This research describes the quest to create 'super-caffeines', substances that only produce the desired effects of caffeine, and unlike caffeine, substances that should only have to be taken in... Show moreThis research describes the quest to create 'super-caffeines', substances that only produce the desired effects of caffeine, and unlike caffeine, substances that should only have to be taken in measured, minute, controlled amounts to achieve these effects. Unless particular steps are taken to avoid it, caffeine is a very prevalent substance in our society, which almost all of us ingest in some manner on a daily basis. It is an integral part of coffee, tea and chocolate-based products, cola drinks and is even used as a supplement in painkillers. Most people recognise caffeine as a stimulant; however, have you ever wondered how and why we get not only the pick-me-up effect, but also less desirable ones, for example, the need to go to the toilet more often and the racing heart? Caffeine is an example of a ligand (a chemical compound) that acts via certain anchor points in the body, the adenosine receptors. These receptors are located throughout the body in a number of different tissues. There are four different categories of this receptor that respond specifically to a substance called adenosine, which is produced within the body when and where it is needed. Once a substance like caffeine enters the body the majority of its effects are as a result of blocking these receptors, thereby not allowing the body's own chemical compound, adenosine, to occupy the receptors. The often welcome stimulatory effects of caffeine have been found to be as a consequence of blocking a particular adenosine receptor, known as the adenosine A1 receptor. The unwelcome sideeffects mentioned earlier are often a result of caffeine's interaction with one or more of the other three adenosine receptors. The therapeutic potential for new __super-caffeines__ (so called adenosine A1 receptor antagonists) are great, for instance as cognition enhancers in the elderly. This thesis describes the design and development of several series of new compounds which help us to define, understand and further the research into adenosine receptor antagonists. The substances themselves are novel in chemical structure, have excellent affinity for the adenosine A1 receptor (very much better than that measured for caffeine) and are selective for this particular receptor above the rest of the adenosine receptor family. Show less
Simultaneous with the improved survival of very preterm and low birth weight infants, the awareness increased that not all survive without sequelae. Mild developmental disturbances that interfere... Show moreSimultaneous with the improved survival of very preterm and low birth weight infants, the awareness increased that not all survive without sequelae. Mild developmental disturbances that interfere with the acquisition of everyday skills and normal learning appeared to be very frequent and were not detected until at school age. The expectation was that such developmental disabilities were temporary side effects and would diminish with increasing perinatal knowledge and experience. The data in this thesis show that impairments, disabilities and handicaps remain invariably high, with the exception of the decreased incidence of visual problems. The increased incidence of cerebral palsy of children born in 1993, compared to 1983, is worrisome. Factors that are responsible for a decreased mortality such as antenatal steroids, artificial ventilation and surfactant, do not decrease these developmental problems in the surviving children. The use of dexamethasone in the neonatal period is a serious extra risk factor for developmental problems. Severe developmental problems are mostly diagnosed at the age oaf two years. Diagnosis of mild motor problems, learning disabilities and problem behaviour however, is mostly delayed until school age. When with advancing age the demands imposed by society increase, the problem rate increases even further. Singularly, these deficits may be subtle, but combined, without compensation in other domains, they may pose a lifelong burden. Therefore, long term longitudinal follow up of these children is necessary. Paediatricians who assess very preterm and low birth weight infants with assessments that include structured elements from the Touwen examination, Denver Development Screening Test, Dutch Language Screening Test and a shortlist from the Child behaviour Checklist overlook developmental motor coordination disorders and learning and behavioural problems. As the movement ABC is an accurate and widely used instrument to detect these motor coordination disorders, the movement ABC should be included in the follow up of very preterm and low birth weight infants at the age of five. To detect all neurological problems a neurological assessment is also necessary. Cognitive problems are indicated by the appearance of learning difficulties at school. As the presence of learning difficulties in very preterm and low birth weight infants is an alarm-signal for cognitive delay, referral and formal cognitive assessment by a child psychologist is indicated. Repeating the school year may not be a good solution. To identify cognitive delays that may interfere with learning before school age, formal cognitive assessment before six years of age should be incorporated in a systematic follow up program. As over one half of all very preterm and low birth weight infants show these developmental problems, routine assessment of all very preterm and low birth weight infants before school age is necessary. Standardised and normalised test instruments that cover all developmental domains must have a rigid structure for managing the test process and calculating the results General judgement by paediatricians in a routine outpatient clinic, even when these paediatricians are well trained, is insufficient. Follow up studies that do not include detailed standardised tests for several domains will underestimate developmental problems in survivors of neonatal intensive care. There is no simple way to identify children in need of extra help or to enable a true evaluation of neonatal intensive care. This thesis deals with problems in very preterm and low birth weight infants. It also documented, however, that modern intensive care saves the lives of many children 'born to soon or born too small' 56 and that many of them grow up without any problem at all. Although modern neonatal intensive care will not restore complete integrity of all preterm born infants, it certainly is worthwhile. Show less
