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Biomedical subjects

S Perlman

Publications and source records attributed to S Perlman.

At least 55 records · Page 3Linked to original sources
PubMed1997

Ophthalmologic findings in patients with ataxia.

PURPOSE: To determine the frequency and spectrum of ophthalmologic findings in a large, heterogeneous group of patients with ataxia. METHODS: Medical records of 184 patients from a university-based ataxia clinic were retrospectively reviewed. Patients were classified as having Friedreich's ataxia, spinocerebellar degeneration, cerebellar degeneration, familial or sporadic olivo-pontocerebellar atrophy, multisystem atrophy, spastic ataxia, myoclonic ataxia, or other diagnoses such as mitochondrial myopathy. All had complete ophthalmologic examinations, and 107 underwent electro-oculography. RESULTS: Among 184 patients with ataxia, diplopia was present in 52 (28%), best-corrected visual acuity was decreased in 29 (16%), and oscillopsia was present in 10 (5%). Diplopia was usually caused by an intermittent, small-angle heterotropia. The reduction in best-corrected visual acuity varied from mild to profound and was caused by optic atrophy, retinal degeneration, or both. Optic atrophy was present most frequently in spastic ataxia (five of 22 patients) and myoclonic ataxia (two of eight patients), followed by Friedreich's ataxia (three of 26 patients). Retinal degeneration and ophthalmoplegia were most characteristically associated with familial olivopontocerebellar atrophy and mitochondrial myopathy. Laboratory testing of ocular motility showed frequent abnormalities in all groups. Fixation instability was most characteristic of Friedreich's ataxia, whereas saccadic slowing was noticeably absent from patients with purely cerebellar degenerations. CONCLUSIONS: The ataxias may be associated with visual dysfunction caused by retinal degeneration, optic atrophy, oculomotor disturbance, or a combination of these.

Adolescent↗
PubMed1997

Nitric oxide synthase type II expression by different cell types in MHV-JHM encephalitis suggests distinct roles for nitric oxide in acute versus persistent virus infection.

Intranasal inoculation with mouse hepatitis virus strain JHM (MHV-JHM) results in acute meningoencephalitis. We found NOS II mRNA expression in brains of acutely infected animals on days 5 through 7 after infection. In situ hybridization and immunohistochemistry demonstrated NOS II message and protein in infiltrating macrophages. Persistent infection with MHV-JHM results in chronic demyelinating encephalomyelitis. NOS II mRNA was detected in persistently infected spinal cords. In situ hybridization and immunohistochemistry showed expression of NOS II in astrocytes in and around demyelinated lesions. These results suggest the role of NO release in acute versus persistent infection with this virus, and its contribution to the resulting pathology, may be different.

Acute Disease↗
PubMed1997

Follow-up of abnormal Papanicolaou smears in a hospital-based adolescent clinic.

STUDY OBJECTIVE: To present data on the spectrum of abnormal Papanicolaou (PAP) smears in adolescents and to determine factors that influence compliance with recommendations to return for repeat PAP smears or for colposcopic examination. DESIGN: Retrospective chart review with follow-up telephone calls to patients who did not follow recommendations for colposcopy. SETTING: Adolescents receiving health care in a hospital-based adolescent clinic. PARTICIPANTS: Patients with abnormal PAP smears between July 1, 1994 and June 30, 1995. MAIN OUTCOME MEASURES: Compliance with follow-up for abnormal PAP smears including referral to the colposcopy clinic, and the results of repeat PAP smears and colposcopy. RESULTS: Of 888 adolescents undergoing PAP smear evaluation 119 (13.4%) had an abnormal PAP smear during the study year (index PAP). The results of the index PAP were 97 (81.5%) atypia and 22 (18.5%) squamous intraepithelial lesion low grade (SIL LG). The index PAP was the first abnormal PAP smear for 92 of the patients (77%); 27 had one or more previous abnormal PAP smears (18 atypia, 7 SIL LG, 2 SIL high grade [HG]), and 13 had been referred for colposcopy in the past. For 76 of 92 patients with atypia on index PAP (84%), the index PAP was the first abnormal PAP smear. Of these 76 patients, 51 had a second PAP smear: 27 (53%) were normal, 13 (25%) atypia, and 11 (22%) SIL LG. Sixty patients were referred to the colposcopy clinic, but only 37 actually kept the colposcopy appointment despite outreach. The only significant factor for obtaining colposcopy was a visit to the Adolescent Clinic after notification of the abnormal PAP smear result and before the colposcopy appointment; 79% of those who had a visit obtained colposcopy compared with 45% of those who did not have such a visit (p = 0.007). There were no significant differences by race, insurance status, age, PAP smear result, previous referral for colposcopy, or number of reminders with compliance with recommendations for repeat PAP smears or colposcopy. CONCLUSIONS: Although a sizable proportion of adolescents with abnormal PAP smears have significant pathology on repeat PAP smears, adolescents with abnormal PAP smears have a high failure rate in keeping appointments for follow-up PAP smears and colposcopy. Interventions that target all adolescents with abnormal PAP smears need to be designed and tested to aid follow-up.

Adolescent↗
PubMed1997

Dual agonistic and antagonistic property of nonpeptide angiotensin AT1 ligands: susceptibility to receptor mutations.

Two nonpeptide ligands that differ chemically by only a single methyl group but have agonistic (L-162,782) and antagonistic (L-162,389) properties in vivo were characterized on the cloned angiotensin AT1 receptor. Both compounds bound with high affinity (K(I) = 8 and 28 nM, respectively) to the AT1 receptor expressed transiently in COS-7 cells as determined in radioligand competition assays. L-162,782 acted as a powerful partial agonist, stimulating phosphatidylinositol turnover with a bell-shaped dose-response curve to 64% of the maximal level reached in response to angiotensin II. Surprisingly, L-162,389 also stimulated phosphatidylinositol turnover, albeit only to a small percentage of the angiotensin response. The prototype nonpeptide AT1 agonist L-162,313 gave a response of approximately 50%. The apparent EC50 values for all three compounds in stimulating phosphatidylinositol turnover were similar, approximately 30 nM, corresponding to their binding affinity. Each of the three compounds also acted as angiotensin antagonists, yet in this capacity the compounds differed markedly, with IC50 values ranging from 1.05 x 10(-7) M for L-162,389 to 6.5 x 10(-6) for L-162,782. A series of point mutations in the transmembrane segments (TMs) of the AT1 receptor had only minor effect on the binding affinity of the nonpeptide compounds, with the exception of A104V at the top of TM III, which selectively impaired the binding of L-162,782 and L-162,389. Substitutions in the middle of TM III, VI, or VII, which did not affect the binding affinity of the compounds, impaired or eliminated the agonistic efficacy of the nonpeptides but with only minor or no effect on the angiotensin potency or efficacy. Thus, in the N295D rat AT1 construct, L-162,782, L-162,313, and L-162,389 all antagonized the angiotensin-induced phosphatidylinositol turnover with surprisingly similar IC50 values (90-180 nM), and they all bound with unaltered, high affinity (22-36 nM). However, L-162,313 and L-162,782 could stimulate phosphatidylinositol turnover to only 20% of that of angiotensin. It is concluded that minor chemical modifications of either the compound or the receptor can dramatically alter the agonistic efficacy of biphenyl imidazole compounds on the AT1 receptor without affecting their affinity, as determined in binding assays, and that a number of substitutions in the middle of the TM segments affect the efficacy of nonpeptide agonists as opposed to angiotensin.

Angiotensin II↗
PubMed1997

Cytotoxic T-cell-resistant variants arise at early times after infection in C57BL/6 but not in SCID mice infected with a neurotropic coronavirus.

Under certain conditions, C57BL/6 mice persistently infected with mouse hepatitis virus strain JHM (MHV-JHM) develop clinical disease and histological evidence of demyelination several weeks after inoculation with virus. In a previous report, we showed that mutations in the RNA encoding an immunodominant CD8 T-cell epitope within the surface glycoprotein (epitope S-510-518) were present in all persistently infected animals and that these mutations abrogated recognition by virus-specific cytotoxic T cells (CTLs) in direct ex vivo cytotoxicity assays. To obtain further evidence that these mutations were necessary for the development of clinical disease, the temporal course of their appearance was determined. Mutations in the epitope were identified by 10 to 12 days after inoculation, and in some mice, virus containing mutated epitope was the dominant species detected by 15 days. In addition, most mice that remain asymptomatic at 80 days after inoculation, a time after which clinical disease almost never develops, were infected with only wild-type virus. Finally, analysis of virus isolated from mice with severe combined immunodeficiency (SCID) revealed the presence only of wild-type epitope S-510-518. These results, by showing that mutations are not selected in SCID mice and occur at early times after inoculation in C57BL/6 mice, support the view that they result from immune pressure and contribute to virus persistence and demyelination in mice infected persistently with MHV-JHM.

Amino Acid Sequence↗
PubMed1997

Friedreich's ataxia GAA repeat expansion in patients with recessive or sporadic ataxia.

To explore the clinical heterogeneity associated with the Friedreich's ataxia (FRDA) expanded repeat and provide preliminary guidance for future gene testing in patients suspected of having FRDA, we tested patients with typical FRDA (group I), late-onset FRDA or FRDA with retained reflexes (group II), as well as those with early onset "non-Friedreich's" recessive or sporadic ataxia (group III). Eighty-seven percent of families in group I tested positive for the FRDA triplet repeat expansion. Thirty-six percent of families in group II demonstrated the FRDA expansion. Only one of 11 patients in group III had the FRDA expansion. Clinical criteria did not clearly distinguish between expansion-positive and expansion-negative individuals in groups I and II. Minimal criteria that were present in all the patients who tested positive were recessive or sporadic inheritance, progressive caudal-rostral gait and limb ataxia, and at least one of the following: dysarthria, Babinski sign, or cardiomyopathy. This study confirms recent findings that some patients in group II can carry the FRDA mutation. However, we did not observe the FRDA expansion in 64% of group II families or in 13% of families with typical FRDA (group I), suggesting other genetic or environmental causes for their ataxia.

Adolescent↗
PubMed1997

Spinocerebellar ataxia type 6. Frequency of the mutation and genotype-phenotype correlations.

Spinocerebellar ataxia type 6 (SCA6) is the most recently identified mutation causing autosomal-dominant cerebellar ataxia without retinal degeneration (ADCA). The SCA6 mutation is allelic with episodic ataxia type 2 (EA-2), but the two differ clinically because of the presence of progressive, rather than episodic, ataxia in SCA6. SCA6 accounts for 12% of families with ADCA in an ethnically heterogeneous population of patients. Clinical examination, quantitative eye movement testing, and imaging data show that the brainstem is normal in most patients with SCA6, especially within the first 10 years of symptoms. Most patients show progressive ataxia from the onset, but several patients show an episodic course resembling EA-2. Thus, SCA6 mutations not only account for patients with ADCA I and ADCA III phenotypes but also for some patients presenting with episodic features that are typical for EA-2. Interestingly, a compound heterozygote for the SCA6 expansion manifested an earlier onset and more rapid course than family members with the same larger expanded allele.

Adolescent↗
PubMed1997

The prevalence and wide clinical spectrum of the spinocerebellar ataxia type 2 trinucleotide repeat in patients with autosomal dominant cerebellar ataxia.

The dominant cerebellar ataxias (ADCAs) represent a clinically and genetically heterogeneous group of disorders linked by progressive deterioration in balance and coordination. The utility of genetic classification of the ADCAs has been highlighted by the striking variability in clinical phenotype observed within families and the overlap in clinical phenotype observed between those with different genotypes. The recent demonstration that spinocerebellar ataxia type 2 (SCA2) is caused by a CAG repeat expansion within the ataxin-2 gene has allowed us to determine the frequency of SCA2 compared with SCA1, SCA3/Machado-Joseph disease (MJD), and dentatorubropallidoluysian atrophy (DRPLA) in patients with sporadic and inherited ataxia. SCA2 accounts for 13% of patients with ADCA (without retinal degeneration), intermediate between SCA1 and SCA3/MJD, which account for 6% and 23%, respectively. Together, SCA1, SCA2, and SCA3/MJD constitute >40% of the mutations leading to ADCA I in our population. No patient without a family history of ataxia, or with a pure cerebellar or spastic syndrome, tested positive for SCA1, SCA2, or SCA3. No overlap in ataxin-2 allele size between normal and disease chromosomes, or intermediate-sized alleles, were observed. Repeat length correlated inversely with age at onset, accounting for approximately 80% of the variability in onset age. Haplotype analysis provided no evidence for a single founder chromosome, and diverse ethnic origins were observed among SCA2 kindreds. In addition, a wide spectrum of clinical phenotypes was observed among SCA2 patients, including typical mild dominant ataxia, the MJD phenotype with facial fasciculations and lid retraction, and early-onset ataxia with a rapid course, chorea, and dementia.

Adolescent↗
PubMed1996

Differential antigen recognition by T cells from the spleen and central nervous system of coronavirus-infected mice.

CD8+ cytotoxic T lymphocytes (CTLs) isolated from the central nervous system (CNS) of C57BI/6 mice acutely infected with mouse hepatitis virus, strain JHM (MHV-JHM), and analyzed in a direct ex vivo cytotoxicity assay recognize two epitopes (H-2Db- and H-2Kb-restricted encompassing amino acids 510-518 and 598-605, respectively) within the surface (S) glycoprotein. In contrast, CD8+ T cells isolated from the spleens of mice inoculated intraperitoneally with MHV-JHM and restimulated in vitro only respond to the H-2Db-restricted epitope. In this report, the preferential recognition of the H-2Db-restricted epitope is confirmed using splenocytes stimulated in vitro with either MHV-JHM-infected MC57 cells or with a cell line expressing the S protein and analyzed in secondary CTL assays. To determine whether these results represent a difference in epitope recognition between the spleen and CNS, secondary CTL assays were performed using spleen cells coated with peptides encompassing the CTL epitopes as stimulators. Under these conditions, both epitopes sensitized cells for lysis by spleen-derived CTLs, suggesting that both epitopes were recognized by splenic CD8+ T cells after infection in vivo. Furthermore, limiting dilution analysis indicated that the precursor frequency of splenic CD8+ T cells specific for both the H-2Kb- and H-2Db-restricted epitopes were not significantly different. Thus, the results suggest that in vitro stimulation of splenocytes specific for the H-2Kb-restricted epitope is inefficient after endogenous processing but that this inefficiency can be corrected if peptide is provided exogenously at sufficiently high concentrations. As a consequence, the results also show that cells responsive to both of the previously identified CNS-derived CD8+ T cell epitopes are present in the infected spleen at nearly the same frequency.

Animals↗
PubMed1996

Cytotoxic T cell-resistant variants are selected in a virus-induced demyelinating disease.

C57BI/6 mice infected with mouse hepatitis virus, strain JHM (MHV-JHM) develop a chronic demyelinating encephalomyelitis. Infectious virus can be isolated only from symptomatic mice. In C57BI/6 mice, two CD8+ T cell epitopes within the MHV-JHM surface glycoprotein were previously identified. Here, we show that mutations in the RNA encoding the immunodominant of the epitopes are present in nearly all virus samples isolated from these mice. Mutations are not present in sequences flanking this epitope or in other CD8+ or CD4+ T cell epitopes. Furthermore, analysis of five peptides corresponding to variant epitopes in direct ex vivo cytotoxicity assays showed that each mutation caused a loss of epitope recognition. These results suggest that escape from CD8+ T cell recognition is necessary for enhanced virus replication and development of clinical disease in these MHV-JHM-infected mice.

Animals↗
PubMed1996

Anterograde, transneuronal transport of herpes simplex virus type 1 strain H129 in the murine visual system.

Herpes simplex virus (HSV) undergoes retrograde and anterograde axonal transport as it establishes latency and later intermittently reactivates. Most strains of HSV show preferential retrograde transport within the central nervous system (CNS), however. Previous experiments suggest that an exception to this is HSV type 1 (HSV-1) strain H129, since this virus appears to spread primarily in the CNS via anterograde, transneuronal movement. The objective of the present study was to test how specifically this virus spreads in the visual system, a system with well-described neuronal connections. In the present study, the pattern of viral spread was examined following inoculation into the murine vitreous body. Virus was initially detected in the retina and optic tract. Virus then appeared in all known primary targets of the retina, including those in the thalamus (e.g., lateral geniculate complex), hypothalamus (suprachiasmatic nucleus), and superior colliculus (superficial layers). In previous studies, many strains of HSV were shown to infect these structures, even though they spread predominantly in a retrograde direction. However, the H129 strain was unique in then spreading, via anterograde transport, to the primary visual cortex (layer 4 of area 17) via thalamocortical connections. At later times after infection, specific labeling was also detected in other cortical and subcortical areas known to receive projections from the visual cortex. No labeling was ever detected in the contralateral retina, which is consistent with a lack of retrograde spread of HSV-1 strain H129. These results demonstrate the specific anterograde movement of this virus from the retina to subcortical and cortical regions, with no clear evidence for retrograde spread. HSV-1 strain H129 should be generally useful for tracing sensory pathways and may provide the basis for designing a virus vector capable of delivering genetic material via anterograde pathways within the CNS.

Animals↗
PubMed1995

Activation of astrocytes in the spinal cord of mice chronically infected with a neurotropic coronavirus.

Mice infected with the neurotropic JHM strain of mouse hepatitis virus (MHV-JHM) develop a demyelinating encephalomyelitis several weeks after infection. Astrogliosis and infiltration of inflammatory cells are prominent findings in the brains and spinal cords of infected mice. In this report, astrocytes in infected spinal cords were analyzed for expression of three pleiotropic cytokines, TNF-alpha, IL-1 beta, and IL-6; Type 2 nitric oxide synthase (iNOS); and MHC class I and II antigen. The data show that all three cytokines and iNOS are expressed by astrocytes in chronically infected spinal cords. These activated astrocytes are localized to areas of virus infection and demyelination, although most of the astrocytes expressing these proteins are not MHV-infected. MHC class I and II antigen can be detected in these spinal cords as well, but not in cells with the typical morphology of astrocytes. TNF-alpha, IL-6, and iNOS are also evident in the brains of mice with MHV-induced acute encephalitis, but in marked contrast to the results obtained with the chronically infected mice, most of the cells expressing these cytokines or iNOS had the morphology of macrophages or other mononuclear cells and very few appeared to be astrocytes. Additionally, astrocytes and, most likely, oligodendrocytes are infected in the spinal cords of mice with chronic demyelination. These results are consistent with a role for both viral infection of glial cells and high localized levels of proinflammatory cytokines and nitric oxide in the demyelinating process in mice infected with MHV-JHM. They also show that analogously to the human demyelinating disease, multiple sclerosis, astrocytes are a major cellular source for these cytokines in mice with chronic, but not acute disease.

Acute Disease↗
PubMed1995

Identification of a CD4+ T cell epitope within the M protein of a neurotropic coronavirus.

A significant CD4+ T cell response against the transmembrane (M) protein can be detected in the spleens of C57Bl/6 mice infected intraperitoneally with a sublethal injection of the neurotropic JHM strain of mouse hepatitis virus (MHV-JHM), but not in those of mice with the chronic demyelinating encephalomyelitis caused by this virus. With the ultimate goal of determining the role of the M-specific response in the pathogenesis of MHV-JHM-induced neurological diseases, CD4+ T cell epitopes within the M protein were identified using vaccinia virus recombinants expressing truncated forms of the protein and peptides spanning most of the M protein in cell proliferation assays. Peptides covering residues 128-147 contain at least one CD4+ T cell epitope for MHV-JHM. Within this region is a sequence (residues 135-143) which matches the recently described MHC class II I-Ab binding motif. Delineation of this epitope should facilitate analysis of the role of the M-specific CD4+ T cell response in the development of acute and chronic neurological infections caused by MHV-JHM.

Animals↗
PubMed1995

Non-peptide angiotensin agonist. Functional and molecular interaction with the AT1 receptor.

Non-peptide ligands for peptide receptors for the G-protein-coupled type are generally antagonists, except in the opiate system. Recently, it was observed that a subset of biphenylimidazole derivatives surprisingly possessed angiotensin-like activity in vivo. In COS-7 cells transfected with the rat AT1 receptor a prototype of these compounds, L-162,313 stimulated phosphoinositide hydrolysis with an EC50 of 33 +/- 11 nM. The maximal response to the compound was 50% of that of angiotensin II in COS-7 cells but only 3% in stably transfected Chinese hamster ovary cells. The agonistic effect of L-162,313 was blocked by the AT1-specific antagonist L-158,809 and was not observed in untransfected cells. In Chinese hamster ovary cells, L-162,313 also acted as an insurmountable antagonist of the angiotensin stimulated phosphoinositide hydrolysis. In contrast to previously tested non-peptide ligands, L-162,313 bound with reasonably high affinity to the Xenopus laevis AT1 receptor. In the human receptor, the binding of L-162,313 was found to be unaffected by point mutations in transmembrane segments III and VII, which impaired the binding of biphenylimidazole antagonists. Substitutions in the extracellular domains of the human and rat receptor, which impaired the binding of angiotensin II, did not affect the binding of L-162,313. It is concluded that a subset of biphenylimidazole compounds can act as high affinity partial agonists on the AT1 receptor. These compounds have molecular interactions with the receptor which appear to differ both from that of the structurally similar non-peptide antagonists and from that of their functional counterpart, the peptide agonist.

Amino Acid Sequence↗
PubMed1995

Spread of MHV-JHM from nasal cavity to white matter of spinal cord. Transneuronal movement and involvement of astrocytes.

C57B1/6 mice infected intranasally with mouse hepatitis virus, strain JHM (MHV-JHM) develop hindlimb paralysis with histological evidence of demyelination several weeks after inoculation. Virus must spread from the site of inoculation, the nasal cavity, to the site of disease, the white matter of the spinal cord. It has been shown previously that after intranasal inoculation, virus enters the brain via the olfactory nerve and spreads to infect many of its neuroanatomic connections within the central nervous system (CNS). In this report, it is shown that virus infecting the spinal cord is first detected in the gray matter, with spread occurring to the white matter soon thereafter. Astrocytes are heavily infected during the process of spread from the gray to the white matter of the spinal cord. Since astrocytes are in intimate contact with neuronal synapses and are themselves connected via gap junctions, these results suggest that astrocytes may be a conduit for the spread of virus in these mice. Astrocytes provide factors for the proliferation and survival of oligodendrocytes, and widespread infection of these cells might contribute to the demyelinating process eventually observed in these mice. Additionally, since virus first appears at specific locations in the spinal cord, it should be possible to determine the source of the virus infecting the cord. While the results are not definitive, the data are most consistent with virus spreading from the ventral reticular formation to the gray matter of the cervical spinal cord.

Animals↗
PubMed1995

Quantitative analysis of fosinopril sodium by capillary zone electrophoresis and liquid chromatography.

A capillary zone electrophoresis (CZE) method was developed for the quantitative analysis of fosinopril sodium. Validation parameters of the CZE method were evaluated and compared to an existing LC method. In terms of precision and sensitivity. LC performance was superior to that of the CZE method for this application. The CZE method achieved better selectivity for several degradants of interest within a much shorter analysis time than did the LC method. Effects of detection wavelength, applied voltage and buffer concentration on optimization of the CZE method are presented. Effects of diluent composition on capillary loading and peak behaviour are also discussed.

Buffers↗
PubMed1995

CD8+ T-cell epitopes within the surface glycoprotein of a neurotropic coronavirus and correlation with pathogenicity.

CD8+ T cells with cytotoxic activity against the surface glycoprotein (S) of mouse hepatitis virus, strain JHM, have been identified in the central nervous system (CNS) of both acutely and chronically infected C57BL/6 mice. In this report, two specific epitopes recognized by these CNS-derived cells were identified, using a panel of peptides chosen because they conformed to the allele-specific binding motif for MHC class I H-2Kb and H-2Db. The active peptides encompassed residues 510 to 518 (CSLWNGPHL, H-2Db) and 598 to 605 (RCQIFANI, H-2Kb). Both epitopes are located within the region of the S protein previously shown to be prone to deletion after passage in animals. These deleted strains are generally less neurovirulent than the wild-type virus but still are able to cause demyelination. Since C57BL/6 mice become persistently infected more commonly than many other strains of mice, these data are consistent with a role for CD8+ T-cell escape mutants in the pathogenesis of the demyelinating disease. This is the first report of CD8+ T-cell epitope localization within the S protein, the protein most strongly implicated thus far in pathogenesis in the host.

Amino Acid Sequence↗