Cardiovascular consequences of new-onset hyperglycemia after kidney transplantation.

BACKGROUND: New-onset diabetes after transplantation (NODAT) is associated with high cardiovascular (CV) risk and reduced patient survival. It is unclear whether this risk is newly acquired or represents preexisting CV disease in patients with this complication. METHODS: Included are 1146 adults, recipients of first kidney transplants from 1984 to 2008 treated with modern immunosuppressants. RESULTS: One year after transplantation, 29.8% of patients experienced impaired fasting glycemia and 13.4% NODAT. The risk of NODAT related to recipient variables include the following: older age, male gender, higher body mass index, higher pretransplantation glucose and triglyceride levels, and lower high-density lipoprotein level. Increasing fasting glucose levels at 1, 4, or 12 months after transplantation, independent of other factors, related to reduced patient survival (12 months hazard ratio [HR]=1.146 [1.132-1.161], P<0.0001 for 10mg/dL increase in glucose), and this was primarily because of an increase in CV deaths. Hyperglycemia related to all major CV events (MCVE), cardiac (HR=1.113 [1.094-1.132], P<0.0001), vascular (HR=1.168 [1.140-1.197], P<0.0001), and strokes (HR=1.156 [1.123-1.191], P=0.003). These relations were statistically independent of other risk factors. The increased risk of MCVE was noted particularly in patients without MCVE before transplantation (HR=1.145 [1.126-1.165], P<0.0001). Furthermore, among patients with after transplantation MCVE (n=123, 11%), hyperglycemia increases the risk of death (NODAT: HR=2.410 [1.125-5.162], P=0.024). CONCLUSIONS: After transplantation hyperglycemia is a strong independent risk factor for MCVE and death, mainly from CV causes. This risk is independent of the presence of CV disease identified before transplantation.

Inhibition of Eimeria tenella CDK-related kinase 2: From target identification to lead compounds.

Apicomplexan parasites encompass several human- and animal-pathogenic protozoans such as Plasmodium falciparum, Toxoplasma gondii, and Eimeria tenella. E. tenella causes coccidiosis, a disease that afflicts chickens, leading to tremendous economic losses to the global poultry industry. The considerable increase in drug resistance makes it necessary to develop new therapeutic strategies against this parasite. Cyclin-dependent kinases (CDKs) are key molecules in cell-cycle regulation and are therefore prominent target proteins in parasitic diseases. Bioinformatics analysis revealed four potential CDK-like proteins, of which one-E. tenella CDK-related kinase 2 (EtCRK2)-has already been characterized by gene cloning and expression.1 By using the CDK-specific inhibitor flavopiridol in EtCRK2 enzyme assays and schizont maturation assays (SMA), we could chemically validate CDK-like proteins as potential drug targets. An X-ray crystal structure of human CDK2 (HsCDK2) served as a template to build protein models of EtCRK2 by comparative homology modeling. Structural differences in the ATP binding site between EtCRK2 and HsCDK2, as well as chicken CDK3, were addressed for the optimization of selective ATP-competitive inhibitors. Virtual screening and "wet-bench" high-throughput screening campaigns on large compound libraries resulted in an initial set of hit compounds. These compounds were further analyzed and characterized, leading to a set of four promising lead compounds for development as EtCRK2 inhibitors.