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Biomedical subjects

W Gilmore

Publications and source records attributed to W Gilmore.

At least 19 recordsLinked to original sources
PubMed1998

Hyposexuality produced by temporal lobe epilepsy in the cat.

PURPOSE: The hypothesis tested in this study was that a unilateral irritative focal epileptic lesion in the temporal lobe results in hyposexuality. METHODS: Focal epilepsy was produced in male cats by unilateral injection of aluminum hydroxide into either the basolateral amygdala (temporal lobe group) or anterior sigmoid gyrus (motor cortex group). Weekly sex testing trials with estrous females were conducted prior to and after aluminum hydroxide injection, and mating performance scores were compared with those of normal, unoperated cats (normal control group). RESULTS: All animals receiving aluminum hydroxide developed electroencephalographic and behavioral manifestations of epilepsy; i.e., interictal EEG spiking and partial or generalized seizures. Cats in the temporal lobe group exhibited a dramatic and complete suppression of sexual behavior at periods from 6 to 26 weeks after aluminum hydroxide injection. The duration of the hyposexuality varied between individual animals and returned to normal as suddenly as the onset occurred, despite the use of AEDs to prevent or control generalized seizure activity. Interictal EEG epileptiform spiking in the amygdala preceded the onset of hyposexuality by 1-12 weeks. By contrast, cats in the motor cortex and normal control groups showed no sign of sexual dysfunction throughout the experimental period, independent of seizure activity and/or antiepileptic drug (AED) treatment. CONCLUSIONS: These data support the hypothesis that hyposexuality occurs as a result of epileptiform activity in the temporal lobe, but not in the motor cortex. The precise mechanisms by which this occurs are unknown, but are likely to involve abnormally high-frequency neuronal activity in temporal lobe structures known to connect with and/or to regulate hypothalamic nuclei that organize male sexual behavior toward receptive females.

Aluminum Hydroxide↗
PubMed1997

Effect of estradiol on cytokine secretion by proteolipid protein-specific T cell clones isolated from multiple sclerosis patients and normal control subjects.

The ability of estradiol (E2) to modulate the secretion of cytokines by CD4+ T cells was investigated using neuroantigen-specific T cell clones isolated from normal control subjects and patients with the demyelinating disease, multiple sclerosis. In the presence of E2, the majority of the tested clones showed a dose-dependent enhancement of Ag-stimulated IL-10 secretion. The secretion of IFN-gamma was also enhanced, although the peak enhancement occurred at lower E2 concentrations and at lower magnitude than observed for IL-10. By contrast, the effect of E2 on Ag-stimulated secretion of TNF-alphabeta was biphasic, with enhancement occurring at low doses, and inhibition present at high concentrations. E2 had no effect on the secretion of IL-4 or TGF-beta. These data indicate that E2 is capable of modulating both pro- and anti-inflammatory activities of CD4+ T cells and thus has the potential to influence the outcome of CD4+ T cell-mediated immune responsiveness.

Adult↗
PubMed1996

p53-deficient mice are protected against adrenalectomy-induced apoptosis.

The p53 tumor suppressor gene, an important regulator of the cell cycle, has been implicated in apoptotic cell death in vitro, and more recently in neuronal degeneration in vivo. The present study investigated the importance of p53 expression in the apoptotic death of hippocampal granule cells following adrenalectomy. Mice, either homozygous or heterozygous for the p53 null allele and wild-type controls were sacrificed 16 days after adrenalectomy. Hippocampal morphology was assessed in paraffin sections stained with hematoxylin and eosin. Cells exhibiting features characteristic of apoptosis were evident in hippocampi from wild-type mice. A significant decrease in the number of apoptotic cells was observed in both homozygous and heterozygous mice. These findings demonstrate that absence or attenuation of p53 expression protects granule cells from adrenalectomy-induced apoptosis and, combined with the results of other studies, suggest that p53 is required for certain types of neuronal degeneration.

Adrenalectomy↗
PubMed1996

Defective post-thymic tolerance mechanisms during the chronic progressive stage of multiple sclerosis.

We have recently isolated a panel of T-cell clones from chronic progressive multiple sclerosis (MS) patients that are capable of functioning as antigen-presenting cells and of expressing the costimulatory molecules B7-1 and B7-2. In this report we show that these T-cell clones are resistant to inhibitory regulation, including the induction of anergy and sensitivity to tumor growth factor-beta (TGF-beta)-induced growth inhibition. The resistance to anergy induction was associated with expression of B7 costimulatory molecules. These data suggest that lack of responsiveness to peripheral inhibitory signals may account for the entry of autoimmune diseases into a chronic progressive phase.

Adult↗
PubMed1995

Patterns of cytokine secretion by autoreactive proteolipid protein-specific T cell clones during the course of multiple sclerosis.

To determine whether cytokine secretion patterns change with disease status in patients with multiple sclerosis (MS), we measured IFN-gamma, TNF-alpha beta, IL-4, IL-6, IL-10 and TGF-beta secretion in a panel of T cell clones (TCCs) specific for proteolipid protein (PLP) after stimulation with PLP peptides or polyclonal activators. During acute attack, the predominant pattern of cytokine secretion resembled that of murine Th1 cells; i.e, IFN-gamma and TNF-alpha beta, and appeared to be restricted to PLP-reactive TCCs. None of the TCCs isolated during acute attack produced TGF-beta in response to PLP, Con A, or anti-CD3 Ab. Half of these TCCs were, however, capable of TGF-beta secretion and mRNA expression upon stimulation with PMA and the calcium inonphore A23187, suggesting a possible defect in activation through the TCR/CD3 pathway. During remission in the same patients all but two PLP-TCCs showed patterns of cytokine secretion resembling that of murine Th0, Th1, and Th2 subsets. The levels of IL-10 secreted by these TCCs were significantly higher than those of TCCs isolated during acute attacks and those derived from normal subjects and patients with other noninflammatory neurologic diseases. Furthermore, 50% of these TCCs were capable of producing TGF-beta after Ag-specific or polyclonal stimulation. All TCCs isolated from control subjects exhibited a Th0 like secretion profile. These data indicate that different stages of disease in MS are characterized by different patterns of cytokine secretion by PLP-specific TCCs, suggesting a role for cytokines in clinical events during the course of MS.

Autoantigens↗
PubMed1995

Effect of persistent mouse hepatitis virus infection on MHC class I expression in murine astrocytes.

Neurotropic strains of mouse hepatitis virus (MHV) have been used extensively for the study of viral pathogenesis in the central nervous system (CNS), serving as models for human neurological diseases such as multiple sclerosis (MS). MHV strains A59 and JHMV both cause acute and chronic encephalomyelitis and demyelination in susceptible strains of mice and rats. In acute disease, CNS damage is most likely the result of lytic infection in neurons and oligodendrocytes, and death can be prevented by the adoptive transfer of Class I-restricted CD8+ T cells. However, in later stages of the disease induced by some MHV strains, virus tends to be restricted to astrocytes in a nonlytic infection, and the immune response appears to contribute to CNS damage. These data lead us to suggest that the astrocyte may play a central role in the neuropathogenesis of MHV infection. Consistent with this possibility, A59 has been reported to induce the expression of Class I molecules of the major histocompatibility complex (MHC) in glial cells following infection in vivo and in vitro. In this communication, we have examined the influence of persistent infection by both A59 and JHMV on MHC Class I expression in primary murine astrocytes. Persistence was characterized by the presence of intracellular viral antigen and mRNA in the absence of detectable infectious virus particles. Under these conditions, JHMV, but not A59, inhibited constitutive expression of the H-2 Kb molecule, with the magnitude of inhibition increasing with postinfection time. A59 was not able to induce Class I during persistence, presumably due to the lack of infectious virus particles. Class I expression was restored by the addition of gamma-interferon (IFN-gamma) to astrocytes persistently infected with either A59 or JHMV. Thus, Class I inhibition is not a permanent consequence of JHMV persistence, and persistence does not interfere with normal signalling pathways for Class I induction.

Animals↗
PubMed1995

Neuropathogenicity of mouse hepatitis virus JHM isolates differing in hemagglutinin-esterase protein expression.

The hemagglutinin-esterase (HE) protein of mouse hepatitis virus (MHV) is an optional envelope protein present in only some MHV isolates. Its expression is regulated by the copy number of a UCUAA pentanucleotide sequence present in the leader sequence of the viral genomic RNA. The functional significance of this viral protein so far is not clear. In this report, we compared the neuropathogenicity of two MHV isolates, JHM(2) and JHM(3), which express different amounts of HE protein. Intracerebral inoculation of these two viruses into C57BL/6 mice showed that JHM(2), which expresses an abundant amount of HE protein, was more neurovirulent than JHM(3), which expresses very little HE. Histopathology showed that early in infection, JHM(2) infected primarily neurons, while JHM(3) infected mainly glial cells. JHM(3) eventually infected neurons and caused a delayed death relative to JHM(2)-infected mice, suggesting that the progression of JHM(3) infection in the central nervous system was slower than JHM(2). In vitro infection of JHM(3) in primary mixed glial cell cultures of astrocyte-enriched cultures yielded higher virus titers than JHM(2), mimicking the preferential growth of JHM(3) in glial cells in vivo. These findings suggest that the reduced neuropathogenicity of JHM(3) may correlate with its preferential growth in glial cells. Sequence analysis showed that the S genes of these two viruses are identical, thus ruling out the S gene as the cause of the difference in neuropathogenicity between these two viruses. We conclude that the HE protein contributes to viral neuropathogenicity by influencing either the rate of virus spread, viral cell tropism or both.

Acetylesterase↗
PubMed1994

Coronavirus induction of class I major histocompatibility complex expression in murine astrocytes is virus strain specific.

Neurotropic strains of mouse hepatitis viruses (MHV) such as MHV-A59 (A59) and MHV-4 (JHMV) cause acute and chronic encephalomyelitis and demyelination in susceptible strains of mice and rats. They are widely used as models of human demyelinating diseases such as multiple sclerosis (MS), in which immune mechanisms are thought to participate in the development of lesions in the central nervous system (CNS). The effects of MHV infection on target cell functions in the CNS are not well understood, but A59 has been shown to induce the expression of MHC class I molecules in glial cells after in vivo and in vitro infection. Changes in class I expression in infected cells may contribute to the immunopathogenesis of MHV infection in the CNS. In this communication, a large panel of MHV strains was tested for their ability to stimulate class I expression in primary astrocytes in vitro. The data show that the more hepatotropic strains, such as MHV-A59, MHV-1, MHV-2, MHV-3, MHV-D, MHV-K, and MHV-NuU, were potent inducers of class I expression in astrocytes during acute infection, measured by radioimmunoassay. The Kb molecule was preferentially expressed over Db. By contrast, JHMV and several viral strains derived from it did not stimulate the expression of class I molecules. Assays of virus infectivity indicated that the class I-inducing activity did not correlate with the ability of the individual viral strain to replicate in astrocytes. However, exposure of the viruses or the supernatants from infected astrocytes to ultraviolet light abolished the class I-inducing activity, indicating that infectious virus is required for class I expression. These data also suggest that class I expression was induced directly by virus infection, and not by the secretion of a soluble substance into the medium by infected astrocytes. Finally, analyses of A59/JHMV recombinant viral strains suggest that class I-inducing activity resides in one of the A59 structural genes.

Animals↗
PubMed1993

Beta-endorphin protects mice from neurological disease induced by the murine coronavirus MHV-JHM.

The neurotropic murine coronavirus, MHV-JHM (JHMV) causes encephalitis and paralytic-demyelinating disease in susceptible strains of mice and rats, serving as a model for human demyelinating diseases such as multiple sclerosis. In this communication, we report that a single intracerebral administration of the naturally occurring neuropeptide, beta-endorphin, reduced the incidence of JHMV-induced paralytic-demyelinating disease 40-50% in C57Bl/6 mice. Protection from disease was accompanied by significantly reduced virus replication in the brain as early as 3 days post-infection and did not occur in irradiated, or immunoincompetent mice. The data suggest that beta-endorphin engages immune mechanisms of host resistance to JHMV infection to protect the mice from disease.

Amino Acid Sequence↗
PubMed1992

Sequential infection of glial cells by the murine hepatitis virus JHM strain (MHV-4) leads to a characteristic distribution of demyelination.

An antigenic variant of the neurotropic murine coronavirus JHMV, designated 2.2-V-1, causes marked demyelination in the relative absence of encephalitis. It is thus useful for the study of the pathogenesis of demyelinating lesions. To better understand the sequential events leading to demyelination, we have examined murine brain and spinal cord tissue at daily intervals after intracerebral inoculation, evaluating them for the distribution of viral antigen, leukocyte infiltration, and demyelination. Immunohistochemical staining indicated that virus established primary infection in the ependymal cells in both brain and spinal cord before spreading into nearby structures and along white matter tracts by cell-to-cell contact. Spread from brain to spinal cord appeared to occur via cerebrospinal fluid. Viral replication was focally cytocidal for ependymal cells, and essentially noncytocidal for other neural cells including glia. In brain, viral antigen and inflammation reached a peak at day 5 postinfection, and rapidly subsided by day 10 postinfection. In spinal cord, viral antigen was less abundant than in brain and was maximal between days 7 and 9 postinfection. The inflammatory response and demyelination, however, were more severe persisting from day 7 through day 19. In the spinal cord, demyelinating lesions developed initially in areas closer to the central canal and were detected most prominently in the anterior funiculi. This finding suggests that the permissiveness of the ependymal cell is crucial to viral entry and that sequential infection of glial cells leads to the characteristic distribution of demyelination.

Animals↗
PubMed1991

Aspergillus flavus and aflatoxins B1, B2, and M1 in corn associated with equine death.

Corn from an Arkansas farm, where three horses died and others became sick, was investigated for causative principles. Necropsy of the three horses revealed what appeared to be severe hepatic necrosis. Histopathological examination indicated a pattern of hepatic lesions that was suggestive of aflatoxin contamination of the feed. Mycological examination of the corn by dilution plating revealed 95% of the colonies as Aspergillus flavus. Chemical analysis of the corn for mycotoxins was positive for aflatoxin B1, B2, and M1 at concentrations of 114, 10, and 6 micrograms/Kg, respectively. Cyclopiazonic acid, sterigmatocystin, and the Fusarium toxins, vomitoxin (deoxynivalenol), T-2 toxin, and diacetoxyscirpenol, were not detected. The presence of aflatoxin metabolites in the moldy corn and the presence of appropriate lesions were compatible with the diagnosis, equine aflatoxicosis.

Aflatoxins↗
PubMed1990

Stressor induced variations of intracranial self-stimulation from the mesocortex in several strains of mice.

Intracranial self-stimulation (ICSS) from the mesocortex was assessed in BALB/cByJ, C57BL/6J and DBA/2J mice immediately, 24 h and again 168 h following stressor application. Stressor exposure failed to influence ICSS performance in C57BL/6J mice, while self-stimulation performance was reduced among BALB/cByJ mice only in the immediate post-stressor interval. In contrast, DBA/2J mice exhibited reduced rates of responding for brain stimulation at each of the post-stressor intervals. The potential contribution of DA alterations to the strain-dependent variations of ICSS performance induced by uncontrollable footshock are discussed.

Animals↗
PubMed1990

The enhancement of polyclonal T cell proliferation by beta-endorphin.

Beta-endorphin (beta-end) is a naturally occurring opioid peptide that has been implicated as a modulator of immune function. In this communication, data are presented to illustrate that beta-end enhances proliferation of murine splenocytes stimulated by the T cell mitogen, Con A. The T cell sensitivity of this effect was demonstrated in cell preparations enriched for T cells by nylon wool separation. The opioid specificity of the enhancement indicates that the C-terminus of the 31 amino acid peptide contributed significantly to the effect. In addition, the magnitude and the incidence of the enhancement was highly dependent on the concentration of Con A, the density of the tested cells and the timing of the addition of beta-end relative to that of Con A. These observations suggest that the state of activation of the T cell is a principal determinant of its sensitivity to beta-end. Overall, the data provide compelling evidence for the existence of an immunomodulatory role for beta-end.

Animals↗
PubMed1989

Evidence for a subpopulation of antigen-presenting cells specific for the induction of the delayed-type hypersensitivity response.

Young adult SJL mice (8 weeks of age or younger) do not mount a delayed-type hypersensitivity (DTH) response due to the failure of a macrophage antigen-presenting cell (APC) to induce TDTH effector cells. SJL mice that are 10 weeks of age or older produce a normal DTH response. This genetic defect provides a model for the investigation of functional subpopulations of APC which interact with specific subpopulations of T cells. In this study, we used this model to examine whether macrophage APC impairment involves APC-dependent immune responses other than DTH. No age-dependent differences were found in the ability of spleen cells from SJL mice to proliferate and synthesize interleukin-2 in response to concanavalin A; nor was the proliferative response to a variety of antigenic stimuli affected. In addition, no differences were observed in the contact sensitivity response or in the in vitro generation of allogeneic cytotoxic T lymphocytes (CTL). In contrast, the in vivo generation of allogeneic CTL was significantly depressed in 6-week-old SJL and could not be restored to normal by the adoptive transfer of macrophages from DTH responsive 12-week-old SJL mice. Finally, examination of the humoral response of 6-week-old SJL indicated no impairment in IgM or IgG serum antibody levels or in the induction of splenic B cells. Thus, the macrophage APC regulating the induction of TDTH effector cells does not appear to participate in the induction of T helper cells for other cellular and humoral responses. These data support the hypothesis that distinct subpopulations of APC may regulate the induction of specific immune effector mechanisms.

Animals↗
PubMed1988

Antigenic assessment of coronaviruses isolated from patients with multiple sclerosis.

Many studies have either supported or discounted the role of coronaviruses as etiologic agents in multiple sclerosis (MS). Two new approaches were applied to investigate this controversy. First, monoclonal antibodies specific for either murine coronaviruses (mouse hepatitis viruses) or human coronaviruses were used to characterize the antigenic features of MS-derived coronaviruses SK and SD. Both isolates were found to have a mouse hepatitis virus-type profile. Second, serum and cerebrospinal fluid antibodies to different coronaviruses, including SD, were measured in MS and control groups. No significant difference in antibody level to coronaviruses was found between MS and control samples. The results of these antigenic studies do not support a specific association between MS and coronaviruses.

Adult↗
PubMed1988

The effects of pertussis toxin and cholera toxin on mitogen-induced interleukin-2 production: evidence for G protein involvement in signal transduction.

GTP-binding proteins, known as G proteins, play important roles in transducing signals generated by the binding of specific ligands to cell surface receptors. We examined the possibility that a G protein is involved in transducing the concanavalin A (Con A) signal for IL-2 production using a T-cell hybridoma, FS6-14.13, and the bacterial toxins, pertussis toxin (PTX) and cholera toxin (CTX). These toxins are known to interact with and modify the functions of G proteins. High concentrations of PTX (25-50 micrograms/ml) stimulated IL-2 production in the FS-6 cells in the absence of Con A, presumably due to the ability of its B subunit to crosslink membrane proteins. However, in the presence of Con A, PTX inhibited IL-2 production at concentrations ranging from 0.05 to 50 micrograms/ml. It is unlikely that this inhibition was due to a competitive interaction between Con A and PTX for binding sites at the cell surface, since high concentrations of PTX only minimally reduced Con A-FITC binding, evaluated by FACS analysis. In addition, concentrations of PTX which were not able to stimulate IL-2 production in the absence of Con A, retained their ability to inhibit IL-2 production in the presence of Con A. These data suggest the involvement of the PTX A subunit in this activity. In support of this possibility, PTX catalyzed ADP-ribosylation of a Mr = 41,000-Da protein in FS-6 membranes. This strongly suggests that a PTX substrate is involved in transducing the Con A signal for IL-2 production in FS-6 cells. CTX also inhibited Con A-induced IL-2 production, an effect mimicked by the addition of dibutyryl-cAMP. This suggests that a CTX substrate linked to the adenylyl cyclase-cAMP pathway is probably not involved in transducing the stimulatory Con A signal, but may play a role in downregulating T-cell activation.

Adenosine Diphosphate Ribose↗