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The study objective was to determine whether early 2 nd trimester amniotic fluid (AF) erythropoietin (EPO) was associated with and predictive of (a) development of maternal gestational diabetes (GDM) and (b) the infant outcome parameters of (i) gestational age at birth (GAAB) assessed exclusively among spontaneous vaginal deliveries or (ii) birth weight (measured in grams and percentiles). Enzyme-linked-immunosorbent assay was used to determine the EPO concentration of 170 biobanked AF samples. Student's t-test revealed no difference between GDM and non-GDM subjects. AF EPO was not predictive of GAAB despite being significantly greater among preterm infants compared to post-term infants. In contrast, AF EPO was significantly higher among the smallest infants using both birth weight classification schemes. However, following inclusion of known covariates AF EPO was predictive of gram birth weight only. Early 2nd trimester AF EPO may emerge as a useful biomarker of fetal nutritional status and/or growth.

Severe anemia is a major life-threatening complication of malaria. Inappropriately low reticulocytosis in malaria patients with anemia suggests insufficient erythropoiesis, of which the mechanisms and implications are not clear. The principle growth factor that promotes erythropoiesis is erythropoietin (Epo). Studies determining the serum level of Epo in malaria infected patients have been inconclusive. Furthermore, the role of Epo and the erythropoietic response to Epo stimulation during malaria have never been examined. The purpose of the experiments performed in this thesis was, thus, to investigate the role of Epo and erythropoiesis in relation to anemia during blood-stage malaria using the murine model of Plasmodium chabaudi AS. A murine Epo specific ELISA, which was determined to be less biased by the presence of other cytokines in the samples as compared to the conventional Epo bioassay, was first developed to facilitate the research. The kinetics of Epo production in the kidney and the levels in the serum were characterized. It was demonstrated that Epo production during blood-stage malaria is mainly regulated by the degree of anemia and that renal cytokines may have only a minor effect on this response. Next, the roles of Epo and erythropoiesis during blood-stage malaria were investigated by neutralization of endogenous Epo or by administration of exogenous Epo. Timely onset of Epo-induced reticulocytosis was shown to be important for the alleviation of malarial anemia and survival. However, reticulocytosis in response to Epo stimulation is severely suppressed by infection with malaria. Dissection of the upstream events of erythropoiesis demonstrated that blood-stage malaria compromises the generation of reticulocytes by suppressing the proliferation, differentiation, and maturation of erythroid-lineage cells at various stages of erythroid development. Taken together, our data provide important insights for understanding the patho

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

Thesis (Ph.D. )--University of Tennessee Health Science Center, 2008. / Title from title page screen (viewed on October 7, 2008 ). Research advisor: Paul A. Ney, M.D. Document formatted into pages (xi, 122 p. : ill.). Vita. Abstract. Includes bibliographical references (p. 78-110).

Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 109-124).

Tez (Tıpta Uzmanlık) - Süleyman Demirel Üniversitesi, Tıp Fakültesi, Çocuk Sağlığı ve Hastalıkları Anabilim Dalı, 2007. / Bibliyografya var.

Tübingen, Univ., Diss., 2007.

Made available in DSpace on 2014-09-24T12:58:29Z (GMT). No. of bitstreams: 2 license.txt: 1748 bytes, checksum: 8a4605be74aa9ea9d79846c1fba20a33 (MD5) 157.pdf: 1202080 bytes, checksum: e4ae8cb25f3ce32fa7537d73814aa79f (MD5) Previous issue date: 2004 / A avaliação da potência biológica da eritropoetina humana recombinante (rhEPO), presente em sete produtos farmacêuticos, foi efetuada, comparativamente ao Padrão biológico da Farmacopéia Européia F.E.(2002), em camundongos normocitêmicos fêmeas, de 8 semanas de idade da linhagem Swiss Webster (SW), através da administração subcutânea do hormônio, numa sequência logarítmica de base 3 (10, 30 e 90 Ul/animaì Â dose múltipla, subdividida em quatro sucessivas aplicações diárias, seguida da coleta de amostra sangüínea 24h após a última aplicação da dose múltipla, ilsando-se o método visual da hemólise seletiva, para a contagem dos reticulócitos. (...)Empregando o mesmo Padrão, confirmamos dados da literatura, que demonstram que a seqüência logarítmica das doses na base 2 (20, 40 e 80 Ul/animal), aplicadas em esquema de dose única seguida da coleta do sangue 96 h após, preconizada pela F .E., é menos discriminativa da seqüência na base 3, bem como comprovamos a maior sensibilidade e menor variabilidade dos resultados empregando-se a metodologia de dose múltipla, a qual proporcionou ensaios biológicos altamente válidos, evidenciados através da aplicação do método das retas paralelas (3:3,6 pontos) que revelou a elevada significância das regressões lineares (P<0,01) bem como desvios não-significativos da linearidade e do paralelismo (P>0,05). Uma primeira tentativa de aplicação do ensaio 2:2, 4 pontos, reduzindo significativamente o número de animais, revelou-se válida, porém, na vigência de variabilidade mínima dos resultados experimentais, meta que, embora difícil, espera-se seja atingida corri, o emprego do método automatizado de contagem dos reticulócitos, isto é, a Citometria de Fluxo, a qual é de precisão sensivelmente maior que o método visual. O estudo comparativo entre as linhagens B6D2Fl, preconizada pela F.E., e a SW, revelou maior sensibilidade da primeira (24 por cento), embora este valor se afigure relativo, face a significativa diferença entre os pesos corporais das fêmeas da B6D2Fl (16,8 a 20,2 g) e da SW (29,2 a 37,9 g) e ao fato da rhEPO ser aplicada por animal e não por unidade de peso. Por outro lado, as respostas proporcionais das fêmeas da linhagem SW, aos diferentes estímulos do hormônio, se afiguram suficientes para torná-la altamente sugestiva como alternativa válida, em termos de linhagem de camundongos normocitêmicos, para o ensaio biológico de potência da rhEPO.

L’hypoxie est l’une des principales causes de résistance aux traitements dans les glioblastomes. Des stratégies permettant de lever l’hypoxie ou de limiter ses effets sont de ce fait nécessaires. Ces travaux de thèse s’intéressent à deux stratégies de vectorisation ciblée agissant contre l’hypoxie. La première stratégie vise à lutter contre les effets de l’hypoxie par une approche combinée de vectorisation cellulaire et moléculaire ciblant une protéine à action pro-tumorale : l’érythropoïétine. Des macrophages ont ainsi été modifiés génétiquement pour leur permettre de surexprimer une forme tronquée de récepteur à l’érythropoïétine conduisant à un ralentissement de la croissance d’un modèle de glioblastome. Les constructions moléculaires ont ensuite été modifiées pour rendre la surexpression inductible par l’hypoxie. La deuxième stratégie vise à réoxygéner spécifiquement la tumeur en se basant sur des nanozéolithes vectrices de gaz hyperoxiques. Les résultats montrent que ces nanoparticules microporeuses ne présentent pas d’effets toxiques majeurs in vitro et in vivo. L’incorporation de fer dans les zéolithes augmente significativement la capacité de transport d’O2 et le gadolinium permet leur utilisation comme agent de contraste en imagerie par résonance magnétique. D’autre part, les nanozéolithes vectrices de CO2/O2 s’accumulent spécifiquement dans le tissu tumoral et augmentent localement le volume sanguin et la quantité d’oxygène. Ainsi, les deux approches développées au cours de cette thèse démontrent le potentiel des stratégies ciblées dirigées contre l’hypoxie dans les glioblastomes. / Hypoxia is one of the main causes of resistance to treatments in glioblastoma, the worst primary brain tumor in term of survival. Two targeted vectorization strategies directed against hypoxia are presented in this thesis work. The first strategy was designed to inhibit hypoxia-induced erythropoietin through the use of macrophages. Macrophages were genetically engineered to overexpress a truncated form of the erythropoietin receptor resulting in a decrease in the tumor volume in a hypoxic model of glioblastoma in vivo. Hypoxia-inducible constructs were then developed. The second strategy aimed to use nanozeolites carrying hyperoxic gases as a tool to specifically reoxygenate the tumor. Results show that these microporous nanoparticles have no adverse effects in vitro and in vivo. The incorporation of iron in the zeolites significantly increases their oxygen transport capacity and the gadolinium allows their use as a contrast agent for magnetic resonance imaging. In addition, nanozeolites carrying CO2/O2 accumulate specifically in the tumor tissue and locally increase the blood volume/oxygenation. Thus, the two strategies developed during this thesis demonstrate the potential to fight against hypoxia specifically in glioblastoma.