Cathepsin K Deficiency Prevents the Aggravated Vascular Remodeling Response to Flow Cessation in ApoE^-/- Mice

Cathepsin K (catK) is a potent lysosomal cysteine protease involved in extracellular matrix (ECM) degradation and inflammatory remodeling responses. Here we have investigated the contribution of catK deficiency on carotid arterial remodeling in response to flow cessation in apoE-/- and wild type (wt) background. Ligation-induced hyperplasia is considerably aggravated in apoE-/- versus wt mice. CatK protein expression was significantly increased in neointimal lesions of apoE-/- compared with wt mice, suggesting a role for catK in intimal hyperplasia under hyperlipidemic conditions. Surprisingly, CatK deficiency completely blunted the augmented hyperplastic response to flow cessation in apoE-/-, whereas vascular remodeling in wt mice was unaffected. As catK deficiency did neither alter lesion collagen content and elastic laminae fragmentation in vivo, we focused on effects of catK on (systemic) inflammatory responses. CatK deficiency significantly reduced circulating CD3 T-cell numbers, but increased the regulatory T cell subset in apoE-/- but not wt mice. Moreover, catK deficiency changed CD11b+Ly6G-Ly6C high monocyte distribution in apoE-/- but not wt mice and tended to favour macrophage M2a polarization. In conclusion, catK deficiency almost completely blunted the increased vascular remodeling response of apoE-/- mice to flow cessation, possibly by correcting hyperlipidemia-associated pro-inflammatory effects on the peripheral immune response

Cathepsin cysteine proteases in cardiovascular disease

Extracellular matrix (ECM) remodeling is one of the underlying mechanisms in cardiovascular diseases. Cathepsin cysteine proteases have a central role in ECM remodeling and have been implicated in the development and progression of cardiovascular diseases. Cathepsins also show differential expression in various stages of atherosclerosis, and in vivo knockout studies revealed that deficiency of cathepsin K or S reduces atherosclerosis. Furthermore, cathepsins are involved in lipid metabolism. Cathepsins have the capability to degrade low-density lipoprotein and reduce cholesterol efflux from macrophages, aggravating foam cell formation. Although expression studies also demonstrated differential expression of cathepsins in cardiovascular diseases like aneurysm formation, neointima formation, and neovascularization, in vivo studies to define the exact role of cathepsins in these processes are lacking. Evaluation of the feasibility of cathepsins as a diagnostic tool revealed that serum levels of cathepsins L and S seem to be promising as biomarkers in the diagnosis of atherosclerosis, whereas cathepsin B shows potential as an imaging tool. Furthermore, cathepsin K and S inhibitors showed effectiveness in (pre) clinical evaluation for the treatment of osteoporosis and osteoarthritis, suggesting that cathepsin inhibitors may also have therapeutic effects for the treatment of atherosclerosi

Outcomes-Based Selection Into Medical School:Predicting Excellence in Multiple Competencies During the Clinical Years

Purpose Medical school selection committees aim to identify the best possible students and, ultimately, the best future doctors from a large, well-qualified, generally homogeneous pool of applicants. Constructive alignment of medical school selection, curricula, and assessment with the ultimate outcomes (e.g., CanMEDS roles) has been proposed as means to attain this goal. Whether this approach is effective has not yet been established. The authors addressed this gap by assessing the relationship between performance in an outcomes-based selection procedure and performance during the clinical years of medical school. Method Two groups of students were compared: (1) those admitted into Maastricht University Medical School via an outcomes-based selection procedure and (2) those rejected through this procedure who were admitted into the program through a national, grade-point-average-based lottery. The authors compared performance scores of students from the 2 groups on all 7 CanMEDS roles, using assessment data gathered during clinical rotations. The authors examined data from 3 cohorts (2011-2013). Results Students admitted through the local, outcomes-based selection procedure significantly outperformed the initially rejected but lottery-admitted students in all years, and the differences between groups increased over time. The selected students performed significantly better in the CanMEDS roles of Communicator, Collaborator, and Professional in the first year of clinical rotations; in these 3 roles-plus Organizer-in the second year; and in 2 additional roles (Advocate and Scholar-all except Medical Expert) at the end of their clinical training. Conclusions A constructively aligned selection procedure has increasing predictive value across the clinical years of medical school compared with a GPA-based lottery procedure. The data reported here suggest that constructive alignment of selection, curricula, and assessment to ultimate outcomes is effective in creating a selection procedure predictive of clinical performance

Genes potentially involved in plaque rupture

Rupture of an atherosclerotic plaque is the predominant underlying event in the pathogenesis of acute coronary syndromes and stroke. While ruptured plaques are morphologically well described, the precise molecular mechanisms involved in plaque rupture are still incompletely understood. Over the last few years, techniques like microarray, suppression subtractive hybridization and differential display enabled us to study complex gene expression profiles that occur during the process of atherogenesis. In this review we focus on recent large-scale gene expression profiles performed on whole mount vascular specimens. The gene expression profiles on whole mount vascular tissue confirmed that at least three mechanisms are involved in plaque rupture: (1) a disturbed balance in extracellular matrix turnover, (2) disturbed regulation of cell turnover and (3) processes involved in lipid metabolism. Animal models exhibiting features of plaque rupture reflect the involvement of these three mechanisms. The most dramatic mouse phenotypes were observed after interventions in at least two of these mechanisms. The observation of plaque rupture in recent mice models is indicative of the multifactorial process of plaque rupture. This multifactorial character of plaque rupture suggests that interventions may be most effective when they influence more than one mechanisms at a tim

Inflammation and restenosis: implications for therapy

Restenosis is the process of luminal narrowing in an atherosclerotic artery after an intra-arterial intervention such as balloon angioplasty and stenting. It is believed that this process is mainly characterized by migration and proliferation of smooth muscle cells and extracellular matrix accumulation. However, there is now increasing evidence for a role of inflammation in the development of restenosis. The underlying molecular mechanisms of restenosis are, in fact, most probably regulated by inflammatory mediators, such as cytokines. Understanding the molecular mechanisms in restenosis is crucial for the development of a suitable therapy for this disease. Recently, the use of immunosuppressives in drug-eluting stents has provided very promising results in the treatment of restenosis. In this review, we will describe the molecular mechanisms involved in restenosis with a focus on the role of inflammation and the use of immunosuppressive therap

Robust, defensible, and fair: the AMEE guide to selection into medical school: AMEE Guide No. 153

Selection is the first assessment of medical education and training. Medical schools must select from a pool of academically successful applicants and ensure that the way in which they choose future clinicians is robust, defensible, fair to all who apply and cost-effective. However, there is no comprehensive and evidence-informed guide to help those tasked with setting up or rejuvenating their local selection process. To address this gap, our guide draws on the latest research, international case studies and consideration of common dilemmas to provide practical guidance for designing, implementing and evaluating an effective medical school selection system. We draw on a model from the field of instructional design to frame the many different activities involved in doing so: the ADDIE model. ADDIE provides a systematic framework of Analysis (of the outcomes to be achieved by the selection process, and the barriers and facilitators to achieving these), Design (what tools and content are needed so the goals of selection are achieved), Development (what materials and resources are needed and available), Implementation (plan [including piloting], do study and adjust) and Evaluation (quality assurance is embedded throughout but the last step involves extensive evaluation of the entire process and its outcomes).Submitted/Accepted versio

Both early and delayed anti-CD40L antibody treatment induces a stable plaque phenotype

In the present study, we investigated the role of the CD40L-CD40 pathway in a model of progressive atherosclerosis. ApoE−/− mice were treated with an anti-CD40L antibody or a control antibody for 12 wk. Antibody treatment started early (age 5 wk) or was delayed until after the establishment of atherosclerosis (age 17 wk). In both the early and delayed treatment groups, anti-CD40L antibody did not decrease plaque area or inhibit lesion initiation or age-related increase in lesion area. The morphology of initial lesions was not affected, except for a decrease in T-lymphocyte content. Effects of anti-CD40L antibody treatment on the morphology of advanced lesions were pronounced. In both the early and delayed treatment groups, T-lymphocyte content was significantly decreased. Furthermore, a pronounced increase in collagen content, vascular smooth muscle cell/myofibroblast content, and fibrous cap thickness was observed. In the delayed treatment group, a decrease in lipid core and macrophage content occurred. Interestingly, advanced lesions of anti-CD40L antibody-treated mice exhibited an increased transforming growth factor β1 immunoreactivity, especially in macrophages. In conclusion, both early and delayed treatment with an anti-CD40L antibody do not affect atherosclerotic lesion initiation but do result in the development of a lipid-poor collagen-rich stable plaque phenotype. Furthermore, delayed treatment with anti-CD40L antibody can transform the lesion profile from a lipid-rich to a lipid-poor collagen-rich phenotype. Postulated mechanisms of this effect on plaque phenotype are the down-regulation of proinflammatory pathways and up-regulation of collagen-promoting factors like transforming growth factor β

HURUF AL JAR FI QISHAH ANA AL MAUT AL QASIRAH LI TAUFIQ AL HAKIM : DIRASAH TAHLILIYAH NAHWIYAH

Dalam tata bahasa Arab, kata (kalimat dalam bahasa Arab) sebagai satuan terkecil bahasa, sebagaimana dalam bahasa yang lain dapat dikelompokkan menjadi tiga macam; pertama isim, fi’il dan huruf. Yang kemudian dapat lebih mudah untuk dipelajari namun, penulis dalam hal ini hanya akan sedikit membahas bagian yang terakhir yang berkaitan dengan huruf khusunya huruf jer. Pembahasan dalam skripsi ini mengkaji tentang Huruf Jer dalam cerpen “Akulah Kematian” karya Taufiq Hakim, dengan pendekatan ilmu Nahwu. Masalah yang dikemukakan dalam rumusan masalah ini meliputi dua hal yaitu; huruf jer apa saja yang terdapat dalam cerpen “Akulah Kematian” karya Taufiq Hakim dan apa saja makna huruf jer yang terdapat dalam cerpen “Akulah Kematian” karya Taufiq Hakim. Dalam pembahasan skripsi ini peneliti menggunakan ilmu nahwu sebagai pisau analisis dan ilmu kebahasaan sebagai pendekatannya. Peneliti mengambil beberapa teori nahwu dari buku-buku yang mudah dimengerti dalam penjelasannya seperti kitab Jamiud Durus. Adapun tujuan pembahasan ini adalah untuk mengungkap ilmu kebahasan yang terdapat dalam cerpen “Akulah Kematian” karya Taufiq Hakim, sedangkan metode penelitian yang dipakai adalah metode penelitian deskriptif kualitatif. Huruf Jer secara umum yang banyak dikemukakan oleh ahli nahwu berjumlah 20 huruf, sedangkan dalam cerpen “Akulah Kematian” karya Taufiq Hakim berjumlah 9 huruf yang terdiri dari (الباء، من، إلى، حتى، على، الكاف، عن، اللام، في) Adapun kesimpulan dalam penelitian ini bahwa di dalam cerpen “Akulah Kematian” terdapat 395 huruf jer, pertama: huruf jer berbentuk ba’ dengan makna ilshoq, mushohabah, as-sababiyyah wa at-ta’lil, at-ta’diyah, al-ist’la’, al-isti’anah, adz-dzhorfiyah, al-badal, al-‘iwadh. Harfu min dengan makna al-ibtida’ at-tab’iid, at-ta’kid, adz-dzorfiyah, dan makna ‘an. Harfu ila dengan makna al-intiha’, al-mushohabah, makna ‘inda. Huruf jer hatta dengan makna lil intiha’ ka ila. Huruf jer ‘an dengan makna almujawazah wal bu’du, makna min, dan makna ‘ala. Huruf jer ‘ala dengan makna al-isti’la’, makna min, makna ba’, makna ‘an, makna fi. Huruf jer fi dengan makna adz-dzorfiyah, al-muhohabah, al-isti’la’, dan makna ba. Huruf jer kaf dengan makna at-ta’lil, as-sababiyah, dan makna ‘ala. Huruf jer lam dengan makna al-isti’la’, al-milku, lamul-ikhtishah, as-sababiyah wat-ta’lil, sibhul-miku, dan taukid

Atherosclerotic plaque rupture: local or systemic process?

It is generally established that the unstable plaque is the major cause of acute clinical sequelae of atherosclerosis. Unfortunately, terms indicating lesions prone to plaque instability, such as "vulnerable plaque," and the different phenotypes of unstable plaques, such as plaque rupture, plaque fissuring, intraplaque hemorrhage, and erosion, are often used interchangeably. Moreover, the different phenotypes of the unstable plaque are mostly referred to as plaque rupture. In the first part of this review, we will focus on the definition of true plaque rupture and the definitions of other phenotypes of plaque instability, especially on intraplaque hemorrhage, and discuss the phenotypes of available animal models of plaque instability. The second part of this review will address the pathogenesis of plaque rupture from a local and a systemic perspective. Plaque rupture is thought to occur because of changes in the plaque itself or systemic changes in the patient. Interestingly, contributing factors seem to overlap to a great extent and might even be interrelated. Finally, we will propose an integrative view on the pathogenesis of plaque ruptur