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D M Asher

Publications and source records attributed to D M Asher.

At least 55 records · Page 3Linked to original sources
PubMed1990

Reevaluation of the ultrastructural pathology of experimental Creutzfeldt-Jakob disease. Serial studies of the Fujisaki strain of Creutzfeldt-Jakob disease virus in mice.

We describe the serial ultrastructural pathology of experimental Creutzfeldt-Jakob disease (CJD) in mice. Spongiform vacuoles, widespread myelin and axonal pathology, accompanied by abundant macrophagic reaction and neuroaxonal dystrophy, were consistently found in mice infected with CJD virus. By contrast, intranuclear vacuolation and swelling of astrocytic and neuronal processes were nonspecific changes that also occurred in control animals. We conclude that CJD-related neuropathological phenomena do not accumulate gradually through the incubation period but develop relatively abruptly and in complete form.

Animals↗
PubMed1989

Mutations in familial Creutzfeldt-Jakob disease and Gerstmann-Sträussler-Scheinker's syndrome.

A host protein encoded by the gene specifying the scrapie amyloid precursor affects pathogenesis of the transmissible spongiform encephalopathies: Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker's syndrome (GSS), and kuru in man, and scrapie in animals. We found a mutation in this gene of two patients with CJD from one family and a second mutation in the same gene in three patients with GSS from another family. The mutation in two related familial CJD patients changed glutamine in position 200 tolysine. This mutation was absent in other individuals including unrelated patients with familial CJD, sporadic CJD, and GSS. The other mutation in three GSS patients changed proline in position 102 to leucine, the same mutation described recently in some GSS families. We did not find it in six unaffected relatives of the GSS patients or in other individuals including sporadic and familial CJD patients. A rare insertion described earlier in one CJD family was also absent in all tested individuals.

Base Sequence↗
PubMed1989

Serial ultrastructural studies of scrapie in hamsters.

We report sequential studies of the ultrastructural neuropathology of the subcortical grey matter of hamsters infected with the 263K strain of scrapie virus. Vacuolation in this model develops relatively late in the incubation period, while tubulovesicular structures appear early. Furthermore, neuroaxonal dystrophy, accumulations of branching tubules, and neuronal change consisting of intracytoplasmic "whorls" of proliferating membranes constitute prominent features of scrapie-related neurodegeneration.

Animals↗
PubMed1989

Scrapie-induced diabetes mellitus in hamsters.

Scrapie-infected hamsters had slightly elevated non-fasting plasma glucose levels, markedly abnormal glucose tolerance tests, and impaired release of insulin in response to a glucose load. Plasma cortisol levels were essentially the same in infected and uninfected animals. Histological examination of the pancreas revealed no morphological changes in infected animals with no alteration in distribution of cells secreting insulin, glucagon and somatostatin. In contrast, brains of scrapie-infected animals had the diffuse vacuolation typical of spongiform encephalopathy. These experiments suggest that scrapie-induced diabetes mellitus in hamsters may result from damage to the central nervous system.

Animals↗
PubMed1988

Intracerebral inoculation of experimental animals with brain tissue from patients with schizophrenia. Failure to observe consistent or specific behavioral and neuropathological effects.

To test the possibility that some cases of schizophrenia result from infection with a transmissible slow viral agent, 57 experimental animals (six chimpanzees, 12 Old World monkeys, 17 New World monkeys, and 22 guinea pigs) were inoculated intracerebrally with brain tissue from ten patients and followed up for six years. Behavioral comparisons with control animals revealed no consistent behavioral differences. Histological, immunohistochemical, and morphometric examination of brains of animals that died revealed no specific neuropathological abnormalities. These findings do not support a role for a virus-induced slow infection in the pathogenesis of schizophrenia but must be weighed against methodological limitations in animal susceptibility, disease communicability, and assay sensitivity.

Adult↗
PubMed1988

Intrathecal synthesis of IgG antibodies to HTLV-I supports an etiological role for HTLV-I in tropical spastic paraparesis.

High titers of antibody to human T-lymphotropic virus type I (HTLV-I) have been reported in the sera and cerebrospinal fluids of patients with tropical spastic paraparesis. By means of agarose isoelectric focusing and selective immunoblotting, we demonstrated oligoclonal bands of immunoglobulin G antibodies to HTLV-I in the serum and cerebrospinal fluid of patients with tropical spastic paraparesis. Such cerebrospinal fluid-specific immunoglobulin bands indicate intrathecal synthesis of specific antibodies to HTLV-I. These findings mimic the antibody response to measles virus in subacute sclerosing panencephalitis and support an etiological role for HTLV-I in the pathogenesis of tropical spastic paraparesis.

Antibodies, Anti-Idiotypic↗
PubMed1988

Antibodies to HTLV-I in populations of the southwestern Pacific.

Sera collected from 1,102 individuals in 14 populations of the southwestern Pacific between 1956 and 1979 were tested by ELISA for antibodies to human T-cell leukemia virus type I (HTLV-I). Selected sera were also tested by particle agglutination and immunoblotting. Six of the populations had prevalences of antibodies greater than 4%, two populations had prevalences greater than 15%. Six populations had antibody prevalences of 2% or less. Three populations from the coast and northern islands of New Guinea had high prevalences of antibodies, while three New Guinea highland groups had virtually none. One population from the Solomon Islands had a high prevalence, while two others had very low prevalences. Two populations from small remote islands in Vanuatu both had high prevalences. Pacific sera did not neutralize a standard strain of virus readily neutralized by Japanese, European, and American sera. We conclude that infections with HTLV-I, some acquired more than 20 years ago, are widespread throughout the southwestern Pacific, even in several very isolated populations, although others have been spared. Some strains of HTLV-I in populations of the Pacific may have substantially different envelope proteins from prototype strains of America, Europe, and Japan.

Adolescent↗
PubMed1988

Experimental hantavirus infection in nonhuman primates.

Mild, transient proteinuria and azotemia were produced in three cynomolgus monkeys (Macaca fascicularis) and a chimpanzee (Pan troglodytes) following intravenous inoculation with Prospect Hill virus, a hantavirus isolated from meadow voles in the United States. This is the first demonstration of an acute nephropathy in nonhuman primates with the viruses causing hemorrhagic fever with renal syndrome.

Animals↗
PubMed1988

Evidence that DNA is present in abnormal tubulofilamentous structures found in scrapie.

Abnormal tubulofilamentous structures have been identified in electron micrographs of thin sections and negatively stained impression grids prepared from brains of animals with scrapie and other spongiform encephalopathies, and we showed that such tubules contain a core of filamentous structures resembling scrapie-associated fibrils (SAF). We treated impression grids from brains of scrapie-infected hamsters with several substances that bind to or cleave proteins and nucleic acids to see if they had any effect on the abnormal tubulofilamentous structures. Treatment with three proteolytic enzymes reduced the caliber of the tubules from about 50 nm to 30 nm; subsequent treatment of the 30-nm tubules with DNase I left many typical SAF as well as transitional forms in which twisted SAF emerged from tubules. DNase treatment of the original thicker tubules had no effect, and no SAF were seen on grids. Treatment of the 30-nm tubules with any of three other nucleases (micrococcal, mung bean, and BAL-31) also produced SAF. However, treatment with RNase A had no effect either on the original 50-nm tubules or on the 30-nm tubules produced by proteolysis. Detergent treatment of any of the preparations produced SAF. Treatment with ethidium bromide resulted in staining of the tubules that was inhibited by magnesium ions. The data suggest that the abnormal tubulofilamentous particles found in spongiform encephalopathies may consist of an outer cylinder of protein, an inner cylinder of DNA, and an innermost core of SAF.

Animals↗
PubMed1988

Human immunodeficiency virus type 1 neutralization epitope with conserved architecture elicits early type-specific antibodies in experimentally infected chimpanzees.

Chimpanzees are susceptible to infection by divergent strains of human immunodeficiency virus type 1 (HIV-1), none of which cause clinical or immunological abnormalities. Chimpanzees were inoculated with one of four strains of HIV-1: human T-lymphotropic virus (HTLV) type IIIB, lymphadenopathy virus (LAV) type 1, HTLV type IIIRF, or an isolate from the brain of a patient with acquired immunodeficiency syndrome. Within 6 months after inoculation with the closely related strains HTLV-IIIB or LAV-1, six chimpanzees developed serum antibodies to the C-terminal half (amino acids 288-467) of the HTLV-IIIB external envelope glycoprotein gp120. Sera from five of those chimpanzees had HTLV-IIIB cell-fusion-inhibiting antibody titers greater than or equal to 20 at that time, indicating that they neutralized the infecting strain of HIV-1 in vitro. No antibodies to the carboxyl terminus of HTLV-IIIB gp120 were observed in sera of chimpanzees inoculated with HTLV-IIIRF or with the brain-tissue strain, and those sera did not neutralize HTLV-IIIB. A rabbit immunized with the C-terminal portion of gp120 acquired neutralizing antibodies that bound to four domains of the HTLV-IIIB external envelope as analyzed by reactivity to 536 overlapping nonapeptides of gp120. One of these domains in the variable region V3, with the amino acid sequence IRIQRGPGRAFVTIG (amino acids 307-321), bound to all chimpanzee sera that neutralized HTLV-IIIB but not to the serum of the HTLV-IIIRF-inoculated chimpanzee that did not neutralize HTLV-IIIB. The HTLV-IIIRF sequence at the same location, ITKGPGRVIYA, was recognized by the serum of the HTLV-IIIRF-inoculated chimpanzee but not by any sera of the HTLV-IIIB-inoculated or LAV-1-inoculated chimpanzees. The HTLV-IIIB residues RIQR and AFV and the HTLV-IIIRF residues lysine and VIYA, flanking a highly conserved beta-turn (GPGR), appear to be critical for antibody binding and subsequent type-specific virus neutralization. This neutralization epitope, putatively consisting of a loop between two cysteine residues (amino acids 296 and 331) connected by a disulfide bond, is immunodominant in HIV-1-infected chimpanzees and induces antibodies restricted to the homologous viral strain.

Amino Acid Sequence↗
PubMed1987

Intra-blood-brain barrier synthesis of human immunodeficiency virus antigen and antibody in humans and chimpanzees.

The presence of human immunodeficiency virus (HIV) antigens in cerebrospinal fluid (CSF) was associated with progressive encephalopathy in adult and pediatric patients with acquired immunodeficiency syndrome (AIDS). HIV antigen was detected in CSF from 6 of 7 AIDS patients with progressive encephalopathy. By contrast, HIV antigen, whether free or complexed, was detected in CSF from only 1 of 18 HIV antibody seropositive patients without progressive encephalopathy and from 0 of 8 experimentally infected chimpanzees without clinical signs. Intra-blood-brain barrier synthesis of HIV-specific antibody was demonstrated in the majority of patients with AIDS (9/12) or at risk for AIDS (8/13) as well as in the experimentally infected chimpanzees, indicating HIV-specific B-cell reactivity in the brain without apparent neurological signs. In 6 of 11 patients with HIV infection, antibodies synthesized in the central nervous system were directed against HIV envelope proteins. Active viral expression appears to be necessary for both the immunodeficiency and progressive encephalopathy associated with HIV infection.

AIDS-Related Complex↗
PubMed1987

Tubulofilaments in negatively stained scrapie-infected brains: relationship to scrapie-associated fibrils.

A simple method was devised for negative-stain transmission electron microscopy of brain infected with the agent of scrapie. Brains of infected hamsters contained large masses of tubulofilamentous structures with irregular fuzzy surfaces. Brains of mice infected with Creutzfeldt-Jakob disease agent contained similar tubulofilaments in smaller numbers. The abnormal tubulofilaments resembled but were distinguished from normal microtubules. On grids soaked in sodium dodecyl sulfate the abnormal tubulofilaments were found in stages of fragmentation, an outer coat appearing t0 strip from the surface to reveal thinner fibrillary structures resembling scrapie-associated fibrils (SAF). The unmasked fibrils were identified as SAF by immunogold labeling, while the larger tubulofilaments were not labeled. The findings indicate that in infected brain tissue SAF may occur as an internal part of a larger structure that is disrupted by detergent and are not likely to be an artifact formed during extraction procedures.

Actin Cytoskeleton↗
PubMed1987

Persistent infection of chimpanzees with human immunodeficiency virus: serological responses and properties of reisolated viruses.

Persistent infection by human immunodeficiency virus (HIV-1) in the chimpanzee may be valuable for immunopathologic and potential vaccine evaluation. Two HIV strains, the tissue culture-derived human T-cell lymphotropic virus type IIIB (HTLV-IIIB) and in vivo serially passaged lymphadenopathy-associated virus type 1 (LAV-1), were injected intravenously into chimpanzees. Two animals received HTLV-IIIB as either virus-infected H9 cells or cell-free virus. A third animal received chimpanzee-passaged LAV-1. Evaluation of their sera for virus-specific serologic changes, including neutralizations, was done during a 2-year period. During this period all animals had persistently high titers of antibodies to viral core and envelope antigens. All three animals developed a progressively increasing type-specific neutralizing LAV-1 versus HTLV-IIIB antibody titer during the 2-year observation period which broadened in specificity to include HTLV-HIRF, HTLV-IIIMN, and HTLV-IIICC after 6 to 12 months. The antibody titers against both viruses were still increasing by 2 years after experimental virus inoculation. Sera from all animals were capable of neutralizing both homologously and heterologously reisolated virus from chimpanzees. A slightly more rapid type-specific neutralizing response was noted for the animal receiving HTLV-IIIB-infected cells compared with that for cell-free HTLV-IIIB. Sera from all persistently infected chimpanzees were capable of mediating group-specific antibody-mediated complement-dependent cytolysis of HIV-infected cells derived from all isolates tested. Viruses reisolated from all three animals at 20 months after inoculation revealed very similar peptide maps of their respective envelope gp120s, as determined by two-dimensional chymotrypsin oligopeptide analysis. One peptide, however, from the original HTLV-IIIB-inoculated virus was deleted in viruses from all three animals, and in addition, we noted the appearance of a new or modified peptide which was common to LAV-1 as well as to HTLV-IIIB reisolated from infected chimpanzees. It thus appears that a group-specific neutralizing antibody response as well as a group-specific cytotoxic response can develop in chimpanzees after an inoculation of a single HIV variant. This finding suggests that a common, less immunodominant determinant(s) is present on a single HIV strain which could induce group-specific antibodies during viral infection and replication. The identification of this group-specific epitope and the induction of analogous immunity may be relevant to vaccine development against human acquired immunodeficiency syndrome.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Abnormal tubulovesicular particles in brains of hamsters with scrapie.

Abnormal tubulovesicular particles of an average diameter of 23 nm have been observed in brains of mice with scrapie as well as in other animals with spongiform encephalopathies, but they were thought to be absent from the brains of hamsters with scrapie in which the highest known concentrations of the infectious agent occur. We observed in neuronal processes of hamsters as well as mice clusters of those tubulovesicular structures, most often in postsynaptic terminals. Such particles have now been seen regularly in both experimental and natural scrapie in all species examined as well as in other spongiform encephalopathies.

Animals↗