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Biomedical subjects

S D Miller

Publications and source records attributed to S D Miller.

At least 127 records · Page 7Linked to original sources
PubMed1994

Alteration in the level of interferon-gamma results in acceleration of Theiler's virus-induced demyelinating disease.

Intracerebral (i.c.) inoculation of susceptible strains of mice with Theiler's murine encephalomyelitis virus (TMEV) results in immune-mediated demyelination. We examined the role of interferon (IFN)-gamma in this virally induced pathogenesis. Intraperitoneal (i.p.) injection of susceptible mice with an IFN-gamma-neutralizing monoclonal antibody (mAb), DB-1, resulted in a significantly accelerated onset of disease. The anti-IFN-gamma mAb-treated animals showed a strong delayed-type hypersensitivity (DTH) response to the virus similar to that of control mAb-treated animals. Treatment with anti-IFN-gamma mAb had no significant effect on the clinical course of disease. However, intracerebral administration of recombinant IFN-gamma significantly accelerated the onset of TMEV-induced disease, as well as enhanced TMEV-specific T cell proliferation and DTH responses. The enhancing effect of IFN-gamma was completely abrogated by simultaneous treatment with anti-IFN-gamma mAb. Collectively, our data suggest that the level of IFN-gamma plays a key role in the TMEV-induced inflammatory response and a perturbation of this balance may result in an alteration in the course of the demyelinating disease.

Animals↗
PubMed1994

BALB/c substrain differences in susceptibility to Theiler's murine encephalomyelitis virus-induced demyelinating disease.

We report differences among BALB/c substrains in susceptibility to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease, an immune-mediated inflammatory demyelinating disease and experimental model for human multiple sclerosis. BALB/cJ and BALB/cAnNCr mice are susceptible, while BALB/cByJ and BALB/cCum are resistant. Hybrids between BALB/cBy and BALB/cAnNCr were intermediate, although closer to the resistant parent. Backcrosses gave results compatible with differential susceptibility being related to a single segregating locus. Exposure of resistant BALB/cByJ mice to low dose irradiation, 2 days prior to infection, rendered them susceptible to TMEV-induced demyelination. The susceptibility pattern of TMEV-induced demyelinating disease among BALB/c substrains is distinct from those of several autoimmune disorders.

Animals↗
PubMed1994

The immunopathogenesis and regulation of T-cell-mediated demyelinating diseases.

A variety of experimental approaches are currently being evaluated for controlling CD4+ T helper 1 (Th1)-mediated autoimmune pathology. Here, Stephen Miller and William Karpus compare and contrast the efficacies of various antigen-specific regulatory strategies. Particular emphasis is placed on the mechanisms of peripheral immune tolerance and how this may be used in the treatment and analysis of the pathologic T-cell repertoire in autoimmune and virus-induced demyelinating diseases.

Animals↗
PubMed1994

Familial paraganglioma.

Extra-adrenal pheochromocytomas and paragangliomas are rare tumors of neural crest origin, most commonly found in the retroperitoneum. Because these tumors are so uncommon, relatively little is known about their natural history. Comparisons between adrenal pheochromocytomas and extra-adrenal pheochromocytomas have appeared in the medical literature. Like pheochromocytomas, paragangliomas may occur as functional or nonfunctional tumors. Furthermore, although the hereditary occurrence of pheochromocytomas is well documented, the familial nature of paragangliomas is unclear. We present the first report of a mother and son with nonfunctional paragangliomas occurring in the same anatomic location and describe their care and treatment.

Adolescent↗
PubMed1994

Anergy in vivo: down-regulation of antigen-specific CD4+ Th1 but not Th2 cytokine responses.

Efficient immunologic tolerance, defined as antigen-specific unresponsiveness, can be peripherally induced by the i.v. injection of syngeneic splenocytes coupled with antigen using ethylene carbodiimide (ECDI). We have previously reported that unresponsiveness induced via i.v. injection of syngeneic splenocytes coupled with intact, UV-inactivated Theiler's murine encephalomyelitis virus (TMEV-SP) resulted in 'split tolerance'. Both virus-specific delayed-type hypersensitivity and IgG2a levels were inhibited, whereas IgG1 levels were increased when compared with sham tolerized controls. In the present report we demonstrate that tolerance induced by i.v. injection of TMEV-coupled splenocytes resulted in antigen-specific inhibition of T cell proliferation, as well as IL-2 and IFN-gamma production in response to both whole TMEV and the immunodominant viral epitope. Additionally, tolerance induction resulted in abrogation of Th1-derived [IL-2, IFN-gamma and LT/tumor necrosis factor-beta (TNF-beta)] cytokine mRNA expression in response to in vitro stimulation with UV-inactivated TMEV as determined by reverse transcriptase polymerase chain reaction. In contrast, expression of Th2-derived (IL-4, IL-6 and IL-10) cytokine mRNA was not affected in tolerized mice. Tolerance functioned directly at the level of CD4+ Th1 cells at both the induction and effector limbs as depletion of CD8+ T cells both prior to in vivo tolerization or in vitro culture had no effect on inhibition of Th1-specific responses. The mechanism of in vivo tolerance induction appeared to be anergy of CD4+ Th1 cells since IL-2, IFN-gamma and LT/TNF-beta mRNA expression as well as virus-specific proliferative responses could be restored by addition of rIL-2 to in vitro cultures of tolerant, CD4+ Th1 populations. These results suggest that in vivo 'split tolerance' induced by i.v. injection of ECDI-fixed, antigen-coupled splenocytes involves anergy of TMEV-specific, CD4+ Th1 lymphocytes and concomitant priming of Th2 cells. The induction of antigen-specific, in vivo anergy has important implications in the design of therapeutic strategies for immunopathologic diseases mediated by Th1 lymphocytes, especially T cell-mediated autoimmune disorders.

Amino Acid Sequence↗
PubMed1994

Molecular cloning and characterization of the 78-kilodalton glucose-regulated protein of Trypanosoma cruzi.

The protozoan Trypanosoma cruzi is the etiologic agent of Chagas' disease, an illness responsible for morbidity and death among millions of Latin Americans. Mice also develop this disease when infected with T. cruzi and are a useful model organism for the study of parasite-specific immune responses. To identify immunogenic T. cruzi antigens, serum from an infected mouse was used to isolate clones from a T. cruzi epimastigote cDNA expression library. One of these clones was found to encode the 78-kDa glucose-regulated protein (grp78), the endoplasmic reticular member of the 70-kDa heat shock protein (hsp70) family. Like the mammalian and yeast grp78s, the T. cruzi protein contains an endoplasmic reticular leader peptide and a carboxyl-terminal endoplasmic reticular retention sequence. T. cruzi grp78 is encoded by a tandemly arranged family of three genes located on a chromosome of 1.6 Mb. The effects on grp78 expression of heat shock and tunicamycin treatment, the latter of which specifically stimulates mammalian grp78, were investigated. While the level of the grp78 protein remained constant under all circumstances, grp78 mRNA was unaffected by heat shock but induced fivefold by tunicamycin. Finally, we found that grp78 is the most immunogenic of the T. cruzi heat shock proteins we have characterized, reacting strongly in immunoblots with sera from infected mice.

Amino Acid Sequence↗
PubMed1994

Staged arthrodesis for salvage of the septic hallux metatarsophalangeal joint.

Failed surgery at the hallux metatarsophalangeal joint may present substantial difficulties in treatment, especially when complicated by infection. This retrospective study reviews the staged treatment of 5 patients with complications of hallux valgus surgery associated with sepsis of the metatarsophalangeal joint. The initial salvage treatment included debridement with placement of an antibiotic cement spacer and either an intramedullary Kirschner wire (4 patients) or an external fixator (1 patient). At the second stage procedure, the spacer and fixation were removed, and an autogenous tricortical iliac crest graft was inserted into the joint. All patients had clinical control of joint sepsis. Pseudoarthrosis occurred at the proximal end of the tricortical graft in 2 patients. Patients were evaluated at an average of 28 months after the fusion. Staged arthrodesis appears to be a satisfactory approach to postoperative sepsis of the hallux metatarsophalangeal joint.

Adult↗
PubMed1994

Assessment of skin blood content and oxygenation in spinal cord injured subjects during reactive hyperemia.

This study was undertaken to determine whether the reactive hyperemia response following ischemia in spinal cord injured (SCI) individuals is different from that which occurs in able-bodied (AB) individuals. The reactive hyperemia response was produced by applying a pressure of 150 mmHg for 300 s, 600 s, and 900 s to the skin over the greater trochanter in 10 SCI and 10 AB subjects using a computer-controlled pneumatic indentation system. The changes in blood content and oxygenation in the superficial vessels of the skin, associated with indentation, were monitored using reflectance spectrophotometry. A brief pressure of 80 mmHg, to simulate finger pressing (blanching), was applied to the same site to detect changes in reflow behavior during the hyperemic period. The results indicate that the reactive hyperemia response in SCI group was not substantially different from AB group although the reflow rate after load release was slower in the SCI group compared with the AB group.

Adult↗
PubMed1993

Split tolerance of Th1 and Th2 cells in tolerance to Theiler's murine encephalomyelitis virus.

Theiler's murine encephalomyelitis virus (TMEV) produces a chronic, inflammatory demyelinating disease in susceptible mouse strains that is used as a model for multiple sclerosis. Because disease susceptibility correlates temporally with the development of virus-specific delayed-type hypersensitivity (DTH) responses, we studied methods and mechanisms by which virus-specific DTH could be specifically inhibited. The intravenous injection of UV-inactivated TMEV coupled to syngeneic splenocytes via a carbodiimide linkage (TMEV-SP), prior to immunization, induced a significant degree of tolerance in virus-specific helper (Th) cells as determined by decreased DTH and T cell proliferative responses, and decreased interleukin (IL)-2 and interferon (IFN)-gamma protein and mRNA levels. In contrast to the reduced levels of Th1-specific lymphokine mRNA levels, IL-4-specific mRNA levels in response to virus stimulation were not affected in tolerant mice. Surprisingly, the total anti-TMEV antibody response in DTH tolerant mice was enhanced 20-100-fold over sham-tolerized controls and was composed of reduced levels of anti-virus IgG2a, but dramatically increased levels of anti-virus IgG1. The "split-tolerance" was antigen specific, dependent on the concentrations of TMEV and carbodiimide used in the coupling procedure, and varied with the number of coupled syngeneic splenocytes administered. The fixative effects of carbodiimide on antigen-presenting function were necessary for the induction of DTH tolerance with TMEV-SP, since intravenous administration of virus coupled to splenocytes via a biotin-avidin linkage led to enhanced virus-specific antibody responses, but was unable to inhibit DTH unless concomitantly fixed with carbodiimide. Collectively, the data indicate that Th1 cells (mediating DTH, IL-2 and IFN-gamma production, and helper function for IgG2a production) were specifically anergized, with concomitant stimulation of Th2 cells (producing IL-4 and mediating helper function for IgG1 antibody production).

Animals↗
PubMed1993

Class I-deficient resistant mice intracerebrally inoculated with Theiler's virus show an increased T cell response to viral antigens and susceptibility to demyelination.

Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) results in immune-mediated demyelination in susceptible mouse strains. The histology of TMEV-induced demyelination is similar to that seen in patients suffering from multiple sclerosis. It was previously shown that the susceptibility of mice to TMEV-induced demyelination in certain strain combinations is closely associated with the major histocompatibility complex (MHC) class I locus. Here we examine disease susceptibility of beta 2-microglobulin (beta 2M)-deficient transgenic mice lacking class I expression and functional CD8+ T cells. In contrast to TMEV-infected parental C57BL/6 mice, the transgenics develop high levels of virus-specific DTH and T cell proliferation accompanied by an increased frequency of central nervous system (CNS) demyelinating lesions. However, clinical signs of demyelination were not noted. Neither antibody titer nor viral persistence were significantly affected in the beta 2M-deficient mice. These results suggest that in the absence of functional class I/CD8+ cells, the class II-restricted T cell response to TMEV is enhanced and CNS pathogenesis is heightened, although the level is not severe enough to result in clinical disease. When the TMEV-infected mice were subcutaneously immunized with virus, however, the beta 2M-deficient mice displayed clinical symptoms. Therefore, our results strongly suggest that CD8+ T cells do not directly contribute to CNS demyelination. In contrast, such T cells appear to be primarily involved in down-regulation of a potentially damaging CD4+ T cell response in resistant animals, although some of the T cells may play a role in clearing viral persistence in the CNS, resulting in the protection of the host from viral demyelination.

Animals↗
PubMed1993

Elevated levels of serum immunoglobulins in asymptomatic carriers of Clostridium difficile.

Serum levels of IgA, IgM, and polyvalent immunoglobulins reactive with Clostridium difficile were determined by ELISA for asymptomatic carriers (n = 5), symptomatic individuals (n = 21), and a pool of 30 "normal" individuals. Mean IgA concentrations expressed as optical density (OD +/- SD) were significantly higher (P < .001) for asymptomatic carriers (1.252 +/- 0.516) than for symptomatic patients (0.374 +/- 0.145). Mean serum IgM levels also were significantly higher (P < .001) for carriers (1.456 +/- 0.582) than for symptomatic patients (0.727 +/- 0.331), as were mean values for polyvalent immunoglobulins (2.25 +/- 0.718 for carriers vs. 1.457 +/- 0.574 for symptomatic patients; P < .05). Although the patient populations were small, the levels of immunoglobulins reactive with C. difficile antigens differed significantly. This difference might reflect the ability of the host to mount an immune response and might be a factor influencing whether a patient develops disease due to this organism. The ability to detect differences in immunoglobulin levels might also help differentiate infection from colonization.

Antibodies, Bacterial↗
PubMed1993

Transverse myelitis complicating systemic lupus erythematosus: treatment including hydroxychloroquine. Case report.

Transverse myelitis has been cited as a rare and unusual complication of systemic lupus erythematosus (SLE). A review of the literature reveals only 10 cases of transverse myelitis as the initial presentation of SLE, and only one with reported benefits from antimalarial therapy. The case of a 30-year-old woman is reviewed. She presented to the emergency room with complaints of hypogastric and low back pain. The ensuing course was one of frank urinary retention and rapidly progressing quadriparesis. Magnetic resonance imaging of the spine revealed marked edema of the cervical and thoracic spine. A diagnosis of SLE was based on positive antinuclear antibodies and leukopenia. The patient was treated with high dose methylprednisolone, plasmapheresis and pulse cyclophosphamide for 3 months. Subsequently, treatment was begun with hydroxychloroquine, and significant improvement in her neurologic and functional status was achieved after 1 month of therapy. Ten months after her onset of symptoms, the patient suffered an acute exacerbation of paraparesis and urinary retention. Again, she improved clinically after high dose methylprednisolone and pulse cyclophosphamide for 1 month. Hydroxychloroquine was continued throughout the duration of therapy.

Adult↗
PubMed1993

Increasing the adjustment success of the disabled African American.

Adjustment to a physically disabling condition is a challenge for any patient who confronts a future of severe impairment and limited mobility. The emotional trauma is usually devastating at least until the initial shock of the disability dissipates. For the disabled African-American patient, the physical and psychic pain are compounded by personal and social factors not experienced in similar intensity by other disabled patients. A conceptual framework for better understanding the nature of the forces that impinge on the ability of the disabled African-American patient to adjust and an understanding of the impact of multi-level systems on the life of the disabled African-American is provided. The influence of racism, be it intentional or unintentional, is explained as it relates to the services and the attitudes of health care systems. The family as a significant and vital system is discussed as the major contributor to the successful adjustment of African-American disabled persons.

Black or African American↗
PubMed1993

The effect of the entry hole for an intramedullary nail on the strength of the proximal femur.

We used 15 pairs of femora from fresh human cadavers to study the effects of the size and location of the entry hole for an intramedullary nail on the strength of the femur. Right femora were used as controls. Left femora in group 1 had a 10 mm entry hole in the 'ideal' location in the piriformis fossa. Group 2 had a 14 mm entry hole in the same position and group 3 had a 14 mm entry hole anterior to this on the superior aspect of the femoral neck. Femora were equipped with strain gauges and loaded to failure in compression. There was reduced stiffness and load to failure in group 3 specimens, suggesting that the location of the hole was more important than its size.

Aged↗
PubMed1993

Clostridium perfringens infection of an anterior iliac crest bone graft donor site. A case report.

Postoperative infection of elective surgical wounds with Clostridium species has been linked to gastrointestinal tract lesions. A 55-year-old man with a history of peptic ulcer disease was treated by open reduction and internal fixation with autogeneic cancellous bone grafting from an anterior iliac crest donor site for nonunion of the clavicle. A mild serosanguinous drainage from the Penrose drain site at the iliac crest had ceased on postoperative Day 11; the patient complained of pain and a brownish drainage on postoperative Day 15. The infection was documented with cultures positive for Clostridium perfringens. Aggressive emergent surgical and antibiotic therapy resulted in complete clinical recovery. The wound infection did not advance to severe tissue damage and myonecrosis. This case represents the first reported infection of an iliac crest bone graft site with C. perfringens.

Bone Transplantation↗
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↗