Biomedical subjects

J Dinsmore

Publications and source records attributed to J Dinsmore.

24 records · Page 2Linked to original sources

PubMed1992

High-dose magnesium sulfate attenuates pulmonary oxygen toxicity.

BACKGROUND AND METHODS: Rats rapidly develop respiratory distress when exposed to 100% oxygen and die within a few days. Autopsy of the lung shows severe histologic damage characteristic of the adult respiratory distress syndrome. The purpose of this study was to evaluate the effects of magnesium sulfate loading in a rat model of acute oxygen toxicity. Thirty-four rats were divided into three groups. Group 1 (n = 18) served as a control (no magnesium therapy), while group 2 (n = 8) and group 3 (n = 8) received varying amounts of magnesium sulfate. All animals were exposed to 100% oxygen for 96 hrs or until death. Lung damage was quantitated by measuring the lung injury score on histologic examination. RESULTS: Administering magnesium sulfate in moderate doses at infrequent intervals to rats (group 2) resulted in less severe oxygen-induced lung damage than that which occurred in rats not receiving magnesium (control group). However, the difference was not statistically significant. Rats (group 3) given doses of magnesium sulfate in amount and frequency adequate to maintain a serum magnesium concentration recognized as therapeutic in eclampsia significantly reduced oxygen-induced lung damage. CONCLUSION: High-dose magnesium sulfate therapy can reduce lung injury caused by acute oxygen toxicity in rats.

Animals↗

PubMedDate not supplied

Porcine xenografts in Parkinson's disease and Huntington's disease patients: preliminary results.

The observation that fetal neurons are able to survive and function when transplanted into the adult brain fostered the development of cellular therapy as a promising approach to achieve neuronal replacement for treatment of diseases of the adult central nervous system. This approach has been demonstrated to be efficacious in patients with Parkinson's disease after transplantation of human fetal neurons. The use of human fetal tissue is limited by ethical, infectious, regulatory, and practical concerns. Other mammalian fetal neural tissue could serve as an alternative cell source. Pigs are a reasonable source of fetal neuronal tissue because of their brain size, large litters, and the extensive experience in rearing them in captivity under controlled conditions. In Phase I studies porcine fetal neural cells grafted unilaterally into Parkinson's disease (PD) and Huntington's disease (HD) patients are being evaluated for safety and efficacy. Clinical improvement of 19% has been observed in the Unified Parkinson's Disease Rating Scale "off" state scores in 10 PD patients assessed 12 months after unilateral striatal transplantation of 12 million fetal porcine ventral mesencephalic (VM) cells. Several patients have improved more than 30%. In a single autopsied PD patient some porcine fetal VM cells were observed to survive 7 months after transplantation. Twelve HD patients have shown a favorable safety profile and no change in total functional capacity score 1 year after unilateral striatal placement of up to 24 million fetal porcine striatal cells. Xenotransplantation of fetal porcine neurons is a promising approach to delivery of healthy neurons to the CNS. The major challenges to the successful use of xenogeneic fetal neuronal cells in neurodegenerative diseases appear to be minimizing immune-mediated rejection, management of the risk of xenotic (cross-species) infections, and the accurate assessment of clinical outcome of diseases that are slowly progressive.

Adult↗

PubMedDate not supplied

Extensive axonal and glial fiber growth from fetal porcine cortical xenografts in the adult rat cortex.

Axonal growth from cortically placed fetal neural transplants to subcortical targets in adult hosts has been difficult to demonstrate and is assumed to be minimal; however, experiments using xenogeneic neural grafts of either human or porcine fetal tissues into the adult rat striatum, mesencephalon, and spinal cord have demonstrated the capability for long-distance axonal growth. This study reports similar results for porcine cortical xenografts placed in the adult rat cerebral cortex and compares these findings with results from cortical allografts. Adult rats that previously received unilateral cortical lesions by an oblique intracortical stereotaxic injection of quinolinic acid, were implanted with suspensions of either E14 rat or E38 xenogeneic porcine fetal cortical cells. Xenografted rats were immunosuppressed by cyclosporin A. The corpus callosum was intact in all cases and grafts were confined to the overlying cortex. After a 31-34 wk posttransplant survival period, acetylcholinesterase (AChE) staining and tyrosine hydroxylase (TH) immunocytochemistry revealed that both allo- and xenografts received host afferents. Retrograde tracer injections into the ipsilateral striatum and cerebral peduncle in allografted animals failed to show any axonal growth to either subcortical target. Using a porcine-specific axonal marker in xenografted animals, we found graft axons in white matter tracts (corpus callosum, internal capsule, cingulum bundle, and medial forebrain bundle) and within the caudate-putamen and both the ipsilateral and contralateral cerebral cortex. Graft axons were not found in the thalamus, midbrain, or spinal cord. In addition, using an antibody to porcine glial fibers, we observed more extensive graft glial fiber growth into the same host fiber tracts, as far caudally as the cerebral peduncle, but not into gray matter targets outside the cortex. These results demonstrate that porcine cortical xenograft axons and glia can extend from lesioned cerebral cortex to cortical and subcortical targets in the adult rat brain. These findings are relevant for prospects of repairing cortical damage and obtaining functional recovery.

Acetylcholinesterase↗

PubMedDate not supplied

Embryonic stem cells differentiated in vitro as a novel source of cells for transplantation.

The controlled differentiation of mouse embryonic stem (ES) cells into near homogeneous populations of both neurons and skeletal muscle cells that can survive and function in vivo after transplantation is reported. We show that treatment of pluripotent ES cells with retinoic acid (RA) and dimethylsulfoxide (DMSO) induce differentiation of these cells into highly enriched populations of gamma-aminobutyric acid (GABA) expressing neurons and skeletal myoblasts, respectively. For neuronal differentiation, RA alone is sufficient to induce ES cells to differentiate into neuronal cells that show properties of postmitotic neurons both in vitro and in vivo. In vivo function of RA-induced neuronal cells was demonstrated by transplantation into the quinolinic acid lesioned striatum of rats (a rat model for Huntington's disease), where cells integrated and survived for up to 6 wk. The response of embryonic stem cells to DMSO to form muscle was less dramatic than that observed for RA. DMSO-induced ES cells formed mixed populations of muscle cells composed of cardiac, smooth, and skeletal muscle instead of homogeneous populations of a single muscle cell type. To determine whether the response of ES cells to DMSO induction could be further controlled, ES cells were stably transfected with a gene coding for the muscle-specific regulatory factor, MyoD. When induced with DMSO, ES cells constitutively expressing high levels of MyoD differentiated exclusively into skeletal myoblasts (no cardiac or smooth muscle cells) that fused to form myotubes capable of spontaneous contraction. Thus, the specific muscle cell type formed was controlled by the expression of MyoD. These results provided evidence that the specific cell type formed (whether it be muscle, neuronal, or other cell types) can be controlled in vitro. Further, these results demonstrated that ES cells can provide a source of multiple differentiated cell types that can be used for transplantation.

Animals↗

PubMedDate not supplied

Xenogeneic cell therapy: current progress and future developments in porcine cell transplantation.

The multitude of distinct cell types present in mature and developing tissues display unique physiologic characteristics. Cellular therapy is a novel technology with the promise of utilizing this diversity to treat a wide range of human degenerative diseases. Intractable diseases, disorders, and injuries are characterized by cell death or aberrant cellular function. Cell transplantation can replace diseased or lost tissue to provide restorative therapy for these conditions. The limited use of cell transplants as a basis for current therapy can, in part, be attributed to the lack of available human cells suitable for transplantation. This has prevented further realization of the promise of cell transplantation as a platform technology. Accordingly, cell-based therapies such as blood transfusions, for which the cells are readily available, are a standard part of current medical practice. Despite numerous attempts to expand primary human cells in tissue culture, current technological limitations of this approach in regard to proliferative capacity and maintenance of the differentiated phenotype has prevented their use for transplantation. Further, use of human stem cells for the derivation of specific cell types for transplantation is an area of future application with great potential, but hurdles remain in regard to deriving and sufficiently expanding these multipotential cells. Thus, it appears that primary cells are at present a superior source for transplantation. This review focuses on pigs as a source of a variety of primary cells to advance cell therapy to the clinic and implement achievement of its full potential. We outline the advantages and disadvantages of xenogeneic cell therapy while underscoring the utility of transplantable porcine cells for the treatment of human disease.

Animals↗

PubMedDate not supplied

Morris water maze analysis of 192-IgG-saporin-lesioned rats and porcine cholinergic transplants to the hippocampus.

Adults rats were lesioned with 192-IgG-saporin, an immunotoxin that targets cholinergic neurons in the basal forebrain expressing the low-affinity nerve growth factor receptor (p75). One month later, rats received E30-35 porcine cholinergic neurons bilaterally into the hippocampus, and were tested in the Morris water maze and the passive avoidance task 4.5-6 months after transplantation (in two experiments, rats were retested in the water maze) followed by histological and cellular analyses. The 192-IgG-saporin-lesioned animals displayed clear cognitive deficits in the Morris water maze. In all experiments the lesioned animals had spatial probe deficits on day 5 testing. A large variance was found among the transplanted animals, with individual animals exhibiting improved performance, but little overall improvement when compared to lesion-alone animals as a group. The relationships between behavioral performance and graft cholinergic factors were established by histological analyses. Grafted animals exhibited an increase in cholinergic innervation of the dentate gyrus (DG) region of the dorsal hippocampus when compared to lesion-alone animals. There was a significant correlation between the level of cholinergic innervation in the dentate gyrus and spatial navigation performance (latency and spatial probe) in the Morris water maze task. These data provide evidence of memory and spatial deficits following cholinergic denervation, and of target-specific growth of xenogeneic cholinergic neurons into the hippocampus. The lack of a clear treatment (transplant) effect in the behavioral measures leads us to believe that functional restoration of cognitive function would require cholinergic reinnervation of both the hippocampus and the neocortex in this 192-IgG-saporin animal model.

Acetylcholine↗