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Biomedical subjects

R Gold

Publications and source records attributed to R Gold.

At least 19 recordsLinked to original sources
PubMed1999

Usage of Vbeta3.3 T-cell receptor by myelin basic protein-specific encephalitogenic T-cell lines in the Lewis rat.

T-cell receptor (TCR) beta-chain usage in experimental autoimmune encephalomyelitis (EAE) seems to be much more heterogeneous than previously assumed even for a single autoantigen in an inbred animal strain. Owing to the lack of suitable antibodies, this has been demonstrated only at the RNA level so far. To characterize further the TCR elements used in the Lewis rat for the recognition of the main encephalitogenic region of myelin basic protein (MBP), BALB/c mice were immunized with T-cell hybridomas expressing non-Vbeta8.2 TCR specific for guinea pig MBP peptide aa 68-88. Two B-cell hybridomas (clones C-A11 and F-D6) producing TCR Vbeta3.3-specific monoclonal antibodies were selected. Specificity was demonstrated by RT-PCR and cloning of PCR products obtained from sorted T-cell lines and naive T cells. MBP-specific Vbeta3.3 T cells used the L-S motif in the VDJ region, were associated with Valpha2 or Valpha8 chains, and specifically recognized MBP peptide aa 68-88. Vbeta3.3 TCR-positive T cells were detected in all of a panel of six MBP-specific T-cell lines, although to a lesser degree than Vbeta8.2 TCR-positive T cells. After intravenous injection of sorted Vbeta3.3 T cells, animals developed EAE, and Vbeta3.3-positive cells were found by immunocytochemical analyses in the spinal cord. Furthermore, treatment of EAE induced by immunization with MBP was more effective when a combination of anti-Vbeta3.3 and anti-Vbeta8.2 mAbs was used. These results confirm the functional role of TCR Vbeta3.3 and thus underscore the heterogeneity of TCR usage in MBP-associated autoimmunity.

Animals↗
PubMed1999

Apoptosis induction by macrophage-derived reactive oxygen species in myelin-specific T cells requires cell-cell contact.

Apoptosis of autoreactive T cells has been recognized as an important mechanism of immune homeostasis in autoimmune PNS diseases. To examine whether T cells are induced to undergo apoptosis by macrophages (Mphi) via reactive oxygen species (ROS) neuritogenic P2-specific T line cells were exposed to peritoneal Mphi of Lewis rats in vitro. ROS production was stimulated by phorbol myristate acetate (PMA) and inhibited by catalase. Flow cytometric analysis of apoptosis as measured by TUNEL technique revealed that 5-15% of all P2-cells were apoptotic, if cultured alone. This percentage increased slightly, but did not exceed 20% when P2-cells were cocultivated with PMA-stimulated Mphi in a two-chamber culture plate separated by a cell-impermeable membrane. Direct cocultivation caused apoptotic cell death of more than 40% of P2-cells, which was completely abrogated by catalase. These results suggest a requirement for close cell-cell contact for apoptosis induction of T cells via Mphi-derived ROS. Thus Mphi may contribute to termination of inflammation in vivo through the release of highly reactive oxygen species that mediate apoptotic cell death of autoaggressive T lymphocytes.

Animals↗
PubMed1999

T-cell apoptosis in inflammatory neuromuscular disorders associated with human immunodeficiency virus infection.

BACKGROUND: Apoptosis is one of the major mechanisms of CD4+ T-cell depletion in human immunodeficiency virus (HIV) infection. T cells in human inflammatory myopathies in HIV-negative individuals rarely undergo apoptosis. Currently, there is no information available concerning the fate of T cells in HIV-associated myositis and polyneuropathies. OBJECTIVE: To investigate whether apoptosis occurs in inflammatory lesions of muscle and nerve biopsy specimens of untreated HIV-positive patients with neuromuscular disorders. METHODS: T-cell apoptosis was investigated in muscle and nerve specimens from 12 patients with HIV-associated polymyositis and 8 patients with HIV-associated inflammatory polyneuropathy. These were compared with specimens from 36 HIV-negative patients with other inflammatory myopathies and from 18 patients with inflammatory polyneuropathies. Apoptosis was assessed according to morphological criteria and with the use of in situ labeling methods. RESULTS: In none of the HIV-associated disorders did we observe a substantial proportion of apoptotic T cells as assessed by nuclear morphological findings and in situ labeling techniques. Fas expression was up-regulated only in a few inflammatory cells. Positive labeling for Fas ligand was not associated with increased apoptosis of surrounding T cells. Nuclei of degenerating muscle fibers and macrophages did not show morphological signs of apoptosis and were not labeled by the tailing reaction. CONCLUSIONS: Similar to their idiopathic counterparts, in HIV-related polymyositis and inflammatory neuropathy, T-cell inflammation is not cleared by apoptosis. The observations are consistent with the non-self-limited nature of endomysial or endoneural inflammation and suggest that in HIV-positive patients, the T-cell elimination is differentially regulated in the lymphoid organs as compared with neuromuscular tissues.

Apoptosis↗
PubMed1999

Mechanisms of high-dose intravenous immunoglobulins in demyelinating diseases.

Administration of high-dose intravenous immunoglobulins has become one of the most successful new treatment regimens for demyelinating diseases. In a decade of molecular medicine, it came as a surprise that a natural blood product would prove effective in several disorders, including Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, multifocal motor neuropathy, and, probably, multiple sclerosis. Many experimental studies, both in vivo and in vitro, have shown that intravenous immunoglobulins can interfere with the immune system at several levels. In addition, intravenous immunoglobulins may promote remyelination in demyelinating disease associated with viral infections. At present, no single mode of action has been identified as the crucial mechanism, which leads us to suggest that multiple effects may act in concert.

Antibodies, Anti-Idiotypic↗
PubMed1999

Neurofilament is an autoantigenic determinant in myasthenia gravis.

Intratumorous expression of a 153-kd protein (p153), which contains an acetylcholine receptor-like epitope, is the only tumor marker described to date that significantly associates with thymoma in paraneoplastic myasthenia gravis (MG). Here, we report that p153 is identical to the midsize neurofilament, as verified by immunohistochemistry, immunofluorescence, and western blot analysis. Furthermore, the acetylcholine receptor-like epitope of the midsize neurofilament (NF-M) was identified by peptide epitope mapping. We also show, using T-cell proliferation assays, a significantly increased response of intratumorous T cells to a recombinant midsize neurofilament fragment in thymoma patients with MG compared with MG patients with thymic follicular hyperplasia or thymoma patients without MG. The T cells of thymic follicular hyperplasia and thymoma patients without MG seem to be unresponsive to NF-M. In contrast, we found increased T-cell responses to recombinant acetylcholine receptor fragments in MG patients in general compared with non-MG patients. Increased T-cell responses to NF-M in patients with paraneoplastic MG might be the result of an abnormal positive selection of immature T cells within thymomas, caused by the expression of NF-M in neoplastic thymic epithelial cells. Our results offer further evidence that NF-M expression in thymomas is an autoantigenic determinant in MG.

Epitopes↗
PubMed1999

[Current diagnosis in muscular dystrophies. New developments, methods of examination and case examples].

Recent progress in the field of molecular genetics revealed a broader spectrum of dystrophin-related disorders than previously assumed. In addition, the pathogenetic basis of other types of muscular dystrophies could be identified: some autosomal-recessive limb girdle dystrophies are caused by mutations of sarcoglycan genes, others are caused by deficiency of the sarcoplasmatic enzyme calpain-3. Emery-Dreifuss muscular dystrophy is due to the deficiency of the nuclear membrane protein emerin. About 50% of congenital muscular dystrophies are related to mutations of a extracellular matrix protein merosin (alpha-laminin). A series of monoclonal antibodies for immunohistochemistry is now available recognizing many cytoskeletal muscle proteins. In combination with molecular genetics a diagnostic flow chart can be developed which allows a definite diagnosis in most cases. In this review disease entities are illustrated by case reports. We discuss the significance of immunohistochemical and molecular methods for diagnosis.

Adult↗
PubMed1999

Epidemiology of bacterial meningitis.

Bacterial meningitis caused by Haemophilus influenzae type B (Hib) has almost disappeared from the United States, Canada, and other countries that have implemented routine vaccination with Hib conjugate vaccines. The overall incidence of meningitis in these countries has declined by more than 50%, and the age distribution of susceptibility has shifted, so that the disease is now more common in adults than in children. Another new feature of the epidemiology of bacterial meningitis has been the occurrence of clusters of meningococcal disease. Such clusters have been school related, mainly in adolescents, and most clusters have been associated with a clone of group C, serotype 2a. The role of cigarette smoking as a risk factor for bacterial meningitis has been confirmed and adds urgency to the efforts to control smoking in adolescents and young adults.

Adolescent↗
PubMed1999

Heterogeneity of T-cell receptor usage in experimental autoimmune neuritis in the Lewis rat.

In experimental autoimmune neuritis (EAN), T-cell receptor (TCR) variable (V)-region gene usage by neuritogenic T cells has been reported to be clonally restricted at the RNA level. This study was designed to verify TCR usage by neuritogenic T cells at the protein level. We generated two monoclonal antibodies (mAbs) 7H4 and 8G8 specific for a Vbeta4/Valpha11 associated idiotype expressed by the majority of neuritogenic cells of P2-specific T-cell lines. The remaining neuritogenic P2-specific T cells either exhibited a dominant usage of the TCR Vbeta13 chain recognized by the recently generated mAbs 17D5 and 18B1 or showed diverse Vbeta usage. Treatment of adoptive-transfer (AT)-EAN or of EAN actively induced with the neuritogenic P2 peptide by mAbs 7H4 and 8G8 led to a partial, but significant, reduction of clinical disease. Treatment with Vbeta13-specific mAb 17D5 had no clear effect on active EAN. Our data show that at least three different TCR are used by P2-specific pathogenic T cells in EAN, an animal model for human inflammatory neuropathies.

Adoptive Transfer↗
PubMed1999

Treatment of multiple sclerosis: recent trials and future perspectives.

In the past year, further evidence establishing the usefulness of beta interferons and glatiramer in the treatment of relapsing-remitting multiple sclerosis has been advanced. Interferon-beta-1b was also shown to be efficacious in secondary progressive multiple sclerosis. This and other trials of symptomatic treatments are reviewed. Based on an appraisal of recent experimental studies, future promising approaches to intervene in the chain of immunopathogenetic events are discussed.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1999

Mechanisms of immune regulation in the peripheral nervous system.

The peripheral nervous system (PNS) is a target for heterogenous immune attacks mediated by different components of the systemic immune compartment. T cells, B cells, and macrophages can interact with endogenous, partially immune-competent glial cells and contribute to local inflammation. Cellular and humoral immune functions of Schwann cells have been well characterized in vitro. In addition, the interaction of the humoral and cellular immune system with the cellular and extracellular components in the PNS may determine the extent of tissue inflammation and repair processes such as remyelination and neuronal outgrowth. The animal model experimental autoimmune neuritis (EAN) allows direct monitoring of these immune responses in vivo. In EAN contributions to regulate autoimmunity in the PNS are made by adhesion molecules and by cytokines that orchestrate cellular interactions. The PNS has a significant potential to eliminate T cell inflammation via apoptosis, which is almost lacking in other tissues such as muscle and skin. In vitro experiments suggest different scenarios how specific cellular and humoral elements in the PNS may sensitize autoreactive T cells for apoptosis in vivo. Interestingly several conventional and novel immunotherapeutic approaches like glucocorticosteroids and high-dose antigen therapy induce T cell apoptosis in situ in EAN. A better understanding of immune regulation and its failure in the PNS may help to develop improved, more specific immunotherapies.

Animals↗
PubMed1999

Adolescent abstinence and condom use: are we sure we are really teaching what is safe?

This article reviews existing research on condom and abstinence method- and user-failure rates, and the use of this research in determining sexuality education curricula. Latex condoms effectively prevent pregnancies and most sexually transmitted diseases or infections (STIs), with method-failure rates between 0.5% and 7%, but with user-failure rates between 12% and 70%. Total abstinence presumably has a method-failure rate of zero, but research on periodic abstinence indicates user-failure rates between 26% and 86%. No researchers have attempted to establish total abstinence user-failure rates. Abstinence-only curricula evaluations have demonstrated changes in adolescents' attitudes but little change in sexual behaviors. Comprehensive sexuality education curricula have demonstrated attitudinal changes and delays in adolescents' sexual activity. Since inconsistent use of either condoms or abstinence threatens adolescents' health, this article urges more scientific research on total abstinence user-failure rates, better and clearer dissemination of research findings, and encourages funders to require educators to show thorough knowledge of research findings.

Adolescent↗
PubMed1999

Spontaneous bilateral vertebral artery dissections: case report and literature review.

Vertebral artery dissection (VAD) has been increasingly identified as a cause of ischemic stroke in young adults. We report the clinical and radiographic findings in a case of spontaneous bilateral VADs and review the literature on the causes, pathophysiology, diagnostic considerations, and treatment options for VAD. A 29-year-old man was admitted to our hospital after sudden onset of headache and nuchal rigidity that progressed to a posterior lateral medullary syndrome in a 2-week period. The diagnosis of bilateral VADs was based on findings on cranial magnetic resonance imaging and conventional angiography. The patient was given anticoagulant therapy and had no further neurologic deterioration. The differential diagnosis of craniocervical pain in young patients should include arterial dissection of the neck because early diagnosis and treatment may reduce the chances of long-term neurologic sequelae.

Adult↗
PubMed1998

Intravenous immunoglobulin treatment of neurological autoimmune diseases.

Intravenous immunoglobulin (IVIg) has been widely used in neurological diseases during the last decade. The current indications of IVIg in neurological diseases are reviewed and discussed on the basis of the available experimental data and clinical trials. Compared to other immunomodulating treatments used in neurological diseases, IVIg has only few side effects with a small risk of transmission of infectious agents. Good clinical evidence for the effectiveness is available for Guillain-Barré-Syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy. In conditions like myasthenia gravis and myositis favourable effects of IVIg were reported, but future studies have to be awaited. For all other neurological conditions where IVIg has been administered, there is currently no support for the use of IVIg other than in controlled trials. In conclusion, IVIg is a promising immunomodulary therapy that has been shown to be effective in some neurological autoimmune diseases. Routine use in neurological practice should be restricted to diseases for which a positive effect has been proven in controlled trials. For all other conditions no definite recommendations can presently be made.

Autoimmune Diseases↗
PubMed1998

[Standardized bicycle ergometry test in mitochondrial myopathies. Indications, interferences and clinical parameters].

Exercise tests are widely used as simple, non-invasive screening methods in the differential diagnosis of metabolic myopathies. Exercise protocols have not been standardized with regard to duration of the test, workload, or monitored metabolic parameters. Potentially interfering parameters such as gender or maximal isometric force of the individuals have not been investigated. Here we describe a standardized bicycle ergometry protocol with a stepwise increasing workload between 30 and 100 watts. The venous lactate/pyruvate (L/P) ratio proved to be the one clinically most useful parameter in the functional diagnosis of mitochondrial myopathies with pathological exercise values in all nine examined patients. Additionally, the effects of coenzyme Q therapy in these patients were most clearly mirrored by changes in the L/P ratio. Nonspecifically elevated venous lactate concentrations above 5 mmol/l are rarely found in healthy female volunteers with low maximal isometric force of the M. quadriceps femoris. Other parameters such as serum free fatty acids, ketone bodies, intermediate products of the Krebs cycle or spirometric investigations add only little additional information. The exercise test described may be useful as an additional investigation in the differential diagnosis of metabolic myopathies.

Adult↗
PubMed1998

Metabolic changes in patients with mitochondrial myopathies and effects of coenzyme Q10 therapy.

We used a standardized bicycle ergometry protocol with a stepwise increasing workload (30-100 W) to evaluate various metabolic factors for the diagnosis and metabolic monitoring of mitochondrial encephalomyopathies. All patients (n = 9) showed pathological venous lactate/pyruvate (L/P) ratios, which normalized in three patients after 6 months of coenzyme Q10 (CoQ) therapy. Thus, the L/P ratio proved to be the clinically most useful parameter in the evaluation and monitoring of mitochondrial diseases, showing higher sensitivity than lactate measurements only. CoQ may exert a favourable effect in some patients with mitochondrial diseases.

Adolescent↗
PubMed1998

Plasma membrane phospholipid asymmetry precedes DNA fragmentation in different apoptotic cell models.

Biochemical alterations occurring in many cell types during apoptosis include the loss of plasma membrane phospholipid asymmetry and nuclear DNA fragmentation. Annexin V staining detects phosphatidylserine translocation into the outer plasma membrane layer occurring during cell death, while the in situ tailing (IST or TUNEL) reaction labels the DNA strand breaks typical of apoptosis. To compare the time course of these processes we investigated methylprednisolone-induced apoptosis of rat thymocytes, topoisomerase inhibitor-induced apoptosis in the human histiocytic lymphoma cell line U937, and serum deprivation-induced apoptosis in the rat pheochromocytoma cell line, PC12. At all time points, FACS analysis and quantitative fluorescence light microscopy showed a higher proportion of annexin V-positive than IST-positive cells, with significantly different time courses in the apoptotic cell models investigated (Anova test). Results were confirmed by confocal microscopy. Our data indicate that the exposure of phosphatidylserine, a potential phagocyte recognition signal on the cell surface of apoptotic cells in vivo, precedes DNA strand breaks during apoptosis in different cell types.

Animals↗