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.     

Cyclosporin A in Fat Emulsion Carriers: Experimental Studies on Pharmacokinetics and Tissue Distribution

Abstract: In the commercially available intravenous formulation of Cyclosporin A (Sandimmun®), polyoxyethylated castor oil (Cremophor®EL) is used as a solubilizing agent. We have recently reported that the acute nephrotoxic effect of this preparation was alleviated by replacing Cremophor®EL with a soybean oil-based fat emulsion in a rat model. To further explore the potential of fat emulsions as carriers for cyclosporin A, data on the in vivo pharmacokinetics and tissue distribution are required. In this study in pigs, the pharmacokinetics of soybean oil-cyclosporin A was compared to that of Sandimmun®. The two formulations seemed bioequivalent, as there were no significant differences in the systemic clearances, volumes of distribution or elimination half-lives. Moreover, the tissue distributions of soybean oil-cyclosporin A and Sandimmun® were compared in rats. These studies also included two additional lipid-based carriers: one based on iodized ester of poppy seed oil and the other on a liposomal preparation. The tissue distributions were found to be similar regardless of the carriers used. Fat emulsion carriers seem to offer possibilities for preparing better tolerated intravenous formulations of cyclosporin A while maintaining the same characteristics concerning pharmacokinetics and tissue distribution.     

Stabilization of an inserted tricalcium phosphate spacer enhances the healing of a segmental tibial defect in sheep

The effect of inserting a tricalcium phosphate (TCP) spacer stabilized by a rigid or non-rigid fixation technique on the healing of segmental tibial defects of critical size was established. The osteotomized tibiae, 11 with and 8 without TCP spacers, were fixed by an external circular device in 11 mature sheep and by plates in 8 mature sheep, respectively. Healing was evaluated roentgenographically 16 weeks after the operation. Compared with the defects without TCP spacers, enhanced stability and healing were observed in the defects with TCP spacers under an identical external fixation. Furthermore, a significantly higher incidence of healing was obtained with plate fixation than with external device fixation in the TCP-implanted defects (P < 0.04). An abundant bridging callus was roentgenograpically demonstrated in most of the healed defects, but none in the unhealed defects. The TCP spacer with its mechanical integrity enhances the stability of external fixation, and the stable immobilization provided by rigid fixation is essential for osteoconduction of an inserted TCP spacer in the healing of segmental diaphyseal defects in sheep.     

A method combining morphological, immunocytochemical and chromosomal examinations of the same cell in the study of lymphoproliferative diseases

6 cases of different lymphoproliferative diseases were studied with the new MAC (Morphology-Antibody-Chromosome) method in order to find out 1) if the abnormal karyotype is confined to the monoclonal cell population, 2) if there are, within this clone, also cells with a normal karyotype, and 3) if the method can help the pathologist to diagnose malignant lymphoproliferative diseases. The MAC method allows a simultaneous study in the same metaphase cell of the karyotype, surface markers, and some morphological features. In all cases in which a monoclonal cell proliferation was detected immunohistologically, the MAC examination showed a chromosomal abnormality for the same light chain as was detected in immunohistology, but not in other cells. In all but a single case, all mitotic cells belonging to the clonal cell proliferation had an abnormal karyotype. In this case with lambda clonality, 2/8 lambda-positive mitoses had a normal karyotype. However, all the normal mitoses occurred in small lymphocytes whereas the abnormal mitoses were seen in large blastic cells. In 1 case, the MAC method helped in confirming the diagnosis of malignant lymphoma (nodular small cleaved cell type). Especially in lymphomas composed of a mixed cell population, the MAC method makes it possible to find out which cell types have an abnormal karyotype and which have a normal karyotype.     

Development of heterotopic ossification around the hip. A long-term follow-up of patients who underwent surgery with two different types of endoprostheses

Heterotopic ossification has been reported in many pathological situations, most important clinically as a sequel to hip arthroplasty and spinal trauma. The etiology of heterotopic ossification is yet not clear, but the disease is supposed to be connected with trauma. Heterotopic bone was found in 53% (1.2% with the severe form) of 623 patients operated on at the Orthopaedic Hospital of the Invalid Foundation, Helsinki, Finland; the operations included 849 arthroplasties. The rate of heterotopic ossification was higher after revision arthroplasty, following operation of the contralateral side, in men, and in primary coxarthrosis, and the incidence was higher with the Brunswik (metal-on-plastic) endoprosthesis than in the McKee-Farrar type (metal-on-metal). Heterotopic bone formation generally seemed to increase and to be more manifest during long-term observation.     

Identification of single amino acid substitutions in the staphylococcal nuclease protein that enhance and diminish T cell clone recognition of naturally processed peptides.

It has been inferred that residue changes that affect T cell recognition of synthetic peptides will have a similar effect in the intact protein. However, since small peptides do not require antigen processing it is possible that residue changes in synthetic peptides will not have an equivalent effect in the intact protein. Mutant proteins of staphylococcal nuclease (Nase) and 15mer synthetic peptides with corresponding substitutions were compared to determine if residue changes within an immunodominant epitope have an effect on the generation of naturally processed peptides. Five different substitutions in the synthetic peptide resulted in loss of reactivity of individual Nase-specific clones. When the same single amino acid changes were made in the intact protein, the naturally-processed peptides were also unable to stimulate the Nase-specific clones. However, two other substitutions in the synthetic peptide were stimulatory for a T cell clone even though the same changes in the intact protein were non-stimulatory. These results suggest that certain residue changes affect recognition of the naturally processed peptide but not the synthetic peptide with the same amino acid change. In addition, these results demonstrate that the effects of amino acid substitutions in synthetic peptides on T cell recognition may not always reflect the effects of these substitutions in the intact protein. Substitutions located outside Nase-specific T cell epitopes were also examined. Thirty different mutant proteins were all stimulatory. Moreover, a number of these mutants proteins were 50- to 100-fold more efficient in their stimulatory capacity than the native Nase protein.(ABSTRACT TRUNCATED AT 250 WORDS)     

A demographic survey of leg and foot ulcer patients in a defined population.

By means of a questionnaire sent to all medical units in Malm?, including primary care, homes for the elderly, and industrial health clinics, 275 patients with leg and foot ulcers were identified. With a population of 232,908 in Malm?, this corresponds to a prevalence of 0.12%, which is lower than reported by others. Since the response rate was high (88% total, Primary Care: 100%), the prevalence of 0.12% is, however, believed to be real and might be explained by the urban area investigated, with easy access to care and proximity to one somatic hospital. 50% of the patients with leg and foot ulcers were treated in Primary Care, and 30% of the leg ulcer patients were treated at the Department of Dermatology. 88% of leg and foot ulcer patients were over 75 years of age. Median age was 79.5 years, with 80 for women and 76.5 for men. In Primary Care the median age was 82. There was a predominance of women in the study population with an overall sex ratio of 3:1. A higher proportion of patients living alone was found in Primary Care. The etiology of the ulcers was considered to be "unknown" or "other" or else no statement was given in 36% of the leg ulcer- and 22% of the foot ulcer patients. This might reflect an overall uncertainty about the underlying etiological cause. Medially and laterally located leg ulcers were reported equally often, but there was also a great proportion of wholly or partially circumferential ulcers. 76% of the foot ulcers were located on the toes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Low prevalence of abdominal aortic aneurysm in hypertensive patients. A population-based study

The prevalence of abdominal aortic aneurysms (AAA) was estimated by ultrasonography in hypertensives in the age group 50-70 years in geographically defined population. Only one case of AAA was found among 245 patients. This rather unexpected result implies a probability of less than 5% that the true prevalence of AAA is as high as 2% in hypertensives. Our population-based study indicates a lower prevalence than earlier studies based on necropsies and is an example of research cooperation between primary health care and specialized hospital care.     

Induction of long-term heart allograft survival in the rat by rabbit ATG

A rat model for induction of transplantation tolerance, by antithymocyte globulin (ATG) as sole immunosuppressive agent, was studied. Vascularized heart allografts were employed. The conditions for establishment of long-term surviving (LTS) grafts were investigated as well as some of the characteristics of the tolerant state. The tolerance-inducing effect of ATG was found to be reproducible and dose-dependent. Treatment before grafting was essential. Preimmunization of the recipient inhibited the tolerance induction, while thymectomy seemed to have the opposite effect. The differences in survival of second allografts, third party or syngeneic to the first, indicated a largely strain-specific tolerance that most probably was the result of a changed host reactivity and for its induction strictly depended on presence of the graft. There were microscopical signs of rejection in the LTS grafts, while almost no such changes could be found in second allografts from the same donor strain, transplanted to the LTS-bearing recipients.