The regenerative capacity of mature mammalian CNS neurons after axonal injury is severely limited by a variety of mechanisms. Retrograde repression is the continuous inhibition of the expression of growth phenotypes by tonic signals produced by target tissues and transmitted to the neuron cell body via retrograde axonal transport. Loss of target contact through axonal injury is thought to interrupt this retrograde signal and allow the up-regulation of growth-associated proteins. Most CNS neurons, however, possess many widespread axon collaterals, such that retrograde repression is maintained by intact sustaining collaterals even if some axons are injured.<p>In this project we investigated whether or not retrograde repression plays a role in limiting the expression of GAP-43 in transcallosal neurons. Because TCNs possess local axon collaterals to nearby cortex and project distal axons to homologous areas of contralateral cortex, we hypothesized that the simultaneous interruption of retrograde repressive signals from both ipsilateral and contralateral cortex would result in an up-regulation of GAP-43 expression in at least some TCNs.<p>We found that a bilateral infusion of a function blocking antibody to FGF-2 into the parietal cortex of rats using implanted osmotic mini-pumps resulted in a significant increase in the level of expression of GAP-43 mRNA in TCNs identified by retrograde fluorescent labeling. In contrast, neither ipsilateral or contralateral antibody infusions alone increased GAP-43 expression significantly compared to controls. The level of expression of GAP-43 in TCNs did not significantly increase after stereotactic callosotomy alone, but callosotomized animals treated with an ipsilateral infusion of anti-FGF-2 had levels of increased GAP-43 expression equivalent to those seen in animals that had received bilateral antibody infusions.<p>We conclude that FGF-2 provides a retrograde repressive signal for at least some mature mammalian TCNs, and that the expression of growth-associated proteins can be up-regulated in CNS neurons by simultaneously blocking retrograde repressive signals from all existing axon collaterals. The ability to alter the gene expression of mature CNS neurons in both normal and injured states through the targeted infusion of a pharmacological agent may have potential clinical implications in the future.

An acute demyelinating syndrome (ADS) in a child may be a monophasic illness or may represent the incident attack of multiple sclerosis (MS) – an inflammatory demyelinating neurodegenerative disorder affecting the brain, spinal cord and optic nerves. The central objective of this dissertation was to identify MRI parameters present at ADS that predict MS diagnosis. A scoring tool was first created containing 14 parameters identified from the literature and demonstrating substantial inter-rater agreement (Cohen’s kappa values ≥0.6). Children aged <16 years were enrolled at incident ADS and are currently followed for five years at 23 Canadian centers. Standardized MRI scans were acquired at onset and serially. MS was defined based on the occurrence of a second demyelinating attack or MRI evidence of new lesions in accordance with McDonald criteria for dissemination in time. Multivariable Cox proportional hazards regression models were used to identify MRI parameters that predicted MS diagnosis. Over 1100 MRI scans in 284 children with ADS were evaluated. To date, 57(20%) children have been diagnosed with MS. For those that developed MS, the median (IQR) time from incident attack to diagnosis was 6.2 (4.7-11.1) months. The presence of ≥1 T1-hypointense lesion (HR 20.6, 95% CI 5.5-78.0) and ≥1 T2 periventricular lesion (3.3, 1.3-8.8) were associated with an increased likelihood for MS diagnosis (sensitivity 84%, specificity 93%, PPV 76%, NPV 96%). The predictive parameters were validated in an independent Dutch cohort of 45 children with ADS (n=15, 33% MS): sensitivity 93%, specificity 87%, PPV 78%, NPV 96%. Finally, it was determined that the 2010 McDonald criteria are applicable for diagnosis of pediatric-onset MS diagnosis in older children with non-ADEM presentations. The work embodied herein emphasizes the value of MRI in predicting MS diagnosis in children with incident ADS. Early identification of children with MS is important for planning clinical care and will be valuable in future pediatric MS treatment trials.

The regenerative capacity of mature mammalian CNS neurons after axonal injury is severely limited by a variety of mechanisms. Retrograde repression is the continuous inhibition of the expression of growth phenotypes by tonic signals produced by target tissues and transmitted to the neuron cell body via retrograde axonal transport. Loss of target contact through axonal injury is thought to interrupt this retrograde signal and allow the up-regulation of growth-associated proteins. Most CNS neurons, however, possess many widespread axon collaterals, such that retrograde repression is maintained by intact sustaining collaterals even if some axons are injured.<p>In this project we investigated whether or not retrograde repression plays a role in limiting the expression of GAP-43 in transcallosal neurons. Because TCNs possess local axon collaterals to nearby cortex and project distal axons to homologous areas of contralateral cortex, we hypothesized that the simultaneous interruption of retrograde repressive signals from both ipsilateral and contralateral cortex would result in an up-regulation of GAP-43 expression in at least some TCNs.<p>We found that a bilateral infusion of a function blocking antibody to FGF-2 into the parietal cortex of rats using implanted osmotic mini-pumps resulted in a significant increase in the level of expression of GAP-43 mRNA in TCNs identified by retrograde fluorescent labeling. In contrast, neither ipsilateral or contralateral antibody infusions alone increased GAP-43 expression significantly compared to controls. The level of expression of GAP-43 in TCNs did not significantly increase after stereotactic callosotomy alone, but callosotomized animals treated with an ipsilateral infusion of anti-FGF-2 had levels of increased GAP-43 expression equivalent to those seen in animals that had received bilateral antibody infusions.<p>We conclude that FGF-2 provides a retrograde repressive signal for at least some mature mammalian TCNs, and that the expression of growth-associated proteins can be up-regulated in CNS neurons by simultaneously blocking retrograde repressive signals from all existing axon collaterals. The ability to alter the gene expression of mature CNS neurons in both normal and injured states through the targeted infusion of a pharmacological agent may have potential clinical implications in the future.

Syfte: Att undersöka om det fanns något samband mellan behandling med centralstimulantia ochavvikande tillväxt hos barn och ungdomar med ADHD, samt att undersöka om eventuellt avvikandetillväxt hade något samband med ålder vid insättande, kön eller olika funktionshinder.Metod: 68 barn med ADHD som behandlats med centralstimulantia i minst två år inkluderades.Journalkopior inhämtades från Habiliteringen för barn och vuxna vid Uppsala läns landsting. Dessakopior innehöll barnens tillväxtkurvor, kön, diagnos och ålder. Kurvorna granskades med hjälp av enutformad granskningsmall. Barnens tillväxt jämfördes mellan åldergrupper, kön och olikafunktionshinder.Resultat: Vid behandlingsstart var åldersgrupperna 6-8 år samt 12-16 år signifikant tyngre ännormalpopulationen i samma åldersgrupper. Det fanns en signifikant skillnad mellan åldergrupperna ilängdavplaning efter ett års behandling, där fler barn i åldrarna 10-16 år avplanade än barn i åldrarna6-10 år. Även mellan funktionshindergrupperna fanns det en signifikant skillnad i längdavplaning eftertvå års behandling. Mellan pojkar och flickor fanns det en signifikant skillnad i viktavplaning efter tvåårs behandling, där fler pojkar avvek nedåt från sin tillväxtkurva.Slutsats: Det framkom få samband mellan behandling med centralstimulantia och avvikande tillväxthos barn och ungdomar med ADHD. Ett litet urval i denna journalgranskning innebar låg power i destatistiska analyserna vilket medförde svårigheter att påvisa signifikanta samband och skillnadermellan de grupper som jämförts. Avplaning i tillväxt vid centralstimulantiabehandling är ett viktigtansvarsområde för sjuksköterskan som bör observera och arbeta förebyggande för att undvika detta.Författarna vidhåller att detta är ett viktigt ämne som berör många barn, föräldrar och sociala instanser,vilket gör det önskvärt med fler större studier som undersöker detta mer grundligt. / Objective: To study whether there was any relation between treatment with stimulants and abnormalgrowth in children and adolescents with ADHD, and to study whether any differences in growth wasrelated to age at initiation, gender or different disabilities.Design: 68 children with ADHD treated with stimulants for at least two years were included. Journalcopies were collected from Habiliteringen vid Uppsala län. These copies contained the children'sgrowth charts, gender, diagnosis and age. These curves were studied using a designed review template.Children's growth was compared between age groups, gender and disabilities.Results: At baseline, the age groups 6-8 years and 12-16 years were significantly heavier than normalpopulation of same age groups. There was a significant difference between age groups in decrease inlength after one year of treatment where more children aged 10-16 years decreases than children aged6-10 years. Also among other disability groups, there was a significant difference in decrease in lengthafter two years of treatment. Between boys and girls, there was a significant difference in decrease inweight after two years of treatment, where more boys departed downward from its growth curve.Conclusion: There were few correlations between treatment with stimulants and abnormal growth inchildren and adolescents with ADHD. A small sample in this journal review meant low power in thestatistical analysis leading to an inability to detect significant correlation and differences between thegroups for comparison. Decrese in growth during treatment with stimulants is an importantresponsibility for the nurse who should observe and work preventively to avoid this. The authorsmaintain that this is an important topic that affects many children, parents and social instances, makingit desirable for more major studies to investigate this more thoroughly.

Thesis (Ph. D.)--University of Missouri--Columbia, 2003. / "December 2003." Typescript. Vita. Includes bibliographical references (leaves 172-205). Also issued on the Internet.

Thesis (Ph. D.)--University of Oregon, 2003. / Typescript. Includes vita and abstract. Includes bibliographical references (leaves 95-102). Also available for download via the World Wide Web; free to University of Oregon users.

Thesis (Ph. D.)--University of Washington, 2003. / Vita. Includes bibliographical references (leaves 97-114).

published_or_final_version / Anatomy / Master / Master of Philosophy

Rubella virus (RUBV) is a significant human pathogen. RUBV infection takes an enormous toll due to congenital rubella syndrome (CRS), a constellation of birth defects including blindness, hearing defects and mental retardation. Little is known about RUBV-induced teratogenesis due to the absence of useful models. This research is now enabled by the availability of human embryonic stem cells (hESCs) and hESC-derived precursor cell lines. Human neural progenitor cells (hNPCs) serve as a particularly relevant model due to the symptoms and complications of CRS related to neural system development. The overarching question addressed in this dissertation is: what is the mechanism underlying the development of neurological abnormalities seen in CRS? In this context, we investigated the cellular responses of hNPCs to RUBV infection comprehensively by: 1) assessing susceptibility of the cells to RUBV infection; 2) analyzing the effect of infection on cell proliferation; and 3) examining the impact of RUBV infection on differentiation of hNPCs into neuronal and astroglial lineages . We found that hNPCs are susceptible to RUBV infection and that the percentage of infected cells closely mimics CRS in which few cells harbor virus. The virus was able to persist in culture for up to one month without significant alteration of cell morphology and stemness marker expression. In addition, RUBV infection moderately attenuated the proliferation of undifferentiated hNPCs by triggering cell cycle arrest, but not apoptosis or other cell death events commonly seen upon virus infection. This lack of apoptosis appeared to be due in part to virus-induced anti-apoptotic suppression. Interestingly, the virus only had a marginal effect on the induction of cell differentiation into both neuronal and astroglial phenotypes. In fact, RUBV infection promoted terminal differentiation of the culture due to depletion of precursor cells. With differentiation, viral replication was suppressed. We thus propose a model for RUBV-induced neurological defects in which the virus acts by depleting precursor cell pools. The results of this study provide clues for elucidating the mechanisms of RUBV teratogenicity at the cellular level and serves as a potential reference study for elucidating mechanisms of teratogenesis induced by other infectious agents.

Mental health of a person depends on the correct functioning of the brain. The brain and the spinal cord contain many types of cells, of which one important type are called the neurons. Neurons are special in the way they connect to each other to form large networks. The chemicals called transmitters are packed at the nerve endings into tiny packets called vesicles and when a signal arrives these vesicles fuse immediately to the attached cell surface and release their contents. The role of the synaptic vesicular transporter proteins is to ensure proper packing of transmitter molecules that can be released upon stimulation. Vesicular packing is an important process. The carrier proteins involved in packing work in coordination to determine the amount and type of transmitters to be packed. Missing a carrier protein from the vesicles might lead to improper packing and inaccurate signaliing. These signaling molecules are known for their implications in many psychiatric and neurological disorders like Alzheimer’s disease, Parkinson’s disease, Schizophrenia, and attention deficit to name just a few.  How a vesicular transporter can affect the modulatory functions of aminergic neurons is the subject of this thesis. This thesis reports on the effects of the loss of a vesicular orphan transporter. Study I demonstrates the localization of this protein to monoaminergic and cholinergic terminals. It reports the effect of the loss of Slc10A4 on vesicular dopamine uptake, synaptic clearance of dopamine and hypersensitivity of animals to dopamine related psychostimulants. Study I also provides evidence for ATP as a possible ligand for SLC10A4 protein. Study II provides data on the clinical relevance of Slc10A4 in playing a protective role against vulnerability to epilepsy. It reports that loss of Slc10A4 renders the animals hypersensitive to cholinergic drugs. Study III provides a closer look at individual cholinergic synapses at neuromuscular junctions in mice lacking Slc10A4. The structural and electrophysiological properties of the NMJ are found compromised because of the loss of this vesicular protein. Taken together, this thesis presents a SV protein’s perspective of viewing at modulation of synaptic transmission.