Characterization of Fms-interacting protein (FMIP), a novel substrate for tyrosine kinase : connection between receptor tyrosine kinase signaling and mRNA-processing

[no abstract

Histone Deacetylase 9 Activates IKK to Regulate Atherosclerotic Plaque Vulnerability

Rationale: Arterial inflammation manifested as atherosclerosis is the leading cause of mortality worldwide. Genome-wide association studies have identified a prominent role of histone deacetylase 9 (HDAC9) in atherosclerosis and its clinical complications including stroke and myocardial infarction. Objective: To determine the mechanisms linking HDAC9 to these vascular pathologies and explore its therapeutic potential for atheroprotection. Methods and Results: We studied the effects of Hdac9 on features of plaque vulnerability using bone marrow reconstitution experiments and pharmacological targeting with a small molecule inhibitor in hyperlipidemic mice. We further employed two-photon and intravital microscopy to study endothelial activation and leukocyte-endothelial interactions. We show that hematopoietic Hdac9 deficiency reduces lesional macrophage content whilst increasing fibrous cap thickness thus conferring plaque stability. We demonstrate that HDAC9 binds to IKKα and β resulting in their deacetylation and subsequent activation, which drives inflammatory responses in both macrophages and endothelial cells. Pharmacological inhibition of HDAC9 with the class IIa HDAC inhibitor TMP195 attenuates lesion formation by reducing endothelial activation and leukocyte recruitment along with limiting pro-inflammatory responses in macrophages. Transcriptional profiling using RNA-Seq revealed that TMP195 downregulates key inflammatory pathways consistent with inhibitory effects on IKKβ. TMP195 mitigates the progression of established lesions and inhibits the infiltration of inflammatory cells. Moreover, TMP195 diminishes features of plaque vulnerability and thereby enhances plaque stability in advanced lesions. Ex vivo treatment of monocytes from patients with established atherosclerosis reduced the production of inflammatory cytokines including IL-1β and IL-6. Conclusions: Our findings identify HDAC9 as a regulator of atherosclerotic plaque stability and IKK activation thus providing a mechanistic explanation for the prominence of HDAC9 as a vascular risk locus in genome-wide association studies. Its therapeutic inhibition may provide a potent lever to alleviate vascular inflammation

The role of expert wi̇tness testi̇mony i̇n medi̇cal malprracti̇ce cases

Thesis (M.A.)--Özyeğin University, Graduate School of Social Sciences, Department of Institute of Social Sciences Department of Private Law, 2014.Bilirkişi görüşlerinin davaların sonuçlandırılmasında çok etkili bir rolü vardır. Mahkemeler, ceza ve hukuk davalarında, Hakimlerin çözmekte zorlandığı bilimsel konulara açıklık getirmek için bilirkişilerin görüşlerine başvururlar. Ülkemizde son yıllarda hatalı tıbbi müdahale iddiasıyla açılan davalarda büyük bir artış gözlenmektedir. Mahkemeler ve Hakimler, bilirkişilerin temel tıp kurallarına, kabul edilebilir tedavi seçeneklerine ilişkin açıklamaları ve yorumları olmadan tıbbi müdahale hatalarını komplikasyonlardan ayıramazlar. Ülkemizdeki kanunlara göre, mesleği yapmaya yetkili olan tüm hekimlerin tıbbi bilirkişilik yükümlülüğü de vardır. Adli Tıp Kurumu, Yüksek Sağlık Şurası, Adli Tıp Enstitüleri ve Üniversiteler halen ülkemizde bilirkişilik hizmeti veren kurumlardır. Biz burada, tıp camiasında, mahkemelerde ve sosyal mediada sıklıkla tartışma konusu olan tıbbi müdahale hatasıyla komplikasyonun ayırımını inceledik. Adli Tıp Kurumu ve Yüksek Sağlık Şurası tarafından verilen bir takım hatalı, eksik ve bilimsel olmayan tıbbi bilirkişi raporlarını mercek altına aldık. Bu çalışma güvenilir, tarafsız, objektif ve bilimsel tıbbi bilirkişi raporlarının hatalı tıbbi müdahale davalarındaki önemini tartışmakta, tıbbi bilirkişilerin bilginin tarafsız taşıyıcısı olmaları gerektiğini vurgulamaktadır. Tıbbi bilirkişilerin verdikleri hizmetin kalitesini arttırmak ve nihayetinde daha doğru, dürüst ve adil sonuçlara ulaşabilmesi için tavsiyelerde bulunduk. İnsanların daha sağlıklı ve adil bir yaşam sürmelerini sağlayarak, global düzeyde iyi olma halini hedefleyen tıp ve hukuk bilim dallarının birlikte harmoni içinde çalışmaları halinde çok daha etkili olabilecekleri sonucuna vardık.The expert witness testimony plays an essential role in the litigation process. Courts rely on expert witness testimony in most civil and criminal cases to explain scientific matters that may not be understood by judges. Malpractice litigation proceedings begin to rise significiantly in our country recenntly. Courts and Judges can not distinguish malpractice cases from the compliciations without the medical expert's explanation of the acceptable treatment modalities and interpretation of medical facts. We here examined the issue of deciding between a medical complication and a medical error, the subject which has been frequently debated among doctors, at court trials and in media. According to the legislation laws in our country, medical expert testimony charge has been given to all physicians that are authorized in their profession. Forensic Medicine Institution, Superior Healt Council, Forensic Medicine Institudes and Universities currently serve as medical experts in our country. We focused on the some inaccurate, incomplete or unscientific expert testimony reports given by the Forensic Medicine Institution and Superior Healt Cuncil in medical malpractice law cases. The paper discusses the importance of reliable, objective, unbiased and scientific expert witness testimony in medical malpractices cases and stresses that expert witnesses should be unbiased conveyers of information. We made some recommendations in order to improve the quality of medical expert witnesss testimony in legal malpractice proceedings and thereby, achieve the much more fair, honest and equitable outcomes. We concluded that Both law and medicine are critical tools for improving health and well-being on a global level, and each profession is more effective when the two work together

D-dopachrome tautomerase in cardiovascular and inflammatory diseases-A new kid on the block or just another MIF?

Macrophage migration inhibitory factor (MIF) as well as its more recently described structural homolog D-dopachrome tautomerase (D-DT), now also termed MIF-2, are atypical cytokines and chemokines with key roles in host immunity. They also have an important pathogenic role in acute and chronic inflammatory conditions, cardiovascular diseases, lung diseases, adipose tissue inflammation, and cancer. Although our mechanistic understanding of MIF-2 is relatively limited compared to the extensive body of evidence available for MIF, emerging data suggests that MIF-2 is not only a functional phenocopy of MIF, but may have differential or even oppositional activities, depending on the disease and context. In this review, we summarize and discuss the similarities and differences between MIF and MIF-2, with a focus on their structures, receptors, signaling pathways, and their roles in diseases. While mainly covering the roles of the MIF homologs in cardiovascular, inflammatory, autoimmune, and metabolic diseases, we also discuss their involvement in cancer, sepsis, and chronic obstructive lung disease (COPD). A particular emphasis is laid upon potential mechanistic explanations for synergistic or cooperative activities of the MIF homologs in cancer, myocardial diseases, and COPD as opposed to emerging disparate or antagonistic activities in adipose tissue inflammation, metabolic diseases, and atherosclerosis. Lastly, we discuss potential future opportunities of jointly targeting MIF and MIF-2 in certain diseases, whereas precision targeting of only one homolog might be preferable in other conditions. Together, this article provides an update of the mechanisms and future therapeutic avenues of human MIF proteins with a focus on their emerging, surprisingly disparate activities, suggesting that MIF-2 displays a variety of activities that are distinct from those of MIF