Endothelial Phenotype Evoked by Low Dose Carvedilol in Pulmonary Hypertension

Background: The therapeutic benefits of β-blockers are well established in left heart failure. The Pulmonary Arterial Hypertension Treatment with Carvedilol for Heart Failure [PAHTCH] study showed safety and possible benefit of carvedilol in pulmonary arterial hypertension (PAH) associated right heart failure over 6 months. This study aims at evaluating the short-term cardiovascular effects and early mechanistic biomarkers of carvedilol therapy.Methods: Thirty patients with pulmonary hypertension (PH) received low dose carvedilol (3.125 mg twice daily) for 1 week prior to randomization to placebo, low-dose, or dose-escalating carvedilol therapy. Echocardiography was performed at baseline and 1 week. Exercise capacity was assessed by 6 min walk distance (6MWD). The L-arginine/nitric oxide pathway and other biological markers of endothelial function were measured.Results: All participants tolerated 1 week of carvedilol without adverse effects. After 1 week of carvedilol, 6MWD and heart rate at peak exercise did not vary (both p > 0.1). Heart rate at rest and 1 min post walk dropped significantly (both p < 0.05) with a trend for increase in heart rate recovery (p = 0.08). Right ventricular systolic pressure (RVSP) decreased by an average of 13 mmHg (p = 0.002). Patients who had a decrease in RVSP of more than 10 mm Hg were defined as responders (n = 17), and those with a lesser drop as non-responders (n = 13). Responders had a significant drop in pulmonary vascular resistance (PVR) after 1 week of carvedilol (p = 0.004). In addition, responders had a greater decrease in heart rate at rest and 1 min post walk compared to non-responders (both p < 0.05). Responders had higher plasma arginine and global bioavailability of arginine at baseline compared to non-responders (p = 0.03 and p = 0.05, respectively). After 1 week of carvedilol, responders had greater increase in urinary nitrate (p = 0.04). Responders treated with carvedilol had a sustained drop in RVSP and PVR after 6 months of carvedilol with no change in cardiac output.Conclusions: Low-dose carvedilol for 1 week can potentially identify a PH responder phenotype that may benefit from β-blockers that is associated with less endothelial dysfunction.Clinical Trial Registration:http://www.clinicaltrials.gov. identifier: NCT01586156

Evolving and evaluating the OMERACT fellows program: insights and implications from OMERACT 2023 fellows

Objective: To describe the evolution of the OMERACT Fellows Program (OM FP) and to evaluate the innovative changes implemented in the 2023 program. Methods: The OM FP, the first of its kind in global rheumatology, was developed in 2000 to mentor early career researchers in methods and processes for reaching evidence-driven consensus for outcome measures in clinical studies. The OM FP has evolved through continuing iterations of face to face and online feedback. Key new features delivered in 2023 included e-learning modules, virtual introductory pre-meetings, increased networking with Patient Research Partners (PRPs), learning opportunities to give and receive personal feedback, ongoing performance feedback during the meeting from Fellow peers, PRPs, senior OMERACTers (members of the OMERACT community) and Emerging Leader mentors, involvement in pitching promotions, two-minute Lightning Talks in a plenary session and an embedded poster tour. An online survey was distributed after the meeting to evaluate the program. Results: OM FP has included 208 fellows from 16 countries across 4 continents covering 47 different aspects of rheumatology outcomes since its inception. Over 50 % have remained engaged with OMERACT work. In 2023, 18 Fellows attended and 15 (83 %) completed the post-meeting survey. A dedicated OM FP was deemed important by all respondents, and 93 % would attend the meeting in future. The PRP/Fellow Connection Carousel and Lightning Talks were rated exceptional by 93 %. Key components to improve included clarification of expectations, overall workload, the Emerging Leaders Mentoring Program, and the content and duration of daily summary sessions. Conclusion: The innovations in the 2023 OM FP were well received by the majority of participants and supports early career rheumatology researchers to develop collaborations, skills and expertise in outcome measurement. Implementation of feedback from Fellows will enhance the program for future meetings, continuing to facilitate learning and succession planning within OMERACT

FUNDAMENTAL RIGHTS IN THE EUROPEAN UNION: ASSESSMENT ON THE ECJ CASE LAW

The European Union (EU) is a supranational organization that has been operating since 1951 with the aim of economic and political integration. With the participation of new members in the organization, it has improved the areas of cooperation. One of these areas is the human rights issue. Although not initially a binding and fundamental document on the EU's human rights, over time, the issue of human rights has become the mainstay of the EU. The influence of the case law of the EU Court of Justice is great. ECJ, an institution that monitors the applicability of the operation of the EU in member states, initially became more cautious about the issues related to the fundamental rights carried forward through the pre-decision procedure. The sensitivities of the member states to basic rights and the fact that the EU does not have an arrangement on this issue raised the question of fundamental rights in the EU. In particular, the actions taken by Member States and individuals on this issue by Justice and the position of the Court of Justice have shaped the development of fundamental rights in the EU. Although, In the beginning, the Court of Justice acted hesitantly in cases involving fundamental rights, along with the progressive case law, basic rights have made it the mainstay of the EU.In this study, the attitude of the EU to fundamental rights in the light of the ECJ case law and the impact of case-law on the development of human rights in the EU will be evaluated. In this context, some basic cases carried out from the member countries to the Court of Justice will be taken as basis.Avrupa Birliği (AB) 1951 yılından itibaren hem ekonomik hem de siyasi bütünleşme hedefiyle hareket etmiş uluslar üstü (supranasyonel) bir örgüttür. Örgüte yeni üyelerin katılmasıyla birlikte iş birliği alanlarını geliştirmiştir. Bu alanlardan biri de insan hakları konusudur. Başlangıçta AB’nin insan haklarına yönelik bağlayıcı ve temel bir belgesi olmasa da zamanla insan hakları konusu AB’nin temel dayanağı haline gelmiştir. Bu durumda AB Adalet Divanı (ABAD) içtihatlarının etkisi büyüktür. AB’nin işleyişinin üye ülkelerde uygulanabilirliğini denetleyen bir kurum olan ABAD, ön karar prosedürü yoluyla kendisine taşınan temel haklara ilişkin sorunlara başlangıçta daha temkinli yaklaşmıştır. Üye ülkelerin temel haklara ilişkin hassasiyetleri ve AB’nin bu konuda bir düzenlemeye sahip olmaması AB’de temel haklar sorununu gündeme taşımıştır. Özellikle üye ülkelerin ve bireylerin Adalet bu konuda taşıdığı davalar ve Adalet Divanı’nın bu yöndeki tutumu AB’de temel hakların gelişimini şekillendirmiştir. Başlangıçta Adalet Divanı temel haklara ilişkin davalarda tereddütlü davransa da ilerleyen içtihatlarla birlikte temel hakları AB’nin temel dayanağı haline getirmiştir.Bu çalışmada, AB’nin ABAD içtihatları ışığında temel haklara ilişkin tutumu ve içtihatların AB’de insan haklarının gelişimine etkisi değerlendirilecektir. Bu kapsamda, üye ülkelerden Adalet Divanı’na taşınan temel bazı davalar baz alınacaktır

AVRUPA BİRLİĞİ’NDE BÖLGESEL KALKINMA AJANSLARINA GEÇİŞ SÜREÇLERİ VE ÜLKE UYGULAMALARI

Regional Development Agencies are organizations which are aiming to help the development of the regions, the improvement of the underdeveloped regions, and thus to be able to compete with each other, via developing regional policies. The European Union gives importance to regional politics and advocates that the new participating countries should harmonize their regional structures. Regional Development Agencies continue to operate within the framework of the European Committee of the Regions that established by the Maastricht Treaty. However, there is a debate about how successful the European Union is in the transition to a coherant and common regional policy in the member countries. Within the framework of this study, it will be discussed whether the countries that are members of the Union have lived in a common regionalization process. First of all, region and regionalization issues will be determined, and regional development agencies will be evaluated. Then, the functioning of the regionalization movements in France, United Kingdom, Poland and the Czech Republic will be examined. Thus, the transition processes of the mentioned countries to regional development agencies will be tried to be compared. Bölgesel Kalkınma Ajansları, bölgesel politikalar geliştirerek, bölgelerin kalkınmasını, geri kalmış bölgelerin iyileştirilmesini ve dolayısıyla birbirleriyle rekabet edebilir hale gelmelerine yardım etmeyi amaçlayan kuruluşlardır. Avrupa Birliği de bölgesel politikalara önem vermekte ve yeni katılan ülkelerin de bölgesel yapılanmalarını uyumlaştırmaları gerektiği düşüncesini savunmaktadır. Bölgesel Kalkınma Ajansları, Maastricht Antlaşması ile oluşturulan Bölgeler Komitesi çerçevesinde işleyişlerini sürdürmektedir. Ancak, Avrupa Birliği’nin üye ülkelerde uyumlu ve ortak bir bölgesel politikaya geçiş aşamasında ne kadar başarılı olduğu tartışma konusu olmaktadır. Bu çalışma çerçevesinde, Birliğe üye olan ülkelerin ortak bir bölgeselleşme süreci yaşayıp yaşamadıkları tartışılacaktır. Bunun için öncelikle bölge ve bölgeselleşme konuları ele alınacak ve bölgesel kalkınma ajansları değerlendirilecektir. Daha sonra Fransa, İngiltere, Polonya ve Çek Cumhuriyeti’ndeki bölgeselleşme hareketlerinin işleyişi incelenecektir. Böylece, adı geçen ülkelerin bölgesel kalkınma ajanslarına geçiş süreçleri karşılaştırılmaya çalışılacaktır.&nbsp

AVRUPA BİRLİĞİ’NDE DEMOKRASİ YOLUNDA BİR ADIM: KOMİSYON BAŞKANLIĞI SEÇİMİ ÜZERİNE BİR SINAV

The European Commission, which was first established as a "High Authority" by the European Coal and Steel Community (ECSC), by the E SC Treaty signed in Paris in 1951, has become the executive organ of the European Union to day with its ever increasing powers. The status of the commission, which has a very important place in terms of its powers, stems from the model difference between the ECSC Treaty and the European Economic Community and the European Atomic Energy Community treaties. However, the most important point here is that the position of the presidency of the Commission, which is the leader of this is the driving force, has become a very important position. In this study, the change caused by the election of the commission president, elected in 2014 after the parliamentary elections, which was an assigned position previously, will be discussed. In this discussion, the change in methods of taking charge in the European Commission will be assessed in consideration of the Founding Treaties and other official documents/fundamental reports. Consequently, before and after the May 2014 Parliamentary Elections, this study attempts to shed allight on the present status of the election system for the European Commission Presidency, after the Lisbon Treaty.Avrupa Kömür ve Çelik Topluluğu’nun (AKÇT) 1951 yılında Paris Antlaşmasıyla ilk olarak “Yüksek Otorite” adı altında bir araya gelen, elinde bulundurduğu yetkilerle giderek güçlenen Avrupa Komisyonu, günümüzde Avrupa Birliği’nin(AB) yürütücü organı olarak hareket etmektedir. Yetkileri açısından oldukça önemli bir yere sahip olan Komisyon’un, kurucu antlaşmaların kendilerini yenilemeleriyle birlikte değişiklere uyum sağlayarak kurumlar içerisindeki rolü yerleşmiştir. Yasa teklifleri hazırlama, bütçe üzerinde Parlamentoyla birlikte hareket etme, Uluslararası Antlaşmaların yapılmasında müzakereci yetkileriyle AB’nin itici gücüdür. Ancak buradaki asıl önemli nokta, bu itici gücün liderliği konumundaki Komisyon başkanlığı makamının oldukça önemli bir konuma gelmiş olmasıdır. Bu çalışmada, önceleri atama yöntemiyle belirlenen Komisyon başkanlığı görevinin 2014 Parlamento seçimleri sonrasında ilk defa göreve seçilerek gelmesinin sağladığı değişim irdelenecektir. Bu irdeleme yapılırken, Avrupa Komisyon başkanlığı seçim yöntemlerindeki değişim Kurucu Antlaşmalar ve temel raporlar dikkate alınarak değerlendirilecektir. Böylece Mayıs 2014 Parlamento seçimleri öncesi ve sonrasında Avrupa Komisyon başkanlığı seçim sisteminin Lizbon Antlaşması ardından geldiği nokta daha net açıklanacaktır.&nbsp

Currently Used Biologic Agents in the Management of Behcet's Syndrome

Behcet's s yndrome (BS) is a multisystem vasculitis with frequent mucocutaneous, joint, eye and visceral organ involvement. From early 2000s, biologic drugs have been increasingly used in the management of BS, enabling rapid and complete remission in most cases with critical organ involvement. Despite the current experience with steroids and traditional immunosuppressives, biologics are exceptionally promising for treatment of resistant cases. Among the biologics used in BS, TNF-alpha antagonists are the oldest and their efficacy has been proven in recalcitrant ocular, vascular, gastrointestinal and neurologic involvements. These drugs have significantly reduced morbidity and mortality in BS and they have an acceptable safety profile. Tocilizumab, an IL6 receptor antibody, has been shown to be effective in BS patients with neurologic involvement and amyloidosis, and IL1 beta antagonists such as anakinra, canakinumab, gevokizumab were effective in the management of ocular involvement. Studies investigating the efficacy of daclizumab, IL2 receptor antibody, and secukinumab, IL17 monoclonal antibody, in the management of BS with eye involvement failed to demonstrate significant clinical improvement and both studies were halted. A monoclonal vascular endothelial growth factor antagonist, bevacizumab, was shown to be effective in BS-related macular edema. Alemtuzumab and ustekinumab are among other biologics which were effective in controlling disease symptoms. In this review, we discuss the efficacy and safety of various recently developed biologic agents targeting different pathways involved in the pathogenesis of BS

No appreciable decrease in fertility in Behcet's syndrome

Objectives. Behcet's syndrome (BS) follows an active course during the childbearing years in both men and women. We formally surveyed the infertility rate and the effect of drugs and types of organ involvement on fertility in BS

Dendritic cell sarcoma: A pooled analysis including 462 cases with presentation of our case series

Dendritic cell tumors are extremely rare and current knowledge on these tumors is limited. The characteristics of three dendritic cell sarcoma subtypes and their optimal treatment approaches are not fully clarified. We aimed to make a systematic review of the literature and enrich the current data with five new cases. Pooled analysis of 462 reported cases revealed that the tumor had no age, gender or racial predilection. Our analysis suggests that the young age, advanced stage, intraabdominal involvement and unfavorable histological features (i.e. large tumor size, absence of lymphoplasmacytic infiltration, coagulative necrosis, high mitotic count) may predict poor prognosis. Subtypes of this tumor have different clinical behaviors with interdigitating dendritic cell sarcoma being the most aggressive form. In general, surgery is the most effective treatment modality and adjuvant radiotherapy has no significant effect on overall survival of patients. The role of chemotherapy for the management of advanced disease is controversial. (C) 2013 Elsevier Ireland Ltd. All rights reserved