Human fetal dopamine neurons grafted into the striatum in two patients with severe Parkinson's disease. A detailed account of methodology and a 6-month follow-up

By using stereotaxic surgical techniques, ventral mesencephalic tissues from aborted human fetuses of 8 to 10 weeks' gestational age were implanted unilaterally into the striata in two patients with advanced Parkinson's disease. The patients were treated with a cyclosporine, azathioprine, and steroid regimen to minimize the risk for graft rejection. They were examined for 6 months preoperatively and 6 months postoperatively and continued to receive the same doses of antiparkinsonian medication. There were no significant postoperative complications. No major therapeutic effect from the operation was observed. However, in the clinical tests, both patients showed small but significant increases of movement speed for repeated pronation-supination, fist clenching, and foot lifting. The rate of walking also increased in the one patient tested. For both patients, there was an initial worsening postoperatively, followed by improvement vs preoperative performance at 1 to 3 months. Both patients also showed significant improvement in the magnitude of response to a single dose of levodopa (L-dopa), but there was no increase in the duration of drug action. The motor readiness potential increased in both patients postoperatively, primarily over the operated hemisphere. Neurophysiological measurements also showed a more rapid performance of simple and complex arm and hand movements on the side contralateral to transplantation in one patient at 5 months postoperatively. Positron emission tomography demonstrated no increased uptake of 6-L-(18F)-fluorodopa in the transplanted striatum at 5 and 6 months. Taken together, these results suggest that the fetal nigral implants may have provided a modest improvement in motor function, consistent with the presence of small surviving grafts. Although our results support further scientific experimentation with transplantation in Parkinson's disease, widespread clinical trials with this procedure are probably not warranted at this time.     

Transplantation of human embryonic retina to adult rat retina

Human embryonic retinas (postconceptional age 3-10 weeks) with or without retinal pigment epithelium were grafted to the retina of immuno-suppressed adult rat hosts. The development of the xenografts was followed up to 37 weeks of total age by histology and by immunohistochemistry for S-antigen. The donor tissue became rearranged in folded sheets with rosettes. The grafts developed approximately according to their intrinsic timetable, but with a developmental delay in the later stages. Occasionally, the grafts were well fused with the host retina. At 13 weeks of total age, the grafts contained areas of inner plexiform layer with presumptive ganglion cells, one neuroblastic layer, and cone precursor cells around rosettes. At 19 weeks, an outer plexiform layer and inner segments of the cones started to form. At 20 weeks, the first immunoreactivity for S-antigen was observed in photoreceptor precursors. Cone inner segments were clearly distinguishable at 28 weeks, and more S-antigen-positive rods were seen. At 31 weeks, rods were more differentiated, showing S-antigen-positive inner and outer segments. An inner limiting membrane with an apparent ganglion cell layer was only seen in one cograft of retina and retinal pigment epithelium at 37 weeks, indicating an important role of retinal pigment epithelium for graft differentiation. This study shows that human embryonic retina can be grafted to immuno-suppressed adult rat retina with long-term survival. A high degree of maturation can be obtained in the grafted tissue comparable to the layering of newborn human retina. It appears that most cell types develop. This model opens up possibilities for studying human retinal development with the goal of reaching a treatment for human degenerative retinal disorders.     

Impotence, smoking, and beta-blocking drugs.

Four patients complaining of erectile dysfunction and using tobacco or propranolol were examined with penile blood pressure measurements and Doppler recordings, calculating the penile acceleration ratio (PAR). After a change in regimen, erectile capacity was restored, PAR returned to normal, and blood pressure measurements revealed increased systolic penile blood pressure in three patients. The changes, especially in PAR, indicate a marked penile vascular reaction during smoking and beta-blocking treatment in these men.     

Direct-vision chorionic villi biopsy for prenatal diagnosis in the first trimester

A technique for chorionic biopsy under direct vision has been developed. It involves the transcervical insertion of a fetoscope into the extraamniotic space during continuous saline infusion. With this technique, not only is contamination with maternal tissue easily avoided, but it is even possible to select by direct vision just those villi considered most suitable for cultivation in vitro--i.e., villi rich in blood vessels and with an abundance of surface buds. As of November 1983 the technique had been used for diagnosis in 21 cases. In 19 pregnancies allowed to continue after sampling there was one fetal loss, and one woman gave birth to a healthy infant in the 39th week.     

Bilateral fetal mesencephalic grafting in two patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)

BACKGROUND. Intracerebral transplantation of fetal dopaminergic neurons is a promising new approach for the treatment of Parkinson's disease. Patients with parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) have a relatively stable lesion limited to the nigrostriatal system, rendering them ideal candidates for transplantation. Improvement of motor function after neural grafting has previously been observed in nonhuman primates with MPTP-induced parkinsonism. METHODS. We grafted human fetal tissue from the ventral mesencephalon (obtained six to eight weeks after conception) bilaterally to the caudate and putamen in two immunosuppressed patients with severe MPTP-induced parkinsonism, using a stereotaxic technique. The patients were assessed regularly with clinical rating scales, timed tests of motor performance, and [18F]fluorodopa positron-emission tomography during the 18 months before the operation and the 22 to 24 months after the operation. RESULTS. Both patients had substantial, sustained improvement in motor function and became much more independent. Postoperatively, the second patient's maintenance dose of levodopa was decreased to 150 mg daily, which was 30 percent of the original dose. Striatal uptake of fluorodopa was unchanged 5 to 6 months postoperatively but was markedly and bilaterally increased at 12 to 13 and 22 to 24 months in both patients, closely paralleling the patients' clinical improvement. There were no serious complications. CONCLUSIONS. Bilateral implantation of fetal mesencephalic tissue can induce substantial long-term functional improvement in patients with parkinsonism and severe dopamine depletion and is accompanied by increased uptake of fluorodopa by the striatum. The results in these patients resemble those obtained in MPTP-treated primates and suggest that this will be a useful model for the assessment of transplantation therapies in Parkinson's disease.