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S L Hauser

Publications and source records attributed to S L Hauser.

At least 19 recordsLinked to original sources
PubMed1992

An antispasticity effect of threonine in multiple sclerosis.

To determine whether the naturally occurring amino acid threonine, a potential precursor for glycine biosynthesis in the spinal cord, has an effect on spasticity in multiple sclerosis, 26 ambulatory patients were entered into a randomized crossover trial. Threonine administered at a total daily dose of 7.5 g reduced signs of spasticity on clinical examination, although no symptomatic improvement could be detected by the examining physician or the patient. In contrast to the side effects of sedation and increased motor weakness associated with antispasticity drugs commonly used for the treatment of multiple sclerosis, no side effects or toxic effects of threonine were identified. Levels of threonine were elevated in serum and cerebrospinal fluid during treatment, but glycine levels did not change. Enhancement by threonine of glycinergic postsynaptic inhibition of the motor reflex arc in the spinal cord may represent a non-sedating, nontoxic approach to the management of spasticity in multiple sclerosis.

Adult↗
PubMed1992

Increased levels of neuronal thread protein in cerebrospinal fluid of patients with Alzheimer's disease.

Neuronal thread protein is a recently characterized, approximately 20-kd protein that accumulates in brains with Alzheimer's disease (AD) lesions. This study examined whether concentrations of neuronal thread protein (NTP) were also increased in the cerebrospinal fluid (CSF) of individuals with probable (clinically diagnosed) and definite (histopathologically proved) AD. Using a highly sensitive three-site monoclonal antibody-based immunoradiometric assay, we measured NTP concentrations in CSF from 84 patients with probable AD and mild dementia (duration, 4.05 +/- 0.36 years), 45 with Parkinson's disease and minimal or no dementia (duration, 4.73 +/- 0.78 years), 73 with multiple sclerosis, and 73 nondemented control subjects. NTP concentrations were also measured in postmortem ventricular fluid and temporal lobe neocortex extracts from 31 subjects with histopathologically proved AD and 14 age-matched control subjects. The mean concentration of NTP in the CSF was higher in AD (4.15 +/- 0.25 ng/ml; 95% confidence interval [CI] limits, 3.65-4.65) than in Parkinson's disease (1.96 +/- 0.16 ng/ml; 95% CI, 1.65-2.27), multiple sclerosis (1.6 +/- 0.14 ng/ml; 95% CI limits, 1.33-1.88), or control subjects (1.27 +/- 0.06 ng/ml; 95% CI limits, 1.15-1.40) (p < 0.001). In addition, 70% of the patients with probable AD had concentrations of NTP in CSF that were higher than 2.5 ng/ml (> upper 99% CI limit in the control group), compared with 23% of Parkinson's disease patients, 11% of multiple sclerosis patients, and 4% of control subjects. The mean concentrations of NTP in the ventricular fluid and brain tissue from individuals with documented AD and end-stage dementia were threefold higher than the levels detected in the CSF from the remaining patients with probable AD and mild dementia. Moreover, of 9 patients with AD, postmortem brain and CSF manifested 5- to 50-fold higher levels of NTP compared with the CSF samples obtained an average of 6 years earlier. These findings demonstrate that NTP levels are elevated in the CSF of individuals with AD and that NTP levels in the CSF increase strikingly with progression of dementia and neuronal degeneration.

Adult↗
PubMed1992

Haplotypic origin of beta-chain genes expressed by human T-cell clones.

A contribution of allelic variation of T-cell receptor (Tcr) genes to the immune response has not been studied. Here we report that the presence of insertion-deletion-related polymorphisms (IDRP) of the Tcr beta chain (Tcrb) can be utilized to distinguish the parental origin of the gene complex that undergoes rearrangement in individual T-cell clones. Phytohemagglutinin stimulated clones from an individual heterozygous for an IDRP located between the variable (V) and diversity (D)-joining (J) region genes were studied for the presence of V to DJ rearrangements in each of the two parental chromosomes. Results indicate that single rearrangements were present in the majority of clones, in contrast to the double rearrangements of D to J genes that were generally present. In this individual, V to DJ rearrangement also occurred with different frequencies on each of the two germline genes. IDRP clonotyping of the Tcrb complex should prove generally applicable to the study of the influence of allelic variation of Tcrb genes in selection of the expressed T-cell repertoire.

Alleles↗
PubMed1992

Experimental allergic encephalomyelitis in cynomolgus monkeys. Quantitation of T cell responses in peripheral blood.

Chronic relapsing-remitting experimental allergic encephalomyelitis (EAE) was induced in cynomolgus monkeys by a single immunization with a homogenate of human brain white matter (BH) in adjuvant. Proliferative T lymphocyte responses to BH, to myelin basic protein (MBP), but not to proteolipid protein, were detected in peripheral blood mononuclear cells (PBMC) of all animals and persisted until their death or, in surviving animals, for greater than 10 mo postimmunization. Responses of higher magnitude tended to be associated with fatal, compared with nonfatal, episodes of clinical EAE. The frequency of MBP-reactive T cells in PBMC of animals with acute EAE was quantitated with a soft agar colony system; the ratio of T cells that proliferated specifically to MBP was estimated at between 5 and 20 per 10(6) PBMC. A similar frequency of peptide-specific T cells was estimated from PBMC of monkeys immunized with a synthetic 14-mer peptide corresponding to a region near the carboxy terminus of MBP. Thus, autoantigen-reactive T cells can be detected in the circulation throughout the course of chronic EAE, are predictive of disease severity, and occur at a frequency similar to that estimated to be present in humans with multiple sclerosis.

Amino Acid Sequence↗
PubMed1992

T-cell receptors: germline polymorphism and patterns of usage in demyelinating diseases.

The genomic organization of the T-cell receptor (TCR) gene complexes accounts for many central aspects of T-cell immunobiology, including specificity and diversity. Recent data indicate that polymorphism of TCR genes is present within a species and may influence the immune phenotype of an individual. Such polymorphism has been detected by RFLP, by the presence of large regions of insertion or deletion of germline DNA, and by allelic variability of individual gene segments that are expressed. In addition to allelic variation of TCR genes, immune responses may also be influenced by the repertoire of the TCR molecules that are expressed by responding T-cell populations. In some situations, pathogenic T-cell responses may involve expression of limited numbers of TCR gene families. This is true, for example, in experimental allergic encephalomyelitis, an autoimmune nervous system disease mediated by T-cells reactive to myelin basic protein. In the human disease counterpart, multiple sclerosis, a more complex pattern of T-cell recognition to the putative autoantigen is generally present, although in some individuals a restricted response may occur. Specific therapies targeted to certain TCR molecules represents a promising approach to chronic inflammatory diseases in humans. The efficacy of such therapies will be determined in part by the TCR repertoire expressed in individual disease situations and by the potential for plasticity in the pathogenic T-cell response that may exist.

Alleles↗
PubMed1991

The role of prolactin in autoimmune demyelination: suppression of experimental allergic encephalomyelitis by bromocriptine.

Several lines of evidence suggest that the anterior pituitary hormone prolactin has a stimulatory role on immune function and that pharmacological suppression of prolactin secretion with the dopamine-agonist bromocriptine suppresses both humoral and cellular immunity. Here, we describe the effects of prolactin-suppression on the course of experimental allergic encephalomyelitis in female Lewis rats. Initiation of continuous bromocriptine treatment before immunization reduced both the severity and incidence of clinical signs of acute experimental allergic encephalomyelitis. Experimental allergic encephalomyelitis-immunized rats experienced a threefold rise in basal prolactin levels on day 4 after immunization and maintained elevated prolactin levels on day 10, before the onset of neurological signs of experimental allergic encephalomyelitis. Bromocriptine treatment reduced prolactin levels to those of sham-immunized rats. In vivo bromocriptine pretreatment inhibited splenic lymphocyte proliferative responses in vitro to the immunizing antigen and to concanavalin A. Moreover, bromocriptine therapy was protective when initiated 1 week after the initial immunization and was also effective in suppression of late disease. These results indicate that (1) prolactin levels are elevated after immunization and before the onset of experimental allergic encephalomyelitis, (2) bromocriptine inhibits both prolactin secretion and the severity of acute experimental allergic encephalomyelitis, and (3) inhibition is also present when treatment is begun after sensitization, suggesting an effect of prolactin on the effector limb of the immune response during experimental allergic encephalomyelitis.

Animals↗
PubMed1991

Fos RNA accumulation in multiple sclerosis white matter tissue.

In order to better characterize the molecular events that accompany lesion development in multiple sclerosis (MS), we studied the accumulation of RNA specific to the nuclear proto-oncogenes c-fos and c-myb in post mortem white matter brain tissue. RNA was prepared from plaque and periplaque regions of 6 different MS brains, from "normal" white matter regions of 3 MS brains and from 6 normal control samples. Quantitation of specific RNA corresponding to each proto-oncogene was performed by Northern blot hybridization and by scanning densitometry. Results indicate a 2-fold increase in c-fos RNA in MS white matter, compared to control tissue. No c-myb signal was identified in any sample. In situ hybridization studies confirmed the selective upregulation of c-fos RNA levels in MS tissue, and suggested that glial cells and not inflammatory cells were responsible for the enhanced c-fos signal. These results suggest that persistent glial cell activation is present within chronic MS lesions irrespective of whether the lesions are active (e.g., inflammatory) or inactive.

Blotting, Northern↗
PubMed1991

Living while dying.

Explore the source record for details and available documents.

Attitude to Death↗
PubMed1990

Multiple sclerosis sibling pairs: clustered onset and familial predisposition.

We evaluated 48 relapsing-remitting multiple sclerosis (R/R MS) sibling pairs derived from 44 families for age and date of onset of MS symptoms, clinical course, and family history of MS. Age- and sex-matched R/R MS clinic patients provided a statistical comparison group. The age of onset tended to cluster within multiplex families. The initial symptom of MS occurred within 5 years of age in 30/48 sibling pairs compared with 16/48 controls. A positive family history of MS (other than siblings) was present in 43% of the multiplex families compared with 20% among simplex controls. In 1st-, 2nd-, and 3rd-degree relatives who had lived into the age at risk, 22/1,134 family members of multiplex sibling pairs had probable or definite MS compared with 10/1,215 control family members. Age of onset clustering in siblings concordant for R/R MS and an increased risk of MS in other family members suggest that factors influencing disease onset may be in part inherited in these kindreds.

Adult↗
PubMed1990

Cytokine accumulations in CSF of multiple sclerosis patients: frequent detection of interleukin-1 and tumor necrosis factor but not interleukin-6.

We identified the cytokines interleukin-1 beta (IL-1 beta), tumor necrosis factor (TNF), and interleukin-6 (IL-6) by specific radioimmunoassays in the CSF of patients with multiple sclerosis (MS) and other neurologic diseases (OND). There was a high incidence of detectable IL-1 beta in patients with active MS compared with inactive MS or OND patients. TNF was also more frequently present in active MS than in OND CSF. By contrast, most MS CSF did not contain detectable IL-6. There was no correlation between the degree of CSF pleocytosis and the level of individual cytokines, suggesting that cytokine accumulations may be derived from CNS, and not CSF, cells. As IL-1 beta and TNF experimentally induce astrogliosis, demyelination, temperature elevation, lassitude, and sleep, and results raise the possibility that these cytokines may contribute to a variety of manifestations in MS and in other disease states.

Humans↗
PubMed1989

Substance P immunoreactive astrocytes are present in multiple sclerosis plaques.

Substance P (SP)-like immunoreactive cells were identified in postmortem white matter tissue from patients with multiple sclerosis (MS). Labelled cells, which by morphologic criteria could be identified as astrocytes, were located at the edge of both active (e.g. inflammatory) and inactive (e.g. non-inflammatory) MS lesions. By contrast, SP-immunoreactive astrocytes were not found in normal controls and were only occasionally present in other conditions associated with astrogliosis. These data suggest that SP, a potent mediator of vasodilatation and local immune responses, may play a role in the genesis of the MS plaque. These results also extend the repertoire of potential interactions which may occur between astrocytes and cells of the immune system.

Adult↗
PubMed1989

Insertion/deletion-related polymorphisms in the human T cell receptor beta gene complex.

Insertion/deletion related polymorphisms (IDRP) involving stretches of 15-30 kb within the human TCR-beta gene complex were revealed by pulse-field gel electrophoresis. Two independent IDRP systems were detected by analysis of Sfi I- and Sal I-digested human DNA samples using probes for TCR C and V region gene segments. The allelic nature of these systems was verified in family studies, and mapping data allowed localization of one area of insertion/deletion among the V gene segments and the other near the C region genes. All but one of 50 individuals tested could be typed for the two allelic systems, and gene frequencies for the two allelic forms were 0.37/0.61 and 0.46/0.54, indicating that these polymorphisms are widespread.

Deoxyribonucleases, Type II Site-Specific↗
PubMed1989

A susceptibility locus for multiple sclerosis is linked to the T cell receptor beta chain complex.

Inheritance of T cell receptor beta chain (TCR beta) genes was analyzed in families of 40 sibling pairs concordant for the relapsing-remitting form of multiple sclerosis (MS). TCR beta haplotypes were determined by segregation analysis of polymorphic markers within the TCR beta complex. The mean proportion of TCR beta haplotypes identical by descent (IBD) inherited by MS sibling pairs was significantly increased compared with expected values (means test, p less than 0.004), whereas the distribution of haplotype sharing was random when MS patients were compared with their unaffected siblings. Furthermore, one allelic form of a TCR beta variable region gene segment was overrepresented on MS chromosomes compared with those parental chromosomes not transmitted to MS offspring both in the MS sibling pair families and in a second group of families containing only one individual affected with MS. These results demonstrate that a gene within the TCR beta complex or a closely linked locus influences susceptibility to MS.

DNA Probes↗
PubMed1989

Extended major histocompatibility complex haplotypes in patients with multiple sclerosis.

We derived complete haplotypes of the major histocompatibility complex for 33 patients with MS and their families. The DR2 allele and DR2-bearing extended haplotypes, in proportion, were overrepresented on chromosomes of MS patients compared with parental chromosomes not transmitted to MS offspring. We did not confirm previous reports that particular alleles at the BF locus are overrepresented in MS or that C2 hypocomplementemia is present. These results suggest that the DR2 allele is a risk factor for MS, and not merely a genetic marker of the population of origin.

Alleles↗
PubMed1987

Immunoregulatory abnormalities induced by experimental reovirus infection: functional alterations in T-cell subpopulations.

A primary anti-sheep red blood cell (SRBC) plaque assay system was used to analyze the effect of reovirus infection on immunoregulatory T-cells. A decrease in the plaque-forming cell (PFC) response of splenic lymphocytes was observed within 24 hr of infection with 10(9) or 10(11) particles of reovirus type 1 or reovirus type 3 and persisted for more than 7 days. In coculture experiments, T-cells from infected mice were found to produce less help to control B-cells and to suppress helper function mediated by control T-cells. This suppression did not require the presence of an Lyt1,2,3 cell. In addition, isolated Lyt1 cells from reovirus-inoculated mice provided less help than did Lyt1 cells from normal controls. These abnormalities were more marked following inoculation with reovirus type 3 than with type 1. Live virus was not required for these effects, as T-cells from mice inoculated with ultraviolet (uv)-inactivated reovirus when added to normal B-cells reproduced the effects of infection with live virus. Furthermore, these changes were not the result of alterations in the percentages or numbers of distinct Lyt-bearing T-cell subpopulations in the spleens of inoculated mice. Thus, humoral hyporesponsiveness following reovirus infection of adult mice is associated both with active T-cell suppression of B-cell help and with decreased help mediated by the Lyt1 subset.

Animals↗
PubMed1985

Increased IgG secretion by unstimulated mononuclear cells in active multiple sclerosis and functional assessment of the T8 subset.

Unseparated mononuclear cells (10(5) cells/well) were cultured both in the presence and absence of pokeweed mitogen (PWM), and IgG secretion was measured by radioimmunoassay. In unstimulated cultures, levels of IgG secretion were found to be higher in a group of patients with multiple sclerosis (MS) than in control groups of healthy individuals or patients with other neurologic diseases (OND). By contrast, PWM-induced IgG secretion was similar in MS patients and in controls. In MS patients, levels of IgG secretion greater than 2500 ng/ml in unstimulated cultures were present in 29 (58%) of 50 patients with active disease and in only 3 (14%) of 21 patients with inactive MS (P less than 0.01; MS active vs inactive). Furthermore, levels of IgG secretion in unstimulated cultures were higher in patients who had abnormalities of circulating T-cell subsets consisting of reduced numbers of suppressor/cytotoxic (T8) cells and elevated helper:suppressor (T4:T8) ratios. In additional experiments using isolated populations of T-cell subsets, T8 cells from MS patients who had low percentages of circulating T8 cells were found to suppress PWM-induced IgG secretion by autologous cells to a similar extent as controls, suggesting that in vitro, T8 cells function normally in these patients. In vitro IgG secretion by unstimulated mononuclear cells in MS appears to be a further reflection of abnormal immune regulation in this disease.

Antibody Formation↗