Vascular autoantibodies in amyotrophic lateral sclerosis.
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Adult↗
Biomedical subjects
A Marx
Publications and source records attributed to A Marx.
Neurofilament epitopes in thymoma and antiaxonal autoantibodies in myasthenia gravis.
Expression by neoplastic thymic epithelial cells of acetylcholine-receptor (AChR) epitopes is associated with the presence of AChR autoantibodies and the development of myasthenia gravis. We studied thymic tumours from patients with and without myasthenia gravis for the expression of neurofilament epitopes by immunohistochemistry with four monoclonal antibodies. There was very little antibody binding in control samples (healthy thymus, or thymitis) or in medullary and mixed thymomas, but neurofilament epitopes were strongly expressed in all cortical thymomas and thymic carcinomas. In addition, the frequency of serum autoantibodies against axons was significantly higher among myasthenic patients with thymic epithelial tumours than among age-matched controls (7/10 vs 3/50; p less than 0.01).
Adolescent↗
Pathogenetic significance of fetal-type acetylcholine receptors on thymic myoid cells in myasthenia gravis.
To investigate the role of thymic myoid cells in the pathogenesis of myasthenia gravis (MG), mRNA of nonneoplastic thymuses from eight MG patients was analyzed by dot blot hybridization for the occurrence of acetylcholine receptor (AChR) subunit transcripts, using the five AChR-subunit cDNAs (alpha, beta, gamma, delta, and epsilon) as probes. Attention was particularly paid to the gamma- and epsilon-subunit transcripts that specify fetal- or adult-type AChR. In all eight thymuses, transcripts of the alpha-, beta-, gamma-, and delta-subunit genes were detected. Relative autoradiographic signal intensities correlated with the frequencies of thymic myoid cells as determined by immunostaining with anti-AChR monoclonal antibodies. In only one of these thymuses were transcripts of the epsilon-subunit gene detected in addition to those of the other subunit genes. Four MG-associated thymomas without myoid cells were devoid of any AChR-subunit mRNA. Our findings imply that fetal-type AChR is expressed in MG thymuses as a rule, whereas adult-type AChR is coexpressed with it only in a minority of cases. A similar pattern of cotranscription is known to occur at certain stages of muscle development, and can be found in human rhabdomyosarcomas with an intermediate stage of myogenesis. Because the serum autoantibodies of MG patients exhibit preferential reactivity with fetal AChRs, the presence of fetal AChRs in the thymus provides circumstantial evidence for an active involvement of thymic myoid cells in the autoimmune process.
Antibodies, Monoclonal↗
A striational muscle antigen and myasthenia gravis-associated thymomas share an acetylcholine-receptor epitope.
The coincidence of autoantibodies against the acetylcholine receptor (AChR) and muscle striational antigens (SA) is a characteristic finding in thymoma-associated myasthenia gravis (MG), but their origins are still unresolved. Some common muscle antigens that were shown to be targets of anti-SA autoantibodies in thymoma-associated MG have also been detected in normal or neoplastic thymic epithelial cells, suggesting that the release of (eventually altered) antigens from the thymic tumors could elicit SA autoimmunity. In contrast to this model, we report here that titin, which is a recently reported target of SA autoimmunity, is not expressed in thymomas. In addition, we show that skeletal muscle type-II fibers exhibit a striational immunoreactivity with monoclonal antibody mAb155, which was previously identified to label a very immunogenic cytoplasmic epitope of the AChR and neoplastic epithelial cells of MG-associated thymomas. We conclude from these findings that titin autoimmunity in thymoma-associated MG is either due to a molecular mimicry mechanism involving tumor antigens (other than titin) or is a secondary phenomenon following release of titin from muscle. Based on the common immunoreactivity of the AChR, a striational antigen and thymoma, we suggest as the pathogenetic mechanism of thymoma-associated MGa "circulus vitiosus" in which SA autoimmunity could help maintain the AChR autoimmunity that is primarily elicited by the thymomas.
Adult↗
[B-cells in thymic epithelial tumors: phenotype, distribution and relation to the intramedullary B-cell population of the normal thymus].
Immunohistochemical analysis of 26 thymomas and thymic carcinomas revealed the occurrence of two different intratumoral B-cell populations. High numbers of B-lymphocytes with formation of lymphoid follicles were found in the extra-epithelial perivascular spaces of cortical thymomas and well differentiated thymic carcinomas associated with myasthenia gravis. On the other hand, B-cells within the epithelial meshwork frequently occurred in organoid medullary islands of predominantly cortical and cortical thymomas. In their distribution and phenotype, these cells correspond to the intramedullary B-cell population of the normal thymus, reflecting a specific intratumoral B-cell homing dependent on medullary epithelial differentiation.
Antigens, CD↗
[Neurofilament expression in thymic epithelial tumors and anti-axonal autoantibodies in myasthenia gravis: a model for autoimmunity by abnormal T cell selection].
Thymic epithelial tumors from myasthenia gravis (MG) patients and non-neoplastic thymuses were investigated by immunohistochemistry for the expression of neurofilament (NF) epitopes. There was little immunoreactivity confined to the medulla in non-neoplastic thymuses and a faint staining only for a 200 kD NF epitope in medullary and mixed thymomas. In contrast, cortical thymomas and well-differentiated thymic carcinomas expressed epitopes of the 68 kD and 160 kD NF. Demonstrating anti-axonal and anti-NF autoantibodies in thymoma patients we conclude that "false-positive T cell selection" is a mechanism of autoimmunity in paraneoplastic MG.
Autoantibodies↗
Immunocytochemical characteristics of small cell lung carcinoma associated with the Lambert-Eaton myasthenic syndrome.
The Lambert-Eaton myasthenic syndrome (LEMS) is characterized by the presence of IgG antibodies to motor nerve terminals, and associates with small cell lung carcinoma in more than 60% of cases. We have carried out a comparative immunocytochemical study on small cell lung carcinoma (SCLC) in five LEMS cases and six non-LEMS cases, using antibodies to tumor markers, MHC Class I and II, macrophages and lymphocytes. The authors found a reduced expression of the 200Kd neurofilament antigen and of MHC Class I antigens in the LEMS cases as well as a greater infiltration of activated macrophages. It is suggested that these findings are consistent with the view that SCLC antigenic determinants trigger the autoantibody response in SCLC-LEMS.
Antigens, Neoplasm↗
A shared epitope in the acetylcholine receptor-alpha subunit and fast troponin I of skeletal muscle. Is it important for myasthenia gravis?
The monoclonal antibody MAb 155, isolated by Tzartos et al, recognizes the alpha subunit of acetylcholine receptor (AChR) and stains type II skeletal muscle fibers but does not decorate heart muscle. In addition it reacts with most myasthenia gravis-associated thymomas. The authors show by immunoblotting techniques that the myofibrillar antigen is a 23 kd protein and by partial protein sequence data identify it as fast troponin I. Fast troponin I from various species contains the sequence EEKSGMEGRK close to the C-terminal end at positions 165 to 174. The first lysine (K) is crucial for MAb 155 reactivity since its substitution by methionine and leucine in slow troponin I and cardiac troponin I, respectively, abolishes MAb 155 reactivity. The epitope identified on troponin I is homologous in sequence with the MAb 155 epitope on the AChR alpha subunit established by direct peptide binding as KSAIEGIK (positions 373-380). The authors consider whether fortuitously shared epitopes can be responsible for the high level of autoantibodies to AChR and to muscle proteins seen in many MG patients.
Amino Acid Sequence↗
Well-differentiated thymic carcinoma. An organotypical low-grade carcinoma with relationship to cortical thymoma.
Based on a study of 26 cases, the well-differentiated thymic carcinoma is described as a distinct organotypical carcinoma of the thymus with low-grade malignancy. It is characterized by a predominance of epithelial cells with usually low mitotic rate, an epidermoid differentiation with slight to moderate cytological atypia, the constant presence of interepithelial immature cortical thymocytes, lobular growth, and formation of epithelial palisades around perivascular spaces. The tumor occurs at age 14 to 76 years in both sexes. An association with myasthenia gravis is found in 77% of the patients, and 83% of the tumors show invasion of adjacent organs or endothoracic metastasis at primary operation. This rate is higher than in cortical thymomas (47%) but lower than in other thymic carcinomas (92%). Two of 18 patients with follow-up died of tumor recurrence and pleural metastasis. Well-differentiated thymic carcinoma can be related to cortical thymoma by common morphological features and a similar immunophenotype of epithelial cells. It must be differentiated from the lymphocyte-depleted cortical thymomas after corticosteroid treatment and from the benign epithelial-rich medullary thymomas.
Adolescent↗
[1989 Basel Mammography Action].
To evaluate the compliance for a breast cancer screening program in the region of Basel, a mammography and a clinical examination has been offered free of charge to women between 40 and 60 years of age, especially to women with familial breast cancer. From September to November 1989, 602 women participated. Results were obtained from an epidemiologic questionnaire and a two-view mammography. The median age was 55.1 years. 70.2% of the women never had a mammography before. 28.8% indicated a history of familial breast cancer. So far 444 women have been evaluated. No pathological results were obtained in 84.8% In 10.7% a second examination has been recommended in the near future. In 4.5% the mammography led to an aspiration biopsy or surgical lumpectomy where 5 (1.2%) neoplasms have been detected. Due to the limited duration of the campaign and the invitation especially addressed to women at risk, our results are not comparable with large-scale screening campaigns known from the literature. Nevertheless, we succeeded to sensitize the female population for this kind of breast care. The overwhelming success shows that the basis for a large-scale screening program may exist.
Adult↗
Genomic organization and lack of transcription of the nicotinic acetylcholine receptor subunit genes in myasthenia gravis-associated thymoma.
To investigate the relationship between anti-acetylcholine receptor (AchR) autoimmunity and the occurrence of thymoma in a particular group of myasthenia gravis (MG) patients we analyzed DNA and RNA from MG-associated thymomas and control tissue by Southern and Northern blotting, respectively, using the AchR alpha, beta, gamma, delta and epsilon-subunit cDNAs or oligonucleotides as probes. Restriction analysis of genomic DNA showed an organization of AchR subunit genes in thymomas identical with that of normal tissues. In particular, in thymomas, there was no deletion of exon 4 of the alpha-subunit which encodes the main immunogenic region of the AchR. Dot and Northern blot analysis did not reveal transcription of any AchR subunit gene in thymomas. Instead, an RNA nucleotide sequence was identified in MG-associated thymomas that hybridized to an AchR oligonucleotide probe coding for amino acids 371-378 of the AchR alpha-subunit. With this sequence as a probe, three DNA restriction fragments in addition to a restriction fragment of the AchR alpha-subunit gene could be identified in the human gene. The findings suggest that proteins with extensive homology to the AchR are not expressed in MG-associated thymomas. However, there are three genomic loci in thymoma genomes with a very restricted homology to the AchR alpha-subunit gene. One of these loci might code for the cross-reacting AchR epitope detected in almost all MG-associated thymomas in contrast to thymomas without MG.
Adult↗
[Proximal femoral fractures. Is there an indication for the condylar screw (DCS)?].
Between 1983 and 1989 66 consecutive fractures of the proximal femur were treated with a condylar screw DCS. 42 patients were available for a follow-up study, 12 subtrochanteric fractures (mean age 58.5 years) and 30 intertrochanteric fractures (mean age 73 years). The primary union rate was clearly higher in the subtrochanteric group (10/12) compared to the intertrochanteric group (22/30). All the 8 implant complications (pull-out, metal fatigue) in the intertrochanteric group were associated with important posteromedial comminution in elderly patients who cannot be mobilized with only partial weight bearing postoperatively. Unstable intertrochanteric fractures in elderly patients should not be treated with the DCS. These are indications for the DHS which allows controlled telescoping. The indication for the DCS is limited to proximal shaft fractures in younger patients capable of partial weight bearing.
Adult↗
[Donor allopurinol treatment improves organ preservation of the kidney also when using UW solution].
Kidney function following hypothermic preservation with Eurocollins (EC) was previously shown to be improved by donor treatment with Allopurinol (AP) [1]. The University of Wisconsin organ preservation solution (UW), however, contains Allopurinol (1 mM). A syngeneic rat kidney transplant model was used to investigate concurrent Allopurinol donor-pretreatment (40 mg/kg b.w.). Kidney graft function resulted to be improved by AP pretreatment following organ preservation with both EC or UW as evidenced by significant reduction in serum creatinine values. On day two following transplantation the respective serum creatinine values (mumol/l) with and without AP-pretreatment were 424 +/- 39 and 662 +/- 25 for EC, and 259 +/- 48 and 387 +/- 48 for UW organ preservation. Furthermore survival- and histology-data were also superior for recipients of kidney grafts from AP-pretreated donors. We conclude that Allopurinol concentration in the UW solution might be to low or that adding AP into an organ storage solution is not the best application modality.
Adenosine↗
[Atraumatic Clostridium septicum infection in granulocytopenia].
A fatal Clostridium septicum infection occurred in three patients. Case 1. A 55-year-old man died of septicaemia resulting from granulocytopenia of uncertain aetiology; it was associated with perforation of ileal mucosal ulcers. Autopsy revealed neutropenic enterocolitis and diffuse gas formation, especially in the brain, caused by Clostridium septicum. Case 2. A 18-year-old boy developed a caecal invagination during imipenem-induced granulocytopenia. A fulminant postoperative Clostridium septicum infection ended fatally. At autopsy many ulcers were found at the site of invagination with gas formation involving all organs. Case 3. Myonecrosis of the left arm, caused by Clostridium septicum, developed without external cause in a 12-year-old girl with congenital neutropenia. Despite aggressive surgical intervention she died of toxic shock. Autopsy revealed caecal mucosal ulcers as the portal of entry of Clostridium septicum.
Adolescent↗
Sodium and potassium channels in epithelial cells from thymus glands and thymomas of myasthenia gravis patients.
In both normal and neoplastic epithelial cells from human thymus glands and thymomas, respectively, we found voltage-gated sodium and potassium channels that resemble the adult-type Na channel and the delayed outward rectifier K channel, respectively, of human skeletal muscle and mammalian nervous system. These voltage-gated ion channels might be part of a communication system between epithelial cells and other components of the microenvironment of the thymus.
Electric Conductivity↗
Absence of acetylcholine-induced current in epithelial cells from thymus glands and thymomas of myasthenia gravis patients.
We investigated the activity of ion channels in epithelial cells from human thymus glands and thymomas kept in short-term cell culture by clamping the membrane potential of the cells at -85 mV and determining the membrane current flowing on application of acetylcholine, glycine, or gamma-aminobutyric acid. In concentrations of up to 10(-3) M, none of the neurotransmitters induced any detectable current. This suggests (1) that there are no acetylcholine receptors (AChRs) or other products of the AChR gene family having ion-channel properties in the membranes of these epithelial cells, and (2) that the alpha-bungarotoxin-binding protein of thymus and thymoma has no AChR-like ion-channel property. These results support the hypothesis that the cross-reacting structures that elicit the anti-AChR autoimmune response in thymoma-associated myasthenia gravis are antigens having only limited homology with the AChR. Myasthenia gravis not associated with thymoma might have a different pathogenesis.
Acetylcholine↗
Protective effect of allopurinol and superoxide dismutase in renal isografts in cyclosporin A-treated rats.
Acute tubular necrosis (ATN) after renal transplantation is related to the duration of warm and cold ischemia and leads to temporary or permanent impairment of graft function. An increased incidence of ATN has been reported since the introduction of cyclosporin A. Kidney damage resulting from hypothermic storage is generated in part during reperfusion rather than during ischemia itself. Potential mediators of the reperfusion injury are oxygen-derived free radicals. Therefore, the influence of two oxygen radical antagonists, allopurinol and superoxide dismutase, was evaluated in syngeneic rat kidney transplantation with and without concurrent administration of cyclosporin A. At 15 h cold ischemia, 28-day survival increased from 8% (no treatment) to 22% (superoxide dismutase), 33% (superoxide dismutase and allopurinol), and 73% (allopurinol). Cyclosporin A cotreatment (10 mg/kg over 14 days) resulted in survival rates of 0%, 25%, 17%, and 50% for the respective treatment groups. The results of serum creatinine values and morphological evaluation of biopsies paralleled the survival rates. Cyclosporin A nephrotoxicity was evidenced by significant serum creatinine elevations throughout the 28-day period of observation. In conclusion, allopurinol significantly protects syngeneic rat kidney transplants against a critical duration of cold ischemia. Under the conditions of this experiment, allopurinol was clearly superior to superoxide dismutase treatment. Cyclosporin A nephrotoxicity was, however, not ablated by the oxygen radical antagonists employed.
Allopurinol↗
Characterization of a protein with an acetylcholine receptor epitope from myasthenia gravis-associated thymomas.
Immunohistochemical studies have shown that almost all thymomas of myasthenia gravis patients contain at least one protein sharing an antigenic determinant with the nicotinic acetylcholine receptor (AchR) of human muscle. We describe the characterization of this protein (p153) which has a molecular weight of 153 and an isoelectric point of 5.0. By treatment of p153 with endoglycosidases, no significant glycosylation has been detected. Immunologically, p153 crossreacts with monoclonal antibodies against the amino acid sequence 371-378 of the alpha-chain of the AchR. No cross-reactivity to the main immunogenic region of the AchR nor an alpha-bungarotoxin binding site are found. By Western blotting, p153 was generally neither detectable in normal tissues nor extrathymic tumors with the exception of paraganglioma and neuroblastoma. In conclusion, the structure of p153 is apparently unrelated to the AchR from muscle or the alpha-bungarotoxin binding proteins from thymoma. Since there is no evidence for an AchR expression in thymoma, the antigenic homology of p153 with the nicotinic AchR might be relevant for triggering an intrathymomatous autosensitization of maturing T cells and could be responsible for the high association of thymomas with myasthenia gravis.
Antibodies, Monoclonal↗