Search PubMed⌕ Search

Biomedical subjects

S Perlman

Publications and source records attributed to S Perlman.

At least 37 records · Page 2Linked to original sources
PubMed2000

Human coronavirus 229E infects polarized airway epithelia from the apical surface.

Gene transfer to differentiated airway epithelia with existing viral vectors is very inefficient when they are applied to the apical surface. This largely reflects the polarized distribution of receptors on the basolateral surface. To identify new receptor-ligand interactions that might be used to redirect vectors to the apical surface, we investigated the process of infection of airway epithelial cells by human coronavirus 229E (HCoV-229E), a common cause of respiratory tract infections. Using immunohistochemistry, we found the receptor for HCoV-229E (CD13 or aminopeptidase N) localized mainly to the apical surface of airway epithelia. When HCoV-229E was applied to the apical or basolateral surface of well-differentiated primary cultures of human airway epithelia, infection primarily occurred from the apical side. Similar results were noted when the virus was applied to cultured human tracheal explants. Newly synthesized virions were released mainly to the apical side. Thus, HCoV-229E preferentially infects human airway epithelia from the apical surface. The spike glycoprotein that mediates HCoV-229E binding and fusion to CD13 is a candidate for pseudotyping retroviral envelopes or modifying other viral vectors.

Cell Line↗
PubMed2000

Helping special olympics athletes sport good smiles. An effort to reach out to people with special needs.

For the millions of people in the world with special needs, dental care is usually not a priority, often taking a back seat to more pressing and complicated medical issues. This article offers a brief overview of the integration of a dental program into the Special Olympics organization. This overview is followed by a discussion on dental education with regard to people with special needs, and then reviews measures for the prevention of injuries.

Athletic Injuries↗
PubMed2000

Women with HIV: conflicts and synergy of prayer within the realm of medical care.

In a recent survey of women with HIV, prayer was mentioned as a very important source in decision making about HIV antiretroviral therapy. As a follow-up to this finding, we conducted in-depth interviews with 51 women attending a comprehensive HIV care center to better understand the role of prayer in their decisions about taking antiretroviral therapy. The sample consisted predominately of African American (80%) women with a median age of 31 years from St. Louis and surrounding areas. Forty-seven (92%) reported that prayer was an important source for HIV medication decision making, with 30 (59%) considering prayer more important than the physician. Twenty-nine (57%) perceived a qualitative difference between prayer and the physician, which created a sense of conflict for some. Thirty (59%) wished that the physician knew more about the role of prayer in their lives. Our findings reveal compelling issues: (a) the willingness of the women to talk about prayer as a resource and its importance in HIV disease management, (b) the roles that prayer and the physician play in HIV medication decision-making, and (c) ways prayer can be addressed in a medical setting.

Adolescent↗
PubMed1999

Selection of CTL escape mutants in mice infected with a neurotropic coronavirus: quantitative estimate of TCR diversity in the infected central nervous system.

Variant viruses mutated in the immunodominant cytotoxic T cell epitope surface (S) glycoprotein S-510-518 are selected in mice chronically infected with mouse hepatitis virus, strain JHM. We determined whether this selection occurred in the presence of an oligoclonal or polyclonal T cell response using soluble MHC/peptide tetramers in direct ex vivo analyses of CNS-derived lymphocytes. A total of 42% (range, 29-60%) of CD8 T cells in the CNS of mice with acute encephalitis recognized epitope S-510-518. A total of 34% (range, 18-62%) of cells from mice with hind limb paralysis (and chronic demyelination) were also epitope specific, even though only virus expressing mutated epitope is detected in these animals. Sequence analysis of the beta-chain CDR3 of 487 tetramer S-510-518-positive cDNA clones from nine mice showed that a majority of clonotypes were identified in more than one mouse. From these analyses, we estimated that 300-500 different CD8 T cell clonotypes responsive to epitope S-510-518 were present in each acutely infected brain, while 100-900 were present in the CNS of each mouse with chronic disease. In conclusion, a polyclonal CD8 T cell response to an epitope does not preclude the selection of T cell escape mutants, and epitope-specific T cells are still present at high levels even after RNA-encoding wild-type sequence is no longer detectable.

Acute Disease↗
PubMed1999

Gammadelta T cell response induced by vaginal Herpes simplex 2 infection.

The purpose of the present studies was to determine whether acute vaginal infection with Herpes virus 2 altered the vaginal population of gammadelta T cells, and whether gammadelta T cells influenced the vaginal clearance of HSV-2. BALB/c mice were infected intravaginally with the progressively lethal wild type 333 strain, or the non-lethal thymidine kinase deficient (deltaTK- -HSV-2) mutant strain of HSV-2 virus. Changes in vaginal T cell composition were examined by FACS analysis 4 days after infection. Clearance of vaginal deltaTK- -HSV-2 infection was compared between mice with normal gammadelta T cell populations (BALB/c) and transgenic mice in which all the gammadelta T cells express a receptor that is specific for the b allotype of MHC class Ib T10 antigen (G8/BALB/c). In HSV-2 infected BALB/c mice, but not G8/BALB/c, a subset of gammadelta T cells that express a Vgamma2 TCR accumulated in the vaginal mucosa by the fourth day after infection. Unexpectedly, we found that gammadelta TCR transgenic mice exhibited a more rapid clearance of the virus than control mice (P < 0.05). These findings argue against the hypothesis that the normal populations of vaginal intraepithelial gammadelta T cells play a direct role in the elimination of virally infected epithelial cells.

Animals↗
PubMed1999

Immune response to the immunodominant epitope of mouse hepatitis virus is polyclonal, but functionally monospecific in C57Bl/6 mice.

Mutations in an immunodominant CD8 CTL epitope (S-510-518) are selected in mice persistently infected with the neurotropic JHM strain of mouse hepatitis virus. These mutations abrogate recognition by T cells harvested from the infected CNS in direct ex vivo cytotoxicity assays. Previous reports have suggested that, in general, an oligoclonal, monospecific T cell response contributes to the selection of CTL escape mutants. Herein, we show that, in MHV-JHM-infected mice, the CD8 T cell response after intraperitoneal infection is polyclonal and diverse. This diverse response was shown to include both polyclonal and oligoclonal components. The polyclonal data were shown to fit a logarithmic distribution. With regard to specificity, we used a panel of peptide analogues of epitope S-510-518 and spleen-derived CD8 T cell lines to determine why only a subset of possible mutations was selected in persistently infected mice. At a given position in the epitope, the mutations identified in in vivo isolates were among those that resulted in the greatest loss of recognition. However, not all such mutations were selected, suggesting that additional factors must contribute to selection in vivo. By extrapolation of these results to the persistently infected CNS, they suggest that the selection of CTL escape mutants requires the presence of a monospecific T cell response but also show that this response need not be oligoclonal.

Animals↗
PubMed1999

Increased basal ganglia iron levels in Huntington disease.

OBJECTIVE: To quantify in vivo brain ferritin iron levels in patients with Huntington disease (HD) and normal control subjects. DESIGN AND SUBJECTS: A magnetic resonance imaging method that can quantify ferritin iron levels with specificity in vivo was employed to study 11 patients with HD and a matched group of 27 normal controls. Three basal ganglia structures (caudate, putamen, and globus pallidus) and 1 comparison region (frontal lobe white matter) were evaluated. RESULTS: Basal ganglia iron levels were significantly increased (P<.002) in patients with HD, and this increase occurred early in the disease process. This was not a generalized phenomenon, as white matter iron levels were lower in patients with HD. CONCLUSIONS: The data suggest that increased iron levels may be related to the pattern of neurotoxicity observed in HD. Reducing the oxidative stress associated with increased iron levels may offer novel ways to delay the rate of progression and possibly defer the onset of HD.

Adult↗
PubMed1999

Macrophage infiltration, but not apoptosis, is correlated with immune-mediated demyelination following murine infection with a neurotropic coronavirus.

Mice infected with mouse hepatitis virus strain JHM (MHV-JHM) develop a chronic demyelinating encephalomyelitis that is in large part immune mediated. Potential mechanisms of immune activity were assessed using an adoptive transfer system. Mice deficient in recombinase-activating gene function (RAG1(-/-)), defective in B- and T-cell maturation, become persistently infected with MHV but do not develop demyelination. Adoptive transfer of splenocytes from mice immunized to MHV into RAG1(-/-) mice infected with an attenuated strain of the virus results in the rapid and progressive development of demyelination. Most striking, adoptive transfer resulted, within 5 to 6 days, in extensive recruitment of activated macrophages/microglia to sites of demyelination within the spinal cord. Clearance of virus antigen occurred preferentially from the gray matter of the spinal cord. Apoptotic cells were identified in both the gray and white matter of the central nervous system (CNS) from RAG1(-/-) mice before and after adoptive transfer, with a moderate increase in number, but not distribution, of apoptotic cells following the development of demyelination. These results suggest that apoptosis following MHV-JHM infection of the murine CNS is not sufficient to cause demyelination. These results, showing that macrophage recruitment and myelin destruction occur rapidly after immune reconstitution of RAG(-/-) mice, suggest that this will be a useful system for investigating MHV-induced demyelination.

Animals↗
PubMed1999

Depletion of blood-borne macrophages does not reduce demyelination in mice infected with a neurotropic coronavirus.

Mice infected with the neurotropic coronavirus mouse hepatitis virus strain JHM (MHV-JHM) develop a chronic demyelinating disease with symptoms of hindlimb paralysis. Histological examination of the brains and spinal cords of these animals reveals the presence of large numbers of activated macrophages/microglia. In two other experimental models of demyelination, experimental allergic encephalomyelitis and Theiler's murine encephalomyelitis virus-induced demyelination, depletion of hematogenous macrophages abrogates the demyelinating process. In both of these diseases, early events in the demyelinating process are inhibited by macrophage depletion. From these studies, it was not possible to determine whether infiltrating macrophages were required for late steps in the process, such as myelin removal. In this study, we show that when macrophages are depleted with either unmodified or mannosylated liposomes encapsulating dichloromethylene diphosphate, the amount of demyelination detected in MHV-infected mice is not affected. At a time when these cells were completely depleted from the liver, approximately equivalent numbers of macrophages were present in the spinal cords of control and drug-treated animals. These results suggest that blood-borne macrophages are not required for MHV-induced demyelination and also suggest that other cells, such as perivascular macrophages or microglia, perform the function of these cells in the presence of drug.

Animals↗
PubMed1998

Oculomotor phenotypes in autosomal dominant ataxias.

OBJECTIVE: To quantify the oculomotor features of the common spinocerebellar ataxia (SCA) syndromes. SETTING: University ataxia clinic. PATIENTS: Twenty probands with documented SCA mutations. METHODS: Electro-oculographic recordings of saccadic, smooth pursuit, optokinetic, vestibular, and visual-vestibular eye movements. RESULTS: Distinct phenotype and genotype patterns were identified with modest overlap between patterns. Slowing of saccade peak velocities occurred only in SCA1 and SCA2, being present in 100% of patients with SCA2. Impaired vestibulo-ocular reflex gain occurred with SCA3 only. Patients with SCA6 had prominent deficits in smooth tracking but normal saccade velocities and vestibuloocular reflex gain. CONCLUSIONS: The oculomotor findings are consistent with pure cerebellar involvement in SCA6, pontine involvement in SCA1 and SCA2, and vestibular nerve or nuclei involvement in SCA3. These phenotypes can be useful for clinical diagnosis and for investigating the mechanism of system specificity with the SCA syndromes.

Adult↗
PubMed1998

Role of CTL mutants in demyelination induced by mouse hepatitis virus, strain JHM.

Mouse hepatitis virus, strain JHM (MHV-JHM) is a well described cause of demyelination. C57B1/6 (B6) mice infected at the suckling stage in the presence of protective antibodies remain asymptomatic initially but later develop clinical disease (hindlimb paralysis). Infectious virus can be isolated from these mice. Recently, two MHV-specific target epitopes for cytotoxic CD8 T cells have been identified in B6 mice. Our results show that in all mice with hindlimb paralysis, mutations can be detected in the RNA encoding the immunodominant of the two epitopes. These mutations result in a loss of recognition by MHV-specific cytotoxic T cells. These changes are not detected, for the most part, in mice that remain asymptomatic nor in mice with acute encephalitis. These results suggest that the development of CTL escape mutants is necessary for hindlimb paralysis to develop in this model.

Animals↗
PubMed1998

Analysis of the dynamic mutation in the SCA7 gene shows marked parental effects on CAG repeat transmission.

The gene for spinocerebellar ataxia 7 (SCA7) includes a transcribed, translated CAG tract that is expanded in SCA7 patients. We have determined expansions in 73 individuals from 17 SCA7 kindreds and compared them with repeat lengths of 180 unaffected individuals. Subjects with abnormal expansions comprise 59 clinically affected individuals and 14 at-risk currently unaffected individuals predicted to carry the mutation by haplotype analysis. For expanded alleles, CAG repeat length correlates with disease progression and severity and correlates inversely with age of onset. Increased repeat lengths are seen in generational transmission of the disease allele, consistent with the pattern of clinical anticipation seen in these kindreds. Repeat lengths in expanded alleles show somatic mosaicism in leukocyte DNA, suggesting that these alleles are unstable within individuals as well as between generations. Although dynamic repeat expansions from paternal transmissions are greater than those from maternal transmissions, maternal transmission of disease is more common, suggesting germline or embryonic effects of the repeat expansion.

Adolescent↗
PubMed1998

Recombinant hepatitis A virus antigen: improved production and utility in diagnostic immunoassays.

Hepatitis A virus (HAV) immunoassays use cell culture-derived HAV antigen to detect HAV-specific antibodies. The current method of production of HAV antigen in tissue culture is time-consuming and expensive. We previously expressed the HAV open reading frame in recombinant vaccinia viruses (rV-ORF). The recombinant HAV polyprotein was accurately processed and was assembled into subviral particles. These particles were bound by HAV-neutralizing antibodies and were able to elicit antibodies which were detected by commercial immunoassays. The present investigation compared the production of HAV antigen by standard tissue culture methods to the production of HAV antigen with the recombinant vaccinia virus system. In addition, HAV and rV-ORF antigens were assessed for their utility in diagnostic immunoassays. Serum or plasma samples from HAV antibody-positive and antibody-negative individuals were evaluated by immunoassay that used either HAV or rV-ORF antigen. All samples (86 of 86) in which HAV antibody was detected by a commercial enzyme-linked immunosorbent assay (ELISA) also tested positive by the recombinant antigen-based immunoassay (VacRIA). Similarly, all samples (50 of 50) that were HAV antibody negative also tested negative by the VacRIA. The lower limit of detection of HAV antibody was similar among immunoassays with either HAV or rV-ORF antigen. Thus, in the population studied, the sensitivity and specificity of the VacRIA were equivalent to those of the commercial ELISA. Since production of recombinant antigen is faster and less expensive than production of traditional HAV antigen, the development of diagnostic HAV antibody tests with recombinant HAV antigen appears warranted.

Animals↗
PubMed1998

Infection with cytotoxic T-lymphocyte escape mutants results in increased mortality and growth retardation in mice infected with a neurotropic coronavirus.

C57BL/6 mice infected with mouse hepatitis virus strain JHM (MHV-JHM) develop a chronic demyelinating encephalomyelitis several weeks after inoculation. Previously, we showed that mutations in the immunodominant CD8 T-cell epitope (S-510-518) could be detected in nearly all samples of RNA and virus isolated from these mice. These mutations abrogated recognition by T cells harvested from the central nervous systems of infected mice in direct ex vivo cytotoxicity assays. These results suggested that cytotoxic T-lymphocyte (CTL) escape mutants contributed to virus amplification and the development of clinical disease in mice infected with wild-type virus. In the present study, the importance of these mutations was further evaluated by infecting naive mice with MHV-JHM variants isolated from infected mice and in which epitope S-510-518 was mutated. Compared to mice infected with wild-type virus, variant virus-infected animals showed higher mortality and morbidity manifested by decreased weight gain and neurological signs. Although a delay in the kinetics of virus clearance has been demonstrated in previous studies of CTL escape mutants, this is the first illustration of significant changes in clinical disease resulting from infection with viruses able to evade the CD8 T-cell immune response.

Animals↗
PubMed1998

Pathogenesis of coronavirus-induced infections. Review of pathological and immunological aspects.

Coronaviruses and arteriviruses infect multiple species of mammals, including humans, causing diseases that range from encephalitis to enteritis. Several of these viruses infect domestic animals and cause significant morbidity and mortality, leading to major economic losses. In this category are included such pathogens as transmissible gastroenteritis virus, porcine respiratory and reproductive virus and infectious bronchitis virus. The feline coronaviruses (FECV) generally do not cause infections with high morbidity but in a small percentage of cases, the virus mutates to become more virulent. This virus, feline infectious peritonitis virus (FIPV), causes severe disease in young cats. This disease is in large part immunopathological and understanding it is a major goal of coronavirus research.

Animals↗
PubMed1997

Antigen specificity of CD4 T cell response in the central nervous system of mice infected with mouse hepatitis virus.

Previously, we showed that the transmembrane (M) and surface (S) glycoproteins were recognized by splenic CD4 T lymphocytes harvested from mice infected intraperitoneally with mouse hepatitis virus, strain JHM (MHV-JHM), whereas only the S protein was recognized by splenocytes derived from mice with MHV-induced chronic demyelination. From these results, it could not be determined which proteins were recognized by T cells localized in the infected central nervous system (CNS). Herein, we show that CD4 T cells responding to both the M and S proteins can be detected in the CNS of mice with either acute encephalitis or the chronic demyelinating disease. As part of these analyses, two CD4 T cell epitope regions encompassing residues 328-347 and 358-377 within the S protein were identified. Both epitopes, as well as a previously identified M-specific epitope, were recognized by the CNS-derived lymphocytes. Finally, viral RNA harvested from mice with chronic demyelination was analyzed for mutations in the S specific CD4 T cell epitopes since changes resulting in escape from CD8 T cell surveillance were previously identified in these samples. A mutation in epitope region S(328-347) (ala to thr at position 337) was detected in a minority of samples but this change did not abrogate recognition of the epitope and therefore was unlikely to contribute to virus persistence. In conclusion, these studies identify epitopes recognized by MHV-specific CD4 T cells in the infected CNS and show that these cells are preferentially located at the site of infection in mice with clinical disease.

Animals↗