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Biomedical subjects

W R Tyor

Publications and source records attributed to W R Tyor.

At least 19 recordsLinked to original sources
PubMed2001

Update on viral encephalitis.

Over 100 viruses have been associated with acute central nervous system infections. The present review focuses on some of the most common agents of viral encephalitis, as well as important emerging viral encephalitides. In this context, the initial detection of West Nile virus in the Western Hemisphere during the 1999 New York City outbreak, the first description of Nipah virus in Malaysia, and the appearance in Asia of a new neurovirulent enterovirus 71 strain that causes severe neurologic disease are highlighted. In addition, advances regarding diagnosis, neuroimaging and treatment of Japanese and herpes simplex encephalitis are presented.

Brain↗
PubMed2000

Acute multiple sclerosis characterized by extensive mononuclear phagocyte infiltration.

In this study, we examine the clinical, neuroradiological, and immunohistochemical findings of a 51 year old white female who died 27 months after onset of acute multiple sclerosis despite treatment with interferon-beta, azathioprine, corticosteroids, and cyclophosphamide. Immunohistochemical studies revealed extensive gliosis and mononuclear phagocyte infiltration with corresponding upregulation of proinflammatory cytokines (eg. IFN-alpha, TNF-alpha). The significance of immunohistochemical findings with respect to clinical presentation is discussed.

Acute Disease↗
PubMed1999

Do alcohol and cocaine abuse alter the course of HIV-associated dementia complex?

Although psychoactive drugs are commonly used by AIDS patients, it is unclear whether commonly abused drugs, such as cocaine and ethanol, affect the course of HIV-associated dementia (HADC). Epidemiological studies have resulted in conflicting conclusions as to what role, if any, abused drugs play in HADC. In this review we discuss the clinical and pathological evidence that cocaine and ethanol might exacerbate the detrimental effects of HIV infection on the brain. We also review studies of cocaine and ethanol effects on various components of the immune system both in the presence and absence of retroviral infection. Data from these studies indicate that cocaine and ethanol have profound effects on the immune system that, in many respects, are enhanced by retroviral infection. We conclude that abused drugs likely affect the course of HADC but that proof awaits an examination of their interactive effects in an appropriate in vivo system of retroviral encephalitis.

AIDS Dementia Complex↗
PubMed1999

Immunohistochemical localization of kininogen in rat spinal cord and brain.

Kininogen localization has been determined by immunocytochemistry in rat spinal cord and brain using a kinin-directed kininogen monoclonal antibody. In the spinal cord, there were immunostained neurons and fibers in laminae I, II, VII, and IX, intensely stained fibers in the superficial layers of the dorsal horn, and immunoreactive glial and endothelial cells. Small neurons, satellite cells, and Schwann cells immunostained distinctly in the dorsal root ganglion. In the brain stem, there were immunoreactive neurons and fibers in the tractus solitarius and nucleus, trigeminal spinal tract and nuclei, periaqueductal gray matter, vestibular nuclei, cochlear nuclei, trapezoid body, medial geniculate nucleus, and red nucleus. Immunostained neurons and fibers were also found in cerebellum (dentate nucleus), cerebral cortex (layers III and V), hippocampus (pyramidal cell layer), and corpus callosum. Glia and endothelial cells stained in all brain regions. The widespread location of kininogen in neurons and their processes, as well as in glial and endothelial cells, indicates more than one functional role, including those proposed as a mediator, a calpain inhibitor, and a kinin precursor, in a variety of neural activities and responses.

Animals↗
PubMed1999

Interferon beta-1b and childhood multiple sclerosis.

The long-term treatment with interferon beta-1b of a 7-year-old male with relapsing-remitting multiple sclerosis is documented. Thirty-two months after initiating treatment, he demonstrates dramatic clinical improvement, without relapse, despite high titers of neutralizing antibodies to interferon beta-1b. It appears reasonable to attribute a role in his improvement to interferon beta-1b.

Adjuvants, Immunologic↗
PubMed1998

Increased calpain expression in activated glial and inflammatory cells in experimental allergic encephalomyelitis.

In demyelinating diseases such as multiple sclerosis (MS), myelin membrane structure is destabilized as myelin proteins are lost. Calcium-activated neutral proteinase (calpain) is believed to participate in myelin protein degradation because known calpain substrates [myelin basic protein (MBP); myelin-associated glycoprotein] are degraded in this disease. In exploring the role of calpain in demyelinating diseases, we examined calpain expression in Lewis rats with acute experimental allergic encephalomyelitis (EAE), an animal model for MS. Using double-immunofluorescence labeling to identify cells expressing calpain, we labeled rat spinal cord sections for calpain with a polyclonal millicalpain antibody and with mAbs for glial (GFAP, OX42, GalC) and inflammatory (CD2, ED2, interferon gamma) cell-specific markers. Calpain expression was increased in activated microglia (OX42) and infiltrating macrophages (ED2) compared with controls. Oligodendrocytes (galactocerebroside) and astrocytes (GFAP) had constitutive calpain expression in normal spinal cords whereas reactive astrocytes in spinal cords from animals with EAE exhibited markedly increased calpain levels compared with astrocytes in adjuvant controls. Oligodendrocytes in spinal cords from rats with EAE expressed increased calpain levels in some areas, but overall the increases in calpain expression were small. Most T cells in grade 4 EAE expressed low levels of calpain, but interferon gamma-positive cells demonstrated markedly increased calpain expression. These findings suggest that increased levels of calpain in activated glial and inflammatory cells in EAE may contribute to myelin destruction in demyelinating diseases such as MS.

Animals↗
PubMed1998

SCID mice with HIV encephalitis develop behavioral abnormalities.

Severe combined immunodeficient (SCID) mice inoculated intracerebrally (i.c.) with HIV-infected human monocytes develop brain pathology similar to that in humans with HIV encephalitis. This includes HIV-positive macrophages and multinucleated giant cells, astrogliosis, microglial nodules, and neuronal dropout. These xenografts survive about 1 month. To develop a model of chronic HIV encephalitis and to assay the resulting behavioral abnormalities, we reinoculated SCID mice i.c. every 4 weeks for 3 months with either HIV-infected human monocytes (n = 5) or uninfected human macrophages (n = 4) or administered no inoculation (n = 6); these three groups were monitored for behavioral abnormalities. Tests of cognitive function in a Morris water maze 3.5 months after the first inoculation suggested that HIV-infected mice performed poorly compared with controls. Following testing in the water maze on days 4 and 5 of acquisition, motor activity of infected mice was reduced in comparison with that of controls. Retention of goal location when tested 1 week later was impaired in HIV-infected mice compared with controls. Histopathologic analysis of brains revealed significant astrogliosis and strongly suggested higher numbers of major histocompatibility complex (MHC) class II-positive multinucleated macrophages in HIV-infected compared with control mice. Thus, our preliminary studies indicate that SCID mice with HIV encephalitis develop behavioral abnormalities reminiscent of human disease. These behavioral abnormalities are associated with significantly increased astrogliosis, the presence of HIV, and probably multinucleated giant cells. These studies further support the use of this SCID animal model system for studies of the pathogenesis of HIV encephalitis and for drug interventions.

AIDS Dementia Complex↗
PubMed1998

Increased calpain expression in experimental demyelinating optic neuritis: an immunocytochemical study.

Since calcium activated neutral proteinase (calpain) is present in the central nervous system (CNS) and degrades myelin proteins, this endopeptidase has been suggested to play a role in myelin destruction in demyelinating diseases such as multiple sclerosis (MS). In the present study, calpain immunocytochemical expression was examined in Lewis rats with acute experimental allergic encephalomyelitis (EAE), an animal model for MS and optic neuritis. To identify cells expressing calpain, we labeled rat optic nerve sections for calpain with a polyclonal myelin calpain antibody and with monoclonal antibodies for glial (GFAP, OX42) and inflammatory (CD2, ED2, ED1, IFN-gamma) cell-specific markers. The results showed increased calpain expression in microglia (OX42) and infiltrating macrophages (ED1,2) in EAE compared to normal controls. Astrocytes constitutively expressed calpain in controls and acute EAE. Reactive astrocytes in EAE located in or near inflammatory foci, exhibited markedly increased calpain expression. Most T cells in acute EAE showed low level calpain expression while activated IFN-gamma-producing lymphocytes in inflammatory foci exhibited elevated levels of calpain expression. Thus, our results demonstrate increased calpain expression (at transcriptional and/or translational levels) in a rat model of optic neuritis. A role for calpain in myelin destruction during optic neuritis may be relevant to the pathogenesis of this disorder.

Animals↗
PubMed1998

Long-term intracranial cannula stabilization in mice with light cured resin composites.

A simple and rapid method is described for the introduction and stabilization of chronic indwelling cannulae in mice. Materials and adhesive bonding techniques commonly used in restorative dentistry were used to stabilize the cannulae. The effectiveness of this method was evaluated by shear strength testing across time and histological evaluation of coronal brain sections. Shear strength increased during the first week post surgery and remained stable for up to 60 days. The force required to dislodge the cannulae from skulls ranged from 0.70 to 2.45 kg. Histological evaluation revealed no significant infection or inflammatory response due to the materials used. Cannulae stabilization by this technique appears to be suitable for most experimental conditions.

Animals↗
PubMed1997

Transforming growth factor-beta1 in adult human microglia and its stimulated production by interleukin-1.

Ameboid microglia express human immunodeficiency virus 1 (HIV-1) more frequently than do ramified microglia. These two microglial subtypes might also differ in the frequency with which they express transforming growth factor-beta1 (TGF-beta1), a cytokine that regulates HIV-1 expression in monocytes. Results described here show that ameboid and ramified microglia express TGF-beta1. In brain tissues from HIV-1-infected individuals as compared with seronegative controls, ameboid rather than ramified microglia more frequently expressed TGF-beta1. Ameboid microglia, isolated and cultured from postmortem adult human brain more frequently expressed TGF-beta1 in presence of interleukin-1(IL-1), a cytokine that is elevated in brains of HIV-1-infected individuals when compared with seronegative controls. The stimulation of TGF-beta1 by IL-1 was dose and time dependent, occurring with ameboid microglia isolated from either frontal cortex or globus pallidus but not midbrain pons. Ameboid microglia are similar to the RCA-1-positive cells that form clusters, called microglial nodules, in the brain of HIV-1-infected individuals. Pathologic conditions, such as disseminated microglial nodules, are associated with HIV-1 encephalitis, direct infection of the brain, and moderate to severe neurologic impairment. TGF-beta1 expression in ameboid microglia may play a role in HIV-1 neuropathogenesis.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Cocaine/sex type effects on T lymphocytes: a preliminary report.

The influence of gender on the effects of cocaine (5 or 40 mg/kg) on immune function of sexually immature (35-day-old) C57BL/6J mice was assessed. The proliferation of T cells in thymus and spleen stimulated with phytohemagglutinin (PHA) and concanavalin-A(Con-A) was determined by 3H thymidine incorporation 24 hours after cocaine injections. The drug produced a dose-dependent reduction (25-51%) of Con-A and PHA-stimulated T cell proliferation in thymus from both male and female mice. Additionally, the impairment occurred at a lower cocaine dose for female than for male mice when the T cells were challenged with PHA. Under the experimental conditions, cocaine did not alter weights or cell numbers of thymus and spleen or T cell proliferation in spleen.

Analysis of Variance↗
PubMed1995

Unifying hypothesis for the pathogenesis of HIV-associated dementia complex, vacuolar myelopathy, and sensory neuropathy.

Neurological diseases associated with HIV infection include dementia, vacuolar myelopathy, and sensory neuropathy. Although in vitro studies suggest that other nervous system cell types could harbor HIV, immunohistochemical and in situ hybridization studies have indicated that only macrophages/microglia are significantly infected in the central nervous system. In the peripheral nervous system, even HIV-infected macrophages are rare. Therefore, theories regarding the pathogenesis of HIV-associated neurologic disorders have centered around the elaboration of substances that may be toxic to neurons, oligodendrocytes or myelin. These potential toxins include HIV proteins, cellular metabolites, and cytokines. In this review we present evidence that there are large numbers of macrophages/microglia present in the nervous system of patients with these diseases and that they produce tumor necrosis factor (TNF)-alpha. The large increase in macrophage activity late in HIV infection may be due to the diminution in production by CD4-positive T cells of cytokines such as interleukin (IL)-4 and IL-10 which are inhibitors of macrophage activities. We hypothesize that HIV-associated dementia complex, vacuolar myelopathy, and sensory neuropathy are directly or indirectly related to the increased numbers of macrophages found in brain, spinal cord, and peripheral nerve. Future therapies may be directed towards inhibition of macrophage functions.

AIDS Dementia Complex↗
PubMed1995

A potential role for interferon-alpha in the pathogenesis of HIV-associated dementia.

Previous studies in patients receiving interferon-alpha (IFN-alpha) therapy and patients with systemic lupus erythematosus have demonstrated that elevated cerebrospinal fluid (CSF) levels of IFN-alpha are associated with cognitive dysfunction. We measured IFN-alpha levels in CSF and blood by ELISA in human immunodeficiency virus (HIV)-positive patients with (n = 21) and without (n = 23) dementia and HIV-negative controls (n = 48). IFN-alpha was significantly elevated in the CSF of HIV-positive patients with dementia compared to those without dementia and controls. An increasing amount of IFN-alpha in the CSF was correlated with the clinical parameter of increasing Memorial Sloan Kettering scores; although these correlations were not statistically significant, they further suggest an association of increased CSF IFN-alpha with neurocognitive dysfunction in AIDS. Immunocytochemical staining of brains demonstrated IFN-alpha-positive macrophages and astrocytes in frontal cortex and white matter and IFN-alpha mRNA was detected by reverse transcriptase-polymerase chain reaction, further indicating that IFN-alpha is made by cells within the brain and suggesting that the significant increases of IFN-alpha protein found in the CSF of patients with HIV-associated dementia complex are derived from intrinsic brain cells such as macrophages and astrocytes. Increased local production of IFN-alpha during HIV infection may contribute directly or indirectly to the pathogenesis of HIV-associated dementia.

AIDS Dementia Complex↗
PubMed1994

Age-dependent susceptibility to fatal encephalitis: alphavirus infection of neurons.

Sindbis virus encephalitis in mice provides a model for studying age-dependent susceptibility to acute viral encephalitis. The AR339 strain of SV causes fatal encephalitis in newborn mice, but weanling mice recover uneventfully. Increased virulence for older mice is associated with a single amino acid change from Gln to His at position 55 of the E2 glycoprotein. Weanling mice with normal immune systems clear infectious virus from neurons through an antibody-mediated mechanism. This does not happen in newborn mice because the infected neurons die soon after they are infected. Death in immature neurons, as well as most other mammalian cells infected with Sindbis virus, occurs by induction of apoptosis. This can be prevented by cellular expression of bcl-2, an inhibitor of apoptosis, which is expressed by mature neurons in culture. We conclude that mature neurons are resistant to induction of apoptosis after infection with SV through expression of cellular inhibitors of apoptosis. This provides the opportunity for antibody to clear virus by a noncytolytic mechanism.

Aging↗
PubMed1993

Control of astrocytosis by interleukin-1 and transforming growth factor-beta 1 in human brain.

Astrocytosis is a common neurocellular manifestation of brain pathology in individuals with a variety of diseases. It is comprised of astrocytic hyperplasia (an increase in number of astrocytes) and astrocytic hypertrophy (an increase in size of astrocytes). The precise cause(s) of astrocytosis remains unknown. We morphometrically measured the relative extent of astrocytosis in brains of 22 individuals who died with seven different diseases. The relative amounts of interleukin-1 (IL-1) and transforming growth factor-beta 1 (TGF-beta 1) immunoreactive products (IRPs) were next assessed in sections serial to those in which astrocytosis was measured because these cytokines were shown in animal and in vitro experiments to be associated with astrocytosis. The data demonstrate that astrocytosis and these cytokines were co-localized in all examined human tissues. Relative increase in density of astrocytes was correlated with the increase in total IL-1 but not TGF-beta 1. In contrast, the increase in size of astrocytes was correlated with TGF-beta 1 associated only with astrocytes but not with total IL-1. Both IL-1 and TGF-beta 1 IRPs were present in GFAP IRP-containing and other cells, as assessed by double label immunocytochemistry. These observations suggest that IL-1 acts on astrocytes by both, paracrine and autocrine mechanisms whereas, TGF-beta 1 only acts by an autocrine mechanism. Because these correlations were statistically significant and also because a change in number and size of astrocytes constitutes the most frequent response of astrocytes to several diseases or injury, we conclude that these cytokines may mediate the most common pathological change in human brain.

Astrocytes↗
PubMed1993

A model of human immunodeficiency virus encephalitis in scid mice.

Human immunodeficiency virus (HIV)-associated dementia complex is a common and devastating manifestation of the late phases of HIV infection. The pathogenesis of dementia complex is poorly understood and effective treatments have not been developed, in part because of the lack of an appropriate animal model. Mice with severe combined immunodeficiency (scid mice), which accept xenografts without rejection, were intracerebrally inoculated with human peripheral blood mononuclear cells and HIV. One to 4 weeks after inoculation, the brains of these mice contained human macrophages (some of which were HIV p24 antigen positive), occasional multinucleated cells, and striking gliosis by immunocytochemical staining. Human macrophages also were frequently positive for tumor necrosis factor type alpha and occasionally for interleukin 1 and VLA-4. Cultures of these brains for HIV were positive. Generally, human macrophages were not present in the brains of control mice, nor was significant gliosis, and HIV was not recovered from mice that received HIV only intracerebrally. Pathologically, this model of HIV encephalitis in scid mice resembles HIV encephalitis in humans and the data suggest that the activation of macrophages by infection with HIV results in their accumulation and persistence in brain and in the development of gliosis. This model of HIV encephalitis should provide insights into the pathogenesis and treatment of this disorder.

AIDS Dementia Complex↗
PubMed1993

Gliosis in human brain: relationship to size but not other properties of astrocytes.

Gliosis is the most frequent and therefore important neurocellular reaction to brain insult occurring in diseases ranging from AIDS to infarction. Neuropathological diagnosis of gliosis is based on morphological changes of brain glial cells. Changes commonly agreed to reflect gliosis are qualitative increases in size, number and glial fibrillary acidic protein (GFAP) immunoreactivity of astrocytes. These parameters were morphometrically quantified in brain tissues of 22 individuals who died with 7 diseases and statistically compared to the extent of gliosis independently determined by 3 qualified observers. The data indicate that the extent of gliosis correlated with the increase in size of astrocytes in white matter (p = 0.67) and this relationship was statistically significant (P = 0.0006). In contrast, the extent of gliosis was not correlated with the density of astrocytes nor the intensity of GFAP staining.

Acquired Immunodeficiency Syndrome↗