Direct Evidence for P2Y2 Receptor Involvement in Vascular Response to Injury

Objectives Extracellular nucleotide release at the site of arterial injury mediates proliferation and migration of vascular smooth muscle cells (SMC). Our aim was to investigate the role of the P2Y2 nucleotide receptor (P2Y2R) in neointimal hyperplasia. Approach and Results Vascular injury was induced by implantation of a polyethylene cuff around the femoral artery in wild-type and P2Y2 receptor-deficient mice (P2Y2R−/−). Electron microscopy was used to analyze monocyte and lymphocyte influx to the intima 36 hours post-injury. Compared to wild-type (WT) littermates, P2Y2R−/− mice exhibited a 3-fold decreased number of mononuclear leukocytes invading the intima (p<0.05). Concomitantly, migration of smooth muscle cells was decreased by more than 60% (p<0.05) a resulting in a sharp inhibition of intimal thickening formation in P2Y2R−/− mice (n=15) 14 days after cuff placement. In vitro, loss of P2Y2 receptor significantly impaired monocyte migration in response to nucleotide agonists. Furthermore, transgenic rats over-expressing the P2Y2R developed accelerated intimal lesions resulting in more than 95% luminal stenosis (P<0.05, n=10). Conclusions Loss-and gain-of-function approaches established a direct evidence for P2Y2 receptor involvement in neointimal hyperplasia. Specific anti-P2Y2 receptor therapies may be used against restenosis and bypass graft failure

Cardiovascular Disease in Inflammatory Joint Disorders:The interplay between risk factors, inflammation and therapy

Scope of this thesis In this thesis the cardiovascular disease (CVD) risk in inflammatory joint diseases (IJD) was investigated, focusing on rheumatoid arthritis (RA) and psoriatic arthritis (PsA). We aimed to create awareness of this high CVD risk by investigating the magnitude of CVD prevalence in IJD patients over the last decades, also considering new treatment modalities such as biological disease modifying antirheumatic drugs (bDMARD) and imaging techniques such as 18-fluorodeoxyglucose positron emission tomography combined with computed tomography (18F-FDG-PET/CT). In addition, traditional and novel risk factors for CVD and the effects of anti-inflammatory therapy on these risk factors were assessed. Lastly, we revised new EULAR recommendations for CVD risk management in IJD and proposed ideas for future research. Conclusion Atherosclerosis is an inflammatory process, which is further enhanced by the chronic inflammation inherent to IJD. This has implications for health care professionals, especially rheumatologists and cardiologists, but IJD patients should also be aware of their increased CVD risk and take timely precautions. Acknowledging this high risk is an important step preceding the implementation of strategies for prediction, prevention and management of CVD in IJD. There lies an evidence gap which needs to be filled in the future and general practice guidelines need to be developed to reduce CVD risk in these patients

Harmonisasi Pasal 21 Undang-undang Hak Tanggungan dengan Pasal 56 dan Pasal 59 Undang-undang Kepailitan dan Penundaan Kewajiban Pembayaran Utang Terkait Kreditor Separatis Pemegang Hak Tanggungan yang Melekat pada Benda Jaminan

Penelitian ini dilatar belakangi adanya disharmonisasi norma hukum antara Pasal 21 Undang-Undang Hak Tanggungan dengan Pasal 56 dan Pasal 59 Undang-Undang Kepailitan dan PKPU, maka skripsi ini berjudul “Harmonisasi Pasal 21 Undang-Undang Hak Tanggungan Dengan Pasal 56 Dan Pasal 59 Undang-Undang Kepailitan dan PKPU Terkait Kreditor Separatis Pemegang Hak Tanggungan Yang Melekat Pada Benda Jaminan”, dengan 2 (dua) Pokok permasalahan yaitu: (1) Bagaimana Kewenangan Kreditor Pemegang Hak Tanggungan Benda Jaminan Akibat Ketidakharmonisan antara Pasal 21 Undang-undang Hak Tanggungan dengan Pasal 56 dan Pasal 59 Undang-undang Kepailitan dan PKPU? (2) Apakah Perjanjian Utang dengan Hak Tanggungan dapat Memberikan Kepastian Hukum bagi Kreditor Separatis ketika Debitor Pailit?. Penulisan skripsi ini menggunakan metode penelitian hukum normatif. Pendekatan Penelitian dengan pendekatan Perundang-undangan dan pendekatan konseptual. Cara pengumpulan data secara studi pustaka yaitu dengan cara meneliti bahan pustaka atau data sekunder serta mempelajari sumber-sumber atau bahan tertulis yang dijadikan bahan dalam penulisan skripsi ini misalnya buku-buku ilmiah, peraturan Perundang-undangan, jurnal hukum dari internet, dan lain-lain yang memiliki kaitan dengan skripsi ini. Dari hasil penelitian diketahui bahwa (1) Akibat Ketidakharmonisan Antara Pasal 21 Undang-undang Hak Tanggungan dengan Pasal 56 dan Pasal 59 Undang-Undang Kepailitan dan PKPU kewenangan kreditor separatis menjadi disfungsi kewenangan karena terjadi benturan norma hukum yang terdapat dalam pasal-pasal di kedua undang-undang tersebut, tetapi bukan konflik undang-undang. Ketentuan {asa; 56 dan Pasal 59 Undang-undang Kepailitan dan PKPU melemahkan kreditor separatis untuk mengeksekusi sendiri objek hak tanggungan, tetapi kedudukan kreditor pemegang hak tanggungan tetap diutamakan untuk mendapatkan haknya atas objek Hak Tanggunagn sebagai pelunasan piutang sebagaimana pasal 21 Undang-undang Hak Tanggungan. (2) Kepastian Hukum Perjanjian Utang dengan Objek Hak Tanggungan Bagi Kreditor Separatis Ketika Debitor Pailit dapat memberikan kepastian hukum, namun dengan Hak Tanggungan pun Undang-Undang tidak memberikan kepastian pelunasan piutang Kreditor Separatis akan terpenuhi seluruhnya. Adanya ketentuan Pasal 56 dan Pasal 59 Undang-Undang Kepailitan dan PKPU yang sekarang menjadikan proses eksekusi sendiri dapat dibatalkan oleh hukum jika proses eksekusi objek hak tanggungan dilakukan atas title eksekutorial padahal prosedur kepailitan memerlukan biaya dan waktu yang lebih panjang dan tidak terpenuhinya asas lex certa

APP21 transgenic rats develop age-dependent cognitive impairment and microglia accumulation within white matter tracts.

Background Most of the animal models commonly used for preclinical research into Alzheimer\u27s disease (AD) largely fail to address the pathophysiology, including the impact of known risk factors, of the widely diagnosed sporadic form of the disease. Here, we use a transgenic rat (APP21) that does not develop AD-like pathology spontaneously with age, but does develop pathology following vascular stress. To further the potential of this novel rat model as a much-needed pre-clinical animal model of sporadic AD, we characterize APP21 transgenic rats behaviorally and histologically up to 19 months of age. Methods The open field test was used as a measure of activity; and the Morris water maze was used to assess learning, memory, and strategy shift. Neuronal loss and microglia activation were also assessed throughout the brain. Results APP21 transgenic rats showed deficits in working memory from an early age, yet memory recall performance after 24 and 72 h was equal to that of wildtype rats and did not deteriorate with age. A deficit in strategy shift was observed at 19 months of age in APP21 transgenic rats compared to Fischer wildtype rats. Histologically, APP21 transgenic rats demonstrated accelerated white matter inflammation compared to wildtype rats, but interestingly no differences in neuron loss were observed. Conclusions The combined presence of white matter pathology and executive function deficits mirrored what is often found in patients with mild cognitive impairment or early dementia, and suggests that this rat model will be useful for translationally meaningful studies into the development and prevention of sporadic AD. The presence of widespread white matter inflammation as the only observed pathological correlate for cognitive deficits raises new questions as to the role of neuroinflammation in cognitive decline

An approach for identifying collaborative business opportunities for networked organizations : application to connected and autonomous vehicles

This paper presents the results of a study conducted with a network of organizations involved in the connected and autonomous vehicle's technology as an emerging trend, which aimed at developing an approach for the identification of collaborative business opportunities by deploying coopetition theory, design thinking principles, and business model theory. The purpose of this paper is twofold. Firstly, it tries to develop an approach that will enable organisations to identify collaborative business opportunities and, secondly, provides insights into the challenges and requirements for the realization of full scaled solutions for the connected and autonomous vehicles

Demystifying supply chain visibility - a systematic literature review

Supply chain visibility (SCV) has been in trend after the millennium and raised interest of both academics and practitioners. However, there is still an ambiguity on the topic, which hinders a proper SCV application. This study aims to clarify the fuzziness of the area by conducting a systematic literature review. By reviewing 67 articles, we have identified a conceptual model that covers three main roles of information sharing for SCV and their impacts on the positive and negative constructs of SCV. This framework illuminates the inter-construct interactions and, also provides diagnostic insights for the implementation of SCV in the firms