Annals of the New York Academy of Sciences
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Ann. N. Y. Acad. Sci. · May 2005
Magnetic resonance tracking of implanted adult and embryonic stem cells in injured brain and spinal cord.
Stem cells are a promising tool for treating brain and spinal cord injury. Magnetic resonance imaging (MRI) provides a noninvasive method to study the fate of transplanted cells in vivo. We studied implanted rat bone marrow stromal cells (MSCs) and mouse embryonic stem cells (ESCs) labeled with iron-oxide nanoparticles (Endorem) and human CD34+ cells labeled with magnetic MicroBeads (Miltenyi) in rats with a cortical or spinal cord lesion. ⋯ Histologic studies confirmed a decrease in lesion size. We also used 3-D polymer constructs seeded with MSCs to bridge a spinal cord lesion. Our studies demonstrate that grafted adult as well as embryonic stem cells labeled with iron-oxide nanoparticles migrate into a lesion site in brain as well as in spinal cord.
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Ann. N. Y. Acad. Sci. · Apr 2005
Case ReportsPotential role of anti-GAD antibodies in abnormal eye movements.
Glutamic acid decarboxylase (GAD) catalyzes the conversion of glutamic acid to gamma-aminobutyric acid (GABA). Autoantibodies directed against GAD (antiGAD-Ab) have been described in patients with insulin-dependent diabetes mellitus, stiff-man syndrome, and in a few patients with progressive cerebellar ataxia. The presence of these autoantibodies suggests an autoimmune pathophysiological mechanism for the neurological manifestations in these disorders. ⋯ The cases of two patients with subacute cerebellar ataxia associated with antiGAD-Ab presenting with abnormal eye movements are reported. One patient presented a periodic alternating nystagmus (PAN), whereas the other presented a downbeat nystagmus (DBN) and slow vertical saccades. The potential role of antiGAD-Ab and the resultant GABAergic neurotransmission deficit in oculomotor manifestations is discussed.
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Ann. N. Y. Acad. Sci. · Apr 2005
Effect of 3,4-diaminopyridine on the postural control in patients with downbeat nystagmus.
Downbeat nystagmus (DBN) is a common, usually persistent ocular motor sign in vestibulocerebellar midline lesions. Postural imbalance in DBN may increase on lateral gaze when downbeat nystagmus increases. 3,4-Diaminopyridine (3,4-DAP) has been shown to suppress the slow-phase velocity component of downbeat nystagmus and its gravity-dependent component with concomitant improvement of oscillopsia. Because the pharmacological effect is thought to be caused by improvement of the vestibulocerebellar Purkinje cell activity, the effect of 3,4-DAP on the postural control of patients with downbeat nystagmus syndrome was examined. ⋯ Two out of four patients showed an improvement of the area of postural sway by 57% of control (baseline) on eye closure. In contrast, downbeat nystagmus in gaze straight ahead and on lateral gaze did not benefit in these two patients, implying a specific influence of 3,4-DAP on the vestibulocerebellar control of posture. It was concluded that 3,4-DAP may particularly influence the postural performance in patients with downbeat nystagmus.
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Ann. N. Y. Acad. Sci. · Jan 2005
ReviewProgress toward the genetic treatment of the beta-thalassemias.
The beta-thalassemias are congenital anemias that are caused by mutations that reduce or abolish expression of the beta-globin gene. They can be cured by allogeneic hematopoietic stem cell (HSC) transplantation, but this therapeutic option is not available to most patients. The transfer of a regulated beta-globin gene in autologous HSCs is a highly attractive alternative treatment. ⋯ The safe implementation of stem cell-based gene therapy requires the prevention of the formation of replication-competent viral genomes and minimization of the risk of insertional oncogenesis. Importantly, globin vectors, in which transcriptional activity is highly restricted, have a lesser risk of activating oncogenes in hematopoietic progenitors than non-tissue-specific vectors, by virtue of their late-stage erythroid specificity. As such, they provide a general paradigm for improving vector safety in stem cell-based gene therapy.
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Ann. N. Y. Acad. Sci. · Jan 2005
ReviewSuccessful correction of the human Cooley's anemia beta-thalassemia major phenotype using a lentiviral vector flanked by the chicken hypersensitive site 4 chromatin insulator.
beta-Thalassemias are the most common single-gene disorders and are potentially amenable to gene therapy. While retroviral vectors carrying the human beta-globin cassette were notoriously unstable and expressed poorly, considerable progress has now been made using lentiviral vectors (LVs), which stably transmit the beta-globin expression cassette. Mouse studies using LVs have shown correction of the beta-thalassemia-intermedia phenotype and a partial, variable correction of the mouse beta-thalassemia major phenotype, despite the use of beta-globin-hypersensitive sites that are known to result in position-independent effects. ⋯ The gene-corrected human beta-thalassemia progenitor cells were transplanted into immune-deficient mice, where they underwent normal erythroid differentiation, expressed normal levels of human beta-globin, and displayed normal effective erythropoiesis 3-4 months after xenotransplantation. Variability of beta-globin expression in erythroid colonies derived in vitro or from xenograft bone marrow was similar to that seen in normal control subjects. Results show genetic correction of primitive human progenitor cells and normalization of the human thalassemia major phenotype.