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Biomedical subjects

L Olson

Publications and source records attributed to L Olson.

At least 253 records · Page 14Linked to original sources
PubMed1990

Emulation of seizure induced brain damage in neural tissue transplants to the anterior chamber of the eye.

We have developed a model system in which the mechanisms of neuronal damage due to hyperexcitation can be studied in isolation and where extended observation periods can be used. Substantia nigra pars reticulata (SNPR) develops a hypermetabolic necrosis following status epilepticus (Nevander et al. 1985; Auer et al. 1986). We transplanted rat fetal nigral area alone or together with fetal frontal neocortex to the anterior chamber of the eye in adult rats. Following 3 months of transplant maturation the hosts were subjected to status epilepticus for 60 min. In single nigral transplants no sign of structural damage was found. In the double transplants of frontal cortex and the substantia nigra a tissue necrosis had developed in the nigral part. This was demonstrated by a total loss of glial fibrillary acidic protein (GFA) immunoreactivity within a circumscribed necrotic region in the nigral part of the double transplant. Such a loss of GFA immunofluorescence had also developed in the host SNPR, as we have earlier shown (Eriksdotter-Nilsson et al. 1987). Thus, intraocular brain tissue transplants provide a unique model for studies on the development of neuronal damage and functional dependence between different neuronal structures for the development of such damage.

Animals↗
PubMed1990

Truncated IGF-1 exerts trophic effects on fetal brain tissue grafts.

Truncated IGF-1 (tIGF-1), a form of IGF-1 identified in the human brain, has been suggested, from in vitro experiments, to exert neurotrophic effects on developing fetal brain tissue. We studied the effects of tIGF-1 and IGF-1 on small defined areas of the developing central nervous system by using the in vivo model of intraocular transplantation which allows for direct observations of graft survival and growth. Truncated IGF-1 was found to significantly enhance the growth of fetal spinal cord (Embryonic Day (E) 14) and parietal cortex (E16-17) grafts transplanted to the anterior chamber of the eye of adult rats. tIGF-1 increased the volume of cerebral cortex grafts by approximately 100% and of E14 spinal cord grafts by approximately 50%. E18 spinal cord grafts and hippocampal grafts were not stimulated by tIGF-1 as compared to controls given HSA. Effects in cortex were seen with tIGF-1 using concentrations down to at least 10 ng/microliters. Interestingly, intact IGF-1 had no effect on cortical grafts. These findings show for the first time, using an in vivo system, that tIGF-1 is a potent stimulator of growth of grafted fetal cortex cerebri and spinal cord and suggest a possible role for endogenous tIGF-1 in cortical and spinal cord development.

Animals↗
PubMed1990

Localization of brain-derived neurotrophic factor mRNA to neurons in the brain by in situ hybridization.

Brain-derived neurotrophic factor (BDNF) which supports survival of and fiber outgrowth from sensory neurons and retinal ganglion cells has recently been cloned. It is closely related to nerve growth factor (NGF), which we had demonstrated earlier by in situ hybridization to be expressed in the brain by cholinergic target neurons. Using oligonucleotide probes we now describe aspects of the distribution of BDNF mRNA in the adult pig and rat brain. Similar to NGF, BDNF expression in vivo in the central nervous system appeared to be mostly confined to neurons. In the hippocampal formation, strongly labeled neurons were found in and around the pyramidal layer, as well as in the granular layer and the hilus of the dentate gyrus of both pig and rat. Other neurons in these areas were more weakly labeled or unlabeled. High BDNF expression was also shown in scattered neurons in cortex cerebri, in many neurons in claustrum and in certain other areas. These results demonstrate that the similarity in structure between NGF and BDNF is paralleled by a similarity in cellular expression, suggesting that BDNF, like NGF, may act via a direct neuron-to-neuron interaction. It is possible that some neurons, for example, in the hippocampal formation, express both NGF and BDNF. Finally, the localization of BDNF expression in cortical areas and in claustrum suggests that the target neurons for this factor extend beyond the sensory ganglion and retinal ganglion cells.

Animals↗
PubMed1990

Behavioral and electrophysiological correlates of human mesencephalic dopaminergic xenograft function in the rat striatum.

While human fetal xenografts placed into immunocompromised animal hosts have been shown to survive and grow, their ability to function and influence the host tissue has not been fully examined. Therefore, we implanted grafts of human fetal mesencephalic tissue intracranially into rats with unilateral 6-hydroxydopamine lesions of their nigrostriatal dopaminergic innervation and tested the rats behaviorally for reductions in apomorphine-induced rotations. The purpose of this study was to test the ability of these grafts to provide a functional reinnervation by comparing the behavioral changes with the morphology and presence of electrophysiologically active dopaminergic neurons within the graft and with firing rates of host striatal neurons. Adult Sprague-Dawley rats that had been unilaterally lesioned and that showed a stable two peak pattern of apomorphine-induced rotations received grafts of human fetal mesencephalic tissue placed directly into the lesioned striatum. These rats were then further tested each month for five months for reductions in their turning behavior. At 5 to 6 months postgrafting, electrophysiological recordings were made of cells within the graft and within the host striatum. The rats were then examined immunohistochemically to evaluate graft survival and extent of reinnervation of the host tissue. The rats receiving mesencephalic dopaminergic grafts demonstrated a 79% reduction in their apomorphine-induced rotations. Electrophysiological recordings revealed spontaneously active dopaminergic neurons within the graft as well as host striatal cell firing rates consistent with those of dopamine-innervated cells. Furthermore, immunohistochemical studies confirmed graft survival and revealed marked fiber outgrowth from the graft into and throughout the striatum. Taken together these findings provide evidence that grafts of human fetal mesencephalic tissue are able to produce behavioral improvements in lesioned animals which are associated with the presence of dopaminergic neurons within the graft and are consistent with normal host striatal cell activity levels.

Animals↗
PubMed1990

Identification of cells in rat brain and peripheral tissues expressing mRNA for members of the nerve growth factor family.

Cells expressing mRNA for hippocampus-derived neurotrophic factor (HDNF/NT-3) or brain-derived neurotrophic factor (BDNF) were identified by in situ hybridization. In the rat brain, HDNF mRNA was predominantly found in pyramidal neurons in CA1 and CA2 of the hippocampus. Lower levels of HDNF mRNA were found in granular neurons of the dentate gyrus and in neurons of the taenia tecta and induseum griseum. BDNF mRNA-expressing cells were more widely distributed in the rat brain, with high levels in neurons of CA2, CA3, and the hilar region of the dentate gyrus, in the external and internal pyramidal layers of the cerebral cortex, in the claustrum, and in one brainstem structure. Lower levels were seen in CA1 and in the granular layer of the hippocampus, in the taenia tecta, and in the mammillary complex. In peripheral tissues, HDNF mRNA was found in glomerular cells in the kidney, secretory cells in the male rat submandibular gland, and epithelial cells in secondary and tertiary follicles in the ovary. Cells expressing BDNF mRNA were found in the dorsal root ganglia, where neurons of various sizes were labeled.

Animals↗
PubMed1990

Molecular cloning and neurotrophic activities of a protein with structural similarities to nerve growth factor: developmental and topographical expression in the brain.

We have used a pool of degenerate oligonucleotides representing all possible codons in regions of homology between brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) to prime rat hippocampal cDNAs in the polymerase chain reaction. The amplified DNA included a product with significant similarity to NGF and BDNF, which was used to isolate a 1020-nucleotide-long cDNA from a rat hippocampal library. From the nucleotide sequence, a 282-amino-acid-long protein with approximately 45% amino acid similarity to both pig BDNF and rat NGF was deduced. In the adult brain, the mRNA for this protein was predominantly expressed in hippocampus, where it was confined to a subset of pyramidal and granular neurons. The developmental expression in brain showed a clear peak shortly after birth, 1 and 2 weeks earlier than maximal expression of BDNF and NGF, respectively. It was also expressed in several peripheral tissues with the highest level in kidney. The protein, transiently expressed in COS cells, was tested on chicken embryonic neurons and readily stimulated fiber outgrowth from explanted Remak's ganglion and, to a lesser extent, the nodose ganglion. A weak, but consistent, fiber outgrowth response was also seen in the ciliary ganglion and in paravertebral sympathetic ganglia. Moreover, the protein displaced binding of NGF to its receptor, suggesting that it can interact with the NGF receptor. Thus, this factor, although structurally and functionally related to NGF and BDNF, has unique biological activities and represents a member of a family of neurotrophic factors that may cooperate to support the development and maintenance of the vertebrate nervous system.

Aging↗
PubMed1990

Plant-derived neurotoxic amino acids (beta-N-oxalylamino-L-alanine and beta-N-methylamino-L-alanine): effects on central monoamine neurons.

In the present study the subacute effects of beta-N-oxalylamino-L-alanine (BOAA) and beta-N-methylamino-L-alanine (BMAA) on CNS monoamine neurons in rats were investigated following intracisternal injections or local intracerebral administration into substantia nigra. In vitro effects of BOAA and BMAA on high-affinity synaptosomal uptake of dopamine (DA), noradrenaline (NA), and serotonin (5-HT) were also examined. Intracisternal administration of BMAA decreased NA levels in hypothalamus, whereas no effects were seen on DA or 5-HT levels. Following intranigral injections of BOAA, NA levels tended to decrease in several regions, whereas the DA levels and the levels of DA metabolites were unaffected in all regions analyzed. Loss of tyrosine hydroxylase (TH) immunoreactivity in the intranigral injection sites and the presence of TH-immunoreactive pyknotic neurons near the borders of the injection sites were observed following both BOAA and BMAA treatments. Furthermore, substance P-immunoreactive terminals in substantia nigra pars reticulata were also found to have disappeared within the lesioned area following either BOAA or BMAA injections. Incubations with both BOAA and BMAA (10(-5) M) reduced high-affinity [3H]NA uptake in cortical synaptosomes to 69% and 41% of controls, respectively, whereas the striatal high-affinity [3H]DA uptake and the cortical high-affinity [3H]5-HT uptake were unaffected by BOAA or BMAA. The results demonstrate that both BOAA and BMAA can affect central monoamine neurons, although the potency and specificity of these substances on monoamine neurons when administered acutely into cerebral tissue or liquor cerebri seem to be low. However, the in vitro studies indicate selective effects of both compounds on NA neurons in synaptosomal preparations.

Alanine↗
PubMed1990

Grafts and growth factors in CNS. Basic science with clinical promise.

In 1979, we presented the first evidence that grafts of fetal brain tissue to the adult central nervous system could counteract an experimentally induced neurological deficit. Using the unilaterally dopamine-denervated rat model of Parkinson's disease, it was first shown that fetal substantia nigra grafts were effective and, later, that adult adrenal medullary chromaffin tissue might be used as a possible substitute for fetal brain tissue. These observations led to the first clinical trials with chromaffin autografting in severe cases of Parkinson's disease, which were initiated at the Karolinska Hospital in 1982, and several years later to clinical trials with grafts of fetal dopamine neuroblasts obtained after early elective abortions. In parallel with the ongoing intense basic research aimed at optimizing grafting procedures and finding new possible clinical applications, there are now worldwide clinical trials of grafting procedures involving a large number of neurosurgical centers and a large number of patients. Here, I shall review our recent studies of grafts and growth factors as they relate to possible new therapeutic principles applicable not only to Parkinson's disease, but also to Alzheimer's senile dementia and possibly to spinal cord injury and other afflictions. Recent evidence suggests that cholinergic neurons in the brain, known to degenerate in Alzheimer's disease, depend on nerve growth factor. In one approach we have grafted genetically modified cell lines, designed to secrete large amounts of nerve growth factor, and demonstrated that they can rescue lesioned cholinergic neurons that would otherwise die. Nerve growth factor can also serve to enhance survival of, and promote fiber formation by, chromaffin grafts in experimental parkinsonism. Interestingly, a series of other growth factors, such as IGF-1, bFGF, aFGF, BDNF, TGF's, as well as their receptors, are now being cloned and in several cases shown to have interesting temporal and regional distributions as well as effects in the central nervous system. Our own studies using intraocular grafts suggest potent effects on fetal brain tissue growth of truncated IGF-1, bFGF, and aFGF. It thus appears as if neurosurgery is on the verge of entering a new era in which repair in the adult brain and spinal cord, once thought impossible in mammals, will become possible using growth factors and grafts.

Adrenal Medulla↗
PubMed1990

Health education in medical group practices: promoting health or business?

This article attempts to explain differences in the health education activities of medical group practices. Potential explanatory factors examined include: providing prepaid care, group ownership, group size, and specialty composition and mechanism for making group policy. The data used in this analysis were collected by the American Medical Association through the 1986 National Survey of Medical Groups. Results indicate that the conduct of a variety of health education activities was determined primarily by the group's policy mechanism. That groups with more formal policy mechanisms are more likely to conduct health education activities suggests that the provision of health education is a business decision rather than a medical one. Some implications for health educators of the use of health education to promote a practice are discussed.

Group Practice↗
PubMed1990

Toxic effects of lead on neuronal development and function.

The effects of lead on the development of the nervous system are of immediate concern to human health. While it is clear that lead can affect neuronal development at levels of exposure within the range found in the environment, the particular mechanism of the disruption is not readily ascertained. Lack of knowledge of the mechanisms of lead-induced damaged hampers its treatment and prevention. The goal of our research is to develop a model system in which the effects of lead on central nervous system development can be demonstrated. The complexity of the brain hampers such investigations because often it is not clear if apparent toxic effects represents changes secondary to somatic changes, such as endocrine or hematological defects, that could alter brain development, or even transneuronal effects caused by toxicity at a distal site that deprives a brain area of a synaptic input needed for its proper development. A related problem is the redundancy of compensatory systems in the brain. Such system may disguise the severity of the initial toxic insult and themselves can cause functional disturbances. To study neuronal development in a system that minimizes such difficulties, we have grafted discrete brain regions derived from rat fetuses into the anterior chamber of the eye of adult hosts. The brain pieces continue organotypic development of the eye, but are isolated from possible secondary changes due to alterations in the development of the endocrine and other somatic systems because the adult host has these systems already fully developed. Similarly, effects mediated by connecting brain areas are minimized since the transplant is isolated in the anterior chamber of the eye.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic Fibers↗
PubMed1990

The predictive value of needle localization mammographically assisted biopsy of the breast.

This study was done to review critically the experience at the University of California at San Diego in needle localization mammographic biopsy of the breast with regard to use and accuracy in identifying early carcinoma of the breast. Ninety-seven patients underwent needle localization mammographic biopsy of the breast between 1985 and 1987. Indications for this procedure included the presence of microcalcifications or a mass shown on mammographic examination, or both, in conjunction with physical examination which did not define a discrete abnormality in the area. Mammographic, demographic, pathologic, hormone receptor data and staging information were recorded and processed on the MicroVax II computer (Digital Equipment Corporation). Twenty-four per cent of lesions with needle localization mammographic assisted biopsy proved to be malignant. Sixteen lesions were diagnosed as an infiltrating ductal carcinoma and ten of these had an accompanying intraductal carcinoma. Over-all, intraductal carcinoma was present in 16 of the 23 specimens diagnosed as malignant. At biopsy, the margins were clear in 17 of 23, and vascular invasion was present in only one patient with an infiltrating lobular carcinoma. Five were tumor in situ, 12 were stage 1 and five were stage 2 (staging information was not available in one instance). Hormone receptor data were available in 17 of 23 specimens. Estrogen receptors were positive in 13 and progesterone receptors were positive in six. The smallest preinvasive malignant lesion was 4 millimeters, as seen on the mammogram, and the smallest free-standing invasive lesion was 8 millimeters. Preinvasive lesions (intraductal) presented as microcalcifications in 80 per cent. Invasive lesions presented as either a mass (n = 9) or as a mass and microcalcifications (n = 5) in 81 per cent. All five lesions presenting as both a mass and microcalcifications on mammogram proved to be malignant. Multifocal lesions on mammographic examination which proved to be malignant were multifocal pathologically in only 50 per cent. Needle localization mammographic biopsy is useful in detecting early carcinoma of the breast. Biopsy should be done on lesions presenting on mammogram as both a mass and microcalcifications and not observed. Focality of lesions on mammogram does not correlate with focality on biopsy and may be misleading as criteria for operative planning.

Adenofibroma↗
PubMed1990

Electrophysiologic effects of ethanol in human brain xenografts in oculo: antagonism by Ro15-4513.

Human cortex cerebri and cerebelli xenografts from first-trimester fetal tissue fragments were used to study the effects of ethanol on single human central neurons. Transplants were placed into the anterior eye chamber of athymic nude rats and allowed to develop for 3 to 11 months. Immunohistologic analysis revealed graft structures that stained positively for a number of neuronal, transmitter-related, glial and vascular markers. Superfusion of ethanol (EtOH) elicited a reversible and dose-dependent depression of action potential discharge. At least two populations of neurons could be identified--a more sensitive group with an EC50 of 3.0 mM and a less sensitive group with an EC50 of 22.4 mM. These EtOH levels are within the range eliciting behavioral signs of intoxication in humans. EtOH-induced depressions could be antagonized by administration of the benzodiazepine inverse agonist Ro 15-4513. This study represents the first demonstration, to our knowledge, of the electrophysiologic actions of EtOH on single neurons from human brain, and provides dose-response data collected with known concentrations of EtOH as well as evidence for the blockade of these EtOH effects by the Roche compound.

Animals↗
PubMed1989

Survival of adult 5-HT neurons following intraocular transplantation.

The present study was undertaken to provide an improved environment in which to examine the capacity of more mature CNS tissue to survive following transplantation. Tissue containing serotonin (5-HT) neurons from nucleus raphe dorsalis of 4- and 8-week-old rats was transplanted to the anterior chamber of the eye. Baseline conditions were improved by minimizing the time of the grafting procedure and enhancing the nutrition and oxygenation of the grafting medium. Additional treatment of the grafts during the 4 weeks of in oculo development included either: (1) intermittent hyperbaric oxygen (HBO), (2) continuous hyperoxia, or (3) control. In vivo measurement revealed that all grafts decreased significantly in size, a majority of which still demonstrated a small degree of vascularization. Microscopically, a significant percentage of the grafts demonstrated 5-HT-immunoreactive (5-HT-ir) fiber outgrowth into the host irides, although 5-HT-ir cell bodies could not always be discerned. In terms of percentage of grafts with surviving 5-HT-ir fibers, the best results were seen with the grafts treated with continuous hyperoxia (3 out of 4), as compared to HBO-treated grafts (4/18) and the control group (3/24). For both the HBO-treated and control groups, slightly better results were seen with 4-week-old vs 8-week-old donor tissue. The density and the surface area covered by the 5-HT-ir fibers was not correlated with either treatment or donor age. Thus, while continuous hyperoxia or HBO treatment may have a positive effect, the enhanced baseline conditions appear to provide an environment in which to demonstrate that 5-HT neurons from 4- and 8-week-old rats possess the capacity to survive transplantation.

Age Factors↗
PubMed1989

Induction of GFAP production in human glioma lines grafted into the anterior chamber of the rat eye.

Three established glial fibrillary acidic protein (GFAP)-negative cell lines from human gliomas were transplanted to the anterior chamber of the rat eye. Short-term survival was seen with all transplants. The cells expressed GFAP following transplantation. For comparison, 4 GFAP-positive cell lines were transplanted. With grafting of 5000 cells of any of 6 bipolar cell lines, the transplanted cells could be seen to develop multiple, slender processes reminiscent of mature astrocytes. When 50,000 cells were grafted, vascularized cell mats covering the corneae were seen. The induction of GFAP production and the phenotypic changes were interpreted as signs of differentiation induced by the new environment. All transplanted cells were rejected after 8 weeks.

Animals↗
PubMed1989

Age-related alterations in noradrenergic input to the hippocampal formation: structural and functional studies in intraocular transplants.

Intrinsic versus extrinsic determinants of age-related alterations in hippocampal noradrenergic transmission were investigated using intraocular allografts in rats. Three groups of animals were examined: young hippocampal transplants in young hosts, old transplants in old hosts and young transplants in old hosts. Postsynaptic sensitivity to noradrenaline (NA) was measured by extracellular recordings of spontaneous activity and superfusion with known concentrations of catecholamines in the anterior chamber of the eye. Hill plots demonstrated that the dose-response relationships of NA-induced depressions were linear and parallel in the 3 groups. Aged hippocampal grafts displayed a highly significant subsensitivity to NA of one order of magnitude. The EC50 for this group was 203.1 microM as compared to 29.2 in young grafts. Young intraocular grafts in old hosts responded similarly to transplants in young hosts, with an EC50 of 32.4 microM for the depressant actions of NA. Collaterals of the host iris sympathetic ground plexus invaded the hippocampal grafts. The density of this noradrenergic innervation was estimated by immunohistochemistry for tyrosine hydroxylase. A slightly increased density and fluorescence intensity of the noradrenergic fibers were observed in the old transplants as compared to the young transplants in young and old hosts. This was correlated with a significantly (P less than 0.01) increased content of NA in old transplants, as measured with high performance liquid chromatography. The old transplants also contained a large number of autofluorescent lipofuchsin granules, which were absent in the young transplants, regardless of the recipient age. Taken together, these results suggest the existence of alterations in pre- as well as postsynaptic noradrenergic mechanisms in the aging hippocampus. These changes were dependent on transplant age rather than host age, thus suggesting an involvement of intrinsic rather than extrinsic determinants in this model system.

Action Potentials↗
PubMed1989

Abnormal expression of tyrosine hydroxylase-like immunoreactivity in intraocular transplants of rat caudate nucleus.

The purpose of the present study was to examine tyrosine hydroxylase (TH)-like immunoreactivity in single intraocular grafts of caudate nucleus, and in caudate grafts which were co-grafted with substantia nigra. Grafts of caudate obtained from fetal rats (crown-rump length: 15-17 mm) were placed into the anterior chamber of eye of adult female Sprague-Dawley rats, and were allowed to survive from 6 to 20 months. The host rats were then perfused with fixative and the tissue was prepared for immunocytochemistry for TH. In 7 out of 8 surviving caudate grafts, including those containing no substantia nigra, tyrosine TH-like immunoreactive (THLI) cell bodies were present. The results of our study suggest that TH is inappropriately expressed in caudate grafts placed in the anterior chamber of the eye.

Animals↗