Maturation of cytochrome P450 3A mediated drug metabolism: Towards individualized dosing in children

__Abstract__ Most drugs have not been adequately studied in children, leaving this population at an increased risk of underdosing or toxicity. Because of ethical, practical and financial constraints of pediatric clinical trials, there is a high percentage of drugs that is used in an unlicensed or off-label manner, with percentages approximating 70% in children and more than 93% in critically ill neonates. The main limitations in designing and conducting clinical studies in children are ethical, practical and scientific. Ethical issues are e.g. proxy consent, safety concerns and blood volume needed for pharmacokinetics. Practical issues pertain to the limited number of patients available and sample collection challenges. Scientific issues are related to the impact of growth and development on drug disposition, while increasingly attention is put on the long-term impact of early-life drug exposure on the developing brain. In the past the emphasis has been on the evaluation of the short-term direct effects of drugs, such as the increase in blood pressure upon the administration of vasoactive drugs. Fortunately, the current interest in primary outcome measures of drug treatment has led to an increase in the number of studies investigating long-term effects, i.e. neurodevelopmental outcome in children. An example is the recent study in which long-term cardiovascular effects of dobutamine and dopamine have been compared in preterm and low birth weight neonates

Kuvvetli k-uzaylar

06.03.2018 tarihli ve 30352 sayılı Resmi Gazetede yayımlanan “Yükseköğretim Kanunu İle Bazı Kanun Ve Kanun Hükmünde Kararnamelerde Değişiklik Yapılması Hakkında Kanun” ile 18.06.2018 tarihli “Lisansüstü Tezlerin Elektronik Ortamda Toplanması, Düzenlenmesi ve Erişime Açılmasına İlişkin Yönerge” gereğince tam metin erişime açılmıştır.Bu tez beş bölümden oluşmaktadır. Birinci bölüm giriş kısmına ayrılmıştır. İkinci bölümde ön-açık (ön-kapalı) küme, ön-topolojik uzay, kümenin ön-içi (ön-kapanışı), kümenin ön-sınırı, ön-limit noktası, ön-komşuluk, ön-dış küme, ön-kararsız fonksiyon, kuvvetli kompakt küme ve ön-Hausdorff uzayına ilişkin temel tanımlar verilmiştir. Üçüncü bölümde k-uzayların birbirine denk olan tanımları verilmiş ve karşılaştırılmıştır. Buna ek olarak, bir uzayın k-uzay olabilmesi için gerekli ve yeterli koşullar sıralanmıştır. Dördüncü bölüm bu çalışmanın orijinal kısmını oluşturmaktadır. Bu bölümün giriş kısmında kuvvetli k-uzay kavramı tanıtıldıktan sonra yerel kuvvetli kompakt uzayların ve birinci sayılabilir uzayların kuvvetli k-uzay olması için gerek ve yeter şartlar verilmiştir. Ayrıca bu şartları verebilmek için gerekli olan lemmalar bu bölümde ifade ve ispat edilmiştir. Son olarak kuvvetli k-uzayların alt uzaylarının kuvvetli k-uzay olması koşulları ifade edilmiştir. Beşinci bölümde tüm çalışmanın kısa bir özeti yapılmış ve bundan sonra yapılacak yeni araştırmalara yönelik öneride bulunulmuştur.This thesis consists of five chapters. The first chapter is devoted to the introduction. In the second chapter, the basic definitions of pre-open (pre-closed) set, pre-topological space, pre-interior (pre-closure) of a set, pre-frontier of a set, pre-accumulation point, pre-neighborhood, pre-exterior of a set, pre-irresolute function, strongly compact set and pre-Hausdorff space are summarized. In the third chapter, definitions of k-spaces which are equivalent to each other are introduced and compared. Also, the necessary and sufficient criteria are given for any space to be a k-space. The fourth chapter is the original part of this study. At the beginning of this chapter, strongly k-spaces are introduced. The necessary and sufficient conditions for the locally strongly compact spaces and the first countable spaces to be a k-space are obtained. Furthermore to give these conditions, the necessary lemmas are stated and proved. Finally the requirements of the subspaces to be k-spaces are expressed. In fifth chapter of this thesis, a brief summary of the study is given and a suggestion is proposed for new investigations

Retrospective study of 146 intracranial meningioma cases, diagnosed between 1977-1990

Bu çalışmada Patoloji laboratuvarımıza 1 Ocak 1977-31 Aralık 1990 tarihleri arasında gönderilen ameliyat piyesleri içinde intrakranial tümör tanısı konan 699 olgu materyal olarak kullanılmıştır. Bu tümörler içerisinde yer alan 146 intrakranial meningioma olgusuna ait dökümanlar tekrar gözden geçirilmiştir. Meningiomların yaş ve cinsiyet dağılımı, intrakranial lokalizasyonları, histolojik tipleri ile sekonder değişiklikleri kaynaklardaki bilgi ve bulgularla karşılaştırılarak tartışılmıştır.In this study, 699 intracranial tumor cases have been used as a material, from surgical specimens sent to our pathology laboratory between January 1, 1977 December 31, 1990. In this tumor series, 146 intracranial meningioma cases were restudied. Discussion of age and sex distributions of the meningiomas as well as intracranial localization, histological typing and sekonder changes have been evaluated with the comparison of the knowledge and findings in the literature

A Different Way of Coronary Lesion Preparation: Stentablation and Rotastenting

Calcified coronary lesions are challenging to deal with, as they require optimal lesion preparation. Direct stenting in this scenario is associated with risk of stent-underexpansion, which is related to in-stent restenosis, target lesion revascularization and stent-thrombosis. We report on the interventional management of an underexpanded bare-metal stent not amenable to high-pressure balloon dilation and cutting-balloon. By using rotablation we could abrade the underexpanded stent struts and the calcification with subsequent implantation of a drug-eluting stent. Follow-up of 6 months revealed good results without evidence of significant restenosis. Our clinical experience and case reports in the literature suggest that this strategy might be an option for underexpanded stents not amenable to conventional techniques

Koyunlarda Yemlemeden Sonra Kan Oksidan-antioksidan Denge ile Bazı Biyokimyasal Parametrelerdeki Değişimlerin Belirlenmesi

Daily variations in the concentration of urea, glutamine, glucose, cortisone, malondialdehyde (MDA) and antioxidant potential (AOP) were evaluated in the blood of sheep fed once a day. The study was carried out on 10 Anatolian Merinos sheep, average 1.5 years old and healthy. Animals were fed once per day with 61.3 % forage and 38.7 % concentrate mixture throughout the experimental period for 15 days. The blood samples were taken from the animals at first hour before and at 1, 3, 5, 7, 9, 12, 18 and 24th hours after feeding. Urea concentration decreased at first hour after feeding compared to before feeding and started augmentation after that and reached to levels before feeding at 12th hour after feeding. Glucose concentration increased at first hour after feeding compared to before feeding and started decline after that and reached to levels before feeding at 5th hour after feeding. Glutamine and cortisone concentrations decreased from at first hour to at 7th hour after feeding compared to before feeding and reached to levels before feeding at 7th hour after feeding. MDA levels decreased at first and 5th hours after feeding compared to before feeding and started increasing after 7th hour and reached significantly higher levels than before feeding in samples taken from at 12th hour to at 24th hour after feeding. While AOP increased at 3th and 9th hours after feeding, it decreased at 5, 7 and 12th hours after feeding. We concluded that the blood metabolic profiles and oxidant and antioxidant balance in sheep vary depending on time after feeding. In order to maximize the diagnostic value of these the blood metabolic profiles, the most suitable time for blood collection seems to be just before the feeding in sheep fed once a day.Bu proje çalışması, koyunlarda beslemeden sonra geçen zamana bağlı olarak kan metabolik profili ile oksidan-antioksidan dengede meydana gelen değişiklikleri tespit etmek amacıyla yapıldı. Araştırma; ortalama 1,5 yaşlı, sağlıklı 10 Anadolu Merinosu koyunda gerçekleştirildi. Hayvanlar 15 gün süren deneme boyunca % 61.3 kaba yem ve % 38.7 karma yemden oluşan rasyonla günde bir kez beslendiler. Hayvanlardan besleme öncesi ve beslemeden sonraki 1, 3, 5, 7, 9, 12, 18 ve 24. saatlerde kan örnekleri alındı. Kan örneklerinde, üre, glikoz, glutamin ve kortizol düzeyleri ile malondialdehid (MDA) ve antioksidan potansiyel (AOP) belirlendi. Üre düzeyleri besleme öncesine göre besleme sonrası ilk saatte düştü, bu saatten sonra artmaya başladı ve besleme önceki düzeylerine beslemeden sonraki 12. saatte ulaştı. Glikoz düzeyleri besleme öncesine göre beslemeden sonraki ilk saatte önemli oranda arttı, bu saatten sonra düşerek beslemeden sonraki 5. saatte besleme öncesi düzeylerine ulaştı. Glutamin ve kortizol düzeyleri besleme öncesine göre beslemeden sonraki ilk saatten 7.saate kadar önemli düzeyde düşüş gösterdi ve beslemeden sonraki 7.saatte besleme öncesi düzeylere ulaştığı bulundu. MDA düzeyleri beslemeden sonraki ilk ve 5. saat örneklerinde önemli düzeyde düşüş gösterdi ve 7. saatten sonra artmaya başlayarak 12 saatten 24. saate kadar alınan örneklerde önemli düzeyde arttığı tespit edildi. AOP beslemeden sonraki 3. ve 9. saatlerde önemli oranda artarken, 5, 7 ve 12. saatlerde önemli oranda azaldığı bulundu. Sonuç olarak, koyunlarda kan metabolik profil ile oksidan-antioksidan dengenin beslemeden sonra geçen zamana bağlı olarak değişmektedir

Load path sensitivity and fatigue life estimation of 30CrNiMo8HH

The final publication is available at Elsevier via http://dx.doi.org/10.1016/j.ijfatigue.2011.10.009 © 2012. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/A set of strain-controlled biaxial proportional and non-proportional tests were conducted on solid and tubular specimens of 30CrNiMo8HH steel. The effect of the phase angle on fatigue life was studied. This effect becomes noticeable when applying a 90 degrees out-of-phase loading, reducing the fatigue life by a factor up to 5. It has been shown that the material has no additional hardening due to out-of-phase loading. To account for this severe path dependency, a material dependent non-proportionality modification factor is proposed. This path dependent sensitivity factor is applied to six different fatigue parameters including maximum equivalent total strain, maximum equivalent stress, Smith-Watson-Topper, Fatemi-Socie, plastic strain energy density and total strain energy density to correlate the fatigue results. The predicted fatigue lives are compared with the experiments. The cyclic plasticity models of Mroz and Chaboche were successfully employed to model the cyclic behavior of 30CrNiM08HH steel. It has been shown that estimations based on the proposed non-proportionality modification factor agree well with the experimental results.Natural Sciences and Engineering Research Council (NSERC) of Canad