was important in the FGF23 signaling axis. Then high quality rabbit anti-mouse HBEGF antibodies were made to better study HBEGF activity in vivo and in vitro. A new cell model was characterized to test FGF23 effects on HBEGF signaling using Western blots and immunofluorescence. Lastly, the location of HBEGF activity was examined in the kidney in vivo. Immunostaining suggested that HBEGF activated the mitogen activated protein kinase (MAPK) pathway. This mapping may provide important information for the molecular relationships between FGF23 and HBEGF.

Made available in DSpace on 2011-05-04T12:36:22Z (GMT). No. of bitstreams: 0 Previous issue date: 2009 / Entre os objetivos da Política Nacional de Medicamentos constam o acesso e o financiamento dos denominados medicamentos de dispensação em caráter excepcional (MDCE). Estes, conhecidos por representarem um gasto governamental relativamente alto, se destinam ao tratamento de doenças em sua maioria, crônicas , que atingem uma pequena parcela da população. Para respaldar sua utilização promovendo adequada alocação dos recursos e o uso racional, o Ministério da Saúde publica protocolos clínicos e diretrizes terapêuticas (PCDT), cujo cumprimento é pré-requisito para o acesso dos pacientes a esses medicamentos pelo programa governamental. A adesão dos prescritores aos protocolos é fator imprescindível ao sucesso desta estratégia. O presente estudo busca verificar, mediante critérios objetivos, o grau de cumprimento pelos prescritores dos procedimentos-chave eleitos a partir do PDCT selecionado. Realizado estudo transversal descritivo com prontuário como fonte de dados e sua revisão como estratégia. Tratamento da anemia em pacientes portadores de Insuficiência Renal Crônica (IRC) com o medicamento eritropoetina humana recombinante (EPO) foi eleita como situação traçadora. Escolhidas três unidades de saúde, sendo critérios o número de pacientes acompanhados e a natureza da organização. No banco de dados da Secretaria de Estado de Saúde do Rio de Janeiro, destinado ao acompanhamento da dispensação dos MDCE identificou-se universo de 411 pacientes com CID principal registrado para autorização de dispensação N18.0 e N18.8, que retiraram o medicamento em algum momento entre janeiro de 2004 a dezembro de 2005. Elegidos procedimentos chave do fluxograma de tratamento do PCDT para a condição traçadora como critérios de verificação. Foram revisados prontuários de 202 pacientes renais crônicos que receberam o medicamento por um período de até dois anos de acompanhamento. Quanto ao grau de adesão ao PDCT, 38,1% foram classificados como adequados, 48,5% como regular, 10,4% como insuficiente e 3% como inadequado. Os critérios mais seguidos foram: critério de inclusão valor do hematócrito ou da hemoglobina, realização inicial de hemograma completo e de contagem de plaquetas e exame de monitorização desses últimos. Os menos seguidos foram: dose inicial e suspensão temporária. No geral, há uma boa adesão, porém essa pode ser melhorada. A análise de possíveis barreiras a adesão faz-se mister. / One of the National Medicines Policy goals is to guarantee the access and funding of the group of drugs called medicines of dispensation in exceptional character (MDEC). These expensive drugs are intended for the treatment of diseases - most of them, chronic - that affect a small portion of the population. In this way, they are know to represent high cost to the public service in Brazil. To support the appropriate allocation of resources and rational use, the Health Ministry develops and public the Clinical protocols and standard treatment guidelines (CPSTG) which is essential for the patient access to the governmental program. To perceive this benefits physicians adherence is necessary. The study aims to evaluate, by objective criteria, the degree of physicians’ adherence to CPSTG. A descriptive cross-sectional study was conducted, using medical records review. CPSTG for the treatment of anemia in chronic renal patients with recombinant human erythropoietin (EPO) was chose to evaluation the adherence. Three units of health were chosen to participate due to number of patients and nature of the organization. The population was picked out from the database of the Secretary of State of Health of Rio de Janeiro, which monitor the distribution of MDEC. The universe was 411 patients with principal ICD registered N18.0 and N18.8, which withdrew the drug at some time between January 2004 to December 2005. To verify the adherence to statements from CPSTG was elected key procedures from CPSTG the treatment of anemia in patients with Chronic Renal Failure (CRF) using EPO flowchart. 202 chronic renal patients medical records were reviewed who received the drug for up to two years of monitoring. The characteristics of patients in the study were similar to the patients described in the 2008 Brazilian Census of Dialysis. Among the comorbidities presented by patients, 76.24% had hypertension and 7.42% ischemic heart disease or congestive heart failure. Regarding adherence, 38.1% were classified as adequate, 48.5% regular, 10.4% insufficient and 3% as inadequate. The most followed criterias were: criterion for inclusion of the value of hematocrit or hemoglobin, achieving initial complete blood platelet count monitoring and examination of these latter. The least followed were: initial dose and temporary. It follows that a good adherence was obtained from the study, but this can be improved. It is indispensable the analysis of possible barriers to adherence.

Text in English with abstracts in English and isiZulu / Poor adherence to their prescribed diet, medications and treatment contributes to increased mortality and morbidity in patients with end-stage renal disease. These patients must change their diet when receiving dialysis treatment, but cultural beliefs and practices can affect their adherence to the prescribed diet. The purpose of this qualitative, descriptive, exploratory study was to improve health education on prescribed diet adherence to patients living on haemodialysis at a haemodialysis unit in eThekwini Municipality. Data from a sample of 20 patients was collected using semi-structured interviews and analysed using qualitative content analysis. The findings revealed that haemodialysis patients’ prescribed diet adherence was influenced by cultural and religious views, and by family support. Food availability, patients’ geographical location and patients’ financial means hindered their adherence to their prescribed diet. A multi-disciplinary health care team including nurses, should be sensitive to patients’ different cultural beliefs and practices when providing health education. / Ukungabambeleli endleleni emisiwe yokudla, amakhambi nasekwelashweni kunomthelela ekwandiseni izimpawu zesifo sezinso esingapheli (ESRD) futhi kwandisa isibalo sabantu ababulawa yilesisifo. Iziguli ezinalesisifo zidinga ukushitsha indlela yokuphila, iziphuzo kanye nokulandela indlela emisiwe yokudla kakhulukazi mabe ngaphansi kokwelashwa ngokuhlanzwa kwegazi ngomshini (dialysis). Izinkolelo zamasiko nendlela zokuphila ezihambisana namasiko kwenze imfundiso nge ezempilo maqondana nendlela emisiwe yokudla yaba lukhuni. Inhloso yalolucwaningo bekuwukwandisa ulwazi nemfundiso ngezempilo mayelana nokulandela indlela emisiwe yokudla kwiziguli izithola ukulashwa ngokuhlanzwa kwegazi ngomshini (haemodialysis) esikhungweni esikuMasipala weTheku. Kusetshenziwe indlela yokwenza ucwaningo esezingeni elifanele, Imininingwano eqoqiwe eqembini (sample) leziguli ezingamashumi amabili (20) ezithola ukwelashwange haemodialyisis. Imininigwane iqoqwe kusetshenziswa izingxoxo ezihleliwe. Imigomo elawula ukuhlaziya ilandeliwe yonke ngenkathi kwenziwe lolucwaningo. Lolucwaningo luveze ukuthi indlela yokudla emisiwe yeziguli ezikwi dialysis iphazanyiswa imobono yamasiko, inkolo kanye nokusekelwa nokuzimbandakanya kwamalungu omndeni. Izinselelo ezinjengokutholakala, indawo isiguli esihlala kuyo nezinkinga zemali zivimbela ukubambelela endleleni emisiwe yokudla. Abasebenzi bezempilo kumele banakekele indima edlalwa izinkolelo namasiko uma befundisa ngezempilo ezigulini eziphethwe izinso. / Nursing Science / M.A. (Nursing Science)

La prostaglandine E2 est une hormone lipidique produite abondamment dans le corps, incluant dans le rein où elle agit localement pour réguler les fonctions rénales. Un couplage à la protéine Gαs menant à une production d’AMPc a classiquement été attribué au récepteur EP4 de PGE2. La signalisation d’EP4 s’est cependant avérée plus complexe et implique aussi un couplage aux protéines sensibles à la PTX Gαi et des effets reliés aux β-arrestines. Il y a maintenant plusieurs exemples de l’activation sélective de voies de signalisation indépendantes par des ligands des récepteurs couplés aux protéines G (RCPG), et ce concept désigné sélectivité fonctionnelle pourrait être exploité dans le développement de nouveaux médicaments plus spécifiques et efficaces. Dans une première étude, la puissance et l’activité intrinsèque d’une série de ligands d’EP4 pour l’activation de Gαs, Gαi et de la ß-arrestine ont été systématiquement déterminées relativement au ligand endogène PGE2. Dans ce but, trois essais de transfert d’énergie de résonance de bioluminescence (BRET) ont été adaptés pour évaluer les différentes voies dans des cellules vivantes. Nos résultats montrent une sélectivité fonctionnelle importante parmi les agonistes évalués et ont une implication pour l’utilisation d’analogues de la PGE2 dans un contexte expérimental et possiblement clinique, puisque leur spectre d’activité diffère de l’agoniste naturel. La méthodologie basée sur le BRET utilisée lors de cette première évaluation systématique d’une série d’agonistes d’EP4 devrait être applicable à l’étude d’autres RCPG. Dans une deuxième étude, des peptides reproduisant des régions juxtamembranaires extracellulaires du récepteur EP4 ont été conçus selon le raisonnement que des peptides ciblant des régions éloignées du site de liaison du ligand naturel ont le potentiel de ne moduler qu’une partie des activités du récepteur. L’insuffisance rénale aiguë est une complication médicale grave caractérisée par un déclin brusque et soutenu de la fonction rénale et pour laquelle il n’y a pas de traitement efficace à l’heure actuelle. Nos résultats montrent que le peptidomimétique dérivé d’EP4 optimisé (THG213.29) améliore significativement les fonctions rénales et les changements histologiques dans une insuffisance rénale aiguë induite par cisplatine ou par occlusion des artères rénales dans des rats Sprague-Dawley. Le THG213.29 ne compétitionnait pas la liaison de la PGE2 à EP4, mais modulait la cinétique de dissociation de la PGE2, suggérant une liaison à un site allostérique d’EP4. Le THG213.29 démontrait une sélectivité fonctionnelle, puisqu’il inhibait partiellement la production d’AMPc induite par EP4 mais n’affectait pas l’activation de Gαi ou le recrutement de la ß-arrestine. Nos résultats indiquent que le THG213.29 représente une nouvelle classe d’agent diurétique possédant les propriétés d’un modulateur allostérique non-compétitif des fonctions du récepteur EP4 pour l’amélioration des fonctions rénales suite à une insuffisance rénale aiguë. / Prostaglandin E2 (PGE2) is a lipid hormone mediator widely produced in the body, including in the kidney where it acts locally to regulate renal function. Classically, the PGE2 receptor EP4 has been classified as coupling to the Gαs subunit, leading to intracellular cAMP increases. However EP4 signaling has been revealed to be more complex and also involves coupling to PTX-sensitive Gαi proteins and ß-arrestin mediated effects. There are now many examples of selective activation of independent pathways by G-protein coupled receptor (GPCR) ligands, a concept referred to as functional selectivity that could be exploited for the development of more specific and efficacious drugs. In a first study, the potencies and efficacies of a panel of EP4 ligands were systematically determined for the activation of Gαs, Gαi and ß-arrestin relative to the endogenous ligand PGE2. For this purpose, three bioluminescence resonance energy transfer (BRET) assays were adapted to evaluate the respective pathways in living cells. Our results suggest considerable functional selectivity among the tested, structurally related agonists and have implications for the use of PGE2 analogues in experimental and possibly clinical settings, as their activity spectra on EP4 differ from that of the native agonist. The BRET-based methodology used for this first systematic assessment of a set of EP4 agonists should be applicable for the study of other GPCRs. In a second study, peptides were derived from extracellular juxtamembranous regions of the EP4 receptor following the rationale that peptides that target regions of the receptor remote of the ligand-binding site might modulate a subset of the EP4-mediated activities. Acute renal failure is a serious medical complication characterized by an abrupt and sustained decline in renal function and for which there is currently no effective treatment. Our results show that the optimized EP4-derived peptidomimetic THG213.29 significantly improved renal functions and histological changes in acute renal failure induced by either cisplatin or renal artery occlusion in Sprague-Dawley rats. THG213.29 did not displace PGE2 binding to EP4, but modulated PGE2 binding dissociation kinetics, indicative of an allosteric binding mode. THG213.29 exhibited functional selectivity, as it partially inhibited EP4-mediated cAMP production but did not affect Gαi activation or ß-arrestin recruitment. Our results demonstrate that THG213.29 represents a novel class of diuretic agent with noncompetitive allosteric modulator effects on EP4 receptor function for improving renal function following acute renal failure.

Introdução: A nefrotoxicidade dos antiretrovirais constituem atualmente fator importante na morbidade e mortalidade de pacientes com HIV. O tenofovir DF (TDF) se enquadra em um dos antiretrovirais mais lesivos ao rim. Conhecer seu mecanismo de nefrotoxicidade e estudar medidas protetoras podem melhorar seu uso clínico. Material e Métodos: Ratos foram tratados durante 30 dias com uma de duas doses de TDF (50 ou 300mg/Kg de dieta), sendo que um grupo teve adicionado em sua dieta maleato de rosiglitazona (RSG) na dose de 92mg/Kg de dieta nos últimos 15 dias. Após esse período, os ratos foram colocados em gaiola metabólica e sacrificados. Foram estudados parâmetros bioquímicos, fluxo sanguíneo renal e os rins extraídos para expressão semiquantitativa dos transportadores epiteliais tubulares. Resultados: Os animais que receberam TDF em dose alta apresentaram insuficiência renal severa acompanhada de redução da expressão da oxido-nítrico sintase endotelial e vasoconstricção renal intensa. Todos esses parâmetros foram parcialmente revertidos pela administração de RSG. Baixas doses de TDF não causou alteração significativa do ritmo de filtração glomerular, porém induziu fosfatúria, acidose tubular proximal, poliúria e redução da capacidade de concentração urinária. Essas alterações foram associadas a redução da expressão de alguns transportadores epiteliais (cotransportador sódio-fosforo, contratransportador sódio-hidrogênio tipo 3 e aquaporina tipo 2). Não foi caracterizado síndrome de Fanconi, pois não houve proteinúria ou glicosúria. O tratamento com RSG reverteu todos os parâmetros de nefrotoxicidade estudados, normalizando as alterações bioquímicas urinárias e a expressão dos transportadores de membrana. Conclusões: Os achados desses experimentos tem potencial aplicação clínica em pacientes com nefrotoxicidade induzida pelo TDF, especialmente naqueles com hipofosfatemia e/ou redução do ritmo de filtração glomerular. / Objective: To characterize the mechanisms of tenofovir disoproxil fumarate (TDF)- induced nephrotoxicity and the protective effects of rosiglitazone (RSG), a peroxisome proliferator-activated receptor-y agonist. Methods: Rats were treated for 30 days with one of two TDF doses (50 or 300 mg/kg of food), to which RSG (92 mg/kg of food) was added for the last 15 days. Biochemical parameters were measured, and renal tissue was extracted for immunoblotting. Results: Mean daily ingestion was comparable among all the treated groups. Highdose TDF induced severe renal failure accompanied by reduced expression of endothelial nitric-oxide synthase and intense renal vasoconstriction. All of these features were ameliorated by RSG administration. Low-dose TDF did not alter the glomerular filtration rate but induced significant phosphaturia, proximal tubular acidosis and polyuria, as well as reducing urinary concentrating ability. These alterations were caused by specific downregulation of the sodium-phosphorus cotransporter, sodium/hydrogen exchanger 3 and aquaporin 2. No Fanconi\'s syndrome was identified (proteinuria was normal and there was no glycosuria). Treatment with RSG reversed TDF-induced tubular nephrotoxicity, normalizing urinary biochemical parameters and membrane transporter protein expression. Conclusion: These findings have potential clinical applications in patients presenting with TFV-induced nephrotoxicity, especially in those presenting with hypophosphatemia or a reduction in glomerular filtration rate.

Ο ιός του αιμορραγικού πυρετού Κριμαίας-Κογκό (Crimean-Congo Hemorrhagic Fever Virus, CCHFV), καθώς και οι χανταϊοί (hantaviruses) προκαλούν στον άνθρωπο αιμορραγικό πυρετό. Αυτοί παρουσιάζουν ευρεία γεωγραφική κατανομή και αποτελούν απειλή για τη δημόσια υγεία, λόγω του υψηλού ποσοστού θνητότητας που σημειώνουν και της απουσίας αποτελεσματικής θεραπευτικής αγωγής. Παρότι επιδημιολογικές μελέτες δείχνουν την παρουσία αντισωμάτων στον ελληνικό πληθυσμό, περιορισμένες είναι οι αναφορές κλινικών περιστατικών CCHF και HFRS στην Ελλάδα. Σκοπός της παρούσας μελέτης είναι να προσδιορίσει τον επιπολασμό της μόλυνσης με τον CCHFV και τους χανταϊούς στον Ν. Αχαΐας, που αν και παρουσιάζει ευνοϊκές συνθήκες για την κυκλοφορία των δύο ιών, δεν έχει μελετηθεί στο παρελθόν. Σχεδιάσθηκε διατμηματική μελέτη και συγκεντρώθηκαν προοπτικά 207 δείγματα ορού φαινομενικά υγιών ατόμων-κατοίκων της περιοχής, τα οποία εξετάστηκαν με τη μέθοδο ELISA και έμμεσου ανοσοφθορισμού για την ύπαρξη αντισωμάτων έναντι του CCHFV και των χανταϊών. Ο επιπολασμός για τη μόλυνση με CCHFV βρέθηκε 3,4% και 9,7% για τη μόλυνση με χανταϊούς, ενώ κανένα από τα οροθετικά άτομα δεν ανακαλούσε συμπτώματα παρόμοια με αυτά του CCHF ή του HFRS. Για τον CCHFV, βρέθηκε ότι η ηλικία, η αγροτοκτηνοτροφική ενασχόληση, η κατοχή/εκτροφή αιγοπροβάτων, το ιστορικό νύγματος κρότωνα, η μόνιμη διαμονή σε υψόμετρο ≥400μ., η μόνιμη διαμονή σε μη αρδευόμενες αρόσιμες εκτάσεις ή σε αγροτικές εκτάσεις με σημαντικό ποσοστό φυσικής βλάστησης, καθώς και η μόνιμη διαμονή σε αγροτική περιοχή είναι σημαντικοί παράγοντες κινδύνου. Από αυτούς, το νύγμα κρότωνα, η αγροτοκτηνοτροφική ενασχόληση και η μόνιμη διαμονή σε υψόμετρο ≥400μ. βρέθηκαν να προβλέπουν καλύτερα την οροθετικότητα ενός ατόμου. Επίσης, βρέθηκε ότι παράγοντες που σχετίζονται με τη μόλυνση με χανταϊούς είναι: η ηλικία, η θέαση τρωκτικών σε ακτίνα <200μ. γύρω από την οικία και η ιδιοκτησία υπόγειας αποθήκης. Από αυτούς, μόνο η ηλικία βρέθηκε να προβλέπει καλύτερα την οροθετικότητα ενός ατόμου. Επιπλέον, παρατηρήθηκε ότι σχεδόν το 75% των θετικών ατόμων για αντισώματα έναντι των χανταϊών παρουσίαζαν ήπια επηρεασμένη νεφρική λειτουργία. Εντοπίστηκαν, επίσης, ενδημικές εστίες των ιών στον νομό: ο Δ. Ερυμάνθου για τον CCHFV και ο Δ. Δυτικής Αχαΐας για του χανταϊούς. Λαμβάνοντας υπόψη τα παραπάνω αποτελέσματα, θα πρέπει οι κλινικοί γιατροί της περιοχής να συμπεριλαμβάνουν τον CCHF και τον HFRS στη διαφορική διάγνωση εμπύρετων νοσημάτων, ιδίως όταν αυτά συνοδεύονται από θρομβοπενία ή επηρεασμένη νεφρική λειτουργία. / Crimean-Congo hemorrhagic fever virus (CCHFV) and hantaviruses cause to humans fever with hemorrhagic manifestations. These viruses present wide geographic distribution and represent major threats for public health, because of the high fatality rate that they present and the lack of appropriate treatment. Although seroprevalence studies show the presence of antibodies against CCHFV and hantaviruses in the greek population, only some reports of human cases have been reported to date in Greece. The aim of the present study is to estimate seroprevalence for CCHFV and hantaviruses in humans in the prefecture of Achaia, where the local conditions potentially favor the circulation of these viruses and which has not been previously studied. A cross-sectional study was designed and 207 human sera were collected from apparently healthy individuals living in Achaia, which were tested for CCHFV and hantaviruses IgG antibodies by ELISA and by indirect immunofluorescence assay (IFA). Seroprevalence for CCHFV infection was estimated at 3.4%, whereas for hantaviruses at 9.7%; none recalled any illness resembling CCHF or HFRS. For CCHFV, it was found that age, agro-pastoral occupation, tending sheep and/or goats, tick bite, living in areas at an altitude of ≥400m., living at rural areas, living on non-irrigated arable land or on land principally occupied by agriculture, with significant areas of natural vegetation are significantly related to seropositivity. Among them, tick bite, agro-pastoral occupation and living in areas at an altitude of ≥400m. better predict seropositivity of an individual. For hantaviruses, it was found that age, rodent sighting around home and the ownership of an underground shed are significantly related to seropositivity. Among them, it seems that only age can predict seropositivity of an individual. Moreover, it was observed that almost 75% of the seropositive for hantaviruses individuals presented mild renal dysfunction. In this study, endemic foci were also detected: the municipality of Erimanthos for CCHFV and the municipality of Western Achaia for hantaviruses. Clinicians should include CCHF and HFRS in the differential diagnosis of an acute febrile case, especially when thrombocytopenia or impaired renal function is encountered.

No description available.

La prostaglandine E2 est une hormone lipidique produite abondamment dans le corps, incluant dans le rein où elle agit localement pour réguler les fonctions rénales. Un couplage à la protéine Gαs menant à une production d’AMPc a classiquement été attribué au récepteur EP4 de PGE2. La signalisation d’EP4 s’est cependant avérée plus complexe et implique aussi un couplage aux protéines sensibles à la PTX Gαi et des effets reliés aux β-arrestines. Il y a maintenant plusieurs exemples de l’activation sélective de voies de signalisation indépendantes par des ligands des récepteurs couplés aux protéines G (RCPG), et ce concept désigné sélectivité fonctionnelle pourrait être exploité dans le développement de nouveaux médicaments plus spécifiques et efficaces. Dans une première étude, la puissance et l’activité intrinsèque d’une série de ligands d’EP4 pour l’activation de Gαs, Gαi et de la ß-arrestine ont été systématiquement déterminées relativement au ligand endogène PGE2. Dans ce but, trois essais de transfert d’énergie de résonance de bioluminescence (BRET) ont été adaptés pour évaluer les différentes voies dans des cellules vivantes. Nos résultats montrent une sélectivité fonctionnelle importante parmi les agonistes évalués et ont une implication pour l’utilisation d’analogues de la PGE2 dans un contexte expérimental et possiblement clinique, puisque leur spectre d’activité diffère de l’agoniste naturel. La méthodologie basée sur le BRET utilisée lors de cette première évaluation systématique d’une série d’agonistes d’EP4 devrait être applicable à l’étude d’autres RCPG. Dans une deuxième étude, des peptides reproduisant des régions juxtamembranaires extracellulaires du récepteur EP4 ont été conçus selon le raisonnement que des peptides ciblant des régions éloignées du site de liaison du ligand naturel ont le potentiel de ne moduler qu’une partie des activités du récepteur. L’insuffisance rénale aiguë est une complication médicale grave caractérisée par un déclin brusque et soutenu de la fonction rénale et pour laquelle il n’y a pas de traitement efficace à l’heure actuelle. Nos résultats montrent que le peptidomimétique dérivé d’EP4 optimisé (THG213.29) améliore significativement les fonctions rénales et les changements histologiques dans une insuffisance rénale aiguë induite par cisplatine ou par occlusion des artères rénales dans des rats Sprague-Dawley. Le THG213.29 ne compétitionnait pas la liaison de la PGE2 à EP4, mais modulait la cinétique de dissociation de la PGE2, suggérant une liaison à un site allostérique d’EP4. Le THG213.29 démontrait une sélectivité fonctionnelle, puisqu’il inhibait partiellement la production d’AMPc induite par EP4 mais n’affectait pas l’activation de Gαi ou le recrutement de la ß-arrestine. Nos résultats indiquent que le THG213.29 représente une nouvelle classe d’agent diurétique possédant les propriétés d’un modulateur allostérique non-compétitif des fonctions du récepteur EP4 pour l’amélioration des fonctions rénales suite à une insuffisance rénale aiguë. / Prostaglandin E2 (PGE2) is a lipid hormone mediator widely produced in the body, including in the kidney where it acts locally to regulate renal function. Classically, the PGE2 receptor EP4 has been classified as coupling to the Gαs subunit, leading to intracellular cAMP increases. However EP4 signaling has been revealed to be more complex and also involves coupling to PTX-sensitive Gαi proteins and ß-arrestin mediated effects. There are now many examples of selective activation of independent pathways by G-protein coupled receptor (GPCR) ligands, a concept referred to as functional selectivity that could be exploited for the development of more specific and efficacious drugs. In a first study, the potencies and efficacies of a panel of EP4 ligands were systematically determined for the activation of Gαs, Gαi and ß-arrestin relative to the endogenous ligand PGE2. For this purpose, three bioluminescence resonance energy transfer (BRET) assays were adapted to evaluate the respective pathways in living cells. Our results suggest considerable functional selectivity among the tested, structurally related agonists and have implications for the use of PGE2 analogues in experimental and possibly clinical settings, as their activity spectra on EP4 differ from that of the native agonist. The BRET-based methodology used for this first systematic assessment of a set of EP4 agonists should be applicable for the study of other GPCRs. In a second study, peptides were derived from extracellular juxtamembranous regions of the EP4 receptor following the rationale that peptides that target regions of the receptor remote of the ligand-binding site might modulate a subset of the EP4-mediated activities. Acute renal failure is a serious medical complication characterized by an abrupt and sustained decline in renal function and for which there is currently no effective treatment. Our results show that the optimized EP4-derived peptidomimetic THG213.29 significantly improved renal functions and histological changes in acute renal failure induced by either cisplatin or renal artery occlusion in Sprague-Dawley rats. THG213.29 did not displace PGE2 binding to EP4, but modulated PGE2 binding dissociation kinetics, indicative of an allosteric binding mode. THG213.29 exhibited functional selectivity, as it partially inhibited EP4-mediated cAMP production but did not affect Gαi activation or ß-arrestin recruitment. Our results demonstrate that THG213.29 represents a novel class of diuretic agent with noncompetitive allosteric modulator effects on EP4 receptor function for improving renal function following acute renal failure.