Parkinson''s disease: from pallidotomy to L-dopa and back to pallidotomy

CR3 (iC3b receptor), composed of CD11b/CD18, is a beta 2 integrin. A protein that shares antigenic and structural homology with the alpha-chain of CD11b/CD18 has been isolated from the surface of Candida albicans. This molecule is thought to be essential in the pathogenesis of disseminated candidiasis. To evaluate the effects of anti-iC3b receptor antibodies on adhesion between human dermal microvascular endothelial cells (HDMEC) and C. albicans, and in treatment of candidal infection, a binding assay of C. albicans to cultured HDMEC was performed in vitro. An anti-iC3b receptor-specific monoclonal antibody was administered to mice infected with C. albicans. The mice were monitored for mortality and renal involvement by culture and histopathological findings. Flow cytometric analysis demonstrated surface expression of iC3b receptor on C. albicans. The adherence of C. albicans to HDMEC was significantly decreased by treatment with anti-iC3b receptor antibodies. Anti-iC3b receptor antibodies significantly increased the survival time and rate while lowering the renal fungal burden. The iC3b receptors are involved in the adherence of C. albicans to vascular endothelial cells and are likely to be involved in the pathogenesis of disseminated candidiasis. The increased survival in mice infected with C. albicans after treatment with anti-iC3b receptor antibodies indicates that this modality may be beneficial for future development of a new therapy for candidiasis.     

Posteroventral medial pallidotomy in levodopa-unresponsive parkinsonism

PURPOSE: The purpose of this study was to test whether structural modifications improve the intestinal absorption of DMP 728 (cyclo(D-Abu-NMeArg-Gly-Asp-Amb)), a GPIIb/IIIa receptor antagonist. METHODS: In vitro permeabilities of prodrugs and analogs of DMP 728 across excised rat intestinal segments were determined. RESULTS: n-Butyl and n-octyl esters of DMP 728 were relatively stable during in vitro permeation of rat intestine. Intestinal permeation rates of these compounds were no greater than that of DMP 728, even though the octyl ester was much more lipophilic. A pivaloyloxymethyl ester, which was hydrolyzed to DMP 728 during intestinal permeation, also did not improve permeability. In another approach, analogs with an additional methyl substituent on various amide nitrogens were evaluated. Cyclo(D-Val-NMeArg-Gly-Asp-NMeAmb), cyclo(D-Abu-diN-MeLys-Gly-Asp-Amb), and cyclo(NMeGly-NMeArg-Gly-Asp-Amb) each had about 2-fold greater permeability than DMP 728. Two other analogs with improved permeability were linear Ac-D-Abu-NMeArg-Gly-Asp-Amb and a DMP 728 derivative in which the Asp was rearranged. An analog in which the charged amino acids were replaced by neutral amino acids had permeability similar to DMP 728. CONCLUSIONS: Within this series of peptides, hydrogen bonding tendency and structural constraint influenced intestinal permeation, but not always in ways consistent with the literature, whereas charge and lipophilicity were not shown to influence intestinal permeability. The failure of these approaches to improve permeation more significantly could be due to the influence of secretory transport.     

Posteroventral medial pallidotomy in advanced Parkinson's disease

BACKGROUND: Posteroventral medial pallidotomy sometimes produces striking improvement in patients with advanced Parkinson's disease, but the studies to date have involved small numbers of patients and short-term follow-up. METHODS: Forty patients with Parkinson's disease underwent serial, detailed assessments both after drug withdrawal ("off" period) and while taking their optimal medical regimens ("on" period). All patients were examined preoperatively and 39 were examined at six months; 27 of the patients were also examined at one year, and 11 at two years. RESULTS: The percent improvements at six months were as follows: off-period score for overall motor function, 28 percent (95 percent confidence interval, 19 to 38 percent), with most of the improvement in the contralateral limbs; off-period score for activities of daily living, 29 percent (95 percent confidence interval, 19 to 39 percent); on-period score for contralateral dyskinesias, 82 percent (95 percent confidence interval, 72 to 91 percent); and on-period score for ipsilateral dyskinesias, 44 percent (95 percent confidence interval, 29 to 59 percent). The improvements in dyskinesias and the total scores for off-period parkinsonism, contralateral bradykinesia, and rigidity were sustained in the 11 patients examined at two years. The improvement in ipsilateral dyskinesias was lost after one year, and the improvements in postural stability and gait lasted only three to six months. Approximately half the patients who had been dependent on assistance in activities of daily living in the off period before surgery became independent after surgery. The complications of surgery were generally well tolerated, and there were no significant changes in the use of medication. CONCLUSIONS: In late-stage Parkinson's disease, pallidotomy significantly reduces levodopa-induced dyskinesias and off-period disability. Much of the benefit is sustained at two years, although some improvements, such as those on the ipsilateral side and in axial symptoms, wane within the first year. The on-period symptoms that are resistant to dopaminergic therapy do not respond to pallidotomy.     

Localizing value of bilateral cheiro-oral sensory impairment

We present a case of bilateral cheiro-oral syndrome with paresthesia in the right toes following pontine infarction. The causative lesions were situated in the bilateral paramedian pontine tegmentum (PPM). As the lesion on the left side was larger than that on the right, the foot area in the left medial lemniscus was involved, causing paresthesia in the right toes. Bilateral cheiro-oral sensory impairment is rare, and there have been only 4 previous reports. The responsible lesion of complete bilateral cheiro-oral syndrome showing paresthesia in the hand and mouth region on both sides is in the bilateral PPM, while that of incomplete bilateral cheiro-oral syndrome showing paresthesia around both sides of the mouth and in the unilateral hand is in the PPM contralateral to the hand with paresthesia. Bilateral cheiro-oral sensory impairment can occur only in the brainstem.     

Outcomes after stereotactically guided pallidotomy for advanced Parkinson's disease

OBJECT: Parkinson's disease (PD) is a prevalent neurodegenerative disorder that becomes refractory to medication as the disease progresses. Although in the past 5 years increasing numbers of patients have undergone stereotactically guided posteroventral pallidotomy for advanced PD, the safety and efficacy of surgery remains to be documented. The goal in this study was to determine the potential operative morbidity and types of functional outcomes by using validated PD rating scales and a patient survey. METHODS: In a prospective analysis of a consecutive surgical series the authors evaluated 58 patients with advanced PD who ranged in age from 40 to 79 years (mean 67 years) and who had undergone surgery between 1994 and 1997. They used a patient survey and the Unified Parkinson's Disease Rating Scale (UPDRS) to study patients during periods of medication administration ("on") and withdrawal ("off"; mean off score before surgery = 96). Temporary surgical morbidity was found in four patients (6.9%), three of whom developed transient dysarthria and one of whom exhibited transient confusion (1.7%). One patient had persistent dysarthria (1.7%). No patient developed a visual field deficit or sustained a brain hemorrhage. All patients were discharged from the hospital within 24 hours. Significant postsurgical improvements were noted in the UPDRS off-period total and motor scores, as well as in tremor, rigidity, bradykinesia, and contralateral dyskinesia (p < 0.005). Improvements persisted in dyskinesia and tremor for the 21 patients who were evaluated past 1 year. The authors found no improvement in any on-period symptoms except dyskinesia. Thirty-one (61 %) of 51 patients surveyed reported functional gains and/or dramatic improvement in symptoms, 17 (33%) reported symptomatic improvement without functional gains, and three (6%) had minimal or no change in symptoms. No change in the mini mental state examination score was noted during follow up. There were no significant postoperative changes in the use of medication. CONCLUSIONS: In advanced PD associated with either a medically refractory state with significant off periods or levodopa-induced dyskinesias, magnetic resonance imaging-guided pallidotomy with macrostimulation was associated with minimal morbidity and yet significantly reduced dyskinesia and off-period disability. These improvements were of value to the patient and persisted beyond the 1st year.     

Bilateral posteroventral pallidotomy in advanced Parkinson's disease in three patients

In this report, we describe the effect of staged bilateral posteroventral pallidotomy in three patients with advanced Parkinson's disease who were all of the young-onset type. Two patients had developed response fluctuations after the use of levodopa, with severe hypokinesia, painful dystonia, and rigidity in the "off" phase and violent dyskinesias in the "on" phase. One patient, in a continuous hypokinetic rigid state, was totally unresponsive to dopaminergic medication. All were at Hoehn and Yahr stage 5 in the "off" phase before surgery. After surgery, the hypokinetic state was reversed and dyskinesias were abolished in all patients. Hoehn and Yahr stages were 3 in the "off" phase postoperatively. Overall functional improvement was marked and lasting after follow-up for 7, 12, and 13 months, respectively. Complications were visual field deficit and transient central facial paresis, both in the same patient. Bilateral posteroventral pallidotomy can ameliorate response fluctuations, hypokinesia, rigidity, and painful dystonia in advanced Parkinson's disease.     

Medial posteroventral pallidotomy for the treatment of Parkinson's disease]

Stereotactic medial posteroventral pallidotomy for treatment of Parkinson's disease attracts increasing attention. We report on the preliminary results of 12 patients at 1 year after microelectrode-guided unilateral pallidotomy. The primary indications were severe bradykinesia and levodopa-induced dyskinesias. After radiofrequency lesioning all patients had immediate improvement of contralateral parkinsonian signs. Postoperative magnetic resonance imaging confirmed the localization of the lesions. At the 1-year follow-up, all patients had sustained benefit. The global improvement was rated as moderate in six cases, and as marked in six other cases. The mean values of various subscores of the Unified Parkinson's Disease Rating Scale (UPDRS) showed highly significant changes in the "off" state (pre/postoperatively): UPDRS Motor score (60.3/31). UPDRS Activities of Daily Living (ADL) score (33.2/18.3), gait/postural stability score (13.8/7.0), and subscores for contralateral rigidity (4.9/2.1), tremor (7.1/1.4) and bradykinesia (11.6/5.3). There was also significant improvement of ipsilateral bradykinesia and rigidity. Furthermore, we found significant changes of the mean values of the UPDRS ADL and motor "on" scores, an increase of the percentage of "on" time with reduced on-off fluctuations, and a decrease of the percentage of levodopa-induced dyskinesias, with marked improvement or complete abolition of contralateral dyskinesias in particular. The preoperative levodopa regimen was maintained, in general, or only slightly modified, if necessary. Two patients had transient complications: one patient suffered postoperative pneumonia and altered mental status; another patient displayed mild Broca's aphasia secondary to a small stroke involving the dorsal thalamus and the adjacent white matter. There were no persistent side effects at the 1-year follow-up. Contemporary unilateral pallidotomy is an effective and promising therapeutical option for surgical treatment of advanced Parkinson's disease.     

Neuropsychological consequences of posteroventral pallidotomy for the treatment of Parkinson''s disease

The proapoptotic protein BAX contains a single predicted transmembrane domain at its COOH terminus. In unstimulated cells, BAX is located in the cytosol and in peripheral association with intracellular membranes including mitochondria, but inserts into mitochondrial membranes after a death signal. This failure to insert into mitochondrial membrane in the absence of a death signal correlates with repression of the transmembrane signal-anchor function of BAX by the NH2-terminal domain. Targeting can be instated by deleting the domain or by replacing the BAX transmembrane segment with that of BCL-2. In stimulated cells, the contribution of the NH2 terminus of BAX correlates with further exposure of this domain after membrane insertion of the protein. The peptidyl caspase inhibitor zVAD-fmk partly blocks the stimulated mitochondrial membrane insertion of BAX in vivo, which is consistent with the ability of apoptotic cell extracts to support mitochondrial targeting of BAX in vitro, dependent on activation of caspase(s). Taken together, our results suggest that regulated targeting of BAX to mitochondria in response to a death signal is mediated by discrete domains within the BAX polypeptide. The contribution of one or more caspases may reflect an initiation and/or amplification of this regulated targeting.     

Delayed internal capsule infarctions following radiofrequency pallidotomy. Report of three cases

The authors report on a series of patients with idiopathic Parkinson's disease (IPD) who underwent stereotactic radiofrequency (RF) pallidotomies, three of whom suffered delayed postoperative strokes. These three belonged to a group consisting of 42 patients with medically intractable IPD in whom 50 pallidotomies were performed. All three patients had significant previous vascular disease and were in a high-risk group for cerebral infarction. A postoperative magnetic resonance (MR) image was obtained immediately after the pallidotomy was performed to document the placement of the RF lesion and to rule out any hematoma. The delayed strokes occurred on postoperative Days 10, 51, and 117 in patients with previous vascular disease (Group 1, 11 patients). No strokes occurred in the group with the vascular disease risk factor (Group 2, 11 patients) or in the group with no risk factors for vascular disease (Group 3, 20 patients). This observation is statistically significant (p < 0.05). The T2-weighted MR images showed the lesions as high-intensity signals extending to the posterior limb of the internal capsule ipsilateral to the pallidotomy site. The poststroke T1-weighted images obtained in two patients showed persistent contrast enhancement of the RF lesion and no enhancement around the stroke lesion. Clinically and radiographically, these discrete new lesions represent delayed infarctions, suggesting that RF lesioning can induce delayed injury in adjacent tissue. Patients with previously identified vasculopathy may be at risk for delayed capsular infarction following RF pallidotomy.     

Stereotactic pallidotomy and thalamotomy using individual variations of anatomic landmarks for localization

OBJECTIVE: The optimal choice of imaging and localization for stereotactic surgery for movement disorders remains uncertain, with controversy surrounding the use of microelectrode recording and the role of distortion of magnetic resonance imaging (MRI) scans in reducing the accuracy of lesion placement. We review our experience with 67 pallidotomies and 35 thalamotomies performed without microelectrode recording, using instead individual variations in anatomic landmarks. METHODS: Computed tomography is used as the primary modality, with comparison with carefully angled MRI scans and the use of neural structures, such as the mamillary bodies and the vascular anatomy. Pallidal target sites are chosen immediately lateral and superior to the optic tract on a line bisecting the axis of the peduncle, with macrostimulation guiding the final adjustment of target position. Forty-seven patients undergoing unilateral pallidotomies were studied in the "off" state and the "on" state using a modified Unified Rating Scale for Parkinson's disease (URSP) score and a dyskinesia scale, preoperatively and postoperatively at 2 weeks, 2 months, 6 months, and 12 months. In the 31 patients undergoing thalamotomy, tremor was rated preoperatively and postoperatively as near-complete resolution, partial resolution, and failure. RESULTS: The "off" state Unified Rating Scale for Parkinson's disease motor score declined from 42.0 to 32.2 at 2 weeks after surgery (P < 0.0001, n = 42). The Unified Rating Scale for Parkinson's disease motor score was 34.2 at 2 months (P < 0.0001, n = 35), 29.4 at 6 months (P < 0.0001, n = 27), and 24.9 at 12 months (P = 0.005, n = 12), representing an overall improvement in "off" state motor function of approximately 25 to 40%. The "on" state dyskinesia score fell from 5.5 to 2.0 at 2 weeks (P < 0.0001) and persisted in the later visits. The dyskinesia score for the contralateral side fell from 2.5 preoperatively to 0.26 at 2 weeks, 0.28 at 2 months, 0.22 at 6 months, and 0.0 at 12 months. Of the patients undergoing thalamotomies, 65% experienced near-complete or complete tremor resolution, 23% experienced partial tremor relief, and 13% were considered treatment failures. CONCLUSION: Stereotactic procedures for movement disorders requiring high precision can be safely and successfully performed without the use of microelectrode recording techniques. Meticulous alignment of MRI and computed tomographic scans based on visualized anatomy allows precise lesion placement and avoids the distortion inherent in MRI scans.     

Microelectrode recording during posteroventral pallidotomy: impact on target selection and complications

OBJECTIVE: To assess the practical usefulness of single-cell microelectrode recording (MER) when performing posteroventral pallidotomy. METHODS: A retrospective comparison of the initial, magnetic resonance imaging-derived coordinates of the pallidotomy target to the final, MER-refined lesion coordinates in 132 consecutive pallidotomies was conducted. The time required to perform the procedure and the surgical complications are reported. RESULTS: MER led to targeting changes in 98% of the cases. In 12%, the MER-refined target was more than 4 mm from the original, image-guided site, which is a targeting error that could adversely affect outcome. Although all components of targeting were affected by MER, laterality and depth were impacted most. The ventral border of the globus pallidus pars interna was located within 1 mm of the magnetic resonance imaging-selected target in only 40% of the cases. On average, only 2.2 MER trajectories were required to perform pallidotomy. During the last 3 years of our study, 85% of the procedures were performed with one or two trajectories. The mean operating time of the operations performed during the last 3 years was 2 hours and 12 minutes. The incidence of intracerebral hemorrhage in our series (1.5%) was no higher than that reported for other large series of stereotactic procedures. No patient suffered an optic tract injury. CONCLUSION: MER provides important targeting information for performing pallidotomy. In particular, the micrometric delineation of the ventral border of the globus pallidus pars interna permits safe lesioning of the posteroventral region of the globus pallidus pars interna with little risk of visual field deficit. These data can be obtained efficiently and without increased surgical risk.     

Localizing and Designing Computer-Based Safety Training Solutions for Hispanic Construction Workers

Despite the construction industry’s generally positive reaction to the use of information and communication technologies (ICTs) in many of its functions, some of the profession’s key players reside in a digital divide and do not benefit from advances in technology. Hispanic construction workers, an at-risk population with high rates of workplace accidents, are affected by that divide because they rarely take advantage of available ICTs at work. One application of ICTs that can help Hispanic/Latino workers is computer-based training (CBT) for occupational safety. However, the design of CBT materials for Spanish-speaking workers needs to go beyond basic localization of existing products in English. A radical localization approach that uses participatory design sessions with construction workers and their supervisors is proposed in this paper. This case study reports that Latino workers reacted positively and retained knowledge from CBT materials, including videos with elements of humor and without graphic representations of accidents, modeled after the genre of a television situation comedy.     

金青顶金矿床成矿流体的空间定位机制

综合评述了金青顶金矿矿化分带、成矿年龄、流体包裹体以及深部采矿露头新资料。经过详细的观察,确认了一批流体成矿构造证据。结合不同赋存标高上的成矿元素、矿物组合、流体包裹体的温度、压力和成分的分布特征,提出了该矿床新的成矿流体定位机理：该矿床是由一期中高温高压成矿流体经降温降压侵入定位、形成成矿流体的固结外壳后,再经未固结的残余流体发生第二次内爆沸腾、快速降温降压固结的产物。金成矿作用发生在两期流体与围岩作用阶段：(1)深部以金为主的降温降压结晶固结,(2)浅部金一多金属隐爆结晶固结,从而导致金青顶金矿的矿化分带现象。对于矿体分带规律的新认识,有助于指导该区区域成矿规律研究和深部找矿工作。     

Left-right differences in motor thresholds after stimulation of the globus pallidus before pallidotomy

A family is presented in whom hereditary angioedema (HAE) and hereditary breast cancer were coexistent, an association not previously reported. A potential for genetic and treatment-related interactions between the two conditions exists. The use of the hormonal agent danazol to suppress HAE is unlikely to adversely affect the development or outcome of breast cancer. Surgery, chemotherapy, and radiotherapy were received by affected family members, without triggering edema. Whether hormonal breast cancer treatment affects the suppression of HAE by danazol remains unknown.