Intercellular communication and tissue growth. II. Tissue regeneration.

Intercellular communication was examined in regenerating rat liver and urodele skin, two tissues of fast but normal growth. In both, cellular communication is in general as good as in their respective normal intact state. This stands in striking contrast to the lack of cellular communication in tissues with cancerous growth. Upon wounding of the urodele skin, the normally permeable junctional membranes of cells near the wound border seal themselves off, thereby insulating the interiors of the communicated cell systems from the exterior. When the cells of two opposing borders make mechanical contact in the course of wound closure, communication between them ensues within 30 min. Within this period all cell movement also ceases ("contact inhibition"). The possible implications of these findings in the control of tissue growth are discussed.

Uncoupling of a nerve cell membrane junction by calcium-ion removal.

Calcium ion participates in maintaining electrical connections between the nerve cells of Retzius (Hirudo medicinalis). The conductance across the junction between these cells decreases with decreasing concentration of free, extracellular Ca(++) At a certain level of Ca(++) withdrawal from the cell system, junctional conductance reaches a critical low point at which the cells become functionally disconnected: the nerve impulses which are normally discharged in synchrony by the cells become asynchronous. These effects of Ca(++) on junctional connection are irreversible, in contrast to those on nonjunctional surface membrane permeability.

Autologous transplantation of adrenal medulla in Parkinson's disease. 18-month results.

Eighteen of 19 patients who underwent autologous adrenal medullary transplantation to the right caudate nucleus have been followed up for 18 months. During the course of this study, a statistically significant improvement was noted in percent "on" time, percent "on" time without dyskinesia, activity of daily living (ADL) scores during the "on" stages, and ADL, motor, and Schwab-England scores during the "off" stages. Benefits tended to be maximal at 6 months and to gradually lessen thereafter, although statistically significant improvement in comparison with baseline was still present at 18 months for ADL, motor, and Hoehn-Yahr scores during the "off" stages. Almost all parameters had deteriorated by 18 months compared with 12 months, including those remaining significantly improved in comparison with baseline. These patterns were similar for each of the three participating centers. Complications were largely restricted to the perioperative period.

Neurosurgical horizons in Parkinson's disease.

Based on recent neuroanatomic and physiologic discoveries, neurosurgical therapies may increasingly complement and extend pharmacologic management of Parkinson's disease. Procedures showing promise include subthalamotomy and pallidotomy; thalamic electrical stimulation may also offer application for tremor control. Transplantation of adrenal chromaffin cells has not been associated with consistent long-term improvement in most patients, and fetal mesencephalic transplantation remains controversial. Trophic factors that may be pivotal to cellular repair and survival of transplanted tissue have potential therapeutic roles when purified and perfused centrally or when the cells that produce the factors are transplanted.

Intraventricular bethanechol infusion for Alzheimer's disease: results of double-blind and escalating-dose trials.

Ten patients with biopsy-proven Alzheimer's disease (AD) received low-dose (0.35 mg/d) intraventricular bethanechol, a muscarinic agonist, and saline placebo in a 24-week double-blind crossover design. Eight of these ten patients later participated in an open escalating-dose (to 1.75 mg/d) trial of bethanechol. Patients' drug responses were assessed by neuropsychological examination and informant measures of activities of daily living, mood disturbance, and abnormal behavior. Bethanechol appears to have a narrow therapeutic window for positive effects; low doses did not reliably alter patient functioning, moderately increased doses appeared to have a palliative effect on patient mood and behavior, and the highest dose was detrimental to patient functioning. Bethanechol does not appear to ameliorate the dementia of AD, but may exert a mildly positive effect on patient behavior and mood.

Deep brain stimulation for essential tremor.

We examined the effects and safety of deep brain stimulation (DBS) as a treatment for essential tremor (ET). Ten ET patients with disabling medication-refractory tremor underwent stereotactic implantation of a DBS lead in the left Vim thalamic nucleus and completed a 6-month follow-up. The Clinical Tremor Rating Scale and disability assessments were performed at baseline, 1-, 3-, and 6-month follow-up. There were significant improvements in dressing, drinking, eating, bathing, and handwriting as reported by the subjects. Tremor severity, writing, pouring, and spiral and line drawing were significantly improved as rated by the examiner. Improvements persisted through the 6-month follow-up period. Although global disability significantly lessened in the group as a whole, one subject with hand-finger tremor accentuated by writing had no change in disability status. In this 6-month open-label study, DBS was effective and safe in reducing tremor and functional disability in ET.

Pallidotomy and bradykinesia: implications for basal ganglia function.

BACKGROUND AND OBJECTIVE: The scientific rationale for pallidotomy as a treatment for PD is that the lesion will reduce excessive tonic inhibition of the thalamus, thereby allowing movement to proceed more normally. If true, then PD patients who move slowly while on medication should increase movement speed following pallidotomy. To test this we used a simple motor task to determine if pallidotomy leads to an improvement in "on" motor performance when those movements are impaired before surgery. METHODS: Nine patients with PD performed elbow flexion movements "as fast as possible" while they were "on" before and 1 month after pallidotomy. Patients with mild PD and healthy control subjects were also tested. RESULTS: The clinical effects of pallidotomy were typical of those found in other studies. "Off" Unified Parkinson's Disease Rating Scale scores improved and dyskinesias were reduced. Although before surgery the patients were far slower while they were "on" than the groups of mild PD patients and healthy control subjects, there was no change in mean peak velocity while they were "on" after pallidotomy. There was no change in other mean "on" motor performance measures such as peak acceleration, peak deceleration, initiation time, and symmetry. There was a decrease in the variability of peak acceleration, symmetry, and initiation time. CONCLUSION: Despite the clinical efficacy of pallidotomy while patients were "off," bradykinesia of elbow flexion movements while patients were "on" is not affected by pallidotomy. Therefore, we conclude that the bradykinesia observed in this experiment is due to a mechanism other than excessive tonic inhibition of the motor thalamus. Our results are consistent with the idea that pallidotomy reduces the noise from the abnormally functioning basal ganglia.

Evaluation of cervical stimulation for chronic treatment of spasticity.

Electrical stimulation of the spinal cord (SCS) to reduce spasticity was evaluated in seven patients who, along with their physicians, perceived significant and prompt benefit from stimulation. In two 24-hour test periods, on or off stimulation, we used two independent methods of evaluation: quantitative measures of joint compliance and stretch reflexes, and a standardized neurologic examination. Neither method did better than chance in determining whether SCS was actually being received. Problems with the experimental protocol are discussed, but the results cannot be interpreted as supporting the efficacy of SCS as a treatment for spasticity.

United Parkinson Foundation Neurotransplantation Registry on adrenal medullary transplants: presurgical, and 1- and 2-year follow-up.

Thirteen centers participated in a multicenter database with systematic evaluation of US and Canadian patients who had adrenal medullary transplantation for Parkinson's disease. This voluntary registry collected demographic, safety, and efficacy data using the same scoring measures over a 2-year follow-up period. Baseline data on 61 patients and 2-year follow-up data on 56 patients were compared. Eighteen percent died during the study period, and one-half of these deaths were related or questionably related to the surgery. Of the remaining 45 patients with data, global improvement, defined as an improved summed score of the "on" and "off" motor and activities of daily living functions from the Unified Parkinson's Disease Rating Scale, occurred in 32% of the patients at 2 years after surgery. At follow-up, significant group improvement persisted in the amount of daily "on" time and the quality of "off" function, but other measures were no better than baseline. When the global improvement calculation was based on the total sample and included deaths and patients lost to follow-up as "not improved," only 19% were improved 2 years after surgery. Twenty-two percent of survivors had persistent psychiatric morbidity not present prior to surgery. These data document a modest group improvement in "off" function after neurotransplantation, but a serious level of mortality and morbidity.

Cortical biopsy results in Alzheimer's disease: correlation with cognitive deficits.

Neuropsychologic and pathologic data are presented for a group of 11 patients with a clinical diagnosis of probable Alzheimer's disease (AD) according to recently proposed criteria. In all cases, the diagnosis was verified by cortical biopsy. In addition, increased cortical plaque counts were associated with greater deficits in language production and comprehension and poorer performance on an index of global mental status. These results suggest that a clinical diagnosis of AD is very accurate when patient selection is restricted to typical cases and that language deficits may provide a useful indicator of severity of disease in AD patients.

Stereotactic pallidotomy for the treatment of Parkinson's disease. Efficacy and adverse effects at 6 months in 26 patients.

We evaluated the safety and efficacy of microelectrode-guided stereotactic pallidotomy in patients with advanced Parkinson's disease (PD). Using diagnostic criteria and evaluations outlined in the Core Assessment Programme in Transplantation (CAPIT) protocol, we studied unilateral pallidotomy in 26 patients with advanced idiophatic PD, motor fluctuations, and peak dose dyskinesias. All underwent unilateral stereotactic pallidotomy. Assessments conducted in the "practically defined off" and "best on" states at baseline and at 1 and 6 months postoperatively included Unified Parkinson's Disease Rating Scale (UPDRS) parts II, III, and IV and timed motor testing as outlined in CAPIT. Motor UPDRS in the "off" state improved at 1 and 6 months after surgery (p = 0.002, p = 0.008) Likewise, the sum of individual "off" contralateral motor UPDRS items improved (p = 0.0002, p = 0.0005). The duration (p = 0.0001 at 1 and p = 0.001 at 6 months) and severity (p = 0.003 at 1 and p = 0.0005 at 6 months) of dyskinesia improved, but other aspects of the "on" function were unchanged. Serious adverse effects occurred in eight patients and included one fatal deep and three nonfatal frontal lobe hemorrhages with resultant language or behavioral deficits. Nonhemorrhagic complications included one hemiparesis and three frontal lobe syndromes. Pallidotomy improves PD motor disability in the "off" state. Peak dose dyskinesias are reduced, although other aspects of "on" motor function are unchanged. Although morbidity may limit its use, pallidotomy is effective in targeting particular symptoms such as unremitting dyskinesia and severe "off" motor disability in advanced PD.

Adrenal medullary transplant to the striatum of patients with advanced Parkinson's disease: 1-year motor and psychomotor data.

We studied motor and psychomotor changes over 1 year after surgery in 7 patients with severe idiopathic Parkinson's disease (PD) who underwent intrastriatal autologous adrenal medulla transplant. Significant clinical improvements were present 1 year after surgery and primarily involved increased quantity of "on" time and increased quality of "off" time: "on" time increased from a mean 60.7% of the waking day to 82.7%, and "off" function improved. In contrast, although "on" function also improved, statistically significant improvement occurred in only 1 measure, the Unified Parkinson's Disease Rating Scale activities of daily living subscale. Medications did not change, and motor fluctuations persisted. Improvement began several weeks after surgery, was maximal at 4 to 6 months, and was sustained thereafter. There was significant group improvement in quality of life measures of sleep and rest, social isolation, and ambulation. One patient had severe, recurrent depression postoperatively. The efficacy of adrenal transplant surgery is not transient, and specific functional improvements can be prolonged.

Adverse effects associated with the intrathecal administration of ziconotide.

The omega-conopeptide, ziconotide, is an N-type calcium-channel blocker that has been shown to produce antinociception in animals using formalin and hot-plate tests. Initial reports of intrathecal administration of ziconotide in cancer and AIDS patients whose pain was unrelieved with opioids demonstrated analgesic efficacy. Although adverse effects were reported, these appeared to be easily managed through dose reduction or symptomatic treatment. This clinical report describes the experiences of three patients with serious adverse effects associated with intrathecal ziconotide.

Intrastriatal and intraventricular infusion of brain-derived neurotrophic factor in the cynomologous monkey: distribution, retrograde transport and co-localization with substantia nigra dopamine-containing neurons.

The distribution and retrograde transport of brain-derived neurotrophic factor was examined using magnetic resonance imaging guided stereotaxic intracerebroventricular and intrastriatal infusion in the cynomologous monkey. Two intracerebroventricular animals were infused with brain-derived neurotrophic factor at a dose of 3 micrograms/h for 21 and 28 days. A third intracerebroventricular animal received sequential infusions of 15, 30 and 60 micrograms/h brain-derived neurotrophic factor each for seven days using an Alzet 2002 minipump. For the multiple intrastriatal animals (n = 5) a dose of 3 micrograms/h was infused into each site. One intrastriatal monkey was infused with vehicle solution of 10 mM phosphate-buffered saline pH 7.4 for 14 days resulting in no brain-derived neurotrophic factor immunoreactivity. Following the lower dose intracerebroventricular infusion, brain-derived neurotrophic factor immunoreactivity was confined to the ventricular ependymal layer. In the sequential higher dose intracerebroventricular case, the cannula was located mainly within the lateral ventricle, although there was damage to the ependymal wall and adjacent caudate nucleus. Brain-derived neurotrophic factor immunoreactivity revealed spread of injectate within the ipsilateral and to a lesser extent the contralateral caudate nucleus, septum, orbital cortex and ventricular ependymal wall. In this case, retrogradely labelled brain-derived neurotrophic factor neurons were found within the parafascicular thalamus and substantia nigra, pars compacta, as well as within cortex, vertical limb of the diagonal band and nucleus basalis. Brain-derived neurotrophic factor intrastriatal infusion retrogradely labelled perikarya within sensory motor cortex, parafascicular thelamus and substantia nigra, pars compacta. Sections from these cases dual-immunoreacted for brain-derived neurotrophic factor and tyrosine hydroxylase, the synthesizing enzyme for dopamine, revealed a subpopulation of pars compacta dopaminergic neurons which contained retrogradely transported brain-derived neurotrophic factor. These findings indicate that a select subgroup of nigral dopamine neurons retrogradely transport brain-derived neurotrophic factor in the primate. Furthermore it remains to be determined whether select nigral cells are responsive to the trophic influences of brain-derived neurotrophic factor in the normal and neuropathologic condition.

Chronic access to endoneurial space using an arterial autograft.

A technique for direct chronic infusion of compounds onto peripheral axons has been investigated in the rat sciatic nerve. A 2 cm segment of the femoral artery was removed and one end inserted into the endoneurial space of the contralateral peroneal nerve fascicle of the same animal. The other end of the artery was connected to a catheter system to allow infusion into the endoneurium, thus bypassing the barrier that the perineurium presents to hydrophilic compounds. The patency of this arterial access system was evaluated by the ability of 20 microliters of 2% lidocaine to inhibit the toe-spreading reflex. The results of the study were that the infusion system remained operational for 3-7 days after transplantation. There were histologic changes in the nerve but there were no functional deficits due to the surgery. Although a long-term endoneurial infusion was not achieved, the limited access time to the axons might be long enough for applications such as the delivery of nerve growth factors to injured nerve.

An antibody in the CSF of Parkinson's disease patients disappears following adrenal medulla transplantation.

CSF from Parkinson's disease (PD) patients undergoing autologous transplantation of adrenal medulla tissue into their lateral ventricle was examined for the presence of IgG. CSF from 6 of 7 patients incubated with rat brain tissue reacted immunocytochemically to neuronal cell bodies in the substantia nigra and ventral tegmental region. This reactivity gradually disappeared in the months following transplantation. Five of 6 CSF samples from non-transplanted PD patients also produced this immunocytochemical reactivity whereas 26 non-PD samples were immunonegative. Possible implications to the transplant procedure are discussed.

Chronic cerebellar stimulation for cerebral palsy: a review.

Chronic cerebellar stimulation for cerebral palsy is a controversial procedure. It is difficult to evaluate objectively because cerebral palsy is not a single disease entity and the clinical syndrome may vary over time. Tests of neurophysiological function, signs of spasticity, and tests of motor function have documented changes, but double-blind evaluations have not. These studies are reviewed, as are the inherent problems in cerebellar stimulation and the physiology of cerebral palsy.

Cerebral edema and neurological function in human beings.

The assumption that cerebral edema necessarily results in neurological deficits was investigated with the computerized scan. Four cases are cited to demonstrate that normal function can be preserved in spite of marked focal edema. Quantitative analysis of the amount of edema showed a large increase in the local water content, while neural activity was apparently not adversely affected.

The brain as a sponge: a computed tomographic look at Hakim's hypothesis.

Hakim's hypothesis, which explains the brain's adaptation to pressure in hydrocephalus and the enlargement of ventricular volume, was studied with computed tomographic (CT) scanning. The critical element in the theory is that brain water decreases when there is a pressure gradient within brain tissue. Extraaxial hematomas uniformly increase the CT density of adjacent brain tissue, and this is best explained by water shifts out of the tissue. In hydrocephalus cases studied early after shunting (10 days or less), a decrease in ventricular volume is accompanied by an overall decrease in the CT density of the brain. These CT changes support Hakim's view of the brain as a sponge that can change its hydration under pathological conditions.