997 resultados para therapeutic doses


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Este trabalho teve como objetivo avaliar o efeito da aplicação de ácido giberélico (GA3) no pegamento, frutificação efetiva e qualidade de frutos de atemoieira 'Gefner', nas condições irrigadas do norte de Minas Gerais. O experimento foi conduzido em pomar comercial de atemoieira 'Gefner', em Matias Cardoso. O delineamento experimental foi o de blocos casualizados, com quatro repetições e cinco frutos por parcela. Os tratamentos utilizados foram diferentes doses do produto comercial Pro-Gibb®, composto por 10% de GA3, na forma de pó solúvel, sendo: 0 (testemunha), 250; 500; 750 e 1.000 mg.L-1. O produto foi aplicado diretamente nas flores de atemoieira, no momento da antese, e repetido nos frutos aos 7; 21 e 35 dias após a antese. Foram avaliados quinzenalmente pegamento, comprimento e diâmetro dos frutos. Após a colheita, as características físico-químicas avaliadas foram submetidas à análise de variância, e os efeitos das doses foram testados e ajustados em equações de regressão. A porcentagem de pegamento e frutificação efetiva dos frutos de atemoieira 'Gefner', a massa de polpa, casca e frutos, e o pH aumentaram com o incremento das doses de GA3. A aplicação de GA3 proporcionou a produção de frutos sem sementes e não influenciou no teor de sólidos solúveis dos frutos de atemoieira 'Gefner'.

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Avec plus de 100000 transplantations d'organes solides (TOS) par année dans le monde, la transplantation d'organes reste actuellement l'un des meilleurs traitements disponibles pour de nombreuses maladies en phase terminale. Bien que les médicaments immunosuppresseurs couramment utilisés soient efficaces dans le contrôle de la réponse immune engendrant le rejet aigu d'une greffe, la survie du greffon à long terme ainsi que la présence d'effets secondaires indésirables restent un enjeu considérable en clinique. C'est pourquoi il est nécessaire de trouver de nouvelles approches thérapeutiques innovantes permettant de contrôler la réponse immunitaire et ainsi d'améliorer les résultats à long terme. L'utilisation des lymphocytes T régulateurs (Treg), suppresseurs naturels de la réponse inflammatoire, a fait l'objet de nombreuses études ces dix dernières années, et pourrait être considérée comme un moyen intéressant d'améliorer la tolérance immunologique de la greffe. Cependant, l'un des obstacles de l'utilisation des Treg comme agent thérapeutique est leur nombre insuffisant non seulement en conditions normales, mais en particulier lors d'une forte réponse immune avec expansion de cellules immunitaires alloréactives. En raison des limitations techniques connues pour l'induction des Treg ex-vivo ou in vitro, nous avons dédié la première partie du travail de thèse à la détermination de l'efficacité de l'induction des Treg in vivo grâce à l'utilisation d'un complexe protéique IL-2/JES6-1 (IL2c). Nous avons montré que l'expansion des Treg par IL2c permettait d'augmenter la survie du greffon sur un modèle murin de transplantation de peau avec mismatch entre le donneur et le receveur pour le complexe majeur d'histocompatibilité (CMH). De plus, nous avons vu qu'en combinant IL2c à une inhibition à court terme de la voie de co-stimulation CD40L-CD40 (anti-CD154/MRl, administré au moment de la transplantation) pour empêcher l'activation des lymphocytes T, il est possible d'induire une tolérance robuste à long terme. Finalement, nos résultats soulignent l'importance de cibler une voie de co-stimulation bien particulière. En effet, l'utilisation d'IL2c combinée au blocage de la co-stimulation CD28-B7.1/2 (CTLA-4 Ig) n'induit qu'une faible prolongation de la survie de la greffe et n'induit pas de tolérance. L'application chez l'humain des traitements induisant la tolérance dans des modèles expérimentaux murins ou de primates n'a malheureusement pas montré de résultats probants en recherche clinique ; une des principales raisons étant la présence de lymphocytes B et T mémoires provenant du systeme d immunité acquise. C est pourquoi nous avons testé si la combinaison d'IL2c et MR1 améliorait la survie de la greffe dans des souris pré¬sensibilisées. Nous avons trouvé qu'en présence de lymphocytes B et T mémoires alloréactifs, l'utilisation d'IL2c et MR1 permettait une amélioration de la survie de la greffe de peau des souris immunocompétentes mais comparé aux souris receveuses naïves, aucune tolérance n'a pu être induite. Toutefois, l'ajout d'un traitement anti-LFA-1 (permettant de bloquer la circulation des lymphocytes T activées) a permis d'améliorer de manière significative la survie de la greffe. Cependant, le rejet chronique, dû à la présence de lymphocytes B activés/mémoires et la production d'anticorps donneur-spécifiques, n'a pas pu être évité. Cibler l'activation des lymphocytes T est la stratégie immunothérapeutique prépondérente après une TOS. C'est pourquoi dans la deuxième partie de cette thèse nous nous sommes intéressés au système de signalisation d'un récepteur des lymphocytes T qui dépend de la paracaspase Malti en tant que nouvelle stratégie immunosuppressive pour le contrôle des lymphocytes T alloréactifs. Nous avons montré que bien que l'inhibition de la signalisation du lymphocyte T en aval de Malti induise une tolérance envers un greffon de peau avec incompatibilités antigéniques mineures, cela ne permet cependant qu'une régulation partielle de l'alloréponse contre des antigènes du CMH. Nous nous sommes aussi intéressés spécifiquement à l'activité protéolytique de Malti. L'inhibition constitutive de l'activité protéolytique de Malti chez les souris Malti-ki s'est révélée délétère pour l'induction de la tolérance car elle diminue la fonction des Treg et augmente l'alloréactivité des cellules Thl. Cependant, lors de l'utilisation d'un inhibiteur peptidique de l'activité protéase de Malti in vitro, il a été possible d'observer une atténuation de l'alloéactivité des lymphocytes T ainsi qu'un maintien de la population des Treg existants. Ces résultats nous laissent penser que des études plus poussées sur le rôle de la signalisation médiée par Malti seraient à envisager dans le domaine de la transplantation. En résumé, les résultats obtenus durant cette thèse nous ont permis d'élucider certains mécanismes immunologiques propres à de nouvelles stratégies thérapeutiques potentielles dont le but est d'induire une tolérance lors de TOS. De plus, ces résultats nous ont permis de souligner l'importance d'utiliser des modèles davantage physiologiques contenant, notamment en tenant compte des lymphocytes B et T mémoires alloréactifs. -- Organ transplantation remains the best available treatment for many forms of end-stage organ diseases, with over 100,000 solid organ transplantations (SOT) occurring worldwide eveiy year. Although the available immunosuppressive (IS) drugs are efficient in controlling acute immune activation and graft rejection, the off-target side effects as well as long-term graft and patient survival remain a challenge in the clinic. Hence, innovative therapeutic approaches are needed to improve long-term outcome across immunological barriers. Based on extensive experimental data obtained over the last decade, it is tempting to consider immunotherapy using Treg; the natural suppressors of overt inflammatory responses, in promoting transplantation tolerance. The first hurdle for the therapeutic use of Treg is their insufficient numbers in non- manipulated individuals, in particular when facing strong immune activation and expanding alloreactive effector cells. Because of the limitations associated with current protocols aiming at ex-vivo expansion or in vitro induction of Treg, the aim of the first part of this thesis was to determine the efficacy of direct in vivo expansion of Treg using the IL-2/JES6- 1 immune complex (IL2c). We found that whilst IL2c mediated Treg expansion alone allowed the prolonged graft survival of fìlli MHC-mismatched skin grafts, its combination with short-term CD40L-CD40 co-stimulation blockade (anti-CD 154/MR1) to inhibit T cell activation administered at the time of transplantation was able to achieve long-term robust tolerance. This study also highlighted the importance of combining Treg based therapies with the appropriate co-stimulation blockade as a combination of IL2c and CD28-B7.1/2 co- stimulation blockade (CTLA-4 Ig) only resulted in slight prolongation of graft survival but not tolerance. The translation of tolerance induction therapies modelled in rodents into non-human primates or into clinical trials has seldom been successful. One main reason being the presence of pre-existing memory T- and B-cells due to acquired immunity in humans versus laboratory animals. Hence, we tested whether IL2c+MRl could promote graft survival in pre-sensitized mice. We found that in the presence of alloreactive memory T- and B-cells, IL2c+MRl combination therapy could prolong MHC-mismatched skin graft survival in immunocompetent mice but tolerance was lost compared to the naïve recipients. The addition of anti-LF A-1 treatment, which prevents the trafficking of memory T cells worked synergistically to significantly further enhance graft survival. However, late rejection mediated by activated/memory B cells and persistent donor-specific alloantibodies still occurred. Immunotherapeutic strategies targeting the activation of T cells are the cornerstone in the current immunosuppressive management after SOT. Therefore, in the next part of this thesis we investigated the paracaspase Malti-dependent T-cell receptor signalling as a novel immunosuppressive strategy to control alloreactive T cells in transplantation. We observed that although the inhibition of Malti downstream T signalling lead to tolerance of a minor H- mismatch skin grafts, it was however not sufficient to regulate alloresponses against MHC mismatches and only prolonged graft survival. Furthermore, we investigated the potential of more selectively targeting the protease activity of Malti. Constitutive inhibition of Malti protease activity in Malti-ki mice was detrimental to tolerance induction as it diminished Treg function and increased Thl alloreactivity. However, when using a small peptide inhibitor of Malti proteolytic activity in vitro, we observed an attenuation of alloreactive T cells and sparing of the pre-existing Treg pool. This indicates that further investigation of the role of Malti signalling in the field of transplantation is required. Collectively, the findings of this thesis provide immunological mechanisms underlying novel therapeutic strategies for the promotion of tolerance in SOT. Moreover, we highlight the importance of testing tolerance induction therapies in more physiological models with pre-existing alloreactive memory T and B cells.

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A bananeira cv. D´Angola demanda grandes quantidades de nutrientes para seu desenvolvimento e produção. Para uma recomendação adequada de fertilizantes, é importante que se conheçam as quantidades de nutrientes absorvidas, exportadas e restituídas ao solo pela planta. Objetivou-se avaliar os acúmulos de fitomassa e macronutrientes na bananeira cv. D´Angola (tipo Terra), em cinco doses de nitrogênio (N) aplicado em fertirrigação por gotejamento. O trabalho foi desenvolvido no campo da Embrapa Mandioca e Fruticultura, no município de Cruz das Almas-BA, em delineamento experimental em blocos casualizados, com quatro repetições. Avaliaram-se a fitomassa e o acúmulo de nutrientes em cinco órgãos da planta (pseudocaule, folhas, frutos, engaço e coração), em cinco doses de N (135; 180; 225; 270 e 315 kg ha-1) aplicadas via água de irrigação. Os resultados indicaram que o acúmulo de fitomassa e nutrientes para a bananeira cv. D´Angola mostrou que há diferentes níveis de absorção, exportação e restituição ao solo de macronutrientes entre os órgãos da planta, em função das doses de N, e que, em média, o pseudocaule e as folhas foram os órgãos que mais acumularam de nutrientes, enquanto o coração foi o que menos acumulou. A ordem decrescente de absorção na planta foi potássio, seguido por nitrogênio e cálcio.

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A qualidade do fruto do abacaxizeiro é influenciada pelos macronutrientes, principalmente N e K. Este trabalho avaliou a influência de doses de N e K2O sobre as características de qualidade físico-químicas e sobre os defeitos externos e internos dos frutos de abacaxizeiro ‘BRS Imperial’. Aplicaram-se quatro doses de N (0; 160; 320; 550 kg ha-1) e quatro de K2O (0; 240;480 e 600 kg ha-1), em delineamento experimental em blocos ao acaso, com cinco repetições, em um fatorial completo 42. As doses de N e K2O influenciaram todas as variáveisfísico-químicasestudadas, exceto a firmeza dos frutos, que apresentaram média de 10,7 kgf. As doses de N reduziram a acidez titulável (AT) e os sólidos solúveis (SS) e aumentaram o pH e o ratio dos frutos, apresentando, na dose de 550 kg ha-1 de N, os valores médios de 0,31%, 17,9 oBrix, 4,02 e 57,7, respectivamente. As doses de K2O aumentaram AT e os SS, e reduziram o ratio dos frutos, apresentando, na dose de 600 kg ha-1 de K2O, os valores médios de 0,41%, 19,4 oBrix e 47,9, respectivamente. O pH respondeu de forma quadrática, com o valor mínimo de 3,95 na dose de 273 kg ha-1 de K2O. As correlações significativas de Pearson indicaram que plantas com maiores teores foliares de N na época da indução floral produziram frutos com menor AT e SS, enquanto aquelas com maiores teores foliares de K apresentaram maior AT e SS nos frutos. Com aplicação de 550 kg ha de-1 N, os frutos apresentaram translucidez entre 50 e 75% sem adubação potássica e de menos de 25% de translucidez na dose de 400 kg ha-1 de K2O.

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Background: Vancomycin is a cornerstone antibiotic for the management of severe Gram positive infections. However, high doses of vancomycin are associated with a risk of nephrotoxicity. This study aimed to evaluate the relationship between the evolution of vancomycin trough concentration and the occurrence of nephrotoxicity, and to identify risk factors for both vancomycin-associated nephrotoxicity and vancomycin overexposure. Methods: A total of 1240 patients records from our hospital therapeutic drug monitoring database between 2007 and 2011 were screened and grouped according to predefined criteria defining vancomycin overexposure (one or more occurrence of a trough level ≥ 20 mg/L) and treatment-related nephrotoxicity (rise of serum creatinine by ≥ 50% over baseline). A representative sample of 150 cases was selected for in depth analysis. Weighted logistic regression analyses were used to test associations between vancomycin overexposure, nephrotoxicity and other predictors of interest. Results: Patients with high trough concentrations were found to be more likely to develop nephrotoxicity (odds ratio: 4.12; p <0.001). Specific risk factors, notably concomitant nephrotoxic treatments and comorbid conditions (heart failure), were found to independently increase the risk of either nephrotoxicity or vancomycin exposure. Finally, the exploration of temporal relationships between variations of vancomycin trough concentrations and creatinine levels were in line with circular causality with some antecedence of vancomycin on creatinine changes. Conclusion: Our results confirm the important nephrotoxic potential of vancomycin and indicate that the utilisation of this drug deserves thorough individualization for conditions susceptible to increase its concentration exposure and reactive adjustment based on therapeutic drug monitoring.

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TCF3-HLF-positive acute lymphoblastic leukemia (ALL) is currently incurable. Using an integrated approach, we uncovered distinct mutation, gene expression and drug response profiles in TCF3-HLF-positive and treatment-responsive TCF3-PBX1-positive ALL. We identified recurrent intragenic deletions of PAX5 or VPREB1 in constellation with the fusion of TCF3 and HLF. Moreover somatic mutations in the non-translocated allele of TCF3 and a reduction of PAX5 gene dosage in TCF3-HLF ALL suggest cooperation within a restricted genetic context. The enrichment for stem cell and myeloid features in the TCF3-HLF signature may reflect reprogramming by TCF3-HLF of a lymphoid-committed cell of origin toward a hybrid, drug-resistant hematopoietic state. Drug response profiling of matched patient-derived xenografts revealed a distinct profile for TCF3-HLF ALL with resistance to conventional chemotherapeutics but sensitivity to glucocorticoids, anthracyclines and agents in clinical development. Striking on-target sensitivity was achieved with the BCL2-specific inhibitor venetoclax (ABT-199). This integrated approach thus provides alternative treatment options for this deadly disease.

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During different forms of neurodegenerative diseases, including the retinal degeneration, several cell cycle proteins are expressed in the dying neurons from Drosophila to human revealing that these proteins are a hallmark of neuronal degeneration. This is true for animal models of Alzheimer's, and Parkinson's diseases, Amyotrophic Lateral Sclerosis and for Retinitis Pigmentosa as well as for acute injuries such as stroke and light damage. Longitudinal investigation and loss-of-function studies attest that cell cycle proteins participate to the process of cell death although with different impacts, depending on the disease. In the retina, inhibition of cell cycle protein action can result to massive protection. Nonetheless, the dissection of the molecular mechanisms of neuronal cell death is necessary to develop adapted therapeutic tools to efficiently protect photoreceptors as well as other neuron types.

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We retrospectively evaluated the efficacy and safety of high doses of onabotulinumtoxinA (from 600 to 800 units) in 26 patients affected by upper and/or lower limb post-stroke spasticity. They were assessed before, 30 and 90 days after treatment. We observed a significant muscle tone reduction and a significant functional improvement (assessed with the Disability Assessment Scale). No adverse events were reported. In our retrospective analysis the treatment with high doses of onabotulinumtoxinA showed to be effective and safe.

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Status epilepticus (SE) is a life-threatening neurological emergency often refractory to available treatment options. It is a very heterogeneous condition in terms of clinical presentation and causes, which besides genetic, vascular and other structural causes also include CNS or severe systemic infections, sudden withdrawal from benzodiazepines or anticonvulsants and rare autoimmune etiologies. Treatment of SE is essentially based on expert opinions and antiepileptic drug treatment per se seems to have no major impact on prognosis. There is, therefore, urgent need of novel therapies that rely upon a better understanding of the basic mechanisms underlying this clinical condition. Accumulating evidence in animal models highlights that inflammation ensuing in the brain during SE may play a determinant role in ongoing seizures and their long-term detrimental consequences, independent of an infection or auto-immune cause; this evidence encourages reconsideration of the treatment flow in SE patients.

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BACKGROUND: Several subsets of non-small-cell lung cancer (NSCLC) are defined by molecular alterations acting as tumor drivers, some of them being currently therapeutically actionable. The rat sarcoma (RAS)-rapidly accelerated fibrosarcoma (RAF)-mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)-extracellular signal-regulated kinase (ERK) pathway constitutes an attractive potential target, as v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutations occur in 2-4% of NSCLC adenocarcinoma. METHODS: Here, we review the latest clinical data on BRAF serine/threonine kinase inhibitors in NSCLC. RESULTS: Treatment of V600E BRAF-mutated NSCLC with BRAF inhibitor monotherapy demonstrated encouraging antitumor activity. Combination of BRAF and MEK inhibitors using dabrafenib and trametinib is under evaluation. Preliminary data suggest superior efficacy compared with BRAF inhibitor monotherapy. CONCLUSION: Targeting BRAF alterations represents a promising new therapeutic approach for a restricted subset of oncogene-addicted NSCLC. Prospect ive trials refining this strategy are ongoing. A next step will probably aim at combining BRAF inhibitors and immunotherapy or alternatively improve a multilevel mitogen-activated protein kinase (MAPK) pathway blockade by combining with ERK inhibitors.

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OBJETIVO: Avaliar a precisão das doses de radiação absorvidas na terapia de transplantes de medula óssea durante a técnica de irradiação de corpo inteiro. MATERIAIS E MÉTODOS: Utilizaram-se 200 pastilhas de sulfato de cálcio com disprósio compactado com teflon (CaSO4 + teflon), calibradas no ar e no "phantom", selecionadas aleatoriamente e dispostas em grupos de cinco no corpo dos pacientes. As leituras dosimétricas foram efetuadas pela leitora Harshaw 4000A. Nove pacientes foram irradiados no corpo inteiro em paralelos e em opostos laterais, utilizando-se unidade de cobalto-60, modelo Alcion II, com taxa de dose de 0,80 Gy/min a 80,5 cm, {campo (10 × 10) cm²}. A dosimetria dessa unidade foi realizada com dosímetro Victoreen 500. Para a determinação da dose média em cada ponto avaliado usaram-se os fatores individuais de calibração das pastilhas no ar e no "phantom", colocando-se um "build up" de 2 mm para superficializar a dose à distância de 300 cm. RESULTADOS: Em 70% dos pacientes obteve-se variação de dose menor que 5% e em 30% dos pacientes essa variação foi inferior a 10%, quando comparados os valores medidos com aqueles calculados em cada ponto. Na cabeça ocorre absorção, em média, de 14% da dose administrada, e nos pulmões, acréscimo de 2% na dose administrada. Nos pacientes com distância látero-lateral maior que 35 cm as variações entre as doses calculadas e medidas podem chegar a 30% da dose desejada, sem o uso de filtros compensadores. CONCLUSÃO: Os valores medidos das doses absorvidas nos diversos pontos anatômicos, comparados aos valores desejados (teóricos), apresentam tolerância de ±10%, considerando-se as diferenças anatômicas existentes, quando utilizados os fatores de calibração individuais das pastilhas.

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L'état de mal épileptique (EME) est la plus fréquente urgence neurologique après les accidents vasculaires cérébraux, avec des hauts taux de morbidité et mortalité (Coeytaux et al., 2000). Son traitement est basé sur une approche en trois étapes (Meiekord et al., 2010). Dans ce contexte, un EME ne répondant pas aux benzodiazépines (1er ligne de traitement) suivi par des médicaments antiépileptiques (2ème ligne de traitement) est appelé EME réfractaire. Pour cette condition, représentant entre le 23% et le 43% des EME (Novy et al., 201O; Holtkamp et al., 2005), les actuelles recommandations préconisent un traitement par coma pharmacologique (3ème ligne de traitement), malgré un faible niveau d'évidence (Rossetti et al., 2011). En effet, l'impact du coma pharmacologique sur l'issue clinique n'a pas encore été clairement établi. Récemment, deux études américaines (Kowalski et al., 2012; Hocker et al., 2013) et une étude suisse (Sutter et al., 2014), ont montré un effet potentiellement délétère de ce type de traitement. Cependant, ces études étaient limitées à des patients hospitalisés aux soins intensifs et les analyses n'étaient pas ajustées pour tous les facteurs pronostiques connus. Le but de notre travail, publié dans Critical Gare Medicine (Marchi et al., 2015), était d'évaluer l'impact spécifique du coma pharmacologique sur le pronostic des patients avec EME, sans limitations aux soins intensifs et avec un·ajustement plus attentif concernant les autres facteurs pronostiques. En utilisant notre registre prospectif des patients avec EME traités aux Centre Hospitalier Universitaire Vaudois, nous avons comparé l'issue clinique à la sortie de l'hôpital des patients traités avec ou sans coma pharmacologique (467 épisodes au total). Ensuite, nous avons utilisé une régression logistique multinomiale pour ajuster les résultats par les autres facteur pronostiques connus (âge, absence de crises épileptiques précédentes, étiologie potentiellement fatale, gravité clinique de l'EME, comorbidités). Nous · avons pu mettre ainsi en évidence que le traitement avec coma pharmacologique est associé avec une mauvaise issue clinique après un EME. De plus, nous avons pu po_ur la première fois montrer que cet effet est d'autant plus important chez les patients avec un EME de type partiel complexe au moment du traitement. Nos résultats suggèrent que l'utilisation du coma pharmacologique ne doit pas être indiscriminée dans l'EME réfractaire et qu'une évaluation de la situation clinique de base permet une optimisation son emploi.

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OBJETIVO: O objetivo deste trabalho é fazer um estudo comparativo das técnicas radiográficas entre o Brasil e a Austrália e avaliar as doses de radiação para os exames radiológicos mais comuns. MATERIAIS E MÉTODOS: A dose de entrada na pele (DEP) e a dose efetiva (DE) foram obtidas com o uso do programa DoseCal. Em ambos os países, o estudo foi realizado em hospitais de grande porte da rede pública. Quatro tipos de exames foram avaliados: tórax, abdome, pelve e coluna torácica em três projeções (ântero-posterior, póstero-anterior e lateral). Na Austrália, todos os equipamentos são digitais e operam no sistema PACS. No Brasil, os aparelhos são convencionais. RESULTADOS: Os valores médios da DEP e da DE são consideravelmente mais altos no Brasil, exceto para os exames de tórax, cujos resultados indicaram índices menores. As maiores diferenças encontradas foram para os exames de pelve (26 vezes maior no Brasil) e de coluna torácica (43 vezes maior no Brasil). O mesmo acontece para os valores da DE. CONCLUSÃO: Nos hospitais australianos, os programas de controle e garantia de qualidade (PCGQ) fazem parte da rotina nos serviços de radiologia. Contam com equipamentos digitais de última geração e os serviços possuem uma equipe de física médica atuante. Esse conjunto de iniciativas resulta na produção de imagens radiográficas de alta qualidade, com baixas doses e índices de rejeição próximos a zero. Tais resultados apontam para a necessidade de se estimular a implantação de PCGQ em toda a rede hospitalar brasileira. No entanto, analisando os resultados de DEP nos exames de tórax, concluímos que doses baixas também são possíveis no Brasil se forem empregadas técnicas radiográficas adequadas.