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Biomedical subjects

L Olson

Publications and source records attributed to L Olson.

At least 181 records · Page 10Linked to original sources
PubMed1994

Role of growth factors in degeneration and regeneration in the central nervous system; clinical experiences with NGF in Parkinson's and Alzheimer's diseases.

Neurotrophin-mediated mechanisms are integral to development and maintenance of the adult central nervous system. Neurotrophin expression has been shown to change rapidly in response to many different types of neuronal stress such as excitotoxic injury, mechanical lesions, epileptogenesis and ischemia. It therefore appears as if they are not only to be regarded as target-derived trophic factors in the classical sense, but also as providers of local trophic support and neuronal protection. These discoveries suggest that neurotrophins or compounds with neurotrophin-like actions might become useful in developing new treatment strategies, not only for neurodegenerative diseases, but also for other diseases and injuries to the nervous system including stroke.

Alzheimer Disease↗
PubMed1994

Human fetal spinal cord xenografted to the eye of athymic nude rats: survival, ultrastructural differentiation, glial responses and vascular interactions.

The ultrastructure of human spinal cord xenografts transplanted to the anterior chamber of athymic nude rats was studied. The grafts displayed long-term survival and expressed several organotypical characteristics of normal human spinal cord. Three cell types of different sizes--small, intermediate, and large--and two different types of neuropil, with and without myelinated axons, were observed in the central cellular layer. The myelin-free area was formed between and round small neurons and was composed of many nonmyelinated fibers and bundles of fine axons. The hostgraft interface, especially around vessels from host iris, exhibited marked interdigitations of astroglial processes and basement membranes. Thick, superficial glial layers containing many fibrous astrocytes and many glial processes were also seen in both the intermediate axonal and central cellular layers. Thin-walled vessels were clustered in the central layer, and their perivascular spaces contained collagen fibers. No central nervous system-type vessels were observed. In conclusion, both the organotypical features of normal spinal cord and the glial responses and abnormal vascular interactions observed in this study must be considered in relation to the long-term survival and functional potential of xenografted neural tissue.

Animals↗
PubMed1994

Glial cell-line derived neurotrophic factor (GDNF) mRNA upregulation in striatum and cortical areas after pilocarpine-induced status epilepticus in rats.

Glial cell-line derived neurotrophic factor (GDNF) has recently been cloned and shown to have trophic effects on dopaminergic nigral neurons. However, GDNF mRNA has not been detected in striatum or other forebrain areas of adult rat. Using limbic motor status epilepticus induced by pilocarpine to activate neurons in motor and limbic areas, we now demonstrate GDNF mRNA signals in the striatum, hippocampus and cortex using in situ hybridisation. The finding of GDNF mRNA in the stimulated striatum opens the possibility that GDNF may be a target-derived, trophic factor in the nigro-striatal system. This expression of GDNF mRNA may be linked to excitatory cortical input. Increases in GDNF mRNA after status epilepticus in hippocampus and neocortex indicate additional roles for GDNF.

Animals↗
PubMed1994

Neurons of the hippocampal formation express glial cell line-derived neurotrophic factor messenger RNA in response to kainate-induced excitation.

Glial cell line-derived neurotrophic factor (GDNF) is a novel member of the transforming growth factor-beta superfamily with potent trophic effects on dopamine neurons. Kainate-induced epileptic seizures have been shown to induce gene expression of trophic factors, particularly members of neurotrophin or fibroblast growth factor families, in the hippocampus. In this study, we examined the effects of kainate (12 mg/kg, i.p.)-induced epileptic seizures on the expression of the novel neurotrophic factor GDNF in the hippocampus. While GDNF messenger RNA was not detected during development or in normal adult rats in the hippocampus, kainate-induced epileptic seizures markedly increased GDNF messenger RNA in scattered neurons in the dentate granule layer 3 h after injection. Six hours after kainate almost all dentate granule cells and expressed GDNF messenger RNA. The increase in GDNF messenger RNA in the dentate granule layer returned almost to control levels 24 h after kainate; however, there was still expression of GDNF messenger RNA in the hilus/CA4 and also in pyramidal neurons in areas CA1-CA3. We conclude that GDNF messenger RNA is regulated, in part, via glutamate-mediated excitation and may play a role in long-lasting structural and/or functional reorganization in the hippocampal formation.

Animals↗
PubMed1994

Localization of cellular retinoid-binding proteins suggests specific roles for retinoids in the adult central nervous system.

Retinoic acid, the active metabolite of retinoids (vitamin A compounds), is thought to act as a gene regulator via ligand-activated transcription factors. In order to investigate possible roles of retinoids and retinoid-controlled gene expression in brain function, we have used immunohistochemistry to localize the possible presence of two intracellular retinoid-binding proteins, cellular retinol-binding protein type I and cellular retinoic acid-binding protein type I, in the adult rat central nervous system. We find a widespread, yet distinct, presence of these two binding proteins in the brain and spinal cord. Most of the immunoreactivity is neuronal, including cell somata, as well as dendritic and axonal processes and axon terminals. Cellular retinol-binding protein type I-immunoreactivity is also found in the walls of cerebral blood vessels, the meninges, the choroid plexus, certain ependymal cells, tanocytes and certain other glial elements. The cellular retinol-binding protein type I- and cellular retinoic acid-binding protein type I-immunoreactivity patterns appear to be almost exclusively non-overlapping. Very strong cellular retinol-binding protein type I-immunoreactivity is found in the dendritic layers of the hippocampal formation and dentate gyrus. Cellular retinol-binding protein type I-immunoreactivity is also present in layer 5 cortical pyramidal neurons and neurons in the glomerular layer of the olfactory bulb. Many other areas, e.g. hypothalamic nuclei and amygdala areas, contain networks of varicose cellular retinol-binding protein type I-immunoreactive nerve fibers. The medial amygdaloid nucleus contains strongly cellular retinol-binding protein type I-positive neurons. Cellular retinoic acid-binding protein type I-immunoreactivity is more restricted in the adult brain. Strong cellular retinoic acid-binding protein type I-immunoreactivity is, however, found in a population of medium-sized neurons scattered throughout the striatum, in neurons in the glomerular layer of the olfactory bulb, the olfactory nerve and in a group of nerve cells close to the third ventricle in hypothalamus. The remarkably selective patterns of cellular retinol-binding protein type I- and cellular retinoic acid-binding protein type I-immunoreactivity discovered in the adult rat brain suggest that retinoids have important roles as regulators of gene expression in normal brain function. The high levels of cellular retinol-binding protein type I-immunoreactivity found in hippocampus suggest that one such role might relate to brain plasticity.

Animals↗
PubMed1994

Neuronal development in embryonic brain tissue derived from schizophrenic women and grafted to animal hosts.

The distribution of schizophrenia in families supports the hypothesis of heritable risk factors in schizophrenia, but there is as yet no identification of an inherited neurobiological defect. Human embryonic brain tissue fragments, derived from first trimester abortions, can be transplanted into rat hosts, where they continue neuronal development and are accessible for neurobiological investigation. Hippocampal transplants derived from three schizophrenic women and a larger series of normal women have been studied. If there are heritable neuronal defects associated with schizophrenia, a proportion of the transplants from schizophrenic women would be expected to carry these defects. The transplants from the first two schizophrenic women showed profound abnormalities in survival and growth, compared to the series of transplants from normal women. The transplants from the third schizophrenic woman showed normal growth and development, as well as typical histological and electrophysiological features. The data must be regarded as preliminary, because of the small number of subjects that have been studied. However, they are consistent with the transmission of a defect in neuronal development to some of the offspring of schizophrenic women, a possibility consistent with other studies of the pathogenesis of schizophrenia. The mechanism of the defect in development remains to be identified.

Adult↗
PubMed1994

Characterization of anti-canine cytokine monoclonal antibodies specific for IFN-gamma: effect of anti-IFN-gamma on renal transplant rejection.

Two murine monoclonal antibodies specific for IFN-gamma, ADI-1, and ADI-23 (both IgG1 kappa), were generated in BALB/c mice. The ADI-1 exhibited a higher avidity for canine rIFN-gamma than for nIFN-gamma and human rIFN-gamma. In contrast, the ADI-23 showed equal avidity for the three IFN-gamma preparations. The anti-canine IFN-gamma mAb did not bind to mouse and rat rIFN-gamma. The ADI-1, and ADI-23 mAb were also tested for binding to human rTFN-alpha and, contrary to our expectations, it was found that ADI-23 showed significant binding to human rTFN-alpha and rIFN-gamma, in contrast to ADI-1. Both anti-canine IFN-gamma mAb stained 48-h PHA-induced dog lymphoblasts. A two-site mAb ELISA was developed, which was linear in the range of 7-500 ng of canine rIFN-gamma, which indicated that the two mAb detected non-overlapping epitopes on the canine rIFN-gamma molecule. We studied the effect of ADI-1 on the prolongation of canine renal allografts. Recipients of kidney allografts, that were treated with ADI-1 by continuous arterial infusion, were prolonged to 22 and 25 days, compared to 9 and 13 days for animals given the IgG1 isotype control.

Animals↗
PubMed1994

Phosphatidylinositol 3-kinase activation is mediated by high-affinity interactions between distinct domains within the p110 and p85 subunits.

Domains of interaction between the p85 and p110 subunits of phosphatidylinositol 3-kinase (PI 3-kinase) were studied with the yeast two-hybrid expression system. A gene fusion between the GAL4 transactivation domain and p85 activated transcription from a GAL1-lacZ reporter gene when complemented with a gene fusion between the GAL4 DNA binding domain and p110. To define subdomains responsible for this interaction, a series of p85 deletion mutants were analyzed. A 192-amino-acid inter-SH2 (IS) fragment (residues 429 to 621) was the smallest determinant identified that specifically associated with p110. In analogous experiments, the subdomain within p110 responsible for interaction with p85 was localized to an EcoRI fragment encoding the amino-terminal 127 residues. Expression of these two subdomains [p85(IS) with p110RI] resulted in 100-fold greater reporter activity than that obtained with full-length p85 and p110. Although the p85(IS) domain conferred a strong interaction with the p110 catalytic subunit, this region was not sufficient to impart phosphotyrosine peptide stimulation of PI 3-kinase activity. In contrast, coexpression of the p110 subunit with full-length p85 or with constructs containing the IS sequences flanked by both SH2 domains of p85 [p85(n/cSH2)] or either of the individual SH2 domains [p85(nSH2+IS) or p85(IS+cSH2)] resulted in PI 3-kinase activity that was activated by a phosphotyrosine peptide. These data suggest that phosphotyrosine peptide binding to either SH2 domain generates an intramolecular signal propagated through the IS region to allosterically activate p110.

Amino Acid Sequence↗
PubMed1994

Flunarizine for treatment of partial seizures: results of a concentration-controlled trial.

The National Institutes of Health sponsored a randomized, double-blind, multicenter, placebo-controlled trial of flunarizine (FNR) in epileptic patients receiving concomitant phenytoin (PHT) or carbamazepine (CBZ). Because of FNR's long half-life (up to 7 weeks), a parallel rather than crossover design was used. Each patient received an individualized loading dose and maintenance dosage targeted at a 60-ng/ml plasma FNR concentration. Of 93 patients randomized, 92 provided seizure data for the full 25-week treatment period; one placebo-treated patient dropped out for personal reasons. Fifty-four patients received CBZ only, nine received PHT only, and 30 received both CBZ and PHT. Eighty-seven patients had a history of complex partial seizures, and 60 had secondarily generalized seizures. Eight patients discontinued FNR prematurely, all because of adverse neurologic or psychiatric signs or symptoms; depression was the specific cause in three cases. Calculated maintenance dosages, based on single-dose pharmacokinetic profiles, ranged from 7 to 138 mg/day (mean, 40 mg/day). Plasma FNR concentrations generally exceeded the target, with the highest concentrations observed immediately after loading; excluding the first three treatment weeks and all concentrations after a FNR dosage change, the median plasma FNR concentration was 71.7 ng/ml. The percent reduction from baseline seizure rate was statistically greater (p = 0.002) in the FNR-treated group (mean, 24.4%) than in the placebo-treated group (mean, 5.7%).

Adolescent↗
PubMed1994

Regulation of brain-derived neurotrophic factor (BDNF) expression and release from hippocampal neurons is mediated by non-NMDA type glutamate receptors.

We have examined the influence of glutamate on cortical brain-derived neurotrophic factor (BDNF) expression using in situ hybridization and immunohistochemistry. Kainic acid (KA) produced an upregulation of hippocampal and neocortical BDNF mRNA as well as BDNF protein that was blocked by a non-NMDA antagonist, 6,7-dinitroquinoxaline-2,3-dione (DNQX), but was not affected by the NMDA antagonist 2-amino-7-phosphonoheptanoic acid (AP7). Basal levels of BDNF mRNA were not affected by NMDA, DNQX, or AP7 treatment. BDNF protein was also increased after kainate exposure with a spatial and temporal course distinct from that seen for the expression of BDNF mRNA. A dramatic shift in BDNF immunoreactivity (-IR) was observed from intracellular compartments to the neuropil surrounding CA3 pyramidal cells 2-3 hr after KA exposure. This shift in localization of BDNF-IR suggests a constitutive release of BDNF at the level of the cell body and dendrites. Moreover, we have localized mRNAs for full-length and truncated trkB, to a co-incident population of neurons and glia. These data suggest the neurons that produce BDNF also express components necessary for a biological response to the same neurotrophic factor. The present study also demonstrates increased BDNF-IR in the mossy fiber terminal zone of hippocampus after exposure to KA, as well as an increase in trkB mRNA, and provides evidence of local release of this neurotrophin into the surrounding neuropil where it would be available for local utilization. The synthesis and putative release of BDNF from somatic and/or dendritic sites within the hippocampus provide evidence of a potential autocrine or paracrine role for BDNF, and establish a local source of trophic support for the maintenance of synaptic plasticity and anatomic reorganization in the mature nervous system.

Animals↗
PubMed1994

NGF and anti-transferrin receptor antibody conjugate: short and long-term effects on survival of cholinergic neurons in intraocular septal transplants.

We describe a new molecular carrier system that allows for the transport of nerve growth factor (NGF) across the blood-brain barrier (BBB), as assessed by trophic effects on intraocular forebrain transplants that contain central cholinergic neurons. The carrier system involves monoclonal antibodies (OX-26) directed against the transferrin receptor, to which NGF molecules are covalently linked. Transferrin receptors are highly concentrated on brain blood vessels and participate in the transport of iron across the BBB. Host rats with septal transplants were divided into four groups, which received OX-26-NGF, OX-26, NGF or saline intravenously at 2, 4, 6 and 8 weeks after grafting. Half of the animals were killed directly after the final injection, whereas the other half were allowed to survive for an additional 5 months. Control experiments revealed that blood vessels in mature brain grafts in oculo contained large amounts of transferrin receptors. Covalent binding of NGF to the OX-26 antibodies did not impede OX-26 binding to CNS transferrin receptors, nor did conjugation affect the bioactivity of NGF. A time-dependent increase in host brain NGF levels was found after injection of OX-26-NGF into the tail vein. Host serum contained some NGF antibodies in the short-term OX-26-NGF group that had disappeared in the long-term group; host adrenals showed no differences in wet weight or norepinephrine or epinephrine whole tissue levels in any of the groups. As previously reported, the overall growth of intraocular septal transplants was approximately twice as great in the OX-26-NGF group relative to all other groups. This difference in final size persisted unabated for at least 5 months after the last injection. Furthermore, the significantly higher numbers of choline acetyl transferase immunoreactive neurons in transplants of OX-26-NGF-treated hosts also persisted during the 5-month postinjection interval. Taken together, the data suggest that the OX-26 conjugate may be a unique approach to permit passage of neurotrophin peptides into the brain in a biologically active form.

Adrenal Glands↗
PubMed1993

Fibroblast growth factors enhance dopamine fiber formation from nigral grafts.

Members of the fibroblast growth factor (FGF) family have earlier been shown to exert potent trophic effects on cells of both the central and peripheral nervous system. The presence of FGF-1 and -2 (FGF-1, acidic FGF; FGF-2, basic FGF) has recently been demonstrated in the dopaminergic cells of substantia nigra in rat and FGF-2 has been shown to be able to increase survival and promote neurite outgrowth of cultured mesencephalic neurons. In the presence study, we have investigated possible trophic effects of FGF-1 and FGF-2 on developing rat ventral mesencephalon of different fetal stages by utilizing the in vivo method of intraocular transplantation to sympathetically denervated hosts. Survival and growth of developing grafts after growth factor treatment was followed in oculo. The Falck-Hillarp technique was used for evaluation of catecholaminergic fiber outgrowth into the host iris in whole-mount preparations. FGF-2 significantly increased the volume of the mesencephalic grafts when compared to grafts treated with the vehicle alone. The mean volume of FGF-1-treated grafts was larger than that of control grafts, but this difference was not statistically significant. FGF-1 significantly increased the area of outgrowth of dopaminergic fibers into the host iris without a corresponding increase in the number of dopaminergic neurons, as evaluated by TH immunohistochemistry. FGF-2 had no effect on dopaminergic fiber outgrowth on grafted E14 ventral mesencephalon but it did have a significant effect on fiber outgrowth from E15 and E16 grafts. Moreover, the FGF-2 treated E16 grafts contained a larger number of dopaminergic neurons as compared to controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Effect of radiologic stage III substage on nonsurgical therapy of non-small cell lung cancer.

BACKGROUND: Patients with Stage III non-small cell lung cancer (NSCLC) whose cases are staged or treated surgically have different prognoses, depending on the substage (IIIa, IIIb). It is not known whether the prognostic differences apply to clinically staged nonsurgical cases. The authors wanted to determine whether radiologic Stage III substages, determined by computerized axial tomography (CT) scans, are prognostically important in these patients with NSCLC: In addition, they wanted to determine whether the observed superior survival of selected patients with Stage III NSCLC receiving chemotherapy in addition to radiation therapy (chemo-RT) (Cancer and Leukemia Group B protocol 8433: N Engl J Med 1990; 323:940-5) was influenced by an imbalance in the radiologic Stage III substage. METHODS: Review of pretreatment chest radiographs and CT scans with determination of TNM status and stage was done by the consensus of three readers, who were unaware of which treatment each patient had received (radiation therapy alone [RT] or chemo-RT). RESULTS: Patient characteristics in the two treatment arms were similar. Fifty-five percent of patients receiving RT had Stage IIIa and 33% Stage IIIb disease; in the chemo-RT treatment arm, 73% had Stage IIIa and 25% Stage IIIb disease (P = 0.11). Seven patients (12%) who received RT and one in the chemo-RT treatment arm (2%) had Stage I-II disease on CT scan. Patients with Stage IIIa disease had superior survival to those with Stage IIIb disease (median, 16.5 versus 10.5 months, respectively; P = 0.0045). Within each substage, survival was superior in the chemo-RT (versus RT) treatment arm (Stage IIIa, 17.2 versus 10.7 months, respectively; P = 0.16; Stage IIIb, 12.0 versus 6.9 months, respectively; P = 0.089). CONCLUSIONS: The survival advantage for selected patients with Stage III NSCLC treated with chemo-RT in this study did not result from a more favorable pretreatment radiologic Stage III substage. An advantage for induction chemotherapy was seen in patients with Stage IIIa and IIIb disease. Future studies in this population should prospectively assess and consider stratification for Stage III substage.

Adipose Tissue↗
PubMed1993

Pentylenetetrazol seizures increase pro-nerve growth factor-like immunoreactivity in the reticular thalamic nucleus and nerve growth factor mRNA in the dentate gyrus.

Neurotrophins may have a neuroprotective role and are probably involved in the control of axonal sprouting and synaptic plasticity. An antibody raised against a pro-sequence of nerve growth factor (NGF) was tested. In control undisturbed rats, a strong immunoreactivity was detected in scattered cells in and around the pyramidal and granule cell layer of the hippocampus and a moderate labeling was found in the reticular thalamic nucleus. In situ hybridization showed specific expression of NGF mRNA in a similar population of scattered cells in the hippocampal formation but not in the reticular thalamic nucleus. Acute epileptic seizures, induced by a convulsive dose of 50 mg/kg pentylenetetrazol (PTZ), strongly increased NGF mRNA in neurons of the granular layer of the dentate gyrus 3 hr but not 6 hr after the injection. No change in pro-NGF-like immunoreactivity was observed in the hippocampus or reticular thalamic nucleus after acute seizures. Chemical kindling was induced by daily injections of subconvulsive doses (30 mg/kg) of PTZ for 4 weeks. This treatment significantly increased pro-NGF-like immunoreactivity in the reticular thalamic nucleus but did not affect NGF mRNA. These data strengthen a role for the reticular thalamic nucleus and NGF in PTZ kindling.

Amino Acid Sequence↗
PubMed1993

NGF and the treatment of Alzheimer's disease.

Issues related to the possible treatment of Alzheimer's disease with nerve growth factor (NGF) are discussed. Animal research has demonstrated that the ascending cholinergic projections in the brain express low- and high-affinity receptors for NGF and are NGF-sensitive as well as probably NGF-dependent. Cholinergic lesions lead to cognitive disturbances, and treatment with NGF can improve cognitive behavior in animals. It thus seems reasonable to attempt to counteract the degeneration of cholinergic systems known to occur in patients with Alzheimer's disease by treatment with NGF. There are several different possible ways of stimulating NGF receptors such as NGF infusion, implantation of slow-release biodegradable pellets, using carrier-mediated transport across the blood-brain barrier, grafting NGF-producing cells, transferring genes directly to the brain, developing NGF receptor agonists, or controlling the endogenous NGF production. The first clinical trial of NGF infusion is described in some detail. Based on background information from intracerebral infusion of NGF in parkinsonian patients, attempting to support intraputaminal chromaffin tissue grafts, a study was initiated using a radio-controlled fully implantable pumping device delivering NGF to the lateral ventricle. Several transient or more long-lasting "improvements" were noted in the pilot case. These involved increases of blood flow and nicotine binding as evaluated by positron-emission tomography as well as improvement of the EEG and certain psychological tests, tapping verbal episodic memory. Negative effects of NGF or formation of antibodies against NGF were not noted. In discussing the pilot case, the one conclusion which appears warranted is that it is reasonable to continue the clinical research with NGF treatment of a low number of patients with Alzheimer's disease. The question of whether neurotrophin-mediated mechanisms are disturbed in Alzheimer's disease is discussed. While this issue cannot be settled at present, it is argued that NGF can be used as a pharmacological agent, whether or not there are any primary disturbances of neurotrophin-mediated mechanisms in Alzheimer's disease. Finally, the possibility that NGF might have other positive or negative effects is discussed. In particular, the increase in blood flow noted in the Alzheimer patient suggests that data from clinical research may also generate a feedback to basic science, thus aiding in attempts to find new treatment strategies for neurodegenerative diseases.

Aged↗