Biomedical subjects

E Lavi

Publications and source records attributed to E Lavi.

At least 37 records · Page 2Linked to original sources

PubMed2001

July 2000: A 70 year old with rigidity, decreased ocular movements, and dementia.

The July Case of the Month (COM): A 70 year old male presented with a four year history of cognitive decline, difficulty expressing himself, and an increasingly unsteady gait with numerous falls. At presentation he was wheel-chair bound. Examination showed some slowing of speech, mild memory impairment, but normal cranial nerves. Spastic weakness and brisk reflexes were also noted, with bilateral ankle clonus. MRI scans were normal. Four years later he was admitted with a urinary tract infection and was mute with severely impaired ocular motility. He died 18 months later and autopsy showed the classic neuropathological findings of typical Progressive supranuclear palsy, including tau-positive glial inclusions.

Aged↗

PubMed2000

Experimental allergic neuritis in the SJL/J mouse: induction of severe and reproducible disease with bovine peripheral nerve myelin and pertussis toxin with or without interleukin-12.

We report a reproducible model of experimental allergic neuritis (EAN) with severe clinical signs and consistent pathological features in mice. Pertussis toxin (PT) in the presence or absence of murine recombinant interleukin-12 (mrIL-12) was used as an adjuvant with bovine peripheral nerve myelin (BPNM) to induce clinical EAN in SJL/J mice. After immunization with a combination of BPNM in complete Freund's adjuvant (CFA) and PT, mice developed severe consistent signs of EAN. The additional treatment of immunized mice with mrIL-12 prolonged the course of EAN characterized by earlier clinical signs of the disease and delayed the recovery stage. Mice injected with BPNM and CFA without PT developed mild clinical signs. Histological examination of the caudae equinae and the sciatic nerves taken from mice with clinical signs of EAN during the recovery stage revealed severe demyelination, remyelination and remnants of mononuclear cell infiltration. Moderate to severe EAN can be induced in SJL/J mice by the injection of a combination of BPNM in CFA and PT. This model can provide a better understanding of mechanism of demyelination in infiltrating peripheral neuropathy.

Animals↗

PubMed2000

Characterization of experimental spinal cord injury with magnetization transfer ratio histograms.

This study was designed to characterize the severity of tissue damage in experimental spinal cord injury using magnetization transfer (MT) histogram analysis. Seven Sprague-Dawley rats were subjected to laminectomy and standard weight-drop injury to the spinal cord (four rats at 15 cm drop-height and three rats at 2.5 cm). Three control animals underwent laminectomy without weight-drop. After sacrifice, the animals were scanned at 1.9 T with a pulsed off-resonance MT technique. Following magnetic resonance (MR) imaging, the cords were embedded in paraffin and sectioned into 5-microm sections for semiquantitative histopathological analysis. Composite histograms were generated using data spanning an axial distance of 3 cm centered on the injury site. MT histogram parameters, such as the amount of tissue with statistical correspondence to normal white matter, were highly predictive of histopathological results, including myelination state and neurofilament damage. Less correlation with edema was observed, suggesting that the technique was most sensitive to true tissue alteration.

Animals↗

PubMed2000

Differential cytokine and chemokine production characterizes experimental autoimmune meningitis and experimental autoimmune encephalomyelitis.

After primary immunization with myelin/oligodendrocyte glycoprotein, CD28(-/-) mice developed experimental autoimmune meningitis (EAM) rather than experimental autoimmune encephalomyelitis (EAE). Cytokine and chemokine production in EAE and EAM were compared to understand the differences in disease phenotype. T cells from the central nervous system lesions of mice with either EAE or EAM expressed intracellular TNF-alpha. Splenic T cells from mice with EAM produced TNF-alpha and IL-6 but no IL-2. Conversely, EAE-derived splenic T cells produced TNF-alpha and IL-2 but no IL-6. Altered T cell differentiation in EAM was not due to a Th1 to Th2 shift, because equivalent amounts of T cell IFN-gamma mRNA were produced in both diseases. Neutrophils also produced inflammatory mediators such as TNF-alpha and IL-6 in EAM. Autocrine production of MIP-2 mRNA was observed in neutrophils from mice with EAM but not EAE. Therefore, distinct patterns of cytokines and chemokines distinguish EAE and EAM.

Amino Acid Sequence↗

PubMed2000

Immunohistochemical analysis of CCR2, CCR3, CCR5, and CXCR4 in the human brain: potential mechanisms for HIV dementia.

The CXC chemokine receptor CXCR4 was the first molecule identified as a coreceptor working in conjunction with CD4 to mediate cellular entry for the human immunodeficiency virus (HIV-1). Since that original discovery, 11 other seven-mtransmembrane domain molecules, many of which are chemokine receptors, have been shown to facilitate HIV entry into cells. These include CCR5, CCR3, CCR2, CCR1, CCR8, CX3CR1, STRL33 (BONZO), GPR15 (BOB), GPR1, US28, and APJ. In studies done by this and other labs, CCR3, CCR5, and CXCR4 have been identified in CNS microglia and several laboratories, including ours, have shown that CXCR4 is expressed in neurons. Neuronal expression of CCR2, CCR3, and CCR5 has been less consistent. We performed a semiquantitative immunohistochemical analysis of the expression of CCR2, CCR3, CCR5, and CXCR4 in 23 regions of the brain and in two sections of the spinal cord. Hippocampal neurons were positive for CCR2, CCR3, and CXCR4, but not for CCR5. In other regions of the brain, neurons, and glial cells reacted with anti-CCR2, anti-CCR3, and anti-CXCR4 antibodies, whereas only glial cells (primarily microglia) were positive for CCR5. The areas of highest expression, however, seem to be subcortical regions and the limbic system. The limbic system plays a key role in memory, and the presence of CXCR4-which can bind the viral envelope protein gp120-min a subset of neurons from this system may play a role in the development of HIV-related dementia.

AIDS Dementia Complex↗

PubMed2000

Demyelination determinants map to the spike glycoprotein gene of coronavirus mouse hepatitis virus.

Demyelination is the pathologic hallmark of the human immune-mediated neurologic disease multiple sclerosis, which may be triggered or exacerbated by viral infections. Several experimental animal models have been developed to study the mechanism of virus-induced demyelination, including coronavirus mouse hepatitis virus (MHV) infection in mice. The envelope spike (S) glycoprotein of MHV contains determinants of properties essential for virus-host interactions. However, the molecular determinants of MHV-induced demyelination are still unknown. To investigate the mechanism of MHV-induced demyelination, we examined whether the S gene of MHV contains determinants of demyelination and whether demyelination is linked to viral persistence. Using targeted RNA recombination, we replaced the S gene of a demyelinating virus (MHV-A59) with the S gene of a closely related, nondemyelinating virus (MHV-2). Recombinant viruses containing an S gene derived from MHV-2 in an MHV-A59 background (Penn98-1 and Penn98-2) exhibited a persistence-positive, demyelination-negative phenotype. Thus, determinants of demyelination map to the S gene of MHV. Furthermore, viral persistence is insufficient to induce demyelination, although it may be a prerequisite for the development of demyelination.

Animals↗

PubMed2000

Anterior uveitis in murine relapsing experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS).

PURPOSE: To investigate whether anterior uveitis (AU), which often accompanies central nervous system (CNS) and systemic inflammatory diseases including multiple sclerosis (MS), also develops in a murine relapsing model of MS, experimental autoimmune encephalomyelitis (EAE) closely resembling relapsing-remitting MS, induced by immunization with myelin basic protein (MBP) in mice. METHODS: (PL/J x SJL) F1 female mice were immunized with MBP in complete Freund's adjuvant (CFA) using Pertussis toxin as co-adjuvant. EAE was scored clinically on a scale of 0-5 based on the degree of paralysis. Uveitis was assessed by slit-lamp biomicroscopy. Histolological analysis of the CNS and eye were performed. RESULTS: All immunized mice developed a characteristic relapsing paralysis. Evidence of AU was present late in the course of EAE, only after the resolution of the first clinical relapse, in 4 of 5 mice (80%) (clinical evidence) and 5 of 5 (100%) (histological evidence). AU was mild to moderate with the exception of one animal, in which it was severe. Involvement was invariably bilateral. Histology showed mononuclear infiltrates in the iris and ciliary body. Bilateral secondary cataracts were observed in the animal with severe inflammation. Paralytic episodes and the AU did not coincide. There were no clinical or histological eye abnormalities in control mice, either non-immunized or immunized with CFA and Pertussis toxin only. CONCLUSION: We report AU in a mouse model of EAE which strongly resembles relapsing MS. These results further suggest shared antigenic determinants between the CNS and the eye, which likely become exposed to the immune system late in the course of CNS inflammation.

Animals↗

PubMed2000

Functional expression of the seven-transmembrane HIV-1 co-receptor APJ in neural cells.

APJ is a recently described seven-transmembrane (7TM) receptor that is abundantly expressed in the central nervous system (CNS). This suggests an important role for APJ in neural development and/or function, but neither its cellular distribution nor its function have been defined. APJ can also serve as a co-receptor with CD4 for fusion and infection by some strains of human immunodeficiency virus (HIV-1) in vitro, suggesting a role in HIV neuropathogenesis if it were expressed on CD4-positive CNS cells. To address this, we examined APJ expression in cultured neurons, astrocytes, oligodendrocytes, microglia and monocyte-derived macrophages utilizing both immunocytochemical staining with a polyclonal anti-APJ antibody and RT - PCR. We also analyzed the ability of a recently identified APJ peptide ligand, apelin, to induce calcium elevations in cultured neural cells. APJ was expressed at a high level in neurons and oligodendrocytes, and at lower levels in astrocytes. In contrast, APJ was not expressed in either primary microglia or monocyte-derived macrophages. Several forms of the APJ peptide ligand induced calcium elevations in neurons. Thus, APJ is selectively expressed in certain CNS cell types and mediates intracellular signals in neurons, suggesting that APJ may normally play a role in signaling in the CNS. However, the absence of APJ expression in microglia and macrophages, the prinicpal CD4-positive cell types in the brain, indicates that APJ is unlikely to mediate HIV-1 infection in the CNS.

Adult↗

PubMed1999

Experimental autoimmune meningitis: a novel neurological disease in CD28-deficient mice.

C57BL/6 mice develop T-cell-mediated experimental autoimmune encephalomyelitis (EAE) after immunization with the neuroantigen myelin oligodendrocyte glycoprotein. (MOG). We immunized CD28-deficient C57BL/6 mice to determine the role of T cell costimulation in the immune response to MOG. CD28-/- mice developed experimental autoimmune meningitis (EAM). EAM is a fatal, acute disease characterized by simultaneous weakness in all limbs, photophobia, irritability, and spatial disorientation. Histologically, EAM consisted of an infiltrate of myeloid, monocytic, and lymphocytic leukocytes within the leptomeninges. In contrast, the brain parenchyma was unaffected. EAM was mediated by CD4+ T cells since CD4 depletion prevented the disease. Upon rechallenge, mice in which EAM was prevented by CD4+ cell depletion developed EAE not EAM. Therefore, the presence or absence of CD28 determines the initial phenotype of the immune response to MOG. EAM, which develops in the absence of CD28, is a unique experimental model for immune-mediated aseptic meningitis.

Amino Acid Sequence↗

PubMed1999

Nidovirus infections: experimental model systems of human neurologic diseases.

The presence of terminally differentiated slow- and non-dividing cells in the central nervous system (CNS) provides a safe harbor for viral persistence and latency and constitutes a unique immunologic environment for viral infections. Studies of experimental model systems of viral infections of the CNS provide insight into mechanisms of viral persistence and immune-mediated pathology. Nidoviruses are comprised of 2 families of viruses, coronaviruses and arteriviruses, and are common pathogens of humans and a variety of animal species. Both families of viruses contain neurotropic strains that produce experimental neurologic diseases in rodents. These include acute meningitis and encephalitis; acute poliomyelitis; and chronic inflammatory, immune-mediated, demyelination. Coronavirus-induced demyelinating disease mimics many of the pathologic features of Multiple Sclerosis (MS).

Animals↗

PubMed1999

Pathogenesis of chimeric MHV4/MHV-A59 recombinant viruses: the murine coronavirus spike protein is a major determinant of neurovirulence.

The mouse hepatitis virus (MHV) spike glycoprotein, S, has been implicated as a major determinant of viral pathogenesis. In the absence of a full-length molecular clone, however, it has been difficult to address the role of individual viral genes in pathogenesis. By using targeted RNA recombination to introduce the S gene of MHV4, a highly neurovirulent strain, into the genome of MHV-A59, a mildly neurovirulent strain, we have been able to directly address the role of the S gene in neurovirulence. In cell culture, the recombinants containing the MHV4 S gene, S4R22 and S4R21, exhibited a small-plaque phenotype and replicated to low levels, similar to wild-type MHV4. Intracranial inoculation of C57BL/6 mice with S4R22 and S4R21 revealed a marked alteration in pathogenesis. Relative to wild-type control recombinant viruses (wtR13 and wtR9), containing the MHV-A59 S gene, the MHV4 S gene recombinants exhibited a dramatic increase in virulence and an increase in both viral antigen staining and inflammation in the central nervous system. There was not, however, an increase in the level of viral replication in the brain. These studies demonstrate that the MHV4 S gene alone is sufficient to confer a highly neurovirulent phenotype to a recombinant virus deriving the remainder of its genome from a mildly neurovirulent virus, MHV-A59. This definitively confirms previous findings, suggesting that the spike is a major determinant of pathogenesis.

Animals↗

PubMed1999

Hemangiopericytoma of the third ventricle. Case report.

The authors present the first reported case of a hemangiopericytoma (HPC) occurring in the third ventricle. Most of these lesions are based in the meninges. There is only one other reported case of an intraventricular HPC; in that case the lesion was found in the lateral ventricle. A 40-year-old right-handed man presented with a 3-month history of headaches. Clinical evaluation, including computerized tomography and magnetic resonance imaging studies, revealed a 1-cm enhancing lesion in the third ventricle. Given the findings on the preoperative imaging studies, the lesion was not consistent with some of the more commonly occurring tumors of the third ventricle, namely colloid cysts. A transcortical approach and resection of the lesion was performed without complication. The final pathological findings were consistent with those of an HPC. Hemangiopericytomas rarely occur in the ventricles and may pose a difficult diagnostic dilemma based on their radiographic and gross appearances, as shown in this case. Because of this difficulty, histological confirmation is required to make a definitive diagnosis. These lesions have a propensity to recur and metastasize in the central nervous system and periphery, thus making the goal of treatment a complete surgical resection followed by postoperative radiation therapy in most cases.

Adult↗

PubMed1998

Antibodies against IL-12 prevent superantigen-induced and spontaneous relapses of experimental autoimmune encephalomyelitis.

Immunization of (PL/J x SJL/J)F1 mice with myelin basic protein (MBP) induces relapsing experimental autoimmune encephalomyelitis (EAE). Relapses occur 7 to 10 days after recovery from the initial paralysis. Staphylococcal enterotoxins (SE) A or B, administered after recovery from the initial paralysis, induce immediate relapses. IL-12 is involved in the induction of EAE. Here, we show that SEA and SEB induce IL-12 in splenocytes from (PL/J x SJL/J)F1 mice in vitro and increase the level of IL-12 in the sera of mice treated with these superantigens. IL-12 administration mimics SE in inducing spontaneous relapses and in enhancing the severity and frequency of spontaneous relapses. IL-12 neutralization blocks SE-induced and subsequent relapses of EAE, and, when instituted after recovery from the initial attack, prevents spontaneous relapse. This is the first report of prevention of relapses of EAE with anti-IL-12 Ab, an approach which may prove useful in the prevention of exacerbations in multiple sclerosis.

Animals↗

PubMed1998

Coronavirus MHV-A59 causes upregulation of interferon-beta RNA in primary glial cell cultures.

Infection of mice with coronavirus mouse hepatitis virus strain MHV-A59 causes focal acute encephalitis, hepatitis and chronic demyelinating disease. To investigate host interferon (IFN) response to viral infection within the brain, RNA was extracted from A59-or MHV-2- infected and mock-infected primary astrocyte cultures from newborn mice, RT-PCR amplified RNA with primers specific for the various IFNs, transferred to nylon membranes and hybridized with IFN specific digoxigenin-labeled probes. Infection of primary astrocyte cultures from newborn mice with either A59 or MHV-2 caused upregulation of IFN-beta RNA, but not IFN-gamma or IFN-alpha. Thus, brain astrocytes are capable of producing a local IFN-beta response upon infection with MHV. The response of the other IFNs following MHV infection may be derived from inflammatory cells.

Animals↗

PubMed1998

The pathogenesis of MHV nucleocapsid gene chimeric viruses.

A set of viruses in which various segments of the nucleocapsid (N) gene of MHV have been substituted with the corresponding segments of bovine coronavirus (BCV) by targeted recombination were analyzed for their biologic properties. Histology for organ pathology and plaque assay for viral titer analysis following intracerebral (IC) inoculation were studied. One chimeric virus (Alb85), in which only a small segment of the N gene was replaced, exhibited a phenotype similar to wild type MHV-A59. However, three of the chimeric viruses (Alb106, Alb112 and Alb100) produced acute encephalitis and demyelination but without hepatitis following IC inoculation. Intravenous (IV) and intrahepatic (IH) inoculations were able to restore the ability of these viruses to produce hepatitis. The common denominator of the three chimeric viruses with a different phenotype is a region between aa 306 and aa 386 in which 17 amino acids (aa) differences exist between the two strains. Thus this region may contain determinants which enable the virus to exit the brain and reach the blood stream.

Animals↗

PubMed1998

Targeted recombination between MHV-2 and MHV-A59 to study neurotropic determinants of MHV.

MHV-A59 produces acute encephalitis, acute hepatitis and chronic demyelination in infected mice. MHV-2 produces only hepatitis and mild meningitis but without encephalitis or demyelination. We have previously studied a set of recombinant viruses between these two strains. The common denominator of viruses that produced encephalitis was a membrane (M) gene derived from MHV-A59. Thus to study the potential contribution of the M gene to acute encephalitis, chimeric viruses were produced in which the M gene of MHV-A59 was substituted with the M gene of MHV-2 by targeted recombination. A control virus was produced in which the M gene of A59 was recombined back into an A59 background. Viruses were then analyzed for their biologic properties and compared with the phenotypes of MHV-A59 and MHV-2 by histopathology and plaque assays for viral titers in organs following intracerebral (IC) inoculation. All three chimeric viruses had a phenotype similar to MHV-A59. Thus, the replacement of the M gene of MHV-A59 with that of MHV-2 is insufficient to produce a phenotype that lacks encephalitis similar to MHV-2.

Animals↗

PubMed1998

The C12 mutant of MHV-A59 is very weakly demyelinating and has five amino acid substitutions restricted to the spike and replicase genes.

C12, an attenuated, fusion defective, very weakly hepatotropic mutant of MHV-A59 has been further characterized. Analysis of C12 in vivo in C57BL/6 mice has shown that despite the fact that this virus replicates in the brain to titers at least as high as wild type and causes acute encephalitis similar to wild type, this virus causes minimal demyelination. Thus acute encephalitis is not sufficient for induction of demyelination by wild type MHV-A59. We have previously shown that C12 has two amino acid substitutions relative to wild type virus in the spike gene, Q159L (in the receptor binding domain of S1) and H716D (in the signal sequence for cleavage of S). We have now sequenced the rest of the 31 kb genome of C12 and compared it to wild type virus. Only three additional amino acids substitutions were found, all within the replicase gene, one in the predicted papain like proteinase (PLP)-2 domain and one in the predicted helicase domain. Thus, determinants of virulence, hepatotropism, and demyelination may map to the replicase gene as well as to the spike gene.

Amino Acid Substitution↗

PubMed1998

The effects of human immunodeficiency virus in the central nervous system.

More than a decade after the first description of HIV DNA in the nervous system the pathophysiology of HIVD remains largely enigmatic, with data supporting a number of potential mechanisms for the development of neuronal dysfunction. Nevertheless, a few key findings have considerable support in the literature devoted to this subject: 1. HIV dementia is caused by HIV itself; no other pathogen has been consistently found in the brains of patients with HIVD. 2. In comparison with other viral encephalopathies, there appears to be a significant discordance between the amount of virus being produced in the brains of patients with HIVD and the degree of neurological deterioration. 3. The key cell types responsible for viral production within the CNS are the resident macrophages or microglial cells. 4. Other elements within the CNS, particularly astrocytes, are probably infected with HIV as well, but all of these infections are highly restricted in terms of production of virus or viral structural proteins. 5. At least one component of the pathogenesis of HIVD may be the generation of neurotoxins by infected microglia, although the type of neurotoxin, and the specific compound most likely to be involved, are quite controversial. Advances with combination antiviral therapy have successfully reduced plasma viral load in a high proportion of individuals, leading to the speculation (previously almost heretical) that it may be possible to eradicate HIV completely from the systemic immune system. If that were the case, potential "sanctuary" sites such as the immunologically protected CNS might remain as important reservoirs for reseeding of lymphoid tissues. Microglia may be particularly suited for this purpose because they are long lived, can produce HIV for several weeks (at least in culture), and they are apparently relatively immune to virus-induced cytopathology such as syncytium formation. One can speculate about several scenarios resulting from the continued presence of replication-competent HIV within brain. In the worst case, a smoldering infection of the nervous system could lead to neurological deterioration without reinfection of systemic immune cells. The epidemiological data indicating that HIVD is a disease primarily associated with immunodeficiency suggest that the systemic immune system plays a role in maintaining virus residing within the CNS under control. Thus it is quite possible that this scenario would not occur for many years after the systemic infection is controlled. Alternatively, virus could be transported from the CNS by circulating lymphocytes and monocytes and reinfect systemic organs. This would necessitate restarting therapy for those individuals who were previously thought to be cured, but presumably virus within the CNS would not have developed resistance to antivirals. In either case, the techniques currently available do not permit an accurate assessment of CNS HIV load in living people, and this question will remain unanswered until antivirals are discontinued in a few individuals with persistently negative tests for systemic virus. In addition to this most critical question, the relationship between viral levels and HIVD is largely unexplored, as is the possibility that some strains are particularly virulent or neuroinvasive. Furthermore, the potential contribution of host genotype in the development of dementia is unknown. In view of the strong influence of major chemokine receptor (CCR5) truncations on HIV replication, it is entirely possible that more discrete genetic polymorphisms have a subtle effect on either brain invasion or virulence.

AIDS Dementia Complex↗