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51.
Chymases (EC 3.4.21.39) are mast cell serine proteinases that are variably expressed in different species and, in most cases, display either chymotryptic or elastolytic substrate specificity. Given that chymase inhibitors have emerged as potential therapeutic agents for treating various inflammatory, allergic, and cardiovascular disorders, it is important to understand interspecies differences of the enzymes as well as the behavior of inhibitors with them. We have expressed chymases from humans, macaques, dogs, sheep (MCP2 and MCP3), guinea pigs, and hamsters (HAM1 and HAM2) in baculovirus-infected insect cells. The enzymes were purified and characterized with kinetic constants by using chromogenic substrates. We evaluated in vitro the potency of five nonpeptide inhibitors, originally targeted against human chymase. The inhibitors exhibited remarkable cross-species variation of sensitivity, with the greatest potency observed against human and macaque chymases, with Ki values ranging from ∼0.4 to 72 nM. Compounds were 10-300-fold less potent, and in some instances ineffective, against chymases from the other species. The X-ray structure of one of the potent phosphinate inhibitors, JNJ-18054478, complexed with human chymase was solved at 1.8 Å resolution to further understand the binding mode. Subtle variations in the residues in the active site that are already known to influence chymase substrate specificity can also strongly affect the compound potency. The results are discussed in the context of selecting a suitable animal model to study compounds ultimately targeted for human chymase. 相似文献
52.
Trine Juhler N?ttrup Stine Sofia Korreman Anders Navrsted Pedersen Lasse Rye Aarup H?kan Nystr?m Mikael Olsen Lena Specht 《Radiotherapy and oncology》2007,84(1):40-48
BACKGROUND AND PURPOSE: This study aimed at quantifying the breathing variations among lung cancer patients over full courses of fractionated radiotherapy. The intention was to relate these variations to the margins assigned to lung tumours, to account for respiratory motion, in fractionated radiotherapy. MATERIALS AND METHODS: Eleven lung cancer patients were included in the study. The patients' chest wall motions were monitored as a surrogate measure for breathing motion during each fraction of radiotherapy by use of an external optical marker. The exhale level variations were evaluated with respect to exhale points and fraction-baseline, defined for intra- and interfraction variations respectively. The breathing amplitude was evaluated as breathing cycle amplitudes and fraction-max-amplitudes defined for intra- and interfraction breathing, respectively. RESULTS: The breathing variations over a full treatment course, including both intra- and interfraction variations, were 15.2mm (median over the patient population), range 5.5-26.7mm, with the variations in exhale level as the major contributing factor. The median interfraction span in exhale level was 14.8mm, whereas the median fraction-max-amplitude was 6.1mm (median of patient individual SD 1.4). The median intrafraction span in exhale level was 1.6mm, and the median breathing cycle amplitude was 4.0mm (median of patient individual SD 1.4). CONCLUSIONS: The variations in externally measured exhale levels are larger than variations in breathing amplitude. The interfraction variations in exhale level are in general are up to 10 times larger than intrafraction variations. Margins to account for respiratory motion cannot safely be based on one planning session, especially not if relying on measuring external marker motion. Margins for lung tumours should include interfraction variations in breathing. 相似文献
53.
54.
Carl E Bartecchi 《Journal of the American College of Cardiology》2006,47(7):1498-9; author reply 1499-500
55.
Carl A Kirker-Head David C Van Sickle Steve W Ek John C McCool 《Journal of orthopaedic research》2006,24(5):1095-1108
Focal full-thickness cartilage lesions of the human medial femoral condyle (MFC) can cause pain and functional impairment. Affected middle-aged patients respond unpredictably to existing treatments and knee arthroplasty may be required, prompting risk of revision. This study assesses the safety of, and biological and functional response to, a metallic resurfacing implant which may delay or obviate the need for traditional arthroplasty. The anatomic contour of the surgically exposed MFC of six adult goats was digitally mapped and an 11 mm diameter full-thickness osteochondral defect was created. An anchor-based Co-Cr resurfacing implant, matching the mapped articular contour, was implanted. Each goat's contralateral unoperated femorotibial joint was used as a control. Postoperative outcome was assessed by lameness examination, radiography, arthroscopy, synoviocentesis, necropsy, and histology up to 26 (n = 3) or 52 (n = 3) weeks. By postoperative week (POW) 4, goats demonstrated normal range of motion, no joint effusion, and only mild lameness in the operated limb. By POW 26 the animals were sound with only occasional very mild lameness. Arthroscopy at POW 14 revealed moderate synovial inflammation and a chondral membrane extending centrally across the implant surface. Radiographs at POWs 14 to 52 implied implant stability in the operated joints, as well as subchondral bone remodeling and mild exostosis formation in the operated and contralateral unoperated joints of some goats. By POW 26, histology revealed new trabecular bone abutting the implant. At POWs 26 and 52 MFC cartilage was metachromatic and intact in the operated and unoperated femorotibial joints. Proximal tibiae of some operated and unoperated limbs demonstrated limited subchondral bone remodeling and foci of articular cartilage fibrillation and thinning. The chondral membrane crossing the prosthesis possessed a metachromatic matrix containing singular and clustered chondrocytes. Our data imply the safety, biocompatibility, and functionality of the implant. Focal articular damage was documented in the operated joints at POWs 26 and 52, but lesions were much reduced over those previously reported in untreated defects. Expanded animal or preclinical human studies are justified. 相似文献
56.
57.
Amyloid A (AA) protein is derived from serum amyloid A (SAA) and deposited as beta-pleated sheet fibrils in reactive amyloidosis, a disease that occurs spontaneously in golden Syrian hamsters. The precursor SAA is an acute-phase reactant in many species including hamsters, and in this report we have defined the in vivo kinetic and dosage responses for SAA mRNA accumulation in hamsters following administration of various cytokines. Elevations in levels of hepatic SAA mRNA were documented when the doses of interleukin-1, interleukin-6, and tumor necrosis factor were increased. The increase in dosages applied ranged from 2 1/2-fold for interleukin-6 to 10-fold for interleukin-1. SAA transcipt levels were highest 8 h following administration of interleukin-6 or tumor necrosis factor, whereas maximal amounts of SAA-specific mRNA were found 24 h after administration of interleukin-1. 相似文献
58.
59.
Anal sphincter size measured by endosonography in healthy volunteers. Effect of age, sex, and parity. 总被引:8,自引:0,他引:8
M B Nielsen C Hauge O O Rasmussen M S?rensen J F Pedersen J Christiansen 《Acta radiologica (Stockholm, Sweden : 1987)》1992,33(5):453-456
The anal sphincter muscles consist of the circular internal and external sphincters together with the sling-shaped associated puborectalis muscle. Ten men, 10 women with no vaginal deliveries, and 10 women with one or more vaginal deliveries were studied with anal endosonography using a 7 MHz multiplanar endoprobe. The thickness of the internal sphincter and the thickness, length, and cross-sectional area of the external sphincter were measured and related to age, sex, and parity. Reproducibility was assessed by similar measurements on different days in 10 volunteers. Anal sphincter size was the same in men and women and was not affected by the number of child births. Internal sphincter muscle thickness increased with age. Anal manometry and electromyography with an anal sponge were performed in all volunteers but the results did not correlate to any of the anal sphincter dimensions. Our conclusion is that although there are some limitations, endosonography can be used to determine the size of the anal sphincter muscles. 相似文献
60.
Summary An infant with persistent truncus arteriosus associated with splenic agenesis and the asplenia syndrome is reported, including clinical, echocardiographic and autopsy findings. To the authors' knowledge this association has not been previously reported. 相似文献