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Biomedical subjects

J R Sladek

Publications and source records attributed to J R Sladek.

At least 55 records · Page 3Linked to original sources
PubMed1989

Fetal research.

This article reviews some of the significant contributions of fetal research and fetal tissue research over the past 20 years. The benefits of fetal research include the development of vaccines, advances in prenatal diagnosis, detection of malformations, assessment of safe and effective medications, and the development of in utero surgical therapies. Fetal tissue research benefits vaccine development, assessment of risk factors and toxicity levels in drug production, development of cell lines, and provides a source of fetal cells for ongoing transplantation trials. Together, fetal research and fetal tissue research offer tremendous potential for the treatment of the fetus, neonate, and adult.

Cell Line↗
PubMed1989

Morphological, neurochemical, and behavioral characterizations associated with the combined treatment of diethyldithiocarbamate and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice.

Changes in striatal dopamine (DA) neurochemistry, tyrosine hydroxylase immunocytochemistry of DA fibers, and behavior following the combined administration of diethyldithiocarbamate (DDC) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mice were assessed. The combined treatment of DDC and MPTP produced a dose-dependent decrease in striatal DA levels and a dose-related increase in the striatal DOPAC:DA ratio. Cumulative doses of MPTP equal to or exceeding 53.0 (26.5 mg/kg x 2. i.p.), given in combination with DDC, were effective in reducing striatal DA levels to less than 25% of control levels 2 weeks after treatment. Tyrosine hydroxylase immunocytochemistry revealed large deafferentation of DA terminal regions in striatum, moderate reductions in nucleus accumbens and dendritic regions of substantia nigra, and slight reductions in the number of DA cell bodies in substantia nigra. Mice treated with DDC and MPTP became hyperactive during the light phase of their diurnal cycle: psychopharmacological data suggest that postsynaptic DA receptors were supersensitized following this treatment. These data provide evidence that the combined treatment of DDC and MPTP produces severe and enduring depletion of mesostriatal DA, and also concomitant behavioral changes in mice.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1989

Fetal hypothalamic transplants promote survival and functional regeneration of axotomized adult supraoptic magnocellular neurons.

This study investigated the mechanisms by which fetal hypothalamic transplants promote functional recovery in neurohypophysectomized rats. Seven days after neurohypophysectomy (resulting in urine osmolalities of about 800 mOsm), young adult male Long-Evans rats received either fetal hypothalamic grafts (n = 10) or sham transplants (n = 7). Recovery from the lesioned-induced diabetes insipidus was monitored for 6 months and then the transplant sites were evaluated by immunocytochemistry. Surviving host supraoptic magnocellular neurons and neurophysin-positive grafted neurons were counted and their formation of neurohemal contacts evaluated by retrograde transport of systemically injected horseradish peroxidase (HRP). There were significantly more surviving supraoptic magnocellular neurons in neurohypophysectomized animals with median eminence-placed grafts (2236 +/- 261 neurons/animal) than in animals with ectopic tissue grafts (895 +/- 142 neurons/animal) or sham implants (1052 +/- 92 neurons/animal). Almost all surviving host magnocellular neurons were labeled with retrogradely transported HRP while virtually none of the grafted neurophysin positive cells showed evidence of HRP uptake. The degree of functional recovery was directly correlated with the increased survival of host neurons. By 8 weeks post-transplantation, animals with median eminence-placed grafts had recovered from their diabetes insipidus and could concentrate their urine to within normal limits (2,120 +/- 110 mOsm). This recovery was stable for the remainder of the 6 month test period. In contrast, animals with ectopic grafts and sham transplants had permanent deficits in fluid regulation. Our results provide evidence for the long-term capacity of fetal neural tissue implants to rescue host neurons from the cell death that typically occurs in the mature central nervous system after axotomy.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Postmortem analysis of adrenal-medulla-to-caudate autograft in a patient with Parkinson's disease.

A 53-year-old physician who had a 10-year history of progressive idiopathic parkinsonism survived for 4 months after an autologous adrenal-medulla-to-right-caudate autograft but he received little clinical benefit. A small number of chromaffin cells in the graft site survived; they expressed neurofilament proteins and chromogranin A, but scant tyrosine hydroxylase. The striatum on both sides showed almost complete loss of [3H]mazindol binding to dopamine-uptake sites; the density of dopamine receptors was decreased adjacent to the transplant but increased rostral to the transplant. These results demonstrate that autografted chromaffin cells can survive for 4 months after transplantation and that related changes in dopamine receptors can be quantified.

Adrenal Medulla↗
PubMed1989

Simultaneous catecholamine histofluorescence and thymidine autoradiography of the sexually dimorphic nucleus of the preoptic area in the rat.

The sexually dimorphic nucleus of the preoptic area (SDN-POA) in the rat represents a morphological substrate in which the influence of gonadal hormones on the process of sexual differentiation of the brain can be seen. Since the medial preoptic area (MPO) is a region rich in catecholamine (CA) terminals, it is possible that catecholamines may play a role either in the differentiation of the perinatal SDN-POA or in the function of this nucleus in the adult. It is not known whether catecholamine terminals exist within the SDN-POA or whether they can directly influence the activity of SDN-POA neurons. The present study was conducted to determine the extent to which catecholamines innervate this nucleus and further to elucidate the possibility of a potential sexual dimorphism in the innervation pattern. In order to determine which of the neurons in the MPO are within the SDN-POA we have utilized the fact that the SDN-POA has a prolonged period of neurogenesis in comparison to other neurons of the MPO. Thus, tritiated thymidine-labeled neurons can be used as a detection criterion for the SDN-POA. To conduct this experiment, timed pregnant Sprague-Dawley females were given a single injection of [3H]thymidine on Day 18 of gestation. Pups were killed as adults and prepared for fluorescence histochemistry of monoamines. Sections adjacent to those examined for catecholamine fluorescence were treated for autoradiographic localization of [3H]thymidine. Fluorescence innervation patterns were plotted within the boundaries of the nucleus following its identification from Nissl sections as well as from adjacent autoradiograms simultaneously viewed in a comparator bridge microscope with dark-field illumination.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Symptomatic and asymptomatic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates: biochemical changes in striatal regions.

Administration of the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, to primates produces an excellent behavioral model of idiopathic Parkinson's disease. In the vervet monkey, regional biochemical differences in the striatum of two 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated groups were examined one to two months after treatment and compared with controls; one group displayed no observable gross motor abnormalities after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment (asymptomatic), whereas the other group became markedly parkinsonian (symptomatic). In both 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated groups massive depletions of dopamine and homovanillic acid concentrations were observed in the striatum; generally, dopamine losses in the symptomatic group (greater than 95%) were greater than in the asymptomatic group (greater than 75%). However, in striatum, a marked heterogeneity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine susceptibility was found; certain striatal regions having 99% depletion of dopamine even in asymptomatic monkeys. Overall, in ventromedial regions of striatum the losses of dopamine and homovanillic acid concentrations were less than in dorsolateral regions at the same coronal level. There was a significant negative correlation between control homovanillic acid/dopamine ratios and susceptibility of examined regions to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity. Unlike idiopathic, but similar to postencephalitic, Parkinson's disease, dopamine and homovanillic acid levels in caudate nucleus were not spared relative to putamen; in fact, in the asymptomatic group caudate nucleus dopamine and homovanillic acid concentrations were depleted to a greater extent than in putamen.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Cryopreservation, culture, and transplantation of human fetal mesencephalic tissue into monkeys.

Studies in animals suggest that fetal neural grafts might restore lost neurological function in Parkinson's disease. In monkeys, such grafts survive for many months and reverse signs of parkinsonism, without attendant graft rejection. The successful and reliable application of a similar transplantation procedure to human patients, however, will require neural tissue obtained from human fetal cadavers, with demonstrated cellular identity, viability, and biological safety. In this report, human fetal neural tissue was successfully grafted into the brains of monkeys. Neural tissue was collected from human fetal cadavers after 9 to 12 weeks of gestation and cryopreserved in liquid nitrogen. Viability after up to 2 months of storage was demonstrated by cell culture and by transplantation into monkeys. Cryopreservation and storage of human fetal neural tissue would allow formation of a tissue bank. The stored cells could then be specifically tested to assure their cellular identity, viability, and bacteriological and virological safety before clinical use. The capacity to collect and maintain viable human fetal neural tissue would also facilitate research efforts to understand the development and function of the human brain and provide opportunities to study neurological diseases.

Animals↗
PubMed1988

Tyrosine hydroxylase-immunoreactive somata within the primate subfornical organ: species specificity.

The present study describes a collection of tyrosine hydroxylase-immunoreactive (TH-ir) somata within the subfornical organ (SFO) of the Cebus monkey. In contrast, no cell bodies, and only sparse TH-ir fibers, were observed within the SFO in rats. In the monkey, these TH-ir neurons were observed throughout the rostrocaudal extent of the SFO, preferentially located at its lateral and dorsal aspects. These neurons were bipolar and multipolar with long, beaded, varicose fibers emanating from the cell soma. Cebus monkeys displayed dopamine beta hydroxylase and phenylethanolamine-N-methyltransferase- immunoreactive neurons within established noradrenergic and adrenergic nuclei respectively, but not within the SFO, suggesting that the neurons which are immunoreactive for TH in this region contain dopamine.

Animals↗
PubMed1988

Transplantation of norepinephrine neurons into aged rats improves performance of a learned task.

A reproducible behavioral correlate of aging in rodents is deficient performance of inhibitory avoidance memory tasks. Impaired performance has been attributed, in part, to age-related changes in brain norepinephrine (NE) system function. To determine whether supplementation of brain NE can ameliorate avoidance deficits in aged animals, we transplanted noradrenergic locus coeruleus neurons from fetal rat donors into the third cerebral ventricle of 24-month-old male F344 rats. Aged rats that received NE-containing grafts exhibited significant improvement of inhibitory avoidance retention performance compared to both unoperated aged animals and aged animals that received grafts of cerebellar tissue. Improved behavioral performance was prevented by pretreatment of NE graft recipients with the beta-adrenergic receptor blocking agent, propranolol, and was mimicked by chronic intraventricular infusion of NE. Taken together, our findings support the view that age-related declines in brain NE content contribute to age-related deficits in inhibitory avoidance performance, and that NE replacement therapy can improve performance of this task in aged rats.

Aging↗
PubMed1988

Transplantation of male mouse submaxillary gland increases survival of axotomized basal forebrain neurons.

Transection of the fimbria-fornix results in a loss of magnocellular neurons in the medial septum and vertical limb of the diagonal band (MS/VDB), possibly due to the deprivation of a retrogradely transported trophic substance, such as nerve growth factor (NGF), derived from the hippocampal formation. We have utilized a transplantation model in which grafts of NGF-rich male mouse submaxillary gland were placed in the lateral ventricle adjacent to the MS/VDB of rats with transections of the fimbria-fornix. At 2-4 weeks following transection, animals with grafted submaxillary glands exhibited enhanced survival of MS/VDB neurons, which stained positive for acetylcholinesterase and were immunoreactive for the NGF receptor. These experiments demonstrate that grafts of male mouse submaxillary gland can facilitate the survival of axotomized MS/VDB cholinergic neurons and may therefore prove beneficial in promoting regeneration of damaged neural systems.

Animals↗
PubMed1988

Nerve-cell grafting in Parkinson's disease.

The successful utilization of fetal nerve-cell grafts as therapeutic tools in animal models of neurodegenerative disease has prompted the first clinical attempts in parkinsonian patients in at least three countries. The extensive scientific data in rodents coupled with the first successful fetal neural grafts in monkeys with experimental parkinsonism suggest that consideration might now be given to clinical applications. Attention is also directed to the various types of donor cells that might be utilized in clinical trials for the treatment of parkinsonism, including potential benefits, risks, and limitations associated with each type of donor material. This review highlights major developments in this field as they relate to basic principles of neural grafting and discusses potential applications in humans.

Animals↗