ABSTRACT
Fourteen patients with primary or secondary dystonia received intrathecal baclofen (ITB) through an implanted pump following a trial dose. Patients were selected for ITB trial if they had clinically unsatisfactory responses to oral antidystonic medications, including oral baclofen. Patients were rated using the Burke-Fahn-Marsden rating scale by a blinded rater after the dose of ITB was optimized. Five patients experienced improvement in symptoms as determined by a change in rating scale scores, although only two had a clear clinical benefit. Etiology of dystonia did not determine the efficacy of ITB therapy, as benefit or failure was seen in both primary and secondary dystonia.
Subject(s)
Baclofen/administration & dosage , Dystonia/drug therapy , Muscle Relaxants, Central/administration & dosage , Adult , Baclofen/adverse effects , Female , Humans , Infusion Pumps, Implantable , Injections, Spinal , Male , Middle Aged , Muscle Relaxants, Central/adverse effects , Treatment OutcomeABSTRACT
OBJECTIVES: We wanted to evaluate chronic subthalamic nucleus (STN) stimulation as an alternative to pallidotomy for severe Parkinson's disease symptomatology. METHODS: Nine patients met clinical criteria for unilateral standard pallidotomy. All had severe medically refractory drug-induced dyskinesia and had reached maximal daily levodopa therapy. Pre- and postoperative videos, neuropsychometric testings and clinical stagings were administered. Three patients were selected to undergo stereotactic implantation of a deep brain stimulator (DBS) after Institutional Review Board approval and informed consent. These were performed using digitized microrecordings. The other group received unilateral pallidotomy. RESULTS: At a mean follow-up of 6 months, our results support recent findings of significant major improvement in motor scores, activity of daily living and decrease in amount of daily levodopa intake by close to 50% after 3 months of stimulation. CONCLUSIONS: Chronic stimulation of the STN appears to provide significant motor improvement in patients with severe Parkinson's disease and is more beneficial than pallidotomy.
Subject(s)
Electric Stimulation Therapy , Globus Pallidus/physiopathology , Monitoring, Intraoperative/methods , Parkinson Disease/therapy , Stereotaxic Techniques , Subthalamic Nucleus/physiopathology , Antiparkinson Agents/administration & dosage , Antiparkinson Agents/therapeutic use , Brain Mapping , Combined Modality Therapy , Electrodes, Implanted , Electrosurgery , Evaluation Studies as Topic , Follow-Up Studies , Globus Pallidus/surgery , Humans , Levodopa/administration & dosage , Levodopa/therapeutic use , Parkinson Disease/drug therapy , Parkinson Disease/surgery , Prospective Studies , Treatment OutcomeABSTRACT
CREB-binding protein (CBP) functions as a coactivator molecule for a number of transcription factors including CREB, c-Fos, c-Jun, c-Myb, and several nuclear receptors. Although binding sites for these factors within CBP have been identified, the regions of CBP responsible for transcriptional activation are unknown. In this report, we show that the N-terminal half of CBP is sufficient for activation of CREB-mediated transcription and that this region contains a strong transcriptional activation domain (TAD). Both deletion of this TAD or sequestering of factors that the TAD binds using a squelching assay were found to greatly decrease the ability of CBP to activate CREB-mediated transcription. In vivo studies by others have shown that p300/CBP associates with TBP; using an in vitro approach, we show the N-terminal TAD binds TBP. We also examined the ability of the C terminus of CBP to activate transcription using GAL-CBP chimeras. With this approach, we identified two C-terminal TADs located adjacent to the c-Fos binding site. In previous studies, cAMP-dependent protein kinase A (PKA) increased the transcriptional activity of a GAL full-length CBP chimera in F9 cells, and of the C terminus in PC-12 cells. Here, we demonstrate that PKA also increased the ability of the N-terminal TADs of CBP to activate transcription in PC-12 but not F9 or COS-7 cells, suggesting that this PKA-responsiveness is cell type-specific.
Subject(s)
Nuclear Proteins/metabolism , Trans-Activators , Transcription Factors/metabolism , Transcription, Genetic , Animals , Binding Sites , COS Cells , CREB-Binding Protein , DNA-Binding Proteins/metabolism , In Vitro Techniques , Mice , Mutagenesis, Site-Directed , Nuclear Proteins/genetics , Plasmids/metabolism , TATA-Box Binding Protein , Transcription Factors/geneticsABSTRACT
The sequences of nine different cytokines, growth hormone, and prolactin have been aligned and their secondary structure predicted. The alignment reveals that each exon has a characteristic sequence pattern shared by all cytokines. The most striking sequence similarity is observed in exon 4, where the residue pair Phe-Leu is conserved in many cytokines. In addition, there are discreet homologous regions between two specific growth factors, including a high degree of homology between granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 3 (IL-3). The secondary structure analysis predicts that exon 3 of all cytokines has an antiparallel helix-turn-helix motif, which is likely to form the central helical segments of a four alpha-helical bundle-type structure. Based on the secondary structure and the disulfide-bonding pattern, the topological connectivity for a number of cytokines has been predicted.
