The aim of this thesis was to gain a better understanding of the deleterious effects of Neonatal Brachial Plexus Palsy (NBPP) on central development by analyzing sensory and motor function.The... Show moreThe aim of this thesis was to gain a better understanding of the deleterious effects of Neonatal Brachial Plexus Palsy (NBPP) on central development by analyzing sensory and motor function.The explanation for problems with hand function was not clear in children who had an upper NBPP where only the C5 and C6 spinal nerves are affected, which predominantly innervate the shoulder and elbow flexion. The main findings of this thesis: Children with an upper NBPP have a diminished sensibility of the thumb and index finger which correlates with diminished dexterity. The ability to localize stimuli to the thumb, index, third and fourth fingers is disturbed in children with an upper NBPP. Most children with an upper NBPP are not aware of the diminished sensibility in their affected hand. Also Grip force of the hand is reduced in children with an upper NBPP lesion. NBPP is a peripheral nervous lesion, which affects the development of the central nervous system as well. The age at which children with NBPP can walk independently is delayed, which does not depend on the severity of the lesion. Treatment of children with a NBPP had to focus on the total development of the child. Show less
Discovery and development of Central Nervous System (CNS) drugs is hampered by high attrition rates. One of the reasons is the lack of blood-based biomarkers that represent the interaction between... Show moreDiscovery and development of Central Nervous System (CNS) drugs is hampered by high attrition rates. One of the reasons is the lack of blood-based biomarkers that represent the interaction between the drug and the neurological systems of interest. Here we present a systems-pharmacology approach that combines a multi-biomarker approach (e.g. metabolomics) with pharmacokinetic/pharmacodynamic (PK/PD) modeling to reveal quantitative pharmacological characteristics that are relevant to dopaminergic drug action. Moreover, we set out to identify biomarkers that can be obtained from the blood as non-invasive sampling site. In the first section of this thesis the methodology is introduced in the context of translational CNS drug development. Moreover, a systematic search is performed to available biomarkers of dopaminergic drug action. Then, in the second part, the multi-biomarker PK/PD approach is applied to biomarkers from the neuroendocrine system as connection between brain and blood. In the third section, the methodology is developed using the simultaneous, time-resolved metabolomics response in brain extracellular fluid and plasma. By applying multi-biomarker PK/PD modeling we revealed quantitative pharmacological characteristics of dopaminergic drugs with regard to multiple biological processes. Moreover, we identified potential blood-based biomarkers of dopaminergic effect in the brain. Show less
The aim of this thesis was to investigate the pathofysiology of neuropsychiatric symptoms in the auto immune disease Systemic Lupus Erythematosus (SLE) using magnetic resonance imaging (MRI) of the... Show moreThe aim of this thesis was to investigate the pathofysiology of neuropsychiatric symptoms in the auto immune disease Systemic Lupus Erythematosus (SLE) using magnetic resonance imaging (MRI) of the brain. To this end MRI abnormalities in SLE patients with neuropsychiatric symptoms were compared with clinical symptoms and serological markers of disease. This thesis shows that immune abnormalities have an influence on the central nervous system in SLE (chapter 3&4). Reversible abnormalities in quantitative brain MRI in NPSLE are associated with clinical symptoms (chapter 2). These abnormalities are associated with neuroimaging features which may be interpreted as reversible axonal and/ or neuronal dysfunction (chapter 5). In line with this, severe ischemia does not appear to play a major role in NPSLE patients without obvious infarction on conventional MRI (chapter 6). Chapter 3 suggests that the influence of auto-immune antibodies is similar to the influence of auto-immune antibodies found in mouse models of NPLSE affecting specific locations of the brain. Using advanced MRI techniques and statistical analysis in chapter 7 suggests that the influence of auto-antibodies in human NPSLE also extends to white matter. Hopefully, these findings will facilitate earlier detection and treatment of neuropsychiatric symptoms in SLE. Show less
This thesis describes different ways of exploring the pharmacological and therapeutic effects of novel GABA-ergic and GABA-like agents in humans. Systematic pharmacodynamic evaluations, using well... Show moreThis thesis describes different ways of exploring the pharmacological and therapeutic effects of novel GABA-ergic and GABA-like agents in humans. Systematic pharmacodynamic evaluations, using well-characterised positive controls, can confirm or refute the unique pharmacological properties of GABAA-subtype selective drugs in healthy volunteers. Such studies can help to predict dosing regimens and therapeutic advantages of these drugs. The distribution of different GABAA-receptor subtypes provides clues for their functional relevance. This knowledge can be used to optimise the desirable and undesirable effect profiles of selective GABA-ergic drugs. Very little is still known about the pathophysiological relevance of GABA-systems in CNS-disorders, although GABA-ergic treatments are in use for a wide range of clinical conditions. The availability of novel compounds with well defined pharmacological characteristics can clarify the involvement of these mechanisms in normal or abnormal physiology. This thesis hopes to show that carefully designed studies, using a range of CNS-measurement that reflect different GABAergic systems, can aid in the development of new GABA-ergic drugs, and help to unravel the role of the different GABA-ergic systems in health and disease. Show less
