Biomedical subjects

R S Morrison

Publications and source records attributed to R S Morrison.

At least 73 records · Page 4Linked to original sources

PubMed1995

Morphologic, immunologic, biochemical, and cytogenetic characteristics of the human glioblastoma-derived cell line, SNB-19.

Human glioma-derived cell cultures and lines have proven to be of significant value in the study of the basic properties that contribute to the highly malignant, invasive and angiogenic phenotype of glioblastoma multiforme tumors. It is frequently difficult to establish lines that retain glial tumor properties in long term culture. The SNB-19 cell line has maintained and exhibited properties of transformation, differentiation, autocrine growth response, and tumorigenesis while remaining in culture for over 13 yr and undergoing over 200 passages. This human line has been utilized in a wide range of studies related to the basic properties of human glioblastoma multiforme. In this report, we summarize the immunologic, biochemical, and cytogenetic properties of this versatile cell line and its utility for additional mechanistic investigation into the pathophysiology of the progression of human malignant gliomas.

Animals↗

PubMed1995

Validation of nursing management diagnoses.

Nursing management diagnosis based on nursing and management science, merges "nursing diagnosis" and "organizational diagnosis". Nursing management diagnosis is a judgment about nursing organizational problems. The diagnoses provide a basis for nurse manager interventions to achieve outcomes for which a nurse manager is accountable. A nursing organizational problem is a discrepancy between what should be happening and what is actually happening that prevents the goals of nursing from being accomplished. The purpose of this study was to validate 73 nursing management diagnoses identified previously in 1992: 71 of the 72 diagnoses were considered valid by at least 70% of 136 participants. Diagnoses considered to have high priority for future research and development were identified by summing the mean scores for perceived frequency of occurrence and level of disruption. Further development of nursing management diagnoses and testing of their effectiveness in enhancing decision making is recommended.

Adult↗

PubMed1995

Astrocytes derived from p53-deficient mice provide a multistep in vitro model for development of malignant gliomas.

Loss or mutation of p53 is thought to be an early event in the malignant transformation of many human astrocytic tumors. To better understand the role of p53 in their growth and transformation, we developed a model employing cultured neonatal astrocytes derived from mice deficient in one (p53 +/-) or both (p53 -/-) p53 alleles, comparing them with wild-type (p53 +/+) cells. Studies of in vitro and in vivo growth and transformation were performed, and flow cytometry and karyotyping were used to correlate changes in growth with genomic instability. Early-passage (EP) p53 -/- astrocytes achieved higher saturation densities and had more rapid growth than EP p53 +/- and +/+ cells. The EP p53 -/- cells were not transformed, as they were unable to grow in serum-free medium or in nude mice. With continued passaging, p53 -/- cells exhibited a multistep progression to a transformed phenotype. Late-passage p53 -/- cells achieved saturation densities 50 times higher than those of p53 +/+ cells and formed large, well-vascularized tumors in nude mice. p53 +/- astrocytes exhibited early loss of the remaining wild-type p53 allele and then evolved in a manner phenotypically similar to p53 -/- astrocytes. In marked contrast, astrocytes retaining both wild-type p53 alleles never exhibited a transformed phenotype and usually senesced after 7 to 10 passages. Dramatic alterations in ploidy and karyotype occurred and were restricted to cells deficient in wild-type p53 following repeated passaging. The results of these studies suggest that loss of wild-type p53 function promotes genomic instability, accelerated growth, and malignant transformation in astrocytes.

Animals↗

PubMed1995

Alternative RNA splicing of the hyaluronic acid receptor CD44 in the normal human brain and in brain tumors.

The cell-surface receptor for hyaluronic acid, CD44, is expressed by both normal and malignant cells. Numerous CD44 isoforms have recently been identified that are derived by alternative ribonucleic acid splicing. The expression of some CD44 isoforms has been shown to be involved in tumor progression and metastatic spread in a rat carcinoma model and in human carcinomas. In the present study, CD44 isoform expression was evaluated by reverse transcriptase-polymerase chain reaction (PCR) analysis in frozen sections derived from three samples of normal brain tissue and from 40 brain tumors, including samples of glioblastoma multiforme, anaplastic astrocytoma, low-grade astrocytoma, cerebral primitive neuroectodermal tumor, medulloblastoma, metastatic colon carcinoma, and metastatic melanoma. Normal brain tissue adjacent to the tumors was also examined in 14 of 18 glioblastomas. In all normal brain and tumor samples, with the exception of metastases from colon carcinoma, PCR analysis demonstrated one prominent product that corresponded to the CD44H hematopoietic form of CD44. Metastases from colon carcinoma demonstrated two prominent PCR amplification products corresponding to CD44H and CD44R1. These results suggest that CD44H is the predominant isoform of this protein in normal human brain tissue and in human neuroectodermal tumors of varying degrees of malignancy. The ability of CD44H to mediate tumor cell motility and invasiveness (in contrast to CD44R1) suggests that the CD44 alternative splicing pattern of neuroectoderm-derived tumors may enhance their local biological aggressiveness and intracerebral spread. The lack of expression of larger molecular weight CD44 variants by primary brain tumors may also partially explain why these tumors rarely metastasize to distant sites.

Alternative Splicing↗

PubMed1995

When there is no cure: palliative care for the dying patient.

Acknowledging that death is a normal and inevitable process is often difficult for both physicians and patients. This article highlights by case example the type of care typically received by the terminally ill in acute care hospitals in the United States. The lack of familiarity with the core concepts of palliative care demonstrated by the medical team in this case reflects the pressing need for death education for health care professionals. We discuss the major principles of palliative care, including breaking bad news, developing a palliative care plan, planning for death, and withdrawal of artificial nutrition and hydration.

Aged↗

PubMed1994

Physician reluctance to discuss advance directives. An empiric investigation of potential barriers.

BACKGROUND: To determine the relative impact of five proposed barriers to physician usage of advance directives with the aim of increasing the number of advance directives generated. METHODS: Questionnaires were sent to 460 internal medicine resident and attending physicians at a large New York, NY, hospital. Of these, 277 (60%) responded. We used multiple regression to measure the impact of five barriers to physician-initiated discussions of advance directives (time constraints, compensation concerns, discomfort with the subject, beliefs about appropriateness, and lack of understanding) on respondents' estimates of the number of advance directives held by respondents' patients, the number of recent advance directive discussions, and the number of discussions initiated by physicians. RESULTS: Physician lack of understanding and erroneous beliefs about appropriateness had particularly strong effects, serving as barriers to recent advance directive discussions (P < .0001 and P < .0001, respectively) and total number of advance directives held (P < .0001 and P < .02). Physicians' lack of knowledge also served as a barrier to the percentage of discussions that were physician initiated (P < .003 and P < .04). Time constraints and lack of comfort affected only discussions that were physician initiated (P < .001). Compensation concerns did not appear to serve as a barrier. Respondents were supportive of the concept of advance directives but reported minimal use of them in appropriate situations. CONCLUSIONS: Attention can now be focused on methods to overcome the five barriers studied and thereby enhance the execution of advance directives.

Adult↗

PubMed1994

Nigral type I astrocytes release a soluble factor that increases dopaminergic neuron survival through mechanisms distinct from basic fibroblast growth factor.

Our studies have been directed to the identification of local, naturally-occurring molecules that support substantia nigra (SN) dopaminergic (DA) neuron survival. We have previously demonstrated that local Type I astrocytes selectively increase the dopaminergic population [30,31]. However, the mechanism of action remains to be defined. To determine whether survival is elicited through diffusible agents, Type I astrocyte conditioned medium (CM) was tested on SN dissociates. After 7 days of exposure to CM, DA neuronal integrity was monitored immunocytochemically with antibody to tyrosine hydroxylase (TH), the DA biosynthetic enzyme, or by TH catalytic assay. CM increased TH+ cell number greater than 2-fold, suggesting that a soluble factor(s) promoted neuron survival. Neurons cultured in serum free medium (SFM) are known to contain few, but detectable numbers of glia [34]. To examine whether CM affected neurons directly, or indirectly through glia, glial populations were stained with antibody against the glial marker, glial fibrillary acidic protein (GFAP). We employed several approaches to define the potential role of glia. Initially, CM was compared to basic fibroblast growth factor (bFGF), a glial mitogen that reportedly enhances nigral DA neuron survival. bFGF enhanced TH activity in our system, as well, but the effect was blocked by the mitotic inhibitor 5-fluorodeoxyuridine (FDUR), which kills dividing glia. In parallel studies CM increased enzyme activity and TH cell number in cultures exhibiting GFAP+ cells. To define the role of these glial cells in the CM effect, we completely eliminated astrocytes in CM-treated cultures employing alpha-aminoadipic acid (AA; 10-30 microM), a specific gliotoxin. At a concentration of AA that eliminated detectable GFAP+ cells, CM continued to elicit a significant increase in TH cell number. These data suggest that, in contrast to effects of bFGF, the DA neurotrophic activity in CM acts directly on nigral neurons to enhance survival.

Animals↗

PubMed1994

Fibroblast growth factor receptor gene expression and immunoreactivity are elevated in human glioblastoma multiforme.

Glioblastomas were examined for abnormalities in fibroblast growth factor receptor (FGFR) expression by polymerase chain reaction and immunocytochemical analysis. Polymerase chain reaction analysis demonstrated that FGFR1 mRNA levels were significantly higher in glioblastomas than in normal brain adjacent to the tumor or in untransformed human brain. These results were consistent with immunocytochemical localization of FGFR1 protein in glioblastomas: glioblastoma cells exhibited intense FGFR1 immunoreactivity in frozen sections of tumor and low to undetectable FGFR1 immunoreactivity in adjacent normal brain or in normal white matter obtained from patients without neoplastic disease. Endothelial cells of capillaries and larger vessels within the tumor were devoid of FGFR1 immunoreactivity. All glioblastomas evaluated in the present study expressed FGFR1 mRNA and FGFR1 immunoreactivity. Examination of the FGFR1 gene by Southern blot analysis indicated that overexpression of FGFR1 mRNA in glioblastomas did not result from gene amplification. These results indicate that glioblastoma cells, in contrast to endothelial cells within the tumor, display increased levels of FGFR1. Therefore, FGFR1 signal transduction may be associated with increased autocrine growth activity of tumor cells and is probably not related to the increased endothelial cell proliferation associated with these tumors.

Base Sequence↗

PubMed1994

Septal neuron cholinergic and GABAergic functions: differential regulation by basic fibroblast growth factor and epidermal growth factor.

Numerous studies suggest that growth and trophic factors play roles in the development and mature function of brain neurons. Recently, growth factors whose actions were previously characterized on non-neuronal cells have been localized to the brain. We sought to determine whether these factors influence septal cholinergic function. Initially, we defined the effects of basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) on septal cholinergic cells in dissociated neuronal culture. Both factors elevated activity of the acetylcholine synthetic enzyme, choline acetyltransferase (CAT). To determine whether the factors acted directly on neurons or whether glia mediated the effects, a mitotic inhibitor, 5-fluorodeoxyuridine (FDUR), was added to the cultures to eliminate dividing glia. The action of EGF was completely blocked by the addition of FDUR. However, bFGF elevated CAT activity even in the presence of FDUR. Consequently, bFGF may regulate septal cholinergic function directly, whereas EGF may affect cholinergic cells indirectly through glia. To determine whether increases in CAT activity reflect increased enzyme activity per neuron or an increase in the number of cholinergic cells, bFGF-treated cultures were stained for acetylcholinesterase (AChE) to determine numbers of cholinergic cells. No differences in AChE-positive cells were noted, suggesting that bFGF increased CAT activity per cholinergic neuron. To determine whether bFGF regulates other populations in the septum, we examined GABAergic neurons by monitoring the activity of glutamic acid decarboxylase (GAD), a GABA synthetic enzyme. Basic FGF significantly increased GAD activity; however, the effect was completely abolished by addition of FDUR. Thus, bFGF may act directly on cholinergic neurons and indirectly on GABA cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗

PubMed1994

Differential expression of two fibroblast growth factor-receptor genes is associated with malignant progression in human astrocytomas.

Malignant astrocytomas, which are highly invasive, vascular neoplasms, compose the majority of nervous system tumors in humans. Elevated expression of fibroblast growth factors (FGFs) in astrocytomas has implicated the FGF family of mitogens in the initiation and progression of astrocyte-derived tumors. In this study, we demonstrated that human astrocytomas undergo parallel changes in FGF-receptor (FGFR) expression during their progression from a benign to a malignant phenotype. FGFR type 2 (BEK) expression was abundant in normal white matter and in all low-grade astrocytomas but was not seen in malignant astrocytomas. Conversely, FGFR type 1 (FLG) expression was absent or barely detectable in normal white matter but was significantly elevated in malignant astrocytomas. Malignant astrocytomas also expressed an alternatively spliced form of FGFR-1 (FGFR-1 beta) containing two immunoglobulin-like disulfide loops, whereas normal human adult and fetal brains expressed a receptor form (FGFR-1 alpha) containing three immunoglobulin-like disulfide loops. Intermediate grades of astrocytic tumors exhibited a gradual loss of FGFR-2 and a shift in expression from FGFR-1 alpha to FGFR-1 beta as they progressed from benign to malignant phenotype. These results suggest that differential expression and alternative splicing of FGFRs may be critical in the malignant progression of astrocytic tumors.

Alternative Splicing↗

PubMed1994

Basic fibroblast growth factor and fibroblast growth factor receptor I are implicated in the growth of human astrocytomas.

Malignant astrocytomas are highly invasive, vascular neoplasms that comprise the majority of nervous system tumors in humans. A strong association has previously been made between malignancy in human astrocytic tumors and increased expression of certain fibroblast growth factor (FGF) family members, including basic and acidic FGF. The influence of endogenous basic FGF on glioblastoma cell growth in vitro was evaluated using basic FGF-specific antisense oligonucleotides. These studies indicated that human glioblastoma cell growth in vitro, can be inhibited by suppressing basic FGF expression. Human astrocytomas also exhibited changes in FGF receptor (FGFR) expression during the course of their progression from a benign to a malignant phenotype. FGFR2 (bek) expression was abundant in normal white matter and in all low grade astrocytomas, but was not observed in glioblastomas. Conversely, FGFR1 (flg) expression was absent or barely detectable in normal white matter, but was significantly elevated in glioblastomas. Glioblastomas also expressed an alternatively spliced form of FGFR1 containing two immunoglobulin-like disulfide loops (FGFR1 beta), whereas normal human adult and fetal brain expressed a form of the receptor containing three immunoglobulin-like disulfide loops (FGFR1 alpha). Intermediate grades of astrocytic tumors exhibited a gradual loss of FGFR2 and a shift in expression from FGFR1 alpha to FGFR1 beta as they progressed from a benign to a malignant phenotype. The underlying cytogenetic changes that contribute to these alterations are not entirely understood, but abnormalities in the p53 tumor suppressor gene may influence expression of bFGF as well as the FGFR. These results suggest that alterations in FGFR signal transduction pathways may play a critical role in the malignant progression of astrocytic tumors.

Astrocytes↗

PubMed1994

Inositolhexakisphosphate (InsP6): an antagonist of fibroblast growth factor receptor binding and activity.

Fibroblast growth factors (FGF), which have been implicated in tumor cell growth and angiogenesis, have biological activities that appear to be mediated by both heparinlike extracellular matrix sites and transmembrane tyrosine kinase receptor sites. In the present study, we demonstrated that inositolhexakisphosphate (InsP6) inhibits basic FGF (bFGF) binding to heparin. Our spectrofluorometric analyses demonstrated that InsP6 not only bound to bFGF, presumably within the bFGF heparin-binding domain, but also protected bFGF from degradation by trypsin. Also, InsP6 inhibited the cellular binding of bFGF and other fibroblast growth factor family members such as acidic FGF (aFGF) and K-FGF in a saturable and dose-dependent manner. Furthermore, concentrations as low as 100 microM InsP6 inhibited bFGF-induced DNA synthesis in AKR-2B fibroblasts, as well as the growth of bFGF- and K-FGF-transfected NIH/3T3 cells. Together, these results indicate that InsP6 may serve as a useful antagonist of FGF activity.

Animals↗

PubMed1993

Basic fibroblast growth factor expression is required for clonogenic growth of human glioma cells.

Basic fibroblast growth factor (bFGF) is a heparin-binding protein, expressing potent mitogenic and angiogenic properties. Elevated levels of bFGF have been identified in human gliomas and glioma cell lines, suggesting that bFGF expression is involved in the aberrant growth patterns associated with these tumors. In the present study, the influence of bFGF on additional parameters of glioma cell malignancy was evaluated utilizing three distinct methods to suppress bFGF expression or activity including antisense oligonucleotide primers, a neutralizing monoclonal antibody or an inhibitor of the agonist action of bFGF: (1) The addition of 30 microM bFGF-specific antisense oligonucleotide primer to the human glioma cell line SNB-19 resulted in a 55% inhibition in colony formation in soft agar. This effect was dose-dependent and specific, as sense strand primer was ineffective in suppressing growth. In addition to exhibiting fewer colonies, antisense treatment significantly altered colony morphology. (2) SNB-19 cell growth in culture was suppressed in the presence of a neutralizing bFGF-specific monoclonal antibody. (3) Inositolhexakisphosphate, a newly identified antagonist of FGF binding and activity, suppressed SNB-19 cell growth in soft agar culture. These results demonstrate that bFGF may regulate glioma growth and progression independent of its role in tumor angiogenesis and that bFGF release or secretion may be required for these actions.

Astrocytes↗

PubMed1993

Scientific integrity in nursing research.

Though scientific knowledge is presumed to be true, misconduct in generation and reporting of research has occurred. Causes of scientific misconduct may be personal, such as excessive ambition, or organizational, such as withholding negative results about a product for economic gain. Ethical conduct of science involves respect for persons, beneficence and justice throughout the research process. The bottom line is researchers must have the integrity to be truthful themselves and the courage to report disreputable practices. Nurses must conduct scientific endeavors and practice the science of nursing with integrity. Maintaining integrity is essential for the advancement of nursing as a science, and therefore, ongoing improvement in nursing care.

Ethics, Nursing↗

PubMed1992

Transforming growth factor beta has neurotrophic actions on sensory neurons in vitro and is synergistic with nerve growth factor.

Transforming growth factor beta (TGF beta) influences the growth and differentiation of a wide variety of nonneuronal cells (nnc) during embryogenesis and in response to wounding. In the present study TGF beta 1 and TGF beta 2 were examined for their neurotrophic actions on neonatal rat dorsal root ganglion (DRG) neurons with ganglionic nnc in dissociated cultures. TGF beta 1 and TGF beta 2 each increased both neuronal survival and levels of the peptide neurotransmitter substance P (SP) expressed per neuron as well as per culture. TGF beta 1 was maximally effective at a concentration of 40 pM, whereas TGF beta 2 was about 10-fold less potent. Survival effects promoted by simultaneous treatment with both factors were not additive. TGF beta 1 also changed the morphology and distribution of DRG nnc which resulted in clustering of DRG neurons on top of the nnc. Cotreatment of the cultures with two different anti-nerve growth factor (NGF) antibodies eliminated the neurotrophic effects of TGF beta 1. However, treatment with TGF beta 1 did not alter NGF mRNA expression in the cultures nor did it change the amount of NGF in the medium. Further, TGF beta 1 greatly enhanced survival effects and SP stimulation promoted by exogenous NGF at concentrations up to 100 ng/ml. The neurotrophic effects of TGF beta 1 were significantly attenuated by decreasing the proportion of the ganglionic nnc, suggesting a role for these cells in mediating TGF beta 1 action on the neurons. It is hypothesized that the neurotrophic activity of TGF beta depended upon the presence of molecules immunologically related to NGF and that the effects of TGF beta were synergistic with NGF. These observations suggest that TGF beta may play a role in the differentiation and regeneration of DRG neurons in vivo.

Animals↗

PubMed1992

Localization of acidic fibroblast growth factor within the mouse brain using biochemical and immunocytochemical techniques.

The localization of acidic fibroblast growth factor (aFGF) in the male mouse brain was studied with biochemical and immunocytochemical techniques. Using two peptide-based aFGF antisera directed against independent epitopes, Western gel analysis of dissected brain demonstrated significant levels of aFGF immunoreactivity in the pons-medulla, hypothalamus and cerebellum. The cortex contained much less immunoreactivity. Consistent with the biochemical data, immunocytochemical analysis with the same two antisera demonstrated that aFGF immunoreactivity is localized in neuronal cell bodies in these regions. Numerous immunoreactive neurons were observed in the reticular formation of the pons and medulla, as well as in several other brainstem nuclei and areas. Immunoreactive neurons were also present in the lateral and medial hypothalamus, and some thalamic, subthalamic and epithalamic nuclei. In the basal ganglia, immunoreactive neurons were present in the amygdala and septum. Few intensely stained immunoreactive neurons were observed in the striatum, pallidum and neocortex. Limbic cortices contained more numerous immunoreactive neurons than neocortex. These results support the concept that aFGF is present in the brain, where it is heterogeneously distributed in neuronal cell bodies in regions involved in sensory, extrapyramidal motor, limbic and autonomic functions. The results are consistent with various neurotrophic, mitogenic, and neuromodulatory functions associated with aFGF in the mammalian central nervous system.

Amino Acid Sequence↗

PubMed1992

Transforming growth factor alpha, but not epidermal growth factor, promotes the survival of sensory neurons in vitro.

Transforming growth factor alpha (TGF alpha) is a mitogenic polypeptide that is structurally homologous to epidermal growth factor (EGF) and appears to bind to the same receptor in all systems tested previously. In the present study, TGF alpha was found to enhance survival and neurite outgrowth of cultured neonatal rat dorsal root ganglion (DRG) neurons in a dose-dependent manner. This effect was observed with TGF alpha concentrations as low as 17.8 pM. By contrast, EGF at concentrations up to 83 nM was ineffective. Moreover, EGF did not antagonize the TGF alpha survival-promoting effect unless present in large excess (500-fold the concentration for which TGF alpha is effective); even in this case, only partial antagonism was achieved. Survival of neurons from nodose, trigeminal, and sympathetic ganglia was not increased by TGF alpha. Both a subpopulation of DRG neurons and of macrophages in the cultures bound iodinated TGF alpha. This binding was inhibited by excess unlabeled TGF alpha but not EGF. Our data are consistent with the possibilities that the actions of TGF alpha on DRG neurons occur indirectly via unidentified neurotrophic molecules other than NGF as well as directly on the neurons themselves. Thus, TGF alpha, in contrast to EGF, may act as a survival or maintenance factor for a subset of rat sensory neurons. Mediation of this neurotrophic effect appears to occur via a new form of TGF alpha receptor.

Animals↗

PubMed1991

A primary encephalocele culture yields a pure population of human astrocytes.

In order to develop a reliable source of human astrocytes for in vitro studies, we established a primary explant culture of a human encephalocele. This culture yielded a population of cells which were karyotypically normal, morphologically resembled astrocytes, expressed glial fibrillary acid protein, and responded mitogenically to exogenous growth factors. We conclude that white matter derived from human encephaloceles can be used to generate pure populations of normal astrocytes.

Astrocytes↗