Tremor is a cardinal symptom of parkinsonism, occurring early on in the disease course and affecting more than 70% of patients. Parkinsonian resting tremor occurs in a frequency range of 3–7 Hz and can be resistant to available pharmacotherapy. Despite its prevalence, and the significant decrease in quality of life associated with it, the pathophysiology of parkinsonian tremor is poorly understood. The tremulous jaw movement (TJM) model is an extensively validated rodent model of tremor. TJMs are induced by conditions that also lead to parkinsonism in humans (i.e., striatal DA depletion, DA antagonism, and cholinomimetic activity) and reversed by several antiparkinsonian drugs (i.e., DA precursors, DA agonists, anticholinergics, and adenosine A2A antagonists). TJMs occur in the same 3–7 Hz frequency range seen in parkinsonian resting tremor, a range distinct from that of dyskinesia (1–2 Hz), and postural tremor (8–14 Hz). Overall, these drug-induced TJMs share many characteristics with human parkinsonian tremor, but do not closely resemble tardive dyskinesia. The current review discusses recent advances in the validation of the TJM model, and illustrates how this model is being used to develop novel therapeutic strategies, both surgical and pharmacological, for the treatment of parkinsonian resting tremor.
We have shown that a COOH-terminal peptide of p53 (amino acids 361 -382, p53p), linked to the truncated homeobox domain of Antennapedia (Ant) as a carrier for transduction, induced rapid apoptosis in human premalignant and malignant cell lines. Here, we report that human and rat glioma lines containing endogenous mutant p53 or wild-type (WT) p53 were induced into apoptosis by exposure to this peptide called p53p-Ant. The peptide was comparatively nontoxic to proliferating nonmalignant human and rat glial cell lines containing WT p53 and proliferating normal human peripheral marrow blood stem cells. Degree of sensitivity to the peptide correlated directly with the level of endogenous p53 expression and mutant p53 conformation. Apoptosis induction by p53p-Ant was quantitated by terminal deoxynucleotidyl transferase -mediated dUTP nick end labeling assay and Annexin V staining in human glioma cells in vitro and in a syngeneic orthotopic 9L glioma rat model using convection-enhanced delivery in vivo. The mechanism of cell death by this peptide was solely through the Fas extrinsic apoptotic pathway. p53p-Ant induced a 3-fold increase in extracellular membrane Fas expression in glioma cells but no significant increase in nonmalignant glial cells. These data suggest that p53 function for inducing Fas-mediated apoptosis in gliomas, which express sufficient quantities of endogenous mutant or WT p53, may be restored or activated, respectively, by a cell-permeable peptide derived from the p53 COOHterminal regulatory domain (p53p-Ant). p53p-Ant may serve as a prototypic model for the development of new anticancer agents with unique selectivity for glioma cancer cells and it can be successfully delivered in vivo into a brain tumor by a convection-enhanced delivery system, which circumvents the blood-brain barrier.
Deep brain stimulation (DBS) has become an important modality in the treatment of refractory Parkinson disease (PD). In patients with comorbid arrhythmias requiring cardiac pacemakers, DBS therapy is complicated by concerns over a possible electrical interaction between the devices (or with device programming) and the inability to use magnetic resonance imaging guidance for implantation. The authors report two cases of PD in which patients with preexisting cardiac pacemakers underwent successful implantation of bilateral DBS electrodes in the subthalamic nucleus (STN). Each patient underwent computerized tomography-guided stereotactic frame-based placement of DBS electrodes with microelectrode recording. Both extension wires were passed from the right side of the head and neck (contralateral to the pacemaker) to place the cranial pulse generators subcutaneously in the left and right abdomen. The cranial pulse generators were placed farther than 6 in from the cardiac pacemaker and from each other to decrease the chance of interference between the devices during telemetry reprogramming. Postoperative management involved brain stimulator programming sessions with simultaneous cardiological monitoring of pacemaker function and cardiac rhythm. No interference was noted at any time, and proper pacemaker function was maintained throughout the follow-up period. With bilateral STN stimulation, both patients experienced a dramatic improvement in their PD symptoms, including elimination of dyskinesias, reduction of "off" severity, and increase of "on" duration. With some modifications of implantation strategy, two patients with cardiac pacemakers were successfully treated with bilateral DBS STN therapy for refractory PD. To our knowledge, this is the first report on patients with cardiac pacemakers undergoing brain stimulator implantation.
Vancomycin is a potential causative agent of Stevens-Johnson syndrome.
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