Formation and breakdown of adenosine in the heart : investigations on myocardial purine metabolismen

Adenosine, a strong coronary vasodilator, is a breakdown product of the myocardial high-energy phosphate ATP. ATP serves as the direct energy source for contraction of the heart. Chapter 1 of this thesis gives a general introduction on contractility dependent ATP-breakdown, the ATP-generating metabolism of the heart and the mechanism which leads to adenosine formation. The applications of purine biochemistry to cardiovascular research are summarized. The in vitro characteristics of other enzymes of purine metabolism (AMP-deaminase and S-adenosylhomocysteine hydrolase) are reported. Additional perfusion studies with specific inhibitors suggest a significant contribution by these enzymes to myocardial purine formation during normoxia (Appendix Papers II and IV) . Several lines of evidence suggest that the purines released from isolated rat hearts are in part degradation products of IMP or GMP instead of AMP. This appears to be especially so during normoxia. If hypoxanthine or inosine are added to the myocardial perfusate, they are slowly incorporated into the ATP-pool of the heart. The incorporation rate is increased after a previous ischemic period and can be further stimulated by simultaneous infusion of ribose. Evidence is presented that increased adenosine formation is directly related to increased formation of AMP (e.g., from ATP). The old hypothesis that adenosine is constantly produced at a high rate and nearly simultaneously reincorporated into AMP appears to be unrealistic. The results suggest an even tighter coupling of adenosine and purine release to the myocardial energy state than had already been assumed. A minor disbalance between ATP-breakdown and ATP-production will lead to increased adenosine and purine release and will eventually lead to significant loss of ATP and myocardial function. Some of the experiments point to ways of breaking through this vicious circle by defining conditions for enhanced myocardial ATP-repletion and possible restoration of function during reperfusio

Decrease in foetal and neonatal mortality in the Netherlands; comparison with other Euro-Peristat countries in 2004, 2010 and 2015

OBJECTIVE: To compare changes in foetal, neonatal and perinatal mortality in the Netherlands in 2015, relative to 2004 and 2010, with changes in other European countries and regions. DESIGN: Descriptive population-wide study. METHOD: Data from 32 European countries and regions within the Euro-Peristat registration area were analysed. These countries and regions were grouped into: the Netherlands, Scandinavia, Western Europe and Eastern Europe. International differences in registration and policies were taken into account by using rates from 28 weeks gestation for foetal mortality and for 24 weeks gestation and beyond for neonatal mortality. Ranking was based on individual countries and regions. RESULTS: Foetal mortality decreased by 24% in the Netherlands, from 2.9 per 1,000 births in 2010 to 2.2 per 1,000 births in 2015; neonatal mortality decreased by 9%, from 2.2 to 2.0 per 1,000 live births. Perinatal mortality (the sum of foetal mortality and neonatal mortality) decreased by 18% from 5.1 to 4.2 per 1,000 births. The Netherlands moved from the 18th place in the European ranking in 2004 to the 10th place in 2015. CONCLUSION: Foetal, neonatal and perinatal mortality in the Netherlands decreased in 2015 when compared with 2004 and 2010. The country's position in the European ranking also improved. Explanations for this decrease are related to changes in the areas of organisation of care, population and risk factors. When mortality rates in other European countries and regions - particularly Scandinavia - are considered there is room for further improvement