Neonatal craniopharyngioma.
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Craniopharyngioma↗
Biomedical subjects
T B Freeman
Publications and source records attributed to T B Freeman.
Polymers, encapsulation, and artificial organs (report on session 26.0). Washington D.C., July 15, 1992.
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Alzheimer Disease↗
The X-gal caution in neural transplantation studies.
Cell transplantation into host brain requires a reliable cell marker to trace lineage and location of grafted cells in host tissue. The lacZ gene encodes the bacterial (E. coli) enzyme beta-galactosidase (beta-gal) and is commonly visualized as a blue intracellular precipitate following its incubation with a substrate, "X gal," in an oxidation reaction. LacZ is the "reporter gene" most commonly employed to follow gene expression in neural tissue or to track the fate of transplanted exogenous cells. If the reaction is not performed carefully-with adequate optimization and individualization of various parameters (e.g.. pH, concentration of reagents, addition of chelators, composition of fixatives) and the establishment of various controls--then misleading nonspecific background X-gal positivity can result, leading to the misidentification of cells. Some of this background results from endogenous nonbacterial beta-gal activity in discrete populations of neurons in the mammalian brain; some results from an excessive oxidation reaction. Surprisingly, few articles have empha sized how to recognize and to eliminate these potential confounding artifacts in order to maximize the utility and credibility of this histochemical technique as a cell marker. We briefly review the phenomenon in general, discuss a specific case that illustrates how an insufficiently scrutinized X-gal positivity can be a pitfall in cell transplantation studies, and then provide recommendations for optimizing the specificity and reliability of this histochemical reaction for discerning E. coli beta-gal activity.
Animals↗
Low-pressure aspiration abortion for obtaining embryonic and early gestational fetal tissue for research purposes.
Successful transplantation of cadaver embryonic neural tissue is highly dependent on the method used to obtain the tissue. It is important that the tissue not be contaminated bacteriologically by vaginal flora during the procedure, and that it not be disrupted mechanically. A low-pressure aspiration abortion technique has been developed that allows for the safe, effective obtainment of embryonic tissue and reduces the risk of transmitting infection. Tissue was cultured in vitro in 102 cases with minimal evidence of contamination by vaginal flora. Transplants of neural tissue into over 300 rodents have resulted in no intracranial abscesses, even in the setting of immunosuppression. The suction apparatus and low-pressure aspiration minimize disruption of the embryonic tissue. Use of low pressure adds no significant additional risk to the patient. In over 300 cases, there have been no medical complications specifically attributable to the technique. Because local anesthetic is used and sonography is not routinely required, the procedure can easily be performed in an outpatient setting during routine elective abortions, with minimal slowing or disruption of the clinic's surgical schedule. In conclusion, the low-pressure aspiration abortion technique can be safely and effectively used to obtain embryonic and early gestational fetal tissue that is almost always free from bacterial, fungal, and yeast contamination and that is frequently structurally intact. It requires no significant alteration in indications for abortion, risks, methodology, timing of the abortion, or patient management.
Abortion, Induced↗
Cyclosporine-A increases spontaneous and dopamine agonist-induced locomotor behavior in normal rats.
Cyclosporine-A (CsA) has been increasingly used as an immunosuppressant concomitant with neural transplantation treatment for different degenerative disorders. However, the possible role that CsA itself may have in the recovery of transplant patients is not known. Some investigators have argued that clinical improvement following transplantation (e.g., myoblast) may be confounded by CsA administration. The present study was conducted to delineate CsA-induced behavioral alterations. Four groups of normal 5-wk old Sprague-Dawley rats (n = 8 per group) were utilized in two separate experiments. In both experiments, two groups of animals were used; each group either received daily injections of 15 mg/kg of CsA or olive oil for 32 days (experiment 1) and 21 days (experiment 2). Animals in both experiments were subsequently tested for nocturnal locomotor behavior. Animals in experiment 2 were further tested in passive avoidance task, motor coordination, and amphetamine-induced locomotor activity. Results demonstrated that CsA-treated animals were significantly hyperactive compared to controls across the 12-h nocturnal activity periods and in amphetamine-induced locomotor activity. No significant differences between the CsA- and vehicle-treated animals were observed in passive avoidance or in motor coordination. Postmortem analyses of dopamine and its metabolites in the striatum and olfactory tubercle did not show any significant differences between the CsA- and the vehicle-treated groups. In summary, CsA significantly increased nocturnal spontaneous and amphetamine-induced locomotor behavior, but the neurochemical correlates for these effects need to be investigated. In addition, while the present study demonstrated that CsA induced motor alterations, any possible effects CsA may have on neurological or dystrophic patients with motor dysfunctions remain to be determined.
Animals↗
The influence of donor age on the survival of solid and suspension intraparenchymal human embryonic nigral grafts.
In many species, graft survival and graft-derived behavioral recovery are affected by the embryonic donor age. We compared the ability of solid and suspension grafts of human embryonic mesencephalic dopaminergic (DA) neurons at different embryonic stages to survive intraparenchymal transplantation into 6-OHDA lesioned immunosuppressed rats. Suspension grafts survived best when donor age was between postconception (PC) days 34 and 56. Transplants displayed numerous healthy tyrosine hydroxylase immunoreactive (TH-IR) neurons which sent extensive neuritic processes into the host striatum. Suspension grafts survived poorly when donor age was greater than 65 days. Solid implants displayed comparable viability of TH-IR neurons when donor age was between 44 and 65 days. No solid grafts contained TH-IR cells when donor tissue was older than 72 days. The suspension and solid methods of transplantation resulted in comparable survival of robust grafts, but solid grafts resulted in more intergraft variability than suspension grafts, particularly among the more marginal implants. Our results demonstrate that the upper limit for survival of human embryonic DA suspension grafts correlates well with the period of development of the human nigrostriatal pathway. The "window" for donor age of solid human embryonic DA grafts appears to be extended by about 9 days in comparison to suspension grafts. These data suggest that the upper age limit for grafting human mesencephalic DA neurons should be PC day 56 for suspension grafts, and PC day 65 for solid implants. Older donors are likely to produce grafts with fewer surviving DA neurons.
Age Factors↗
Development of the human striatum: implications for fetal striatal transplantation in the treatment of Huntington's disease.
Fetal neural transplantation has recently been demonstrated to ameliorate motor and other behavioral deficits in animals models of Huntington's disease, and reconstruct many of the damaged striatal circuits. However, there has been significant variability in the histological appearance of these grafts, most likely related to differences of the regions of dissection of the donor tissue. Selective dissection and transplantation of the lateral ventricular eminence in rodents has resulted in grafts consisting of primarily striatal-like tissue. This data, combined with data from our own and other laboratories has led to a description of the development of human striatum, with a particular emphasis on the relevance of human striatal development to the field of fetal tissue transplantation for the treatment of Huntington's disease. If the goal of transplantation is to graft GABAergic striatal projection neurons, it is our impression that optimal grafting results will occur when transplants are derived from the lateral ventricular eminence and the lateral aspect of the body of the ventricular eminence anterior to the foramen of Monro. Optimal results are likely to occur when donor ages range from Stage 19 to 23, with possible graft success when donor age extends to as late as postovulatory week 22.
Fetal Tissue Transplantation↗
Fetal grafting for Parkinson's disease: expression of immune markers in two patients with functional fetal nigral implants.
In a number of centers throughout the world, fetal nigral transplantation is being performed for the treatment of Parkinson's disease (PD). Clinical results have been inconsistent. One parameter that differs among transplant studies is the degree and manner by which patients are immunosuppressed following transplantation. Indeed, the role of the immune system following fetal grafting in humans is not well understood. Recently, two patients from our open label trial that received fetal nigral implants have come to autopsy. These patients were immunosuppressed with cyclosporin for 6 mo posttransplantation and survived for a total of 18 mo postgrafting. Robust survival of grafted dopamine-containing cells was observed in both cases. Immunostaining for HLA-DR revealed a dense collection of cells within grafts from both cases. HLA-DR staining was rarely observed within the host including nongrafted regions of the striatum. A more detailed analysis of immune markers was performed in Case 2. Numerous pan macrophages, T-cells, and B-cells were observed within graft sites located in the postcommissural putamen. In contrast, staining for these immune cells was not observed within the ungrafted anterior putamen. These findings suggest that even in healthy appearing functional nigral implants, grafts are invaded by host immune cells that could compromise their long-term viability and function. Alternatively, immune cells are known to secrete trophic factors, which may ultimately favor graft survival and function. Further work is needed to understand the role of the immune system in fetal grafting.
Antibody Specificity↗
Infectious issues in human fetal neural transplantation.
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Brain Tissue Transplantation↗
Microcarrier enhanced survival of human and rat fetal ventral mesencephalon cells implanted in the rat striatum.
The transplantation of tissue containing dopamine-producing cells into the mammalian central nervous system is an emerging treatment for Parkinson's disease, despite relatively poor survival of implanted tissue. Recent evidence has suggested that Cytodex microcarriers enhance the survival of dopaminergic rat chromaffin cells transplanted into the rat striatum in the absence of immunosuppression. The current study was undertaken to evaluate the survival of rat and human fetal ventral mesencephalic neurons (VM) implanted alone or after attachment to microcarriers in the striatum of rats without immunosuppression. Rat fetal VM neurons demonstrated enhanced survival in the rat striatum when transplanted on microcarriers, compared to their transplantation alone during the 3-mo period examined in the present study. Transplants of human fetal VM neurons on microcarriers also survived remarkably well in the rat striatum without systemic immunosuppression. In contrast, human fetal VM cells transplanted alone into the rat striatum did not survive without systemic immunosuppression. There was no evidence of TH fiber sprouting in the vicinity of any transplant site. These data indicated that Cytodex microcarriers provide enhanced survival of both rat allograft and human xenograft fetal mesencephalic cells in the rat striatum without the necessity of systemic immunosuppression, perhaps by inducing a unique neuron-glia environment.
Animals↗
Trophic effect of porcine Sertoli cells on rat and human ventral mesencephalic cells and hNT neurons in vitro.
The poor survival of embryonic dopaminergic (DA) neurons transplanted into patients with Parkinson's disease (PD) has encouraged researchers to search for new methods to affect the short- as well as long-term survival of these neurons after transplantation. In several previous rodent studies Sertoli cells increased survival of islet cells and chromaffin cells when cotransplanted in vivo. The aims of this study were to investigate whether porcine Sertoli cells had a positive effect on the survival and maturation of rat and human DA neurons, and whether the Sertoli cells had an effect on differentiation of neurons derived from a human teratocarcinoma cell line (hNT neurons). A significant increase of tyrosine hydroxylase (TH)-positive neurons of both rat and human ventral mesencephalic tissue was found when cocultured with Sertoli cells. Furthermore, there was a significantly increased soma size and neurite outgrowth of neurons in the coculture treated group. The Sertoli cell and hNT coculture also revealed an increased number of TH-positive cells. These results demonstrate that the wide variety of proteins and factors secreted by porcine Sertoli cells benefit the survival and maturation of embryonic DA neurons and suggest that cotransplantation of Sertoli cells and embryonic DA neurons may be useful for a cell transplantation therapy in PD.
Animals↗