Class of 2008 Abstract / Objectives: To determine the cost-effectiveness of adding a thiazolidinedione (TZD) versus insulin glargine (glargine) as a triple regimen for treatment of Type 2 diabetes mellitus for patients not controlled with metformin and a sulfonylurea. Methods: A decision analytic model was developed to compare the clinical outcomes and costs of triple therapy with either a TZD or glargine. Published literature was used to determine treatment efficacy and the frequency of clinically important adverse effects. Cost data were obtained from the 2007 Physician Fee Reference and North Carolina Industrial Commission website. The decision tree was built using TreeAge software. Clinical outcome measures included HgA1c (A1C) control, hypoglycemia frequency, and the development of edema associated with the use of these medications. A Monte Carlo probabilistic sensitivity analysis was conducted to determine the mean and 95% CIs for both treatment efficacy and costs. Results: There was no statistically significant difference in the efficacy of adding either a TZD or glargine in achieving a goal A1C ≤ 7%. However, glargine triple therapy was estimated to be significantly less costly than TZD triple therapy ($3,161/yr; 95% CI $3,116 to $3,356 versus $3,769/yr; 95% CI $3,667 to $3,902, respectively). Conclusions: Most patients requiring triple therapy for the management of T2DM should receive glargine rather than a TZD due to the significantly lower cost producing similar clinical efficacy.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / Endocrine and locally produced factors are involved in the selection of the dominant ovarian follicle in the cow. Studies have been conducted to elucidate the precise mechanism by which, in most cases, only one follicle becomes dominant in monovulatory species. A better understanding of the factors involved in this period can serve as a basis to better exploit the reproductive potential in cattle. A complete knowledge of these factors remains unknown. The receptor peroxisome proliferator activated gamma (PPARγ, also called NR1C3) is a member of the PPAR nuclear receptors family. This family of receptors has been shown to be expressed in reproductive tissues of different species and their role in steroidigenesis and regulation of apoptosis. However, involvement of this receptor in folliculogenesis in cattle remains unknown. This study aimed to evaluate the role of PPARγ during the period of follicle deviation in cattle. At first, the PPARγ mRNA expression was evaluated in granulosa cells of the two largest growing follicles, before (day 2 of the follicular wave), during (day 3) and after (day 4) the follicle deviation period. The mRNA abundance was unchanged during follicular growth in both granulosa and theca cells. In a second experiment, the PPARγ agonist (TZD) was injected intrafollicularly in the dominant follicle in vivo in cows. The agonist caused follicular atresia, demonstrating that the activation of PPARγ in the dominant follicle prevent follicle growth. To determine the mechanism underlying the effects of PPARγ in granulosa cells in vivo, the dominant follicle of each cow was injected with PBS or TZD and the animals were ovariectomized 24 hours post injection. The stimulation of the PPARγ in the dominant follicle reduces the abundance of mRNA encoding the aromatase (CYP19A1) gene, the enzyme responsible for converting androgens to estradiol in granulosa cells and important for follicular development. In conclusion, the increased signaling of PPARγ downregulates aromatase and induces follicular atresia in cattle. / Fatores endócrinos e fatores produzidos localmente estão envolvidos na seleção do folículo dominante. Estudos têm sido realizados no intuito de elucidar o completo mecanismo pelo qual, na maioria das vezes, apenas um folículo torna-se dominante nas espécies monovulatórias. O melhor entendimento dos fatores envolvidos neste período pode servir como base para melhor explorar o potencial reprodutivo dos bovinos. No entanto, o completo entendimento desses fatores permanece desconhecido. O receptor ativado por proliferador de peroxissomo gama (PPARγ, também conhecido como NR1C3) pertence à família de receptores nucleares PPAR e tem sido demonstrado a expressão dessa família de receptores no tecido reprodutivo de diferentes espécies, bem como sua atuação na esteroidogênese e regulação da apoptose. No entanto, pouco se sabe sobre o envolvimento deste receptor na foliculogênese em bovinos. Dessa forma, o presente trabalho teve como objetivo investigar o papel e a regulação do PPARγ durante o período da divergência folicular na espécie bovina. Em um primeiro momento, foi avaliada a expressão de RNAm do PPARγ nas células da granulosa dos dois maiores folículos em crescimento, antes (dia 2 da onda folicular), durante (dia 3) e após (dia 4) o período da divergência folicular. Observou-se que a expressão deste receptor permanece inalterada durante o crescimento folicular nas células da teca e granulosa. Em um segundo experimento, a injeção intrafolicular com o agonista do receptor em estudo (TZD) no folículo dominante ocasionou a atresia dos folículos injetados. Assim, a ativação do PPARγ no folículo dominante impede o crescimento folicular. Para determinar o efeito da ativação do PPARγ, o folículo dominante de cada vaca foi injetado com TZD ou PBS e os animais foram ovariectomizados após 24 horas. A estimulação do PPARγ no folículo dominante diminui a abundância de RNAm que codifica para o gene aromatase (CYP19A1), enzima responsável pela conversão de andrógenos em estradiol nas células da granulosa e importante para o desenvolvimento folicular. Em conclusão, o aumento da sinalização do PPARγ diminui a expressão da enzima aromatase e induz atresia folicular em bovinos.

A utilização de microrreatores nas indústrias químico-farmacêuticas pode possibilitar uma série de vantagens devido ao seu tamanho reduzido comparado aos reatores batelada, sendo estes mais comumente utilizados por esse tipo de indústria. Essas vantagens podem ser associadas à redução dos tempos de reação da ordem de minutos e à redução da geração de resíduos e subprodutos. Existe um aumento de qualidade expressivo na transferência de massa e de calor, o que acarreta em um processo facilmente controlável e seguro, permitindo maior rendimento e seletividade. A indústria químico-farmacêutica beneficia-se desta tecnologia, pois os microrreatores podem gerar uma grande variedade de compostos, em alguns casos várias ordens de grandeza maior em comparação ao processo batelada tradicional e podem diminuir em anos o tempo para produção comercial de um novo fármaco devido à maior facilidade no aumento da escala de produção. O objetivo deste trabalho foi transpor a reação de síntese de um derivado da tiazolidina-2,4-diona, um intermediário utilizado na produção de fármacos no combate à diabetes millitus II, do processo batelada para microrreator em fluxo contínuo. Por meio dos resultados foi determinado que não existe a necessidade de mais de 80 min. de reação para se atingir aproximadamente 98% de rendimento do produto em batelada, tendo o etanol como solvente e utilizando pirrolidina como base ideal na concentração de 0,040 M. Além disso, com o Screening de solventes foi possível entender melhor os aspectos da reação e determinar que tanto o metanol como o etanol são os mais adequados para a reação. Diferentes bases promotoras da reação foram testadas como substitutas da piperidina referenciada na literatura, que teve sua comercialização proibida no país. O processo em fluxo contínuo no microrreator a 140°C, proporcionou maior conversão e rendimento do que o processo batelada. Foi possível estudar os limites do microrreator em termos de temperatura e concentração de base promotora, sendo possível a aplicação dos princípios da intensificação de processos. Esses dados corroboram com os encontrados para o número equivalente de microrreatores (n°MR), onde para o etanol na mesma temperatura de ebulição do solvente (78°C) são necessários aproximadamente 9 microrreatores para ter a mesma produção de um batelada. Porém, com o aumento de temperatura para 140°C, são necessários 2 microrreatores para ter a mesma produção de um batelada. / The use of microreactors in the chemical-pharmaceutical industries may provide a number of advantages due to their reduced size compared to batch reactors, these being more commonly used by this type of industry. These advantages can be associated with the reduction of reaction times and the reduction of generation of residues and byproducts. There is an expressive quality increase in the transfer of mass and heat, which results in an easily controllable and safe process, allowing greater yield and selectivity. The chemical-pharmaceutical industry benefits from this technology because microreactors can generate a wide variety of compounds, in some cases several orders of magnitude larger than the traditional batch process, and may decrease the time for commercial production of a new drug in years due to the possibility of increasing the production through numbering-up. The objective of this project was to transpose the synthesis reaction of a thiazolidine-2,4-dione derivative, an intermediate used in the production of drugs in the fight against diabetes mellitus II, from batch process to microreactor in continuous flow. Through the results it was determined that there is no need for more than 80 min. of reaction to achieve approximately 98% product yield in the batch process, with ethanol as the solvent and using pyrrolidine as the best base at the optimum concentration of 0.040 M. In addition, with the screening of solvents it was possible to better understand the aspects of the reaction and to determine that both methanol and ethanol are the most suitable for the reaction. Different base reaction promoters were tested as substitutes of the usual base used for this type of reaction, piperidine, often cited in the literature, that had its commercialization prohibited in Brazil. The continuous flow process in the microreactor at 140°C, provided higher conversion and yield than the batch process. It was possible to study the limits of the microreactor in terms of temperature and concentration of promoter base, being possible to apply the principles of process intensification. These data corroborate with those found for the equivalent number of microreactors (nºMR), where for ethanol, at the same boiling temperature of the solvent (78ºC), approximately 9 microreactors are required to have the same production of a batch operated for 8 h. However, for higher temperatures the yields are even higher, and for 140°C, 2 microreactors are required to have the same production of a batch.

A key element in evidence-based medicine approaches is the ability for clinicians to evaluate the scientific rigor and relevance of research evidence. In the treatment of diabetes, clinicians make increasingly difficult decisions about which drug regimens are best for their patients with limited evidence-based information. While the consensus is that metformin should be the initial drug treatment when diet and exercise are not sufficient, clinicians disagree on whether sulfonylureas should remain a suitable therapy after metformin. While this would be improved with further research investigating the comparative safety of therapeutic options, there is also need for better ways to synthesize available information to guide evidence-based decision-making in health services research. Study 1 summarizes the pre-existing evidence on the long-term safety risks associated with sulfonylurea therapy relative to other drug classes. Results from a series of meta-analyses provide some evidence that sulfonylureas are associated with elevated all-cause mortality and cardiovascular risks relative to several other medications, either as a monotherapy or in combination with metformin. Study 2 analyzes the comparative safety of second-line treatment in diabetic patients in the Veterans Health Administration to address gaps in the literature. Results suggest that second-line use of sulfonylureas is associated with increased risks compared to thiazolidinediones. Results also suggest that changes to existing metformin therapy may lead to differential hazards. Clinicians may disagree about the quality of the evidence as well as the relevancy to their own treatment population. Improvements in methods for evidence-based medicine that take this into account are needed. Study 3 applies an underutilized research method that allows for a more thoughtful synthesis of all available evidence. This framework allows clinicians to incorporate the scientific rigor and relevancy of previous study results when integrating new data into their current knowledge base. Results suggest an elevated risk in all models for sulfonylureas compared to thiazolidinediones and highlight the need to design more focused research to support clinical decision-making around medication safety. This novel application to evidence synthesis shows promise as applied to a health services research problem and has potential as a useful framework in other health services research areas. / 2017-12-09T00:00:00Z

Monoklonale Antikörper (mAk) werden bereits erfolgreich zur therapeutischen Depletion verschiedener Zellpopulationen in vivo verwendet, die Mechanismen der Depletion sind jedoch unklar geblieben. In dieser Arbeit wurden im Mausmodell die molekularen Grundlagen der CD4+ T-Zelldepletion (CD4 TZD) nach einmaliger Gabe (i.p.) von 100 µg des anti-CD4-mAk YTS191.1 untersucht. Dabei konnte eine starke Korrelation zwischen Depletion und der Modulation des CD4-Moleküls von der Oberfläche beobachtet werden. Gleichzeitig zeigten sich organabhängige Unterschiede, sowohl im zeitlichen Verlauf, als auch in der Effizienz der Depletion. Im Thymus konnten weder Depletion noch Modulation detektiert werden, in Milz und Lymphknoten (Lk) war die CD4 TZD nach starker CD4-Modulation bereits nach 48 h mit 80-90 % maximal, in den Peyer-Plaques jedoch niedriger und verzögert (50-60 % nach 72 h). Anhand C3-defizienter Mäuse konnte ferner kein wesentlicher Beitrag von Komplement an der CD4 TZD beobachtet werden. Im Gegensatz dazu konnte durch die Verwendung verschiedener FcGamma-Rezeptor (FcGammaR)-defizienter Mäuse (FcGammaRI, FcGammaRII, FcGammaRIII, FcGammaRI/III und FcRGamma) wie auch durch die Blockade des FcGammaRIV eine starke, zudem organabhängige Beteiligung von FcGammaR an der CD4 TZD gezeigt werden. Während in der Milz die CD4 TZD von FcGammaRIV vermittelt wurde, waren in den Lk und Peyer-Plaques FcGammaRI/III involviert. Diese Befunde korrelierten mit der starken Expression von FcGammaRIV in Milz, Lunge, Darm, Niere und Leber, während in den Lk nur eine schwache und in Thymus und Peyer-Plaques keine Expression detektiert werden konnte. Innerhalb der Milz konnten erstmalig F4/80hoch Makrophagen als FcGammaRIV+ identifiziert und somit als potenzielle Effektorzellen der CD4 TZD bestimmt werden. Der direkte Vergleich der Depletion von CD4+ T-Zellen mit der Depletion von ICOS+ T-Zellen verdeutlichte darüber hinaus, dass die Effizienz der Zelldepletion nicht nur von den Eigenschaften des verwendeten mAk, sondern auch von denen des Zielmoleküls abhängig ist. / Monoclonal antibodies (mAb) are efficiently used for the therapeutic depletion of various cells in vivo yet the mechanisms of depletion are still unclear. In this work, the molecular principles of CD4+ T cell depletion (CD4 Tcd) by a single application of 100 µg of the anti-CD4 mAb YTS191.1.1 were investigated in the mouse. A strong correlation between the depletion and the surface modulation of the CD4 molecule could be observed. At the same time, organ-dependent differences in the kinetics as well as in the efficiency of depletion could be detected. In the thymus, neither modulation nor depletion were detectable. In the spleen and the lymph nodes (Ln), the modulation was strong and the depletion was maximal (80-90%) 48 h after mAb treatment. Interestingly, both modulation and depletion were decreased and delayed (50-60% after 72 h) in the Peyer`s patches. By using C3-deficient mice, no major contribution of complement to the CD4 Tcd was seen. On the contrary, with the help of different FcGamma-receptor (FcGammaR)-deficient mice (FcGammaRI, FcGammaRII, FcGammaRIII, FcGammaRI/III, and FcRGamma) and through the blockade of FcGammaRIV, a strong organ dependent involvement of FcGammaR could be shown. While the depletion in the spleen was clearly dependent on FcGammaRIV, in the Ln and the Peyer`s patches, FcGammaRI/III were involved. These findings correlated with the strong expression of FcGammaRIV in the spleen, the lung, the colon, the kidney, and the liver, while in the Ln the expression was weak and undetectable in the thymus and the Peyer`s patches. For the first time, F4/80high macrophages in the spleen could be identified as also being FcGammaRIV+, and are therfore considered as the potential effector cells of the CD4 Tcd. The direct comparison of the depletion of T cells via CD4 or ICOS pointed out that the target cell depletion is not only dependent on the properties of the mAb used, but also on those of the target molecule.