Because of its requirement for signaling by multiple cytokines, Janus kinase 3 (JAK3) is an excellent target for clinical immunosuppression. We report the development of a specific, orally active inhibitor of JAK3, CP-690,550, that significantly prolonged survival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease. On the basis of these preclinical results, we believe JAK3 blockade by CP-690,550 has potential for therapeutically desirable immunosuppression in human organ transplantation and in other clinical settings.

The TFI should be useful in both clinical and research settings because of its responsiveness to treatment-related change, validity for scaling the overall severity of tinnitus, and comprehensive coverage of multiple domains of tinnitus severity.

App Store Analysis studies information about applications obtained from app stores. App stores provide a wealth of information derived from users that would not exist had the applications been distributed via previous software deployment methods. App Store Analysis combines this non-technical information with technical information to learn trends and behaviours within these forms of software repositories. Findings from App Store Analysis have a direct and actionable impact on the software teams that develop software for app stores, and have led to techniques for requirements engineering, release planning, software design, security and testing. This survey describes and compares the areas of research that have been explored thus far, drawing out common aspects, trends and directions future research should take to address open problems and challenges.

An inhibitor of human liver glycogen phosphorylase a (HLGPa) has been identified and characterized in vitro and in vivo. This substance, [R-(R*,S*)]-5-chloro-N-[3-(dimethylamino)-2-hydroxy-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide (CP-91149), inhibited HLGPa with an IC 50 of 0.13 M in the presence of 7.5 mM glucose. CP-91149 resembles caffeine, a known allosteric phosphorylase inhibitor, in that it is 5-to 10-fold less potent in the absence of glucose. Further analysis, however, suggests that CP-91149 and caffeine are kinetically distinct. Functionally, CP-91149 inhibited glucagon-stimulated glycogenolysis in isolated rat hepatocytes (P < 0.05 at 10-100 M) and in primary human hepatocytes (2.1 M IC 50 ). In vivo, oral administration of CP-91149 to diabetic ob͞ob mice at 25-50 mg͞kg resulted in rapid (3 h) glucose lowering by 100-120 mg͞dl (P < 0.001) without producing hypoglycemia. Further, CP-91149 treatment did not lower glucose levels in normoglycemic, nondiabetic mice. In ob͞ob mice pretreated with 14 C-glucose to label liver glycogen, CP-91149 administration reduced 14 C-glycogen breakdown, confirming that glucose lowering resulted from inhibition of glycogenolysis in vivo. These findings support the use of CP-91149 in investigating glycogenolytic versus gluconeogenic f lux in hepatic glucose production, and they demonstrate that glycogenolysis inhibitors may be useful in the treatment of type 2 diabetes.