Biomedical subjects

S D Miller

Publications and source records attributed to S D Miller.

At least 19 recordsLinked to original sources

PubMed1992

Regulation of the effector stages of experimental autoimmune encephalomyelitis via neuroantigen-specific tolerance induction. II. Fine specificity of effector T cell inhibition.

Ag-specific tolerance induced by the i.v. administration of splenocytes coupled with mouse spinal cord homogenate, containing a mixture of myelin Ag, dramatically inhibits development and expression of clinical and histologic signs of both active and adoptive forms of relapsing experimental autoimmune encephalomyelitis (R-EAE) in the SJL/J host. Here we examined the dose-dependency, route of tolerogen administration, and fine neuroantigen specificity of inhibition of adoptive R-EAE. Expression of clinical R-EAE induced by a polyclonal population of bovine myelin basic protein (MBP)-specific effector T cells was dramatically inhibited in a dose-dependent manner following the i.v., but not s.c. or i.p., injection of MBP-coupled splenocytes. The exquisite Ag specificity of the inhibition was evident by the observation that splenocytes coupled with intact bovine MBP or species variants of MBP homologous with bovine MBP within the major encephalitogenic region (amino acids 84-104), but not with proteolipid protein or mouse kidney homogenate, were able to suppress disease expression. Splenocytes coupled with the MBP84-104 peptide, containing a nested set of the major SJL/J encephalitogenic epitopes, completely inhibited peptide-specific T cell responses, but only partially inhibited the expression of disease transferred by T cells specific for intact MBP, suggesting the participation of T cell responses specific for additional MBP determinants in disease pathogenesis. However, splenocytes coupled with previously identified minor SJL/J encephalitogenic epitopes (MBP91-104 or MBP17-27), or with the Lewis rat major encephalitogenic epitope (MBP68-86), did not suppress disease expression. Collectively, the results demonstrate that MBP84-104-specific T cells and T cells specific for an as yet unidentified MBP epitope(s) contribute to the pathology of R-EAE. In addition, the results demonstrate that peptide-specific tolerance induction appears to have potential for the treatment of T cell-mediated inflammatory diseases.

Amino Acid Sequence↗

PubMed1992

Sexually transmitted disease surveillance in a child abuse clinic.

The sexually transmitted disease surveillance system instituted at the Child Abuse and Neglect (CAN) clinic of the Transvaal Memorial Institute for Child Health and Development was evaluated after 1 year. The presenting complaint of the vast majority of the 227 patients was sexual abuse. In more than half (52%), child abuse was medically proven, and it was highly suspected in another 18%. In only 6% did no abuse take place. About half the patients suffered non-penetrative sexual abuse, 40% penetrative abuse and 10% suffered non-sexual abuse. Smears for gonorrhoea were positive in 2 out of 152 patients; for Chlamydia in 1 out of 140; for Gardnerella and Trichomonas in 2 and 1 case, respectively. Syphilis serology yielded 3 positive results out of 162, and hepatitis B, 6 out of 143. No positive results were found in tests for HIV and herpes. With the exception of hepatitis B tests, all positive results occurred in children considered on clinical grounds to have medically proven or highly suspected sexual abuse. These results will allow modification of the surveillance system and testing of those children more likely to test positive, while doing fewer tests overall.

Adolescent↗

PubMed1992

A simple medium for the primary isolation of Haemophilus ducreyi.

Two simple, inexpensive media containing gonococcal agar-base, supplemented with 5% Fildes' extract and either chocolated or unchocolated horse blood (GC-FHBC or GC-FHB) were compared with the standard gonococcal agar-based (GC-HgS) and Mueller-Hinton agar-based media (MH-HB) normally used for primary isolation of Haemophilus ducreyi from presumptive chancroid lesions. Overall, Haemophilus ducreyi was recovered from 162 of 178 (91%) samples from primary chancroid lesions. As a single isolation medium GC-HgS proved the most sensitive with an isolation rate of 80% followed by GC-FHB (75%), MH-HB and GC-FHC (both 71%). Use of a combination of GC-HgS and MH-HB resulted in isolation of Haemophilus ducreyi in 160 of 178 cases (90%). Since GC-FHB is approximately one-quarter the cost of the combination and half the cost of GC-HgS or MH-HB alone, this medium could prove suitable for diagnostic purposes in developing countries where chancroid is endemic.

Agar↗

PubMed1992

Antigen-specific inhibition of the adoptive transfer of experimental autoimmune encephalomyelitis in Lewis rats.

The efficacy of antigen-specific immunoregulation as a treatment for the efferent limb of an autoimmune disease was tested in a rat model of adoptive experimental autoimmune encephalomyelitis (EAE). Lewis rats receiving 4-5 x 10(7) guinea pig (GP) myelin basic protein (MBP)-activated lymph node T cell blasts from GPMBP/CFA sensitized donors routinely show clinical signs of disease 5-6 days post transfer. Intravenous injection of GPMBP coupled to syngeneic splenocytes using the chemical cross-linker carbodiimide was effective in completely abrogating the expression of clinical EAE in rats that received MBP-specific T cells 2 days previously. Partial inhibition was also observed in rats injected as early as day 0 (the same day as MBP-specific T cell transfer) and as late as 1 day prior to the onset of clinical signs (days 4-5 post transfer). Unresponsiveness was shown to be dose-dependent, dependent on the route of injection of the neuroantigen-coupled splenocytes, and was antigen-specific. Splenocytes coupled with GP or rat MBP (which are identical within the major encephalitogenic GP68-86 Lewis rat determinant with the exception of the residue at position 80) were equally efficient at eliminating disease expression in recipients of GPMBP-specific T cells. In contrast, splenocytes coupled with bovine or rabbit MBP (which differ significantly from GPMBP within the 68-86 region) had no inhibitory effect. The antigen specificity of the tolerance induction was also illustrated by the fact that splenocytes coupled with GP68-86, but not those coupled with the truncated GP68-84 peptide, induced profound unresponsiveness. Interestingly, de novo antigen processing by the antigen-coupled cells did not appear to be necessary as the inclusion of antigen processing inhibitors had no effect on inhibition of disease. However, the use of the carbodiimide coupling reagent was critical for the induction of unresponsiveness as essentially equivalent amounts of 125I-labelled MBP were bound in its presence or absence, but only splenocytes incubated in the presence of both MBP and carbodiimide inhibited clinical expression of disease. Antigen-specific tolerance is thus an effective means of inhibiting expression of clinical disease in the rat EAE model, and a powerful tool for determining the fine epitope specificity of encephalitogenic T cells.

Animals↗

PubMed1992

Induction of active and adoptive relapsing experimental autoimmune encephalomyelitis (EAE) using an encephalitogenic epitope of proteolipid protein.

Proteolipid protein (PLP) is a major component of the central nervous system (CNS) myelin membrane and has been shown to induce acute experimental autoimmune encephalomyelitis (EAE) in genetically susceptible animals. Here we describe conditions by which a relapsing-remitting form of EAE can be reliably induced in SJL/J mice either actively immunized with the major encephalitogenic PLP peptide, PLP13-151(S), or following adoptive transfer of PLP139-151(S)-specific T cells. The disease follows a reliable relapsing-remitting course with acute clinical signs first appearing 6-20 days after priming or transfer and relapses first appearing at 30-45 days. The initial onset of disease correlates with delayed-type hypersensitivity (DTH) reactivity specific for PLP139-151(S), in the apparent absence of T cell reactivity to the major myelin basic protein (MBP) peptide. Histologically, both the active and adoptive forms of the disease are characterized by extensive mononuclear cell infiltration and severe demyelination of the CNS. These results suggest that T cell responses specific for PLP139-151(S) are sufficient to induce clinical and histological R-EAE in SJL/J mice. This model should prove useful for examination of the cellular and molecular events involved in clinical relapses and perhaps in determining the role of PLP-specific T cell responses in multiple sclerosis (MS).

Amino Acid Sequence↗

PubMed1992

The psychophysiological investigation of multiple personality disorder: review and update.

In 1984 Putnam reviewed the literature on the psychophysiological investigation of multiple personality disorder (MPD). Since his review, a large number of studies have been conducted and reported in the literature and at professional conferences. Currently, psychophysiologic differences reported in the literature include changes in cerebral electrical activity, cerebral blood flow, galvanic skin response, skin temperature, event-related potentials, neuroendocrine profiles, thyroid function, response to medication, perception, visual functioning, visual evoked potentials, and in voice, posture, and motor behavior. We review the new research on the psychophysiological investigation of MPD from published, unpublished, and ongoing studies, and we attempt to place current findings into a conceptual framework. We have noted findings from unpublished and ongoing studies, and, perhaps unfortunately, they represent a large amount of the data presently available. We conclude with a critical analysis of current research methodology and suggestions for future research.

Brain Mapping↗

PubMed1992

Antigen-specific tolerance as a therapy for experimental autoimmune encephalomyelitis.

The effects of neuroantigen-specific tolerance on the induction and effector stages of EAE were examined. Tolerance induced by the i.v. injection of syngeneic splenocytes coupled with purified neuroantigens or encephalitogenic peptides of MBP and PLP using ethylene carbodiimide was extremely effective in both prevention and treatment of acute and relapsing forms of EAE in Lewis rats and SJL/J mice. The unresponsiveness is rapidly-induced, dose-dependent, long-lasting, efficient, MHC class II-restricted, and exquisitely antigen-specific. This procedure targets only effector cells bearing clonotypic receptors specific for the autoantigen/autoepitope and thus does not depend upon the autoimmune response being dominated by a restricted T cell repertoire. Moreover, it does not require that the response to the autoantigen be dominated by recognition of a specific epitope(s) within a particular autoantigen, or even the identification of the specific autoantigen. The results also demonstrate the usefulness of peripheral tolerance induced by antigen-coupled syngeneic splenocytes for identifying the fine specificity of autoimmune T cell responses which appear to change during the progression of relapsing EAE. Thus, this technique offers major advantages over many other currently employed immunoregulatory strategies and is therefore relevant for establishment of therapeutic protocols for the antigen-specific treatment of human T cell-dependent autoimmune disorders.

Animals↗

PubMed1992

IgG subclass responses to Theiler's murine encephalomyelitis virus infection and immunization suggest a dominant role for Th1 cells in susceptible mouse strains.

Inbred mouse strains differ in susceptibility to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease. A strong correlation between disease susceptibility and delayed-type hypersensitivity (DTH) has been previously demonstrated, but no strong correlation between disease susceptibility and total anti-TMEV ELISA titres was shown. Since both DTH and IgG2a antibody production are regulated by CD4+ Th1 cells, we investigated three strains of mice to determine whether antivirus IgG2a antibody levels, like DTH in previous studies, correlated with disease susceptibility. Susceptible SJL/J, intermediately susceptible C3H/HeJ, and resistant C57BL/6 mice were infected intracerebrally (i.c.) with the BeAn strain of TMEV and monitored for clinical signs of demyelination and for levels of TMEV-specific antibody of different IgG subclasses using a particle concentration fluorescence immunoassay (PCFIA). Resistant C57BL/6 mice were found to have significantly lower concentrations of total anti-TMEV antibody than susceptible SJL/J mice and intermediately susceptible C3H/HeJ mice show variable antibody responses. A predominance of anti-TMEV IgG2a (Th1 regulated) antibody was seen in susceptible and intermediately susceptible mice, whereas resistant mice displayed a predominant anti-TMEV IgG1 (Th2 regulated) response accompanied by a marked deficiency of IgG2a. In contrast, immunization of C57BL/6 mice with UV-inactivated TMEV in adjuvant revealed that this strain was not defective either in its ability to generate high levels of anti-TMEV antibody or in its ability to produce IgG2a antibody. These results suggest that the antivirus IgG subclass profile is dependent upon the immunization route, virus viability and/or the use of adjuvant and that the levels of antivirus subclasses may be predictive of disease susceptibility.

Animals↗

PubMed1992

Knowledge of nephrologists and patients about autosomal dominant polycystic kidney disease (ADPKD).

Because of the availability of presymptomatic testing for autosomal dominant polycystic kidney disease (ADPKD), we assessed the response of nephrologists, patients, and at-risk relatives to the introduction of a genetic counselling program for ADPKD. Fifty-six of seventy-six nephrologists responded. Ninety-eight percent reported 'generally' telling their patients that the disease was hereditary, but fewer reported screening relatives (81% for children and 70% for siblings and parents). Ninety percent were interested in referring patients to the service. Fourteen of the 24 patients in one renal clinic and 18 of their at-risk relatives were interviewed. Ten of the patients but only five of the relatives stated that the disease was hereditary. The precise mechanism of inheritance was poorly understood by most patients and relatives. Of 21 patients offered genetic counselling, nine made appointments to see the genetic counsellor. There remains a large gap between advancing technology and the delivery of information to at-risk populations.

Adult↗

PubMed1992

Blood histamine levels following graded cold challenge in atypical acquired cold urticaria.

Acquired cold urticaria with a negative cold stimulation test has been described in seven patients in whom the standard ice cube test did not induce localized urticaria. Subsequent total body cold exposure induced a generalized urticaria. A patient with this syndrome is presented where blood histamine levels rose from 9 to 60 micrograms/dL after a negative local cold stimulation test and from 60 to 90 micrograms/dL after total body cold exposure. Urticaria occurred only after generalized cold exposure. Blood histamine levels following the ice cube test may represent a sensitive method to diagnose this form of atypical acquired cold urticaria, without subjecting the patient to the risk of anaphylaxis reported following total body cold exposure.

Adult↗

PubMed1991

Specific immunoregulation of the induction and effector stages of relapsing EAE via neuroantigen-specific tolerance induction.

The effects of neuroantigen-specific tolerance on the induction and effector stages of relapsing experimental autoimmune encephalomyelitis (R-EAE) were examined. The incidence of clinical and histologic signs of active MSCH-induced R-EAE, and accompanying neuroantigen-specific DTH responses, were dramatically reduced in SJL/J mice tolerized via the i.v. injection of syngeneic splenocytes coupled with MSCH, PLP, or encephalitogenic PLP peptides 7-14 days before priming. MBP-specific tolerance was not effective in preventing active R-EAE. In contrast to MSCH-induced active R-EAE, treatment of recipient mice with splenocytes coupled with MBP and the encephalitogenic MBP 84-104 peptide, but not with PLP, suppressed of clinical signs of adoptive R-EAE mediated by MBP-specific effector T cells in a dose-dependent manner. Neuroantigen-coupled splenocytes were also efficient in treating established disease as tolerization of SJL/J mice after the first incidence of clinical disease significantly reduced the incidence and severity of subsequent paralytic relapses. Antigen-specific tolerance thus provides a powerful approach for the prevention and/or treatment of autoimmune disease.

Amino Acid Sequence↗

PubMed1991

Successful treatment of paralytic relapses in adoptive experimental autoimmune encephalomyelitis via neuroantigen-specific tolerance.

We have previously demonstrated that Ag-specific tolerance induced by the i.v. administration of splenocytes coupled with neuroantigens, such as mouse spinal cord homogenate, myelin basic protein (MBP), and proteolipid protein, and their encephalitogenic peptides, results in dramatic inhibition of clinical and histologic signs of both actively induced and adoptively transferred relapsing experimental autoimmune encephalomyelitis (R-EAE). We report here that the administration of splenocytes coupled with mouse spinal cord homogenate (i.e., a mixture of neuroantigens), after the first paralytic episode of adoptive R-EAE triggered by MBP-specific T cells but before the appearance of the first relapse, effectively reduced the onset and severity of all subsequent relapses, as determined by both clinical and pathologic criteria. In contrast, the i.v. administration of splenocytes coupled with MBP (i.e., the specificity of the initiating T cell response), under similar conditions, effectively inhibited the initial clinical relapse, but subsequent relapses occurred with the same incidence rate and severity as those in control animals. Collectively, these results demonstrate that neuroantigen-specific tolerance is effective at specifically down-regulating an ongoing autoimmune response. This may have potential clinical applicability for treatment of autoimmune diseases. The results also support the hypothesis that the neuroantigen specificity of later relapses of R-EAE may be due to effector T cells with specificities different from those that triggered the initial clinical episode. Thus, potential therapy for the advanced stages of R-EAE, and perhaps other autoimmune diseases, may have to be directed not simply against the effector cells initiating the disease but also against effector cells with differing specificities recruited as a result of tissue damage occurring in the initial acute disease.

Animals↗

PubMed1991

Class II-restricted T cell responses in Theiler's murine encephalomyelitis virus-induced demyelinating disease. IV. Identification of an immunodominant T cell determinant on the N-terminal end of the VP2 capsid protein in susceptible SJL/J mice.

Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease serves as a relevant animal model of human multiple sclerosis. Myelin damage induced by TMEV infection appears to be immune mediated. Disease susceptibility correlates best with the temporal development of chronic, high levels of TMEV-specific, MHC class II-restricted delayed-type hypersensitivity (DTH) responses. We have proposed a model wherein these responses result in CNS demyelination via a macrophage-mediated terminal nonspecific bystander response. As virus-specific DTH responses appear to be intimately involved in the pathogenicity of CNS demyelination, it is critical to determine the specificity of these responses so that effector T cells specific for potential pathogenic epitopes can be targeted to serve as the focus of specific immunoregulatory processes. In the current study, the capsid protein specificity of the TMEV-susceptible SJL/J and TMEV-resistant C57BL/6 mouse strains was examined. DTH and Tprlf responses in both infected and immunized SJL/J mice were found to be predominantly directed toward the VP2 capsid protein, specifically to an epitope(s) contained within the N-terminal 150 amino acids of VP2. This same epitope was also found to be dominant in priming SJL/J mice for responses to challenge with intact virions. In contrast, the T cell-mediated responses of TMEV-resistant C57BL/6 mice did not show preferential reactivity towards VP2, because all three major capsid proteins (VP1, VP2, and VP3) elicited responses with essentially equal potency. The relationship of the restricted VP2 T cell epitope to predicted neutralizing antibody sites on the VP2 protein is discussed as is the potential use of this epitope for prevention and/or treatment of TMEV-induced demyelinating disease via the induction of epitope-specific tolerance.

Animals↗

PubMed1991

Atrial fibrillation associated with autonomic dysreflexia.

Autonomic dysreflexia is an acute disorder of autonomic homeostasis occurring in persons with spinal cord lesions above the major splanchnic sympathetic outflow. Atrial fibrillation is a serious cardiac arrhythmia characterized by disorganized atrial depolarization and an irregular ventricular response. Previously reported complications of autonomic dysreflexia have included seizures, strokes and cardiac arrhythmias other than atrial fibrillation. We present a 60-yr-old man with C-5 incomplete quadriplegia in whom atrial fibrillation was apparently induced by an episode of autonomic dysreflexia. Mechanisms by which autonomic dysreflexia may cause this arrhythmia include altered cardiac autonomic tone as well as atrial distention. The simultaneous occurrence of autonomic dysreflexia and atrial fibrillation poses special diagnostic problems and treatment risks. Atrial fibrillation incidence increases with age in the general population. With the aging of the spinal cord-injured population, we expect to see more episodes of atrial fibrillation associated with autonomic dysreflexia.

Atrial Fibrillation↗

PubMed1991

Optical differences in multiple personality disorder. A second look.

The study was designed as a replication of a study reported in this Journal (Miller S [1989] Optical differences in cases of multiple personality disorder. J. Nerv Ment Dis 177:480-486) which found that subjects with multiple personality disorder (MPD) experienced significantly more changes in visual functioning between alter personalities than a control group simulating the disorder. In the present study, data from 20 patients diagnosed with MPD and 20 control subjects role playing MPD were analyzed for statistical and clinical significance. The findings from the present study appear to confirm results from the earlier study that individuals with MPD experience differences in some aspects of visual functioning between alter personalities. The results further confirm that MPD subjects experience more differences across visual measures than control subjects simulating the disorder. However, the findings from the present study are not entirely consistent across the various visual measures or with findings from previous studies.

Adult↗

PubMed1991

The 5' noncoding sequences from a less virulent Theiler's virus dramatically attenuate GDVII neurovirulence.

RNA transcripts derived from recombinant chimeras between the highly virulent GDVII virus and the less virulent BeAn virus were constructed to study the molecular pathogenesis of Theiler's murine encephalomyelitis virus infection. The presence of the BeAn 5' noncoding sequences in chimera 2 (BeAn 5' noncoding sequences joined with the GDVII nucleotides encoding the polyprotein and present in the 3' end) resulted in dramatic attenuation of GDVII neurovirulence and development of poliomyelitis in mice. This reduced neurovirulence was associated with slower virus growth and lower peak titers in the brain and spinal cord than with parental GDVII virus replication. On the other hand, the sites of replication following chimera 2 infection were the same as those seen in GDVII-infected mice; the distribution of virus antigen and histopathological changes indicated that chimera 2 replicates in neurons in the brain, e.g., in the neocortex, hippocampus, caudate putamen, and brain stem, as well as in anterior-horn cells in the spinal cord. Chimera 2 was efficiently cleared from the mouse central nervous system by day 30 postinfection, in marked contrast to the persistence of the BeAn parent in the central nervous system. This suggests that elements in the BeAn sequences that encode the polyprotein or are present in the 3' noncoding region are necessary for viral persistence. It is of interest that chimera 2-infected mice developed localized inflammatory, demyelinating lesions which were detected at day 28 postinfection but these lesions did not become larger with time. Thus, virus persistence appears to be required for maintenance and progression of immune-mediated demyelination. If the demyelinating lesions become sufficiently large, clinical signs and disease may develop.

Acute Disease↗

PubMed1991

Syphilis serology in patients with primary syphilis and non-treponemal sexually transmitted diseases in southern Africa.

The reactivity of a non-specific reagin (RPR) test and a specific treponemal (FTA-ABS) test were determined in 21 patients with primary syphilis, 430 patients with proven non-treponemal genital ulcerations and 719 patients with acute urethritis presenting at a clinic for sexually transmitted diseases in southern Africa. Excluding those 21 cases of primary syphilis, 358 of 1149 tests performed (31%) were found to be reactive by at least one test. The rate of false positive RPR tests was very low (0.02%). Significantly higher rates of seropositivity were detected in patients with genital ulcerations than in patients with acute urethritis. The highest rates were detected among patients with proven lymphogranuloma venereum (34% RPR positive, FTA-ABS positive; 19% RPR negative, FTA-ABS positive). The geometric mean titres (GMT) of positive RPR tests in non-treponemal infections were found to be lower than in darkfield positive cases of genital ulcer disease.

Acute Disease↗

PubMed1991

Abuse histories in 102 cases of multiple personality disorder.

The authors interviewed 102 individuals with clinical diagnoses of multiple personality disorder at four centres using the Dissociative Disorders Interview Schedule. The patients reported high rates of childhood trauma: 90.2% had been sexually abused, 82.4% physically abused, and 95.1% subjected to one or both forms of child abuse. Over 50% of subjects reported initial physical and sexual abuse before age five. The average duration of both types of abuse was ten years, and numerous different perpetrators were identified. Subjects were equally likely to be physically abused by their mothers or fathers. Sexual abusers were more often male than female, but a substantial amount of sexual abuse was perpetrated by mothers, female relatives, and other females. Multiple personality disorder appears to be a response to chronic trauma originating during a vulnerable period in childhood.

Adolescent↗