Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010.

Abstract not available

Thesis (Ph. D.)--University of Virginia, 2006. / Includes bibliographical references. Also available online through Digital Dissertations.

No description available.

Medulloblastoma (MB) is the most common pediatric malignant brain tumor. Little is known about aggressive forms of this disease. In order to identify pathways mediating aggressiveness in MB, we performed microarray experiments. Primary human MBs were compared to their patient matched recurrent or metastatic counterparts. Murine tumors from two MB mouse models that present with differing clinical severities were also evaluated. We identified the Transforming Growth Factor-beta (TGF-β) as a potential contributor to MB pathogenesis in both species. Smad3, a major downstream component of the TGF-β pathway, was shown to correlate with MB metastasis and survival in human tissue. Similarly, Smad3 expression during development identified a subset of cerebellar neuronal precursors as putative cells of origin for the Smad3 positive MBs. To our knowledge, this is the first study that links TGF-β to MB pathogenesis. Our research suggests that canonical activation of this pathway leads to better prognosis for patients.

Medulloblastoma (MB) is the most common pediatric malignant brain tumor. Little is known about aggressive forms of this disease. In order to identify pathways mediating aggressiveness in MB, we performed microarray experiments. Primary human MBs were compared to their patient matched recurrent or metastatic counterparts. Murine tumors from two MB mouse models that present with differing clinical severities were also evaluated. We identified the Transforming Growth Factor-beta (TGF-β) as a potential contributor to MB pathogenesis in both species. Smad3, a major downstream component of the TGF-β pathway, was shown to correlate with MB metastasis and survival in human tissue. Similarly, Smad3 expression during development identified a subset of cerebellar neuronal precursors as putative cells of origin for the Smad3 positive MBs. To our knowledge, this is the first study that links TGF-β to MB pathogenesis. Our research suggests that canonical activation of this pathway leads to better prognosis for patients.

Seizures are thought to arise primarily from the cerebral cortex. However, the propagation and behavioral manifestations of seizures involve a network of both cortical and subcortical structures. The medial thalamus and upper brainstem reticular formation are crucial areas for the maintenance of normal consciousness. Bilateral involvement of these structures may be responsible for loss of consciousness during partial seizures. Therefore, we sought to investigate the role of the medial thalamus and brainstem in seizures. We performed SPECT ictal-interictal difference imaging co-registered with high-resolution MRI scans to localize regions of cerebral blood flow changes in patients undergoing inpatient monitoring for epilepsy. Ictal-interictal SPECT scans from 43 seizures in 40 patients were analyzed. The medial thalami showed SPECT difference imaging changes of >20% in 18 patients. Of patients with medial thalamic changes, the majority (13 of 18) had seizure onset in the temporal lobe, while only 1 had confirmed onset in extratemporal structures, and the remainder were non-localized. In contrast, in the 22 patients without >20% SPECT changes in the medial thalami, 6 had extratemporal onset, 6 had temporal onset, and the remainder were non-localized. In patients with temporal lobe seizures, the side of greater medial thalamic and brainstem reticular formation involvement was strongly related to SPECT injection timing such that there was a sequential pattern of ipsilateral followed by contralateral changes. Brainstem structures showed >20% SPECT changes in 27 of 43 seizures with no clear relation to temporal or extratemporal onset. We conclude that the medial thalamus is preferentially involved in seizures arising from the temporal lobes, possibly reflecting the strong connections between limbic temporal structures and the medial thalamus. Sequential involvement of ipsilateral followed by contralateral structures in the medial thalamus and upper brainstem may explain how seizures produce peri-ictal loss of consciousness despite incomplete involvement of the cerebral cortex.

No description available.

Although human congenital cerebellar malformations are common, their molecular and developmental basis is still poorly understood. Recently, cilia-related gene deficiencies have been implicated in several congenital disorders that exhibit cerebellar abnormalities such as Joubert syndrome, Meckel-Gruber syndrome, Bardet-Biedl syndrome, and Orofaciodigital syndrome. The association of cilia gene mutations with these syndromes suggests that cilia may be important for cerebellar development, but the nature of cilia involvement has not been elucidated. To assess the importance of cilia-related proteins during cerebellar development, we studied the effects of CNS-specific inactivation of two mouse genes whose protein products are critical for cilia formation and maintenance, IFT88, (also known as polaris or Tg737), which encodes intraflagellar transport 88 homolog, and Kif3a, which encodes kinesin family member 3a. We showed that loss of either of these genes caused severe cerebellar hypoplasia and foliation abnormalities, primarily attributable to a failure of expansion of the neonatal granule cell progenitor population. In addition, granule cell progenitor proliferation was sensitive to partial loss of IFT function in a hypomorphic mutant of IFT88 (IFT88orpk), an effect that was modified by genetic background. IFT88 and Kif3a were not required for the specification and differentiation of most other cerebellar cell types, including Purkinje cells. Together, our observations constitute the first demonstration that cilia proteins are essential for normal cerebellar development and suggest that granule cell proliferation defects may be central to the cerebellar pathology in human cilia-related disorders.

Although headaches are a very common complaint, those accompanied by paresthesia and muscle wasting indicate an underlying neurological disorder. In this review, we present the case of a 58-year-old man with chronic headaches who developed tingling and numbness in his right limbs along with right-hand muscle atrophy.