Vascular relaxation to GTN (nitroglycerin) and other antianginal nitrovasodilators requires bioactivation of the drugs to NO or a related activator of sGC (soluble guanylate cyclase). Conversion of GTN into 1,2-GDN (1,2-glycerol dinitrate) and nitrite by mitochondrial ALDH2 (aldehyde dehydrogenase 2) may be an essential pathway of GTN bioactivation in blood vessels. In the present study, we characterized the profile of GTN biotransformation by purified human liver ALDH2 and rat liver mitochondria, and we used purified sGC as a sensitive detector of GTN bioactivity to examine whether ALDH2-catalysed nitrite formation is linked to sGC activation. In the presence of mitochondria, GTN activated sGC with an EC50 (half-maximally effective concentration) of 3.77+/-0.83 microM. The selective ALDH2 inhibitor, daidzin (0.1 mM), increased the EC50 of GTN to 7.47+/-0.93 microM. Lack of effect of the mitochondrial poisons, rotenone and myxothiazol, suggested that nitrite reduction by components of the respiratory chain is not essential to sGC activation. However, since co-incubation of sGC with purified ALDH2 led to significant stimulation of cGMP formation by GTN that was completely inhibited by 0.1 mM daidzin and NO scavengers, ALDH2 may convert GTN directly into NO or a related species. Studies with rat aortic rings suggested that ALDH2 contributes to GTN bioactivation and showed that maximal relaxation to GTN occurred at cGMP levels that were only 3.4% of the maximal levels obtained with NO. Comparison of sGC activation in the presence of mitochondria with cGMP accumulation in rat aorta revealed a slightly higher potency of GTN to activate sGC in vitro compared with blood vessels. Our results suggest that ALDH2 catalyses the mitochondrial bioactivation of GTN by the formation of a reactive NO-related intermediate that activates sGC. In addition, the previous conflicting notion of the existence of a high-affinity GTN-metabolizing pathway operating in intact blood vessels but not in tissue homogenates is explained.

Background: Neonatal deaths still represent the largest percentage of overall childhood mortality. Many deaths of neonates are preceded by end-of-life decisions; however, decision-making practices have been reported to vary widely from country to country. Objectives: To analyze principal causes and circumstances of all consecutive neonatal deaths at our institution over a 10-year period. Methods: All neonates who had died either in the delivery room (DR) or the neonatal intensive care unit (NICU) between January 1, 1997 and December 31, 2006 were identified. Demographic information, principal causes and circumstances of death were abstracted from the individual medical records. Results: There were approximately 72,000 live births in the catchment area of our center with 15,150 deliveries occurring at the Women’s Hospital of Lucerne. Of the 108 deaths identified, 29 occurred in the DR (DR mortality rate 0.2%) and 79 in the NICU (NICU mortality rate 2.3%). The majority of DR deaths occurred in the setting of primary nonintervention and were related to extreme prematurity (n = 20), lethal congenital malformations (n = 6) and trisomy 13 (n = 2). One patient with severe perinatal asphyxia died despite full resuscitative efforts. In the NICU, overall mortality rate was inversely related to gestational age (GA). Cardiovascular and respiratory system failures were the predominant causes of death in premature infants with a GA <32 weeks, whereas CNS catastrophes accounted for the majority of deaths in the more mature NICU population. End-of-life decisions were common with less than 10% of deaths occurring despite maximal intensive care. Conclusions: In our perinatal center, primary nonintervention and redirection of care are the most common circumstances of death in neonates. This reflects our belief that, apart from futility, quality-of-life considerations are an important part of decision making in neonatology.

Model-based methods are increasingly used in all areas of biopharmaceutical process technology. They can be applied in the field of experimental design, process characterization, process design, monitoring and control. Benefits of these methods are lower experimental effort, process transparency, clear rationality behind decisions and increased process robustness. The possibility of applying methods adopted from different scientific domains accelerates this trend further. In addition, model-based methods can help to implement regulatory requirements as suggested by recent Quality by Design and validation initiatives. The aim of this review is to give an overview of the state of the art of model-based methods, their applications, further challenges and possible solutions in the biopharmaceutical process life cycle. Today, despite these advantages, the potential of model-based methods is still not fully exhausted in bioprocess technology. This is due to a lack of (i) acceptance of the users, (ii) user-friendly tools provided by existing methods, (iii) implementation in existing process control systems and (iv) clear workflows to set up specific process models. We propose that model-based methods be applied throughout the lifecycle of a biopharmaceutical process, starting with the set-up of a process model, which is used for monitoring and control of process parameters, and ending with continuous and iterative process improvement via data mining techniques.

The annual incidence of ISA infection in this study is among the highest described, largely due to a disproportionate burden in Indigenous children. Infections are frequently severe and infection with MRSA is common. Children presenting with suspected ISA in this region should be treated empirically for MRSA.

Continuity of care matters; however, expansion and specialisation of the health system tends to fragment care. Continuity of care is accompanied by a range of patient benefits, including reduced all-cause mortality; lower rates of hospital presentation and preventable admission; and improved patient satisfaction. Potential concerns have been raised about some aspects of continuity of care, but these are outweighed by the perceived benefits. There are many barriers to achieving continuity, especially in rural and remote settings. Some practical solutions have been proposed that include adapting clinic procedures, utilising a small team approach, improving staff retention and ongoing advocacy.