Specificity of the Cyclic GMP-Binding Activity and of a Cyclic GMP-Dependent Cyclic GMP Phosphodiesterase in Dictyostelium discoideum

The nucleotide specificity of the cyclic GMP-binding activity in a homogenate of Dictyostelium discoideum was determined by competition of cyclic GMP derivatives with [8-3H] cyclic GMP for the binding sites. The results indicate that cyclic GMP is bound to the binding proteins by hydrogen bonds at N2H2, N1-H and/or C6 = O, N7, 21-OH and 31-O and possibly via a charge-charge interaction with the phosphate moiety of cyclic GMP. Cyclic AMP only competes with cyclic GMP for binding at a 20000-fold higher concentration. The same cyclic GMP derivatives were used to modify the hydrolysis of [8-3H] cyclic GMP by phosphodiesterase. The phosphodiesterase is activated by cyclic GMP. The nucleotide specificity for activation of the enzyme differs from the specificity of the enzyme for hydrolysis. This indicates that activation by cyclic GMP and hydrolysis of cyclic GMP occur at different sites of the enzyme. Cyclic AMP neither activates the cyclic GMP phosphodiesterase nor competes with cyclic GMP for hydrolysis. This indicates that intracellular cyclic AMP does not interfere with the action of intracellular cyclic GMP in D. discoideum.

Economic Consequences and Potentially Preventable Costs Related to Osteoporosis in the Netherlands

BACKGROUND: Osteoporosis often does not involve symptoms, and so the actual number of patients with osteoporosis is higher than the number of diagnosed individuals. This underdiagnosis results in a treatment gap. OBJECTIVES: To estimate the total health care resource use and costs related to osteoporosis in the Netherlands, explicitly including fractures, and to estimate the proportion of fracture costs that are linked to the treatment gap and might therefore be potentially preventable; to also formulate, on the basis of these findings, strategies to optimize osteoporosis care and treatment and reduce its related costs. METHODS: In this retrospective study, data of the Achmea Health Database representing 4.2 million Dutch inhabitants were used to investigate the economic consequence of osteoporosis in the Netherlands in 2010. Specific cohorts were created to identify osteoporosis-related fractures and their costs. Besides, costs of pharmaceutical treatment regarding osteoporosis were included. Using data from the literature, the treatment gap was estimated. Sensitivity analysis was performed on the base-case results. RESULTS: A total of 108,013 individuals with a history of fractures were included in this study. In this population, 59,193 patients were using anti-osteoporotic medication and 86,776 patients were using preventive supplements. A total number of 3,039 osteoporosis-related fractures occurred. The estimated total costs were €465 million. On the basis of data presented in the literature, the treatment gap in our study population was estimated to vary from 60% to 72%. CONCLUSIONS: The estimated total costs corrected for treatment gap were €1.15 to €1.64 billion. These results indicate room for improvement in the health care policy against osteoporosis