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The combinatorial code of cPcdh isoforms creates a diversified cell-surface molecular signature for cell-cell recognition in neural networks. This genetic architecture, combined with a regulated expression pattern and trans-homophilic binding properties, provides insights into cell specialization and signaling. Anomalies in cPcdhs, which include genetic mutations, epigenetic modifications, structural variations, and altered gene expression profiles, are associated with several neurological, neuropsychiatric, and systemic conditions, highlighting the importance of cPcdh investigations. This study focuses on the transcriptional regulation of the Pcdhα gene cluster. Each neuron displays a specific Pcdhα alternate exon repertoire, necessitating an understanding of the transcriptional dynamics. Using the SK-N-SH human neuroblastoma cell line and methodologies such as cRNA-seq and Start-Seq, these dynamics are examined. The application of CRISPR-Cas9 gene editing and a dCas9-VPR gain-of-function assay in the HEK293T cell line reveals the role of as-lncRNA and its interaction with DNA methylation within the Pcdhα gene cluster. This study identifies the role of noncoding as-lncRNA in RNA transcription and provides information on CTCF binding and Pcdhα promoter activation. The research also examines the gastrointestinal domain, as cPcdhs are linked to various diseases. Shifting focus from the canonical realm of the CNS, the research embarks on a preliminary yet pivotal exploration of the gastrointestinal domain. As cPcdhs intersect with a plethora of diseases, an incisive understanding of their expression could yield revelations into tissue susceptibilities with potential disease ramifications. Employing a novel single-domain antibody technique coupled with immunohistochemistry, the endeavor casts a precise lens into the gastrointestinal expression dynamics of Pcdhα and Pcdhγ. These insights not only fortify the understanding of cPcdh within neural structures but also beckon a deeper inquiry into their multifaceted biological roles.

No / In the November issue (2001) of Neuroscience Letters, Holmin et al. (Neurosci. Lett. 314 (2001) 151) reported that the synthesis of the intermediate filament protein nestin was upregulated by potassium-induced depolarization in the rat cortex. In this letter, we provide supplementary evidence that repeated cortical spreading depression elicited by potassium induces a delayed upregulation of nestin. However, we argue against the authors' conclusion, Nestin expression was N-methyl-D-aspartate (NMDA)-receptor dependent since dizocilpine (MK-801) treatment abolished the response because spreading depression itself is very sensitive to NMDA-receptor block, and the drug treatment was initiated prior to potassium application to the cortex in Holmin et al.'s study.

In patients with Parkinson's disease (PD), the associated pathology follows a characteristic pattern involving inter alia the enteric nervous system (ENS), the dorsal motor nucleus of the vagus (DMV), the intermediolateral nucleus of the spinal cord and the substantia nigra, providing the basis for the neuropathological staging of the disease. Here we report that intragastrically administered rotenone, a commonly used pesticide that inhibits Complex I of the mitochondrial respiratory chain, is able to reproduce PD pathological staging as found in patients. Our results show that low doses of chronically and intragastrically administered rotenone induce alpha-synuclein accumulation in all the above-mentioned nervous system structures of wild-type mice. Moreover, we also observed inflammation and alpha-synuclein phosphorylation in the ENS and DMV. HPLC analysis showed no rotenone levels in the systemic blood or the central nervous system (detection limit [rotenone]<20 nM) and mitochondrial Complex I measurements showed no systemic Complex I inhibition after 1.5 months of treatment. These alterations are sequential, appearing only in synaptically connected nervous structures, treatment time-dependent and accompanied by inflammatory signs and motor dysfunctions. These results strongly suggest that the local effect of pesticides on the ENS might be sufficient to induce PD-like progression and to reproduce the neuroanatomical and neurochemical features of PD staging. It provides new insight into how environmental factors could trigger PD and suggests a transsynaptic mechanism by which PD might spread throughout the central nervous system.

Thesis (DPhil)--Stellenbosch University, 2004. / ENGLISH ABSTRACT: This qualitative study comprised an in-depth investigation into the subjective - the explicitly human - experience of those suffering from Myalgic Encephalomyelitis (ME). I was, firstly, concerned with the nature and meaning of the social side of illness, that is, the sufferer's encounters with doctor, family member, friend and acquaintance alike. I was, secondly, set to develop greater insight into the essentially personal experience of being ill. I was able to conclude that, even amidst the inhumane presence of utter ignorance that permeate the very experience of ME, no ME sufferer is inevitably doomed a victim. They can always make a deliberate decision to have a say in their situation, in their own experience of their circumstances. They have the power of personal choice. Recommendations are, therefore, directed at expanding the potential extent and magnitude of this dynamic power. The substantive focus of my study was enriched by a deliberate concern with the methodological implications of my own intimate involvement within the research process. I was here primarily concerned with my personal contribution to the research process as well as the influence thereof on the research relationships developed and the research strategies chosen and applied. I could not but conclude that the understanding I explicate is, as all social science theory, essentially a human construction, developed by me, in my distinctly human capacity. Recommendations are, therefore, geared to sensitise all social researchers to their own contribution to the construction of that which is eventually presented (and taken) as truthful knowl~dge. In conclusion, I am thoroughly convinced that the experience of both illness and research is fundamentally human. This "humanness" cannot and should not be denied. Instead, I advocate a more deliberate focus on the human dimension of illness and research. Without such a focus, a more comprehensive understanding of either realm will continue to linger as but an elusive ideal. / AFRIKAANSE OPSOMMING: Hierdie kwalitatiewe studie is gebaseer op 'n in-diepte ondersoek gerig op die subjektiewe - die onteenseglik menslike - ervaring van diegene wat ly aan Myaligië Enkefalomiëlitis (ME). Ek was, eerstens, geïnteresseerd in die aard en betekenis van die sosiale dimensie van siekte, dit wil sê, die lyer se ervaring van sosiale kontak met dokters, gesinslede, vriende en kennisse. Ek was, tweedens, gerig op die ontwikkeling van 'n grondige insig in die uiters persoonlike ervaring van siek-wees. Ek het tot die gevolgtrekking gekom dat, selfs te midde van die onmenslike teenwoordigheid van blatante onkunde wat die ganse ervaring van ME kenmerk, geen ME lyer noodwendig tot 'n slagoffer-status gedoem is nie. Hulle kan altyd 'n doelbewuste besluit neem om 'n sê te hê in hul eie situasie, in hul eie ervaring van hul omstandighede. Hulle het die mag van persoonlike keuse. Aanbevelings is dus daarop gerig om die potentiële trefwydte en impak van hierdie dinamiese mag uit te brei. Die substantiewe dimensie van my studie is verryk deur 'n doelbewuste fokus op die metodologiese implikasies van my eie intieme betrokkenheid in die navorsingsproses. Ek was hoofsaaklik gemoeid met my persoonlike bydrae tot die navorsingsproses en die invloed daarvan op die ontwikkel van navorsingsverhoudings en die toepassing van gekose navorsingstrategieë. Hierdie fokus het gelei tot die besef dat die beskrywing wat ek aanbied, soos inderdaad alle sosiale teorie, essensieël 'n menslike konstruksie is, soos ontwikkel deur my, in my uitdruklik menslike kapasiteit. Aanbevelings is dus daarop gerig om alle sosiale navorsers te sensitiseer ten opsigte van hul eie bydrae tot die konstruksie van dit wat uiteindelik voorgestel (en geag) word as die waarheidsgetroue kennis. In slotsom, is ek oortuig dat die ervaring van beide siekte en navorsing fundamenteel menslik is. Hierdie "mensheid" kan en behoort nie ontken te word nie. Inteendeel, ek bepleit 'n doelbewuste fokus op die menslike dimensie van siekte en navorsing. Sonder só 'n fokus sal 'n meer diepgaande begrip van iedere area bloot 'n onbereikbare ideaal bly.

Measles virus (MV) causes an acute childhood disease, associated in certain cases with the infection of the central nervous system (CNS). MV induces a profound immunosuppression, resulting in high infant mortality. The major cellular receptor for MV is CD150, which binds MV hemagglutinin (MV-H). As dendritic cell (DC) dysfunction is considered to be essential for the MV immunopathogenesis, we analyzed consequences of MV-H interaction with DCs. We developed an experimental model allowing us to analyze the direct CD150-MV-H interaction in the absence of infectious context. This interaction caused the downregulation of surface expression of CD80, CD83, CD86 and HLA-DR molecules and inhibition of IL-12 production in DCs. DCs also failed to activate T cell proliferation. The CD150-MV-H interaction in DCs and B cells decreased the phosphorylation of JNK1/2, but not ERK1/2 kinases, after subsequent CD150 ligation with anti-CD150 antibodies. Moreover, MV-H by itself induced Akt phosphorylation via CD150 in DCs and B cells. Engagement of CD150 by MV-H in mice transgenic for human CD150 decreased the inflammatory reaction, contact hypersensitivity response, confirming the immunosuppressive effect of CD150-MV-H interaction in vivo. Furthermore, our studies revealed the CD150 expression in CNS tumors and identified the novel CD150 isoform, containing an additional 83bp exon expressed in lymphoid cells, DCs and CNS tumors. Although its isoforms remain intracellular in tumor cells, CD150 may represent a new marker for human brain tumors. Novel mechanism of CD150-induced immunosuppression and new CD150 isoform identified in these studies shed new light on its immunoregulatory role and CD150 isoform diversity and open perspectives for their clinical applications.

Growth hormone (GH) stimulates growth and metabolism but also displays profound effects on the central nervous system (CNS). GH affects neurogenesis and neuroprotection, and has been shown to counteract drug-induced apoptosis in the brain. Anabolic androgenic steroids (AAS), mainly abused for their anabolic and performance-enhancing properties, can cause several adverse effects, such as cardiovascular complications, sterility, depression, and aggression. GH and AAS are both believed to interact with several signaling systems in the CNS. The aim of this thesis was to further investigate the impact of GH and AAS on neurochemistry and cognitive functions. Recombinant human GH (rhGH) and the steroid nandrolone decanoate (ND) were administered, separately and in combination with each other, to male rats. The results demonstrated that administration of GH improved spatial memory, assessed in a water maze test. Furthermore, GH induced alterations of the GABAB receptor mRNA expression, density, and functionality in the brain, for example in regions associated with cognition. GH also altered the mu opioid peptide (MOP) receptor, but not the delta opioid peptide (DOP) receptor functionality in the brain. Thus, some of the GH effects on cognition may involve effects on the GABAB receptors and MOP receptors. ND, on the contrary, seemed to induce impairments of memory and also altered the GABAB receptor mRNA expression in the brain. Furthermore, ND lowered the IGF-1 plasma concentrations and attenuated the IGF-1, IGF-2, and GHR mRNA expression in the pituitary. In addition, significant effects of GH and ND were found on plasma steroid concentrations, organ weight, as well as body weight. In conclusion, this thesis contributes with further knowledge on the cognitive and neurochemical consequences of GH and ND use. The findings regarding ND are worrying considering the common use of AAS among adolescents. GH improves memory functions and affects signaling systems in the brain associated with cognition, hence the hypothesis that GH can reverse drug-induced impairments is further strengthened.

Purpose: To investigate if apparent diffusion coefficient (ADC) values within primary central nervous system lymphoma correlate with cellularity and proliferative activity in corresponding histological samples. Materials and Methods: Echo-planar diffusion-weighted magnetic resonance images obtained from 21 patients with primary central nervous system lymphoma were reviewed retrospectively. Regions of interest were drawn on ADC maps corresponding to the contrast enhancing parts of the tumors. Biopsies from all 21 patients were histologically analyzed. Nuclei count, total nuclei area and average nuclei area were measured. The proliferation index was estimated as Ki-67 positive nuclei divided by total number of nuclei. Correlations of ADC values and histopathologic parameters were determined statistically. Results: Ki-67 staining revealed a statistically significant correlation with ADCmin (r = -0.454, p = 0.038), ADCmean (r = -0.546, p = 0.010) and ADCmax (r = -0.515, p = 0.017). Furthermore, ADCmean correlated in a statistically significant manner with total nucleic area (r = -0.500, p = 0.021). Conclusion: Low ADCmin, ADCmean and ADCmax values reflect a high proliferative activity of primary cental nervous system lymphoma. Low ADCmean values—in concordance with several previously published studies—indicate an increased cellularity within the tumor.

Les troubles anxieux sont parmi les troubles psychiatriques les plus souvent diagnostiqués chez les adolescents. Ces troubles sont souvent accompagnés de nombreuses comorbidités, dont des difficultés de sommeil. L’objectif principal de cette thèse est de caractériser l’activité corticale à l’éveil et pendant le sommeil à l’aide de l’EEG quantifié chez une population d’adolescents présentant un trouble anxieux, et de la comparer à un groupe témoin d’adolescents. Dans un second temps, on cherche à savoir si l’activité EEG des patients anxieux corrèle avec différentes mesures cliniques. Deux études permettent de répondre à ces objectifs, une première portant sur l’activité EEG au cours de l’éveil, et une seconde portant sur l’activité EEG au cours du sommeil (SL et SP). La première étude démontre que l’activité EEG des deux groupes ne présente pas de différence à l’EEG le soir. Par contre, le matin, les patients anxieux présentent une activité significativement supérieure à celle des contrôles aux électrodes centrales (0,75-10 Hz et 13-20 Hz) ainsi qu’aux électrodes occipitales (2,5-7,75 Hz). Dans la seconde étude, nous avons analysé l’activité EEG absolue et relative en SL et en SP. Nous avons trouvé une activité absolue significativement supérieure à l’EEG de la région centrale chez les participants du groupe anxieux : en SLP (stades 3 et 4) sur l’ensemble des bandes de fréquence, en stade 2 sur les bandes de fréquence thêta, alpha et beta seulement. Finalement, en SP, les différences sont trouvées en alpha et beta, et non en thêta et delta. Les résultats obtenus à ces deux études suggèrent la présence de mécanismes de synchronisation et de filtrage inadéquats au niveau de la boucle thalamo-corticale, entraînant une hypervigilance du SNC. Quant aux corrélations entre l’activité EEG et les mesures cliniques, les résultats obtenus dans les deux études révèlent que les fréquences lentes (thêta et delta) de l’activité d’éveil le matin corrèlent à la fois avec l’anxiété de trait et d’état et les fréquences rapides (Alpha et Beta) de l’EEG du sommeil corrèlent sélectivement avec l’anxiété d’état. Il semble donc exister un lien entre les mesures cliniques et l’activité EEG. Une hausse d’activité EEG pourrait être un indicateur de la sévérité accrue des symptômes anxieux. / Anxiety disorders are among the most diagnosed psychiatric disorders in the adolescent population. These disorders are often accompanied by different comorbidities, such as sleep problems. The main objective of this thesis is to characterize the cortical activity during wake and sleep, using quantified EEG, in a population of adolescents presenting an anxiety disorder, and to compare these results to those of a control group of adolescents. Secondly, we wish to verify if the EEG activity of the anxious participants correlates with different clinical measures. Two different studies are conducted in order to attain our objectives, the first one being on the EEG activity during wake, and the second being on the EEG activity during sleep (slow wave sleep and rapid eye movement sleep). The first study reveals that the EEG activity from both groups does not differ in the evening. However, in the morning, anxious participants display an increased activity on central electrodes (0.75-10 Hz and 13-20 Hz), and on occipital electrodes (2.5-7.75 Hz). In the second study, we demonstrate that anxious participants show an increased absolute EEG activity on central electrodes: in slow wave sleep (stages 3 and 4), it is found on all frequency bands, in stage 2, it is found on the theta, alpha and beta frequency bands. Finally, in rapid eye movement sleep, the differences are only in alpha and beta, and not in theta and delta. These data suggest the impairment of thalamo-cortical gating mechanisms in adolescents with anxiety disorders, leading to CNS hyperarousal. As for the correlations between the EEG activity and the clinical measures, the results from our studies reveal that the slow frequencies (theta and delta) of morning wake EEG correlate with both trait and state anxiety, while fast frequencies (alpha and beta) from the sleep EEG correlate specifically with state anxiety. Thus, there appears to be an association between EEG activity and clinical measures. An increased EEG activity could be an indicator of the severity of the anxious symptoms.

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