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Biomedical subjects

S A Goldman

Publications and source records attributed to S A Goldman.

At least 19 recordsLinked to original sources
PubMed1999

Estrogen promotes the initial migration and inception of NgCAM-dependent calcium-signaling by new neurons of the adult songbird brain.

The adult avian forebrain continues to generate neurons from ventricular zone (VZ) precursor cells, whose neuronal progeny then migrate into the brain parenchyma. Migrating neurons respond to the Ig-family adhesion molecule NgCAM with increments in cytosolic calcium, and migration is disrupted by anti-NgCAM Ig. The calcium response to NgCAM is developmentally restricted to bipolar migrants during a period spanning 6 to 9 DIV. This period corresponds to the postmitotic age at which new neurons leave the adult VZ to traverse a subjacent layer of estrogen-receptive "gatekeeper" neurons. Since neuronal passage through this layer occurs concurrently with the onset of NgCAM-dependent calcium signaling, we asked whether acquisition of the calcium response to NgCAM required estrogen exposure. Among neurons arising from explants of the adult finch neostriatal VZ, only those supplemented with estrogen developed calcium responses to NgCAM; neither explants raised in the absence of estrogen, nor those supplemented with testosterone, did so. Neurons in all three groups expressed NgCAM, had equivalent baseline calcium levels, and responded identically to K+-depolarization. Nonetheless, many more neurons migrated from explants of both finch and canary VZ raised in estrogen-supplemented media than from their estrogen-deprived counterparts, even though no effect of estrogen on neuronal survival per se was noted. These findings suggest that estrogen encourages the initial departure and assumption of signal competence by neurons arising from the adult avian VZ, thereby promoting their parenchymal recruitment and migration success.

Animals↗
PubMed1999

Endothelial trophic support of neuronal production and recruitment from the adult mammalian subependyma.

Vascular endothelial cells are among the first cells that ventricular zone neuroblasts encounter during early development. The ventricular zone cells promote angiogenesis by the invading vasculature, with the release of endothelial mitogens. Yet the feedback support of young neurons by endothelial cells (ECs) has not hitherto been explored. We therefore asked whether ECs might participate in neuronal recruitment, by providing neurotrophic support to newly generated neurons. We used the neurogenic subependymal zone (SZ) of the adult rat forebrain as a model system, because of its well-characterized and relatively homogeneous population of neuronal precursor cells. We found that explants of the adult rat SZ raised on ECs generated more neurons, which survived longer, than explants raised on astrocytes, fibroblasts, or laminin. This endothelial trophic effect was humoral, in that it was also noted in SZ explants raised in noncontiguous coculture with ECs grown on porous inserts. RT-PCR for neurotrophin family members revealed that cultures of both human brain- and umbilical cord-derived ECs produced brain-derived neurotrophic factor (BDNF) mRNA, but no detectable NGF, NT-3, or NT-4 mRNA. ELISA revealed that BDNF protein was secreted by ECs into the medium at >1 ng/ml. The neurotrophic effect of ECs could be replaced by added BDNF, and was blocked by addition of 5 microg/ml trkB-Fc to endothelial-SZ cocultures. Thus, endothelial cells can act as sources of secreted BDNF, through which the capillary microvasculature may act to support neuronal recruitment and survival in the CNS.

Animals↗
PubMed1998

Peritumoral CD1a-positive dendritic cells are associated with improved survival in patients with tongue carcinoma.

OBJECTIVES: To determine if survival and recurrence rates for patients with squamous cell carcinoma of the tongue correlate with the degree of dendritic cell (DC) infiltration of the primary tumor or adjacent tongue tissue and if there is an association between tumor or nodal stage and DC infiltration. DESIGN: Hospital and office medical records were reviewed to obtain 5-year follow-up data. Original pathology specimens were recut and stained for the cell surface markers S100 and CD 1a. The number of DCs present in the specimens was quantified microscopically and compared statistically with patient outcome and staging. SETTING: A university hospital. PATIENTS: All patients who underwent resection of primary squamous cell carcinoma of the tongue from January 1, 1987, through December 31, 1990, for whom 5-year follow-up data and original pathology specimens were available (N=43). MAIN OUTCOME MEASURES: Time to recurrence, death, or both. RESULTS: Patients who had greater numbers of CD1a-positive DCs adjacent to tumor had improved survival (P=.02) and decreased recurrence rates (P=.06). The other subpopulations of DCs examined were not associated with survival or recurrence. In addition, the number of CD 1a-positive DCs in peritumoral epithelium decreased as the tumor stage increased (P=.01) and if nodal metastases were present (P=.05). CONCLUSIONS: Dendritic cells are antigen-presenting cells that are thought to play a major role in the antitumor immune response. The CD1a surface antigen has been shown to mediate T-cell interactions. The association between CD1a-positive peritumoral DCs and patient outcome suggests an important function for this cell population.

Adult↗
PubMed1998

Insulin-like growth factor-1 is a radial cell-associated neurotrophin that promotes neuronal recruitment from the adult songbird edpendyma/subependyma.

In the adult songbird forebrain, neurons continue to be produced from precursor cells in the forebrain ependymal/subependymal zone (SZ), from which they migrate upon radial guide fibers. The new neurons and their radial cell partners may coderive from a common SZ progenitor, which may be the radial cell itself. On this basis, we asked whether radial cells might provide trophic support for the migration or survival of newly generated neurons. We focused upon the insulin-like growth factors (IGFs) IGF-1 and IGF-2, which have previously been shown to support the survival and differentiation of neural progenitor cells. We found that IGF-1 immunoreactivity was expressed heavily by adult zebra finch radial cells and their fibers, with little expression otherwise. IGF-2, in contrast, was expressed by parenchymal astrocytes and exhibited little radial cell expression. Despite their distinct distributions, IGF-1 and IGF-2 exerted similar trophic effects on finch SZ cells in vitro; both greatly increased the number of neurons migrating from explants of the adult finch SZ, relative to explants raised in low-insulin, IGF-1-deficient media. However, neither factor extended neuronal survival. These results suggest that in neurogenic regions of the adult avian forebrain, IGF-1 acts as a radial cell-associated neuronal differentiation and/or departure factor, which may serve to regulate neuronal recruitment into the adult brain.

Animals↗
PubMed1998

Fibroblast growth factor-2/brain-derived neurotrophic factor-associated maturation of new neurons generated from adult human subependymal cells.

The adult mammalian forebrain harbors neuronal precursor cells in the subependymal zone (SZ). Neuronal progenitors also persist in the adult human SZ and have been cultured from epileptic temporal lobe. In the present study, we sought to identify these neural progenitors in situ, and to direct their expansion and neuronal differentiation in vitro. We prepared explants of adult human SZ, obtained from temporal lobe resections of refractory epileptics. The resultant cultures were treated with fibroblast growth factor-2 (FGF-2) for a week, with concurrent exposure to [3H]thymidine, then switched to media containing brain-derived neurotrophic factor (BDNF) for up to 2 months. Sporadic neuronal outgrowth, verified antigenically and physiologically, was observed from SZ cultures regardless of FGF-2/BDNF treatment; however, only FGF-2/BDNF-treated cultures exhibited profuse outgrowth, and these displayed neuronal survival as long as 9 weeks in vitro. In addition, cortical cultures derived from two brains generated microtubule-associated protein-2+ neurons, which incorporated [3H]thymidine and exhibited significant calcium increments to depolarization. In histological sections of the subependyma, both uncommitted and restricted progenitors, defined respectively by musashi and Hu protein expression, were identified. Thus, the adult human subependyma harbors neural progenitors, which are able to give rise to neurons whose numbers can be supported for prolonged periods in vitro.

Adult↗
PubMed1998

Limitations and strengths of spontaneous reports data.

US Food and Drug Administration (FDA) monitoring of the continued safety of marketed medical products depends greatly on spontaneous reporting of serious adverse events by health professionals. Despite its inherent limitations, the national postmarketing surveillance system provides vital information of clinical importance.

Adverse Drug Reaction Reporting Systems↗
PubMed1998

Strategies utilized by migrating neurons of the postnatal vertebrate forebrain.

Structural brain repair has become a possibility with the identification and characterization of persistent neuronal progenitor cells in both the neonatal and adult brain. However, despite recent advances in the identification, propagation and expansion of these cells, they will not be useful therapeutically until methods are available for directing or delivering them to sites of need. As a result, the natural history and induction of neuronal migration into adult brain tissue has assumed new importance in clinical neurobiology. In this review we consider the cellular and molecular bases of neuronal migration into the postnatal forebrain. In particular, we discuss two natural paradigms of postnatal neuronal recruitment: radial-cell-directed neuronal migration to the songbird neostriatum, and neurophilic migration to the rodent olfactory bulb. In each, we will focus on the dynamic interactions between the migrants, their cellular guides and the local environment, and the effect of those interactions on migrational success.

Aging↗
PubMed1998

Fatal meningitis and brain abscess resulting from foreign body-induced otomastoiditis.

Herein we report what we believe to be the only published case of an intracranial complication of otomastoiditis resulting from foreign-body material. The presence of a foreign body must be ruled out in any chronically draining ear, and all foreign material must be removed. The key to minimizing the morbidity of complications of infectious ear disease is early recognition and treatment. Early symptoms of complication include vertigo, new onset of headache or otalgia, or worsening headache or otalgia. Fever, malodorous ear drainage, and the presence of granulation tissue are warming findings. A high index of suspicion of infectious complications must be maintained in evaluating all patients with ear disease.

Bacteria, Anaerobic↗
PubMed1998

Astrocyte-mediated potentiation of inhibitory synaptic transmission.

We investigated the role of astrocytes in activity-dependent modulation of inhibitory synaptic transmission in hippocampal slices. Repetitive firing of an interneuron decreased the probability of synaptic failures in spike-evoked inhibitory postsynaptic currents (unitary IPSCs) in CA1 pyramidal neurons. The GABAB-receptor antagonist CGP55845A abolished this effect. Direct stimulation of astrocytes, or application of the GABAB-receptor agonist baclofen, potentiated miniature inhibitory postsynaptic currents (mIPSCs) in pyramidal neurons. These effects were blocked by inhibition of astrocytic calcium signaling with the calcium chelator BAPTA or by antagonists of the ionotropic glutamate receptors. These observations suggest that interneuronal firing elicits a GABAB-receptor-mediated elevation of calcium in surrounding astrocytes, which in turn potentiates inhibitory transmission. Astrocytes may therefore be a necessary intermediary in activity-dependent modulation of inhibitory synapses in the hippocampus.

Animals↗
PubMed1998

Isolation of neuronal precursors by sorting embryonic forebrain transfected with GFP regulated by the T alpha 1 tubulin promoter.

Neuronal precursor cells are widespread in the forebrain ventricular/subventricular zone, and may provide a cellular substrate for brain repair. Clonal lines derived from single progenitors can become progressively less representative of their parental precursors with time and passage in vitro. We have developed an alternative strategy for the isolation and enrichment of precursor cells, by fluorescence-activated cell sorting of forebrain cells transfected with the gene for green fluorescent protein, driven by the neuronal T alpha 1 tubulin promoter. Using this approach, neural precursors and young neurons can be identified and selectively harvested from a variety of samples, including both avian and mammalian forebrains at different developmental stages.

Animals↗
PubMed1998

Neural stem and progenitor cells: a strategy for gene therapy and brain repair.

The damaged adult mammalian brain is incapable of significant structural self-repair. Although varying degrees of recovery from injury are possible, this is largely because of synaptic and functional plasticity rather than the frank regeneration of neural tissues. The lack of structural plasticity of the adult brain is partly because of its inability to generate new neurons, a limitation that has severely hindered the development of therapies for neurological injury or degeneration. However, a variety of experimental studies, as well as moderately successful clinical engraftment of fetal tissue into the adult parkinsonian brain, suggests that cell replacement is evolving as a valuable treatment modality. Neural stem cells, which are the self-renewing precursors of neurons and glia, have been isolated from both the embryonic and adult mammalian central nervous system. In the adult human brain, both neuronal and oligodendroglial precursors have been identified, and methods for their harvest and enrichment have been established. Neural precursors have several characteristics that make them ideal vectors for brain repair. They may be clonally expanded in tissue culture, providing a renewable supply of material for transplantation. Moreover, progenitors are ideal for genetic manipulation and may be engineered to express exogenous genes for neurotransmitters, neurotrophic factors, and metabolic enzymes. Thus, the persistence of neuronal precursors in the adult mammalian brain may permit us to design novel and effective strategies for central nervous system repair, by which we may yet challenge the irreparability of the structurally damaged adult nervous system.

Animals↗
PubMed1998

Adult neurogenesis: from canaries to the clinic.

Neuronal precursor cells persist in the adult vertebrate forebrain, residing primarily in the ventricular/subventricular zone (SZ). In vivo, SZ precursors yield progeny which may die or give rise to glia. Yet they may also generate neurons, which are recruited to restricted regions such as the avian telencephalon and mammalian olfactory bulb. The survival of neurons arising from adult progenitors is dictated by both the availability of a permissive pathway for migration and the environment into which migration occurs. In the songbird higher vocal center (HVC), both humoral and contact-mediated signals modulate the migration and survival of new neurons, through an orchestrated set of hormonally regulated paracrine interactions. New neurons of the songbird brain depart the SZ to enter the brain parenchyma by migrating upon radial guide fibers, which emanate from cell bodies in the ventricular epithelium. The radial guide cells coderive with new neurons from a common progenitor, which is widespread throughout the songbird SZ. Neural precursors are also widely distributed in the adult mammalian SZ, although it is unclear whether avian and mammalian progenitor cells are homologous: Whereas neuronal recruitment persists throughout much of the songbird forebrain, in mammals it is limited to the olfactory bulb. In humans, the adult SZ appears to largely cease neurogenesis in vivo, although it, too, can produce neurons in vitro. In both rats and humans, the differentiation and survival of neurons arising from the postnatal SZ may be regulated by access to postmitotic trophic factors. Indeed, serial application of fibroblast growth factor-2 (FGF-2) and brain-derived neurotrophic factor (BDNF) has allowed the generation and maintenance of neurons from the adult human SZ. This suggests the feasibility of inducing neurogenesis in the human brain, both in situ and through implanted progenitors. In this regard, using cell-specific neural promoters coupled to fluorescent reporters, defined progenitor phenotypes may now be isolated by fluorescence-activated cell sorting. Together, these findings give hope that structural brain repair through induced neurogenesis and neurogenic implants will soon be a clinical reality.

Aging↗
PubMed1998

Improving patient care by reporting problems with medical devices.

Healthcare practitioners are the primary users of medical devices for direct patient care. As such, they are in the best position to recognize problems that result from the use of medical devices. The outcome of a device-related adverse event or product problem, as with any other medical product, can be serious and result in illness injury, or even death. The sooner that FDA learns about a problem, the sooner the agency can take action to protect patient and user safety. Healthcare practitioners are major contributors to the knowledge base related to device use and safety through astute monitoring, rapid identification of device-related problems, and reporting these problems. An understanding of the voluntary and mandatory mechanism of reporting will ensure that device problems are reported appropriately and in a timely manner. As the primary users of medical equipment for direct patient care, health care professionals have the training and expertise to improve patient care by reporting actual and suspected problems with medical devices.

Adverse Drug Reaction Reporting Systems↗
PubMed1997

Neuronal precursors of the adult rat subependymal zone persist into senescence, with no decline in spatial extent or response to BDNF.

The adult mammalian brain continues to harbor ependymal/subependymal zone (SZ) precursor cells, which can give rise to neurons in vitro. In adult rats, explants of the rostral 6-7 mm of the SZ give rise to neurons in vitro, and over this entire expanse, neuronal survival is supported specifically by brain-derived neurotrophic factor (BDNF). We asked whether either the (a) spatial distribution, (b) abundance, or (c) BDNF responsiveness of the neuronal precursor population was affected by age. Explants of three rostrocaudally defined regions were taken from both young and old rats (3 and 20 months old, respectively), and cultured in 2% fetal bovine serum-containing media with or without added BDNF (20 ng/ml). The extent of neuronal production by these explants varied only minimally with their level of derivation, such that substantial outgrowth was observed at each level tested. Neuronal outgrowth was marginally higher and more rapid in achieving its maximal extent in the 3-month-old rats compared with their aged counterparts, but neuronal outgrowth was robust at each age tested. The duration of survival of SZ-derived neurons did not differ between the young and old rats. At both ages, BDNF supported the survival of these new adult neurons. The extent of BDNF's influence was independent of both the age of the donor rat and the rostrocaudal level at which the parent SZ explant was taken. Thus, the neuronal precursors of the rat brain persist into senescence; the size of the precursor pool attenuates minimally with age, and its spatial extent remains constant. The neurons generated from these precursors can respond to BDNF throughout life.

Aging↗
PubMed1997

The effect of acidic fibroblast growth factor and live yeast cell derivative on tympanic membrane regeneration in a rat model.

The current treatment of choice for chronic tympanic membrane perforations is surgery. Recent studies using various polypeptide growth factors to accelerate closure of tympanic membrane perforations in model systems have produced mixed results. This study evaluates the effect of acidic fibroblast growth factor (AFGF) and live yeast cell derivative (LYCD) on the rate of healing of acute tympanic membrane perforations in a rat model. Thirty-seven rats had both ears separately randomized in a blinded fashion to receive AFGF in one of three concentrations, LYCD, or a control solution. The rats initially underwent subtotal removal of the tympanic membranes bilaterally. Solutions were applied to the randomized ears daily for 3 days, starting at the time of the surgical perforation. The ears were photographed every 3 to 8 days for 35 days. The photographs were digitally scanned and a computer analysis was used to calculate the percentage of residual perforation. No significant difference in the rate of healing was observed for ears treated with AFGF or LYCD versus the controls. Given the potential advantages of medical treatment of tympanic membrane perforations and the established efficacy of growth factors in other model systems, however, further research is warranted.

Animals↗