Study I analysed 150 patients by array comparative genomic hybridization (array CGH, 44K and 244K), with a subsequent 18% diagnostic yield. These results are supported by other studies, indicating an enourmous added diagnostic value of array CGH, compared with conventional cytogenetic analysis. Nevertheless, 80% of the patients remained undiagnosed in Study I. In an effort to diagnose more patients, in Study IV the resolution was increased from 8.9 Kb of the 244K CGH array to 0.7 Kb, by using a single-nucleotide polymorphism (SNP) array. However, no additional pathogenic changes were detected in the 35 patients assessed, and thus, for diagnostic purposes, an array platform with ca 9 Kb resolution appears adequate.

The recent vast increase in reports of detected aberrations and associated phenotypes has enabled characterization of several new syndromes – first based on a common aberration and thereafter by delineation of common clinical characteristics. In Study II, a familial deletion at 9q22.2q22.32 with variable penetrance was described. Despite several reports of aberrations in the adjacent area at 9q associated with Gorlin syndrome, the patients in this family had a unique phenotype and did not present with the syndrome. In Study III, a familial duplication of chromosome 6p22.2 was described. The duplication caused increased expression of an important enzyme of the γ-aminobutyric acid (GABA) degradation pathway, causing oxidative stress of the brain, and thus, very likely, the mild mental retardation of these patients. These two case studies attempted to pinpoint candidate genes and to resolve the pathogenic mechanism causing the clinical characteristics of the patients. Presenting rare genetic and clinical findings to the international science and medical community enables interpretation of similar findings in other patients. The added value of molecular karyotyping in patients with idiopathic DD is evident. As a first line of testing, arrays with a median resolution of at least 9 Kb should be considered and further characterization of detected aberrations undertaken when possible. Diagnostic whole-exome sequencing may be the best option for patients who remain undiagnosed after high-resolution array analysis.

Species B group Ads are important human pathogens. Species B group 2 serotypes are isolated from patients with respiratory tract infections, whereas the Group 1 viruses are described as causing kidney and urinary tract infections. B-group Ad infections often occur in immunocompromised patients, including AIDS patients, recipients of bone marrow transplants, or chemotherapy patients. Recent studies performed in U.S. military training facilities indicate an emergence of diverse species B serotypes at the majority of sites. This included the group 1 serotype 21 and the group 2 serotypes 3, 7, and 14.

CD46-targeting vectors derived from Ad35 and Ad11 are important tools for in vitro gene transfer into human stem cells, including hematopoietic stem cells and induced pluripotent stem cells. Ad35 and Ad11 have been used as tools for cancer therapy, because CD46 appears to be uniformely overexpressed on many cancers. Furthermore, receptor X-targeting vectors, i.e vectors derived from Ad3 or vectors containing Ad3 fibers have shown superior in the transduction of tumor cells both in vitro and in vivo and are currently being used clinically in cancer patients.

While extensive basic virology studies have been done on Ad5, the information of species B group 1 interaction with CD46 is limited. Furthermore, the receptor for a major subgroup of species B Ads (receptor X) is unknown. The goal of this thesis was it therefore to better understand virological and translational aspects of species B Ads. The specific findings described in this thesis include i) the identification of CD46 binding sites within the Ad35 fiber knob, ii) the study of the in vitro and in vivo properties of Ad vectors with increased affinity to CD46. iii) the study of the receptor usage of a newly emergent Ad14a, iv) the identification of desmoglein 2 as the receptor for Ad3, Ad7, Ad11, and Ad14, v) the delineation of structural details of Ad3 virus interaction with DSG2, and vi) the analysis of functional consequences of Ad3-DSG2 interaction. As a result of these basic virology studies two Ad-derived recombinant proteins have been generated that can be used to enhance cancer therapy by monoclonal antibodies.

The mechanisms of motor cortex stimulation in pain relief are still poorly understood although several hypotheses have been proposed. Human studies indicate that the brain systems involved in the emotional appraisal of pain and in the descending pain modulation may have a role in the motor cortex stimulation-induced pain suppression.

Painful signals are modulated in the spinal cord before they reach the supraspinal nervous systems. Supraspinal descending modulation systems, such as the noradrenergic locus coeruleus, serotonergic rostroventromedial medulla (RVM) and opioidergic periaqueductal gray matter filter and modulate nociceptive transmission in the spinal cord. Previous studies indicate that the opioidergic system relays primary motor cortex (M1) stimulation-induced antinociception in neuropathy.

The aim of the thesis was to characterize the M1 stimulation-induced antinociceptive effects, and to find out whether the descending antinociception is relayed through the noradrenergic, serotonergic or dopaminergic pathways in an animal model of chronic neuropathic pain.

The results indicate that the stimulation of M1 attenuates pain-related responses in neuropathic animals through activation of several descending pain inhibitory systems. The RVM and the descending serotonergic pathway acting on the spinal 5-HT1A receptor both contribute to the spinal antinociception induced by M1 stimulation in neuropathic animals. Moreover, supraspinal, presumably striatal and spinal dopamine D2 receptors, are involved in mediating descending antinociceptive actions from M1 to the spinal cord. The dopaminergic A11 cell group is among the relay centers mediating the descending antinociceptive effect as well. A better understanding of the mechanisms involved in the M1 stimulation-induced antinociception could improve the clinical treatment of persistent pain.