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E Lavi

Publications and source records attributed to E Lavi.

At least 73 records · Page 4Linked to original sources
PubMed1996

Late onset of isolated central nervous system metastasis of liposarcoma--a case report.

Metastatic soft-tissue sarcoma of the central nervous system (CNS) is exceedingly rare. We report a case of a 56-year-old male treated for a right lower extremity liposarcoma at the age of 30 years, whose first recurrence was an intracerebral metastasis occurring 26 years after resection of the primary tumor. Initial treatment of the metastasis with surgical resection and adjuvant radiotherapy was followed rapidly by CNS recurrence in 3 months. Further debulking and interstitial brachytherapy were unsuccessful in controlling disease progression. Clinical presentation and treatment of brain metastases in soft-tissue sarcoma are discussed.

Brachytherapy↗
PubMed1996

Cellular reservoirs of HIV-1 in the central nervous system of infected individuals: identification by the combination of in situ polymerase chain reaction and immunohistochemistry.

OBJECTIVES: The majority of HIV-1-infected individuals manifest a plethora of central nervous system (CNS) diseases unrelated to opportunistic infections, including AIDS dementia complex, encephalitis, and various other disorders of the CNS. The present study sought to evaluate the cellular reservoirs and expression patterns of HIV-1 in brain tissue to gain further understanding of HIV-1 neuropathogenesis. DESIGN: CNS tissue, obtained post-mortem from 22 patients with AIDS and four HIV-1-seronegative controls, was analyzed. METHODS: CNS samples were evaluated using a combination of in situ DNA polymerase chain reaction (PCR), reverse transcriptase (RT)-initiated in situ PCR, and immunohistochemistry. By utilizing this triple-staining methodology, HIV-1 proviral DNA and HIV-1-specific mRNA can be identified at the single cell level. RESULTS: HIV-1 was detected in all 22 AIDS brain specimens and in none of the four brains from HIV-1-seronegative individuals. The most commonly infected cells in AIDS brains were microglia cells and macrophages, but variable levels of HIV-1 infections were demonstrated in many of the major histological cell types within the CNS, including neurons, microvascular endothelial cells (MVEC) and astrocytes. The presence of HIV-1-infected cells was not uniform with infected cells unevenly distributed throughout the brain parenchyma. The degree of HIV-1 mRNA expression varied from 39-65% of the cells in the CNS harboring HIV-1 provirus. Choroid plexus and MVEC exhibited relatively high levels of productive infection. CONCLUSION: These findings demonstrate that several cell types in the CNS, in addition to microglia or macrophages, may become infected with HIV-1 in vivo with variable levels of HIV-1 mRNA expression. The diverse cellular reservoirs for HIV-1 in the CNS may be critically linked to the molecular mechanisms involved in HIV-1 neuropathogenesis. In addition, in vivo infection of MVEC, and possibly cells in the choroid plexus, may directly contribute to penetration of the blood-brain barrier by HIV-1.

Adult↗
PubMed1996

Demyelination following transfer of human lymphocytes into mice with severe combined immunodeficiency.

Multiple sclerosis (MS) is an immune-mediated inflammatory demyelinating disease in humans. We investigated adoptive transfer of demyelinating lesions into severe combined immunodeficiency (SCID) mice via injection of peripheral blood lymphocytes (PBLs) from MS patients. PBLs from chronic progressive MS patients were injected 2-7 times at monthly intervals into 8-week-old or newborn SCID mice (n = 51). Immunocompetent mice (n = 10) were injected with similar PBLs from MS patients. Other SCID mice (n = 17) were injected with PBLs obtained from healthy human donors. Mice were sacrificed (2-8 weeks after the last injection); brains and spinal cords were studied with HE and myelin stains, and lymphocytic markers. Demyelinating lesions occurred in 2 mice injected with MS lymphocytes and in one mouse injected with cells from a healthy donor. In addition, occasional meningitis, hydrocephalus, periventricular leukomalacia, lymphomas of either mouse or human origin, and splenomegaly occurred in some mice. Thus transfer of PBLs from MS patients or normal controls can occasionally produce inflammatory demyelinating lesions in SCID mice. This phenomenon which does not appear to be specific to MS lymphocytes may be explained by 'graft-versus-host' of the human lymphocytes against the mouse tissue.

Animals↗
PubMed1996

Identification of Epstein-Barr virus lytic activity in post-transplantation lymphoproliferative disease.

Post-transplantation lymphoproliferative disorder (PTLD) is a serious complication of organ transplantation. The majority of these lymphoid expansions are associated with latent Epstein-Barr virus (EBV) infection, but lytic activity may play an important role in initiating the disease process. Forty-eight specimens from 44 allograft recipients with EBV-associated PTLD were studied by immunohistochemical techniques for EBV lytic proteins, by use of monoclonal antibodies specific for the immediate early latent to lytic switch protein BZLF1 and two early antigens (diffuse and restricted). In addition, the specimens were studied by in situ hybridization for EBV DNA by use of an oligonucleotide probe for the EBV NotI tandem DNA repeats, whose expression seems confined to lytic infection. Thirty specimens were studied by in situ hybridization for immediate early (BZLF1) and late (gp350/220) lytic mRNA transcripts. Ninety-two percent of the specimens demonstrated at least one of the lytic EBV proteins. BZLF1 protein was seen in 81% of the specimens, whereas 54% and 52% of specimens expressed diffuse and restricted early antigens, respectively. Twenty-nine percent of specimens contained all three of the lytic proteins. The NotI tandem DNA probe produced staining in 88% of the specimens, whereas immediate early and late lytic transcripts were seen in 90% of the specimens. The amount of lytic activity did not significantly vary with PTLD histopathologic findings, but monomorphous proliferations localized to a single anatomic site showed a slightly lower reactivity with the antibodies and nucleic acid probes. Lytic activity was highest in patients with multisite disease, although this difference was not statistically significant. In conclusion, a significant proportion of patients with PTLD expressed lytic nucleic acids and proteins. Further work is necessary to analyze the role of lytic EBV infection in the initiation and maintenance of lymphoproliferative disorders in allograft recipients.

Adolescent↗
PubMed1995

The protective role of cytotoxic T cells and interferon against coronavirus invasion of the brain.

MHV-A59 causes focal acute encephalitis, acute hepatitis, and chronic demyelination while MHV-2 causes acute hepatitis and no brain involvement. The difference in organ tropism between these two closely related MHVs is not related to the ability of these viruses to grow in brain cells since both viruses grow equally well in primary glial cell cultures derived from neonatal mouse brains. We postulated therefore that the ability of the virus to stimulate certain host immunological factors may be important for protection of the brain against invasion and replication of the virus. In this study we performed preliminary experiments to investigate the potential role of two host factors in protection of the brain against MHV invasion: cytotoxic T cells and interferon. Four week old beta 2M(-/-) mice, lacking beta 2 microglobulin, MHC class I expression and functional cytotoxic CD8+ T cells were inoculated intracerebrally (IC) with MHV-2 and analyzed at various intervals post infection for histopathology and viral titers in organs. Histology revealed both acute hepatitis and acute encephalitis. Acute encephalitis was observed in periventricular areas. Mononuclear lymphocytic infiltration involved the choroid plexus, the ependyma and in the surrounding brain parenchyma. There was no involvement of other areas of the brain including areas that are typically involved in A59 infection of C57B1/6 mice. By contrast, C57b1/6 mice infected with MHV-2 showed no involvement of the brain parenchyma and only slight inflammation of the choroid plexus was present. High titers of infectious virus was detected by plaque assay in both brains and livers of beta 2M(-/-) mice infected with MHV-2 in contrast to only liver titers in C57B1/6 mice infected with a similar dose of MHV-2.(ABSTRACT TRUNCATED)

Animals↗
PubMed1995

Genomic regions associated with neurotropism identified in MHV by RNA-RNA recombination.

Infection of mice with a neurotropic strain of MHV (MHV-A59), a non-neurotropic strain of MHV (MHV-2), and a set of recombinant viruses (kindly provided by Dr. Michael Lai) were used to map genetic determinants of viral neurotropism and demyelination. Following intracerebral (IC) inoculation of 4-week old C57B1/6 mice, 1LD50 of MHV-A59 produced acute meningoencephalitis and hepatitis, and subsequently chronic CNS demyelinating disease. IC inoculation of 1LD50 of MHV-2 produced acute hepatitis without CNS disease. Recombinants ML-3, ML-11, ML-7, ML-8, ML-9 and ML-10 produced acute encephalitis similar to MHV-A59. According to previous oligonucleotide fingerprinting analysis the only common denominator of the neurotropic recombinant viruses was an M gene derived from MHV-A59. Sequencing of PCR-amplified viral S and M genes confirmed that the M genes of neurotropic viruses are derived from A59 while the S genes of neurotropic viruses are either derived from MHV-2 or from A59. In tissue culture, ML-11, ML-3 and MHV-2 are fusion negative, while A59, ML-7, ML-8 and ML-10 are fusion positive. Thus, neurotropism in MHVs is not linked to fusion or the S gene. Moreover, the M gene may be a significant determinant of neurotropism and acute encephalitis.

Animals↗
PubMed1995

Hepatitis mutants of mouse hepatitis virus strain A59.

MHV-A59 causes acute meningoencephalitis and hepatitis in susceptible mice, and a persistent productive, but nonlytic, infection of cultured glial cells. We have shown previously that viruses isolated from persistently infected glial cell cultures have a fusion-defective phenotype and were impaired in their abilities to cause hepatitis compared to wild-type MHV-A59. Two mutants chosen for detailed study, B11 and C12, display two distinct hepatitis phenotypes. The ability of B11 to replicate in the liver was dependent on infectious dose and route of inoculation, while C12 consistently displayed decreased liver titers regardless of dose and route of inoculation. Sequence analysis of wild-type, mutant and revertant S proteins indicates that 1) a mutation in the N terminal subunit of S, resulting in a glutamine to leucine amino acid substitution (Q159L), may affect ability to cause hepatitis and 2) a cleavage site mutation (H716D) which determines fusogenicity is not responsible for the altered hepatitis phenotype. Sequence analysis indicated that hepatitis-producing revertants did not revert at mutation Q159L, although it is possible that a mutation in the heptad repeat domain of S2 may compensate for the mutation in S1. Since B11, C12 and a nonattenuated fusion mutant (B12) have identical S protein sequences, there must be additional mutations outside of S which influence both virulence and ability to replicate in the liver.

Animals↗
PubMed1995

Mouse hepatitis virus A59-induced demyelination can occur in the absence of CD8+ T cells.

Mouse hepatitis virus causes a chronic demyelinating disease in C57BL/6 mice. While early studies suggested demyelination is due to direct cytolytic effects of virus on oligodendrocytes, there is increasing evidence for the involvement of the immune system in the mechanism of demyelination. In this study we have asked whether demyelination can occur in the absence of functional MHC class I expression and CD8+ T cells. We infected transgenic mice lacking expression of beta 2 microglobulin (beta 2 M -/- mice) with MHV-A59. In beta 2M-/- mice, virus was much more lethal than in either of the parental strains used to produce the mice; furthermore, while clearance from the CNS did occur in beta 2M-/- mice, it was slower than in C57BL/6 mice. This is consistent with the importance of CD8+ cells in viral clearance. Because of the increased sensitivity of the beta 2M-/- mice to infection, only low levels of virus could be used to evaluate chronic disease. Even at these low levels, demyelination did occur in some animals. To compare infection in beta 2M-/- and C57BL/6 mice we used a higher dose of an attenuated variant of MHV-A59, C12. The attenuated variant induced less demyelination in C57BL/6 mice compared to wild type A59, but the levels observed were not significantly different from those seen in beta 2M-/- mice. Thus, MHV-induced demyelination can occur in some animals in the absence of MHC class I and CD8+ cells.

Animals↗
PubMed1995

Primary central nervous system lymphoma following transfer of human peripheral blood lymphocytes into SCID mice.

Severe combined immunodeficiency (SCID) mice are genetically deficient in both B and T cells. To study immune-mediated phenomena in the CNS, myelin basic protein-reactive T cell clones, admixed with peripheral blood lymphocytes as a source of antigen-presenting cells, derived from a healthy human donor, were injected intracerebrally (IC) into 10 SCID mice. One mouse developed quadriplegia 2 months after the last injection. Autopsy revealed marked meningeal and parenchymal infiltration by large cell lymphoma. There was no evidence of lymphoma outside of the CNS. The majority of the tumor cells were positive for L26 (a human pan B cell marker), with some cells positive for UCHL-1 (a human pan T cell marker). The majority of the tumor cells were also positive for Epstein-Barr virus (EBV) genome by in situ hybridization. Thus, primary CNS, EBV-positive B cell lymphoma can be produced in SCID mice by IC injection of nontransformed human peripheral blood lymphocytes. This phenomenon can be used as a model system for the study of primary CNS lymphomas under immunodeficiency conditions.

Adoptive Transfer↗
PubMed1995

Spinal dural arteriovenous fistula: the pathology of venous hypertensive myelopathy.

Spinal dural arteriovenous fistulas (SDAVFs) are the most common type of spinal vascular malformation. The arteriovenous shunts, located entirely outside the spinal cord, cause a clinical picture of chronic progressive myelopathy believed to arise from the effects of increased venous pressure and impaired venous drainage on the spinal cord. Despite their well-described clinical and angiographic features, no reports have documented the spinal cord pathology in a case of angiographically or pathologically proven SDAVF. We report such a patient in whom a spinal cord biopsy supported increased venous pressure as a mechanism of neurologic dysfunction.

Aged↗
PubMed1995

Apolipoprotein(a) deposition in atherosclerotic plaques of cerebral vessels. A potential role for endothelial cells in lesion formation.

Atherosclerosis is the leading cause of death and serious morbidity in economically developed societies through its sequelae of coronary artery and cerebrovascular disease. The causes and mechanisms of atherosclerosis are still largely unknown. Serum levels of a lipoprotein, Lp(a), have been shown, in retrospective and some prospective clinical studies, to be associated with increased risk of myocardial and cerebral infarction. The active part of Lp(a), apo(a), has > 80% homology with plasminogen; thus it may competitively inhibit the thrombolytic action of plasminogen and enhance thrombogenesis. Lp(a) has been shown to be deposited in the vascular wall of the aorta and coronary vessels, but its presence in the cerebral vessels has not yet been shown. Autopsy specimens of vessels of the circle of Willis from 23 patients were examined for degree of atherosclerosis and deposition of apo(a) by immunohistochemistry with apo(a)-specific monoclonal antibodies. The amount of apo(a) deposition in cerebral vessels correlated well with the degree of cerebral atherosclerosis. Arterial deposition of apo(a) was found entirely within the endothelial cell and subendothelial cell layers. There was no staining within the media and adventitia, with the exception of staining within the endothelial cells of the vasa vasorum. Correlation between the morphology of apo(a) deposition and plaque stage was found suggesting that detection of apo(a) in endothelial cells is an early event in the development of the atherosclerotic plaque of cerebral vessels.

Adult↗
PubMed1995

A mucin-like glycoprotein identified by MAG (mouse ascites Golgi) antibodies. Menstrual cycle-dependent localization in human endometrium.

Human endometrial glands synthesize and secrete a high molecular weight mucin-like glycoprotein in a menstrual cycle-dependent fashion. A novel moiety within this Golgi-associated glycoprotein is strongly reactive with IgG antibodies in numerous murine ascites, and has been termed MAG (mouse ascites Golgi). Immunohistochemical staining of 201 endometrial biopsies revealed the following patterns: MAG first appeared in the Golgi on cycle day 5, peaked on day 15, was present on the surface of the luminal epithelium between days 17 and 19, and was no longer detectable after day 19. MAG was also present in cervical, prostate, seminal vesicle, and lacrimal glands, pancreatic acinar cells, gall bladder and bile duct epithelium, and certain cells of the salivary and sweat glands. Interestingly, only tissues from blood group A individuals exhibited this staining. As a common link among all these cell types is the expression of mucins, we speculated that the MAG epitope could be a mucin-associated blood group A-related epitope. This hypothesis was tested by absorption experiments with a variety of glycoconjugates and erythrocytes and by immunoblots of MAG-rich material. The absorption studies demonstrated that only type III porcine mucin (< 1% sialic acid) and blood type A or AB erythrocytes were able to absorb the anti-MAG antibody. Inasmuch as N-acetyl-galactosamine alone, the terminal blood group A carbohydrate, did not block MAG antibody binding, the MAG epitope appears to involve N-acetylgalactosamine plus other determinants. Immunoblots of endometrial extracts and saliva from blood type A individuals revealed MAG-reactive material with a molecular weight > 200 kd under reducing conditions. Because the MAG epitope appears on the endometrial surface during the purported implantation window, we speculate that mucin-like epitopes could play a role in the earliest apposition phases of conceptus-endometrial interaction.

ABO Blood-Group System↗
PubMed1994

Polarity of processes with Golgi apparatus in a subpopulation of type I astrocytes.

The Golgi apparatus-complex (GA), is a key organelle involved in several posttranslational modifications of polypeptides destined for lysosomes, plasma membranes and secretion. As reported from this laboratory, certain astrocytes in rat brain contain cisternae of the GA not only in perikarya, but also in processes. In order to further investigate which type of astrocytes contain GA in processes we conducted the present study using primary cultures of rat astrocytes and organelle specific antibodies against the GA and the rough endoplasmic reticulum (RER). While the perikarya of all cells contained elements of the GA, only a single process of a subset of type I astrocytes, negative to antibodies A2B5 and HNK-1, contained GA. In contrast, elements of the RER were found within perikarya and all processes. In order to confirm that the immunostained structures in processes indeed represent the GA, we exposed cultures to Brefeldin A (BFA), a secretion blocker which disperses the GA and redistributes it to the RER. We observed that BFA disrupted the GA of both perikarya and processes. However, astrocytes were resistant to prolonged incubations with BFA, while a similar treatment killed cultured fibroblasts and PC-12 cells. Furthermore, in astrocytes exposed to BFA for several days, the delicate network of glial fibrillary acidic protein (GFAP), was replaced by large perinuclear masses of the protein. These observations demonstrate that a subset of type I astrocytes have a single process with elements of the GA. We suggest that this specialization of the GA may be related to yet unrecognized secretory or protein processing functions of these cells. The resistance of astrocytes to BFA and the striking changes in their cytoskeleton induced by the drug, may contribute to studies on the mechanism(s) of action of BFA.

Animals↗
PubMed1994

MHV-A59 fusion mutants are attenuated and display altered hepatotropism.

Mouse hepatitis virus strain A59 causes a persistent productive, but nonlytic, infection of cultured glial cells. We have mutants isolated from persistently infected glial cell cultures which have been shown to be fusion-defective due to a histidine to aspartic acid mutation (H716D) near the cleavage site of the peplomer protein, S. Here, we examine the pathogenicity of these mutants and show differences in hepatotropism and virulence compared to wild-type virus (WT). Two mutants chosen for detailed study, B11 and C12, were impaired in their abilities to cause hepatitis and/or replicate in the liver of susceptible mice. Furthermore, B11 and C12 display two separate hepatotropic phenotypes. The ability of B11 to replicate in the liver was dependent on infectious dose and route of inoculation, while C12 consistently displayed decreased hepatotropism regardless of dose and route of inoculation. However, B11 and C12 were shown to replicate in the CNS of infected animals similarly to WT. Like WT, the mutants produced meningoencephalitis during acute infection, with viral antigen exhibiting a similar distribution in the brain, and demyelination during chronic infection. Sequence analysis of wild-type, mutant, and revertant S proteins indicates that (1) a mutation in the N terminal subunit of S (S1), resulting in a glutamine to leucine amino acid substitution (Q159L), may affect hepatotropism and (2) a cleavage site mutation which determines fusogenicity is not responsible for altered hepatotropism. Furthermore, since B11, C12, and a nonattenuated fusion mutant (B12) have identical S protein sequences, there must be additional mutations outside of S which influence both virulence and hepatotropism.

Amino Acid Sequence↗
PubMed1994

Intracerebral hemorrhages and infarction induced by a murine leukemia virus is influenced by host determinants within endothelial cells.

The strain and developmental parameters that control susceptibility to murine leukemia virus (MuLV)-induced intracerebral hemorrhages and infarction were studied using the endothelial cell tropic MuLV TR1.3. Inoculated animals displayed an absolute age dependence on the development of intracerebral vascular disease; however, other genetic determinants affected the timing and magnitude of susceptibility to neurologic disease. BALB/c mice were susceptible to neurologic disease only when inoculated prior to Day 4 postpartum. In contrast, Swiss/NIH and C3H/HeN mice consistently showed a less virulent phenotype and were only susceptible when infected prior to Day 3 postpartum. These studies demonstrate that susceptibility to TR1.3 murine leukemia virus-induced neurologic disease is regulated by age- and strain-dependent factors encoded within cerebral endothelial cells.

Age Factors↗
PubMed1994

A point mutation in the env gene of a murine leukemia virus induces syncytium formation and neurologic disease.

TR1.3 is a Friend-related murine leukemia virus that has been shown to cause intracerebral hemorrhages and neurologic disease due to infection and subsequent cytopathology of cerebral vessel endothelium. A striking feature of this pathology is the formation of endothelial cell syncytia. The pathogenesis of this disease has now been mapped to a single amino acid substitution of tryptophan to glycine in the variable region of the envelope protein. This same mutation enabled TR1.3 to form syncytia and retard cell proliferation in vitro in the SC-1 mouse embryoblast line but did not affect the pH dependence of viral entry. These results demonstrate that subtle molecular changes in retroviral env genes can induce both syncytium formation and overt clinical disease.

Animals↗