http://repub.eur.nl/res/aut/11044/ List of Publications en http://repub.eur.nl/static-eur/img/logo.png http://repub.eur.nl http://repub.eur.nl/res/pub/39954/ 2013-04-16T00:00:00Z A storm surge barrier closing of The Narrows to protect the New York and New Jersey metropolitan area from storm surges has been designed following a systematic design approach. Functions and requirements of the barrier have been determined. Important functions are retaining the storm surge, allowing ships to pass under normal conditions, and allowing sufficient tidal flow in the New York Harbor Bay. A large span of 860 ft., the Narrows is required to allow the biggest ships to pass; the sill level of this gate is 66 ft. below the mean water level. An additional 100,000 sq. ft. wet cross section is estimated to be sufficient for tidal flow. Several design options have been taken into account including sector gates, lifting gates, and flap gates. A combination of a large sliding sector gate with 18 lifting gates has been selected. The choice is based on experience with storm surge barriers in the Netherlands and combining favorable aspects of different types of barriers. Reliability and maintenance are important criteria for the selection. The location for the storm surge barrier is half a mile north of the Verrazano Bridge. This location has many advantages regarding depth of the channel, tie-in structures and length of the closure. The height of the gates is only slightly above the maximum water level of 28 ft. above mean water, allowing for wave overtopping during storm. The reduced height results in a cheaper construction. This is possible because of a large basin behind the barrier. Overtopping waves will add 2 ft. of water to the basin. Since barriers are closed early this limited rise is acceptable. The costs of the storm surge barrier are roughly estimated at US$ 6.5 billion. A significant reduction of costs is possible if the wet cross section can be reduced. This conceptual design of a storm surge barrier in the Verrazano Narrows is presented as a contribution to the debate how to deal with the increasing risks of a storm surge in New York, given the expected impact of climate change and realizing experience in the Netherlands has learned that investment in protection against floods is a good investment. http://repub.eur.nl/res/pub/32957/ 2010-10-08T00:00:00Z Background: Standard treatment of chronic hepatitis C with pegylated interferon and ribavirin is associated with suboptimal virological response rates and substantial side effects. This study describes the in vitro and in vivo development of JTK- 652, a novel pyrrolopyridazin-derived HCV infection inhibitor. Methods: JTK-652 was evaluated in multiple cell lines using an in vitro HCV infection model consisting of HCV pseudotype vesicular stomatitis virus bearing HCV E1/E2 envelope proteins. Safety, tolerability, pharmacokinetics and efficacy of JTK-652 were tested in a randomized double-blind and placebo-controlled study in healthy male volunteers (n=36) and chronic hepatitis C patients. A total of 10 HCV genotype-1-infected patients (treatment-naive [n=2] and treatment-experienced [n=8]) with HCV RNA>1×105IU/ml received an oral dose of 100 mg JTK-652 three times daily or placebo (8:2 ratio) for 4 weeks. Results: JTK-652 showed potent inhibitory activity against HCV genotype 1a and 1b pseudotype viruses bearing HCV E1/E2 envelope proteins in HepG2 cells and in human primary hepatocytes. No significant clinical laboratory, vital sign, ECG or physical examination abnormalities were observed during the Phase I trial. JTK-652 was found to be well tolerated. No significant changes in HCV RNA levels compared with baseline were observed at the end of treatment. Conclusions: Although results from the preclinical studies indicated that JTK-652 has well-established antiviral properties and a Phase I clinical trial has showed that JTK-652 was safe and well tolerated at a 100 mg three times daily dose level, plasma HCV RNA levels in chronically HCV-infected patients did not decrease during 28 days of dosing at a 100 mg three times daily dose level. http://repub.eur.nl/res/pub/8371/ 2005-01-01T00:00:00Z BACKGROUND: Chronic ulcerative colitis (CUC) is associated with increased risk of developing colon cancer through a dysplasia (intraepithelial neoplasia)-carcinoma sequence. AIMS: To investigate the expression of apoptosis and inflammatory related proteins in CUC. METHODS: The expression of proteins involved in apoptosis and inflammation (inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), Bcl-xl, Fas, and active caspase 3) was investigated and compared with that seen in sporadic colon carcinoma. RESULTS: COX-2 was negative in the epithelium of all samples. iNOS was clearly present in inflammatory areas in CUC epithelium, weakly expressed in dysplasia, and absent or weakly expressed in tumour cells. Bcl-xl was absent in CUC, increased in dysplasia, and highly expressed in most carcinomas. Fas expression was positive in the surface epithelium of CUC, dysplasia, and most tumour cells. Activated caspase 3 was weakly positive in all samples, indicating limited apoptosis. Compared with CUC associated carcinoma, iNOS was consistently expressed in sporadic colon carcinoma cells, whereas Bcl-xl was almost absent in these tumour cells and Fas was only weakly expressed. Activated caspase 3 was present in normal mucosal samples and some tumour cells. CONCLUSION: Apoptosis related proteins--particularly iNOS, Bcl-xl, and Fas-show a distinct pattern of expression in the CUC to carcinoma sequence, which differs from that seen in sporadic carcinoma, but bears a striking resemblance to that seen during neoplastic progression in Barrett's oesophagus. These results support a causal role for chronic inflammation in cancer development in CUC, and treatment of ulcerative colitis should aim to minimise inflammation.