Differential diagnosis of acute flaccid paralysis and its role in poliomyelitis surveillance.
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Acute Disease↗
Biomedical subjects
A Marx
Publications and source records attributed to A Marx.
Thymoma.
Thymomas are fascinating tumors because of their multifaceted clinical presentation, including an unrivaled frequency of associated paraneoplastic autoimmune diseases and an astounding histologic heterogeneity. Thus, thymomas challenge the clinician, pathologist, and immunologist alike with complex diagnostic and therapeutic problems in almost all fields of medicine, radiology, nuclear medicine, surgery, radiooncology, and pathology. This review highlights recent progress in these fields, including the new World Health Organization's classification of thymomas, and reports on the beginning discovery of the genetic basis of thymoma oncogenesis and the cellular and molecular immunopathology of thymoma-associated paraneoplastic autoimmunity.
Animals↗
Function of fast- and slow-twitch rat skeletal muscle following ischemia and reperfusion at different intramuscular temperatures.
Fast- (peroneal) and slow-twitch (soleus) skeletal muscles of anesthetized Wistar rats were subjected to 3 h of tourniquet ischemia. The intramuscular temperature of the leg was adjusted to 22, 30 or 35 degrees C (n = 12 per group) during ischemia. After 2 h of reperfusion, the muscles were electrically stimulated in vitro and muscular function was analyzed for maximal force, performance, contractility and fatigue. Contralateral nonischemic muscles served as controls. Three hours of ischemia at 30 degrees C did not reduce the function of the peroneal muscles compared to nonischemic controls. The same ischemic stress significantly reduced the function of the soleus muscles compared to nonischemic controls. The postischemic function of the soleus muscles declined with increasing temperature. The postischemic function of the 35 degrees C group of peroneal muscles was significantly reduced compared to the 22 and the 30 degrees C groups, which did not differ. These results provide evidence that fast-twitch muscles are more resistant to ischemia than slow-twitch muscles. They furthermore show a fiber type-specific dependency of postischemic muscle function on intramuscular temperature during ischemia. Hypothermia-sensitive fast-twitch fibers predominate in the skeletal muscles of the extremities. Mild hypothermia could, therefore, reduce tourniquet ischemia-induced injury after surgery of the extremities.
Animals↗
Preconditioning with short cycles improves ischemic tolerance in rat fast- and slow-twitch skeletal muscle.
AIM: The aim of this study was to investigate whether the efficacy of ischemic preconditioning (IP) in rat skeletal muscle depends on the duration of the preconditioning cycles. METHODS: Rats were divided into four groups (n = 10 each). The right hindlimb of rats in group A were subjected to 2.5 h of tourniquet ischemia followed by 2 h of reperfusion (I-R). Thereafter, muscular function was analyzed in vitro and high-energy phosphates (HEP) were determined by HPLC. Before I-R, right hindlimbs of rats in groups B-D subjected to IP with three cycles each consisting of 2.5, 5 or 10 min of ischemia followed by reperfusion for the same duration. RESULTS: Postischemic function of the extensor muscle was significantly improved with all three preconditioning protocols. Postischemic function of the soleus muscle was only improved by IP with three cycles of 5 min of ischemia and 5 min of reperfusion. Postischemic HEP tissue levels were not influenced by IP. CONCLUSION: This study shows for the first time that IP increases ischemic tolerance not only of fast-twitch but also of slow-twitch skeletal muscle. The efficacy of IP seems to be less dependent on the duration of the single preconditioning cycle than on the number of cycles performed. Three cycles each of 2.5, 5 or 10 min ischemia and reperfusion significantly improved postischemic skeletal muscle function. Tissue levels of HEPs, however, were not influenced by IP indicating that preservation of HEPs does not play a major role in the effects of IP on rodent skeletal muscle.
Adaptation, Physiological↗
On the rigidity of the cytoskeleton: are MAPs crosslinkers or spacers of microtubules?
Microtubules are fibers of the cytoskeleton involved in mitosis, intracellular transport, motility and other functions. They contain microtubule-associated proteins (MAPs) bound to their surface which stabilize microtubules and promote their assembly. There has been a debate on additional functions of MAPs, e.g. whether MAPs crosslink microtubules and thus increase their rigidity, or whether they act as spacers between them. We have studied the packing of microtubules in the presence of MAPs by solution X-ray scattering using synchrotron radiation. Microtubules free in solution produce a scattering pattern typical of an isolated hollow cylinder, whereas tightly packed microtubules generate a pattern dominated by interparticle interference. The interference patterns are interpreted in terms of the Hosemann paracrystal concept, adapted for arrays of parallel fibers with hexagonal arrangement in the plane perpendicular to the fiber axes (Briki et al., 1998). Microtubules without MAPs can rapidly and efficiently be compressed by centrifugation, as judged by the transition from a "free microtubule" to a "packed microtubule" X-ray scattering pattern. MAPs make the microtubule array highly resistant to packing, even at high centrifugal forces. This emphasizes the role of MAPs as spacers of microtubules rather than crosslinkers. A possible function is to keep the microtubule tracks free for the approach of motor proteins carrying vesicle or organelle cargoes along microtubules.
Animals↗
Association of acetylcholine receptor alpha-subunit gene expression in mixed thymoma with myasthenia gravis.
OBJECTIVE: To investigate the association of MG with the transcription of muscular or neuronal acetylcholine receptor (AChR) subunit genes in thymomas. BACKGROUND: Many steps in the pathogenesis of MG have been elucidated but, with rare exceptions, its etiology is unknown. In patients with MG with thymoma, the tumor probably elicits autoimmunity to AChR, but it is enigmatic why MG develops in some patients but not in others. METHODS: Reverse transcriptase (RT)-PCR, immunohistochemistry, and immunofluorescence studies were carried out to investigate AChR expression in 35 patients with thymoma. Statistical analysis was used to specify significant differences between thymoma subtypes. RESULTS: Considering all thymomas (n = 35), no correlation was found between MG status and AChR gene expression as detected by RT-PCR. However, when histologically defined thymoma subtypes were studied separately, transcription of the muscular AChR P3A- alpha-subunit gene was significantly associated (alpha < 0.01) with the occurrence of MG in mixed thymomas (n = 17), but not in thymomas of the cortical type. For the other muscular AChR subunits (P3A+ alpha isoform, beta, gamma, delta, and epsilon) and the alpha2 and beta4 neuronal AChR subunits, no such correlation was detected. CONCLUSIONS: Expression of the P3A AChR alpha-subunit gene might be important for the pathogenesis of MG in mixed thymomas, suggesting etiologic heterogeneity of paraneoplastic MG among patients with histologically different thymoma subtypes.
Adult↗
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↗
Response of the central metabolism in Corynebacterium glutamicum to the use of an NADH-dependent glutamate dehydrogenase.
The extensive use of 13C enrichments in precursor metabolites for flux quantification does not rely on NADPH stoichiometries and can therefore be used to quantify reducing power fluxes. As an application of this concept, the NADPH fluxes were quantified in an L-lysine producer of Corynebacterium glutamicum grown into metabolic and isotopic steady state with [1-13C]glucose. In this case, where the organism's NADPH-dependent glutamate dehydrogenase consumes reducing power, the NADPH flux generated is 210% (molar flux relative to glucose uptake rate) with its major part (72% of the total) generated via the pentose phosphate pathway activity. An isogenic strain in which the glutamate dehydrogenase of C. glutamicum was replaced by the NADH-dependent glutamate dehydrogenase of Peptostreptococcus asaccharolyticus was made and the metabolite fluxes were again estimated. The major response to this local perturbation is a drastically reduced NADPH generation of only 139%. Most of the NADPH (62% of the total) is now generated via the tricarboxylic acid cycle activity. This shows the extraordinary flexibility of the central metabolism and provides a picture of the global regulatory properties of the central metabolism. Furthermore, a detailed analysis of the fluxes and exchange fluxes within the anaplerotic reactions is given. It is hypothesized that these reactions might also serve to balance the total reducing power budget as well as the energy budget within the cell.
Corynebacterium↗
From basic immunobiology to the upcoming WHO-classification of tumors of the thymus. The Second Conference on Biological and Clinical Aspects of Thymic Epithelial Tumors and related recent developments.
The Second Conference on Biological and Clinical Aspects of Thymic Epithelial Tumors in Leiden, The Netherlands, 1998, set the stage for an interdisciplinary meeting of immunologists, pathologists and members of various clinical disciplines to exchange their recent findings in the field of thymus-related biology, pathology, and medicine. The contributions covered such diverse subjects as the role of transcription factors and cytokines in the development of the thymic microenvironment, thymic T, B and NK cell development, the pathogenesis of myasthenia gravis and other thymoma-associated autoimmunities, the pathology of thymic epithelial tumors and germ cell neoplasms, and new approaches to their diagnosis and treatment. This editorial will briefly sum up the data presented at the Conference and will comment on related novel findings that have been reported since then. Because it was also at the Leiden Conference, that the proposal of the WHO committee for the classification of thymic tumors was discussed for the first time, a description of the upcoming WHO Classification of Tumors of the Thymus is given with emphasis on the diagnostic criteria of thymic epithelial tumors, that should now be termed as type A, AB, B1-3 and type C thymomas, to make pathological and clinical studies comparable in the future.
Animals↗
Low-grade metaplastic carcinomas of the thymus: biphasic thymic epithelial tumors with mesenchymal metaplasia--an update.
A group of biphasic low-grade thymic epithelial tumors is presented that we suggest calling low-grade metaplastic carcinoma of the thymus [37]. Four of the patients were men, their age ranging from 44 to 71 years. Three tumors invaded mediastinal fat or pleura. No metastases were present. Histologically, the tumors showed a biphasic pattern with solid carcinomatous areas merging with a spindle cell component. Only few lymphocytes were present. Cytological atypia and mitotic activity were variable in the solid areas, but low in the spindle cell component. The tumors showed expression of cytokeratin, vimentin and/or epithelial membrane antigen (EMA), both in the carcinomatous and in spindle cell components. In two cases, actin expression was also present in both components. In one case, chromogranin, S100 protein, glial fibrillary acidic protein, and neuron specific enolase were expressed in a minority of cells of both components. None of the patients had myasthenia gravis. All patients are alive without distant metastasis, but meanwhile one patient suffers from local recurrence. We conclude that metaplastic carcinoma of the thymus is a clinicopathological entity that is probably distinct from the recently described "thymoma with pseudosarcomatous stroma", and should be distinguished from the usually benign medullary thymomas and the highly aggressive carcinosarcomas and sarcomatoid carcinomas.
Adult↗
Thymic tumours in Denmark. A retrospective study of 213 cases from 1970-1993.
Histological slides of 213 thymic tumours were reviewed twice and classified according to Kirchner and Müller-Hermelink into 122 thymomas (syn. organotypic thymic epithelial tumours (TET)), 58 thymic carcinomas (syn. non-organotypic TET) and 16 lymphomas. Tumour heterogeneity (i.e. features of two subtypes in one tumour) appeared in 38% of the organotypic TET. The overall diagnostic correspondence between the reviews of the 122 organotypic TET was 48%. By reducing the five diagnostic groups to three: organotypic TET benign (medullary and mixed thymomas), organotypic TET low-grade (organoid and cortical thymomas and well-differentiated thymic carcinoma (WDTC)) and non-organotypic TET (usually high-grade thymic carcinomas), and minimising the effect of tumour heterogeneity in this way, the diagnostic correspondence increased to 82%. Correlating histological type with stage, we found that 80% of medullary and 87% of mixed thymomas were stage I, that 85% of cortical and 81% of WDTC were stage II or III, and that non-organotypic TET were stage II or III (86%) or stage IV (14%), respectively. It is suggested to report on the heterogeneity of a given case of thymic epithelial tumour in the pathology reports and give the approximate percentage of each component, telling the clinician which component may determine the prognosis.
Cysts↗
Transcription of the nude gene (WHN) in human normal organs and mediastinal and pulmonary tumors.
Mutations in the winged-helix-nude (WHN) gene in the nude mouse and rat phenotypes lead to loss of hair and athymia. The human nude gene has recently been identified, but to date, its distribution in normal human tissues and thymus tumors has not yet been investigated. We used the RT-PCR technique for the detection of WHN transcripts in normal human organs and various mediastinal tumors, including various subtypes of thymic epithelial tumors. We could show that WHN is highly transcribed in the normal thymus and skin. Unexpectedly, few transcripts were also found in the normal kidney and thyroid gland. WHN mRNA could be detected in all thymoma subtypes (n = 14) and epidermoid thymic carcinomas as well as in all squamous cell carcinomas of the lung (n = 5) investigated, but was totally absent in all other mediastinal tumors (n = 11) lacking an epidermoid differentiation. We conclude that transcription of the human WHN is not strictly specific for human thymus and skin, but is also expressed, though at very low levels, in the normal human kidney and thyroid gland. In addition, WHN gene expression may identify not only thymomas but also epidermoid differentiation in mediastinal and pulmonary tumors.
Adenocarcinoma↗
Probing interactions between HIV-1 reverse transcriptase and its DNA substrate with backbone-modified nucleotides.
BACKGROUND: To gain a molecular understanding of a biochemical process, the crystal structure of enzymes that catalyze the reactions involved is extremely helpful. Often the question arises whether conformations obtained in this way appropriately reflect the reactivity of enzymes, however. Rates that characterize transitions are therefore compulsory experiments for the elucidation of the reaction mechanism. Such experiments have been performed for the reverse transcriptase of the type 1 human immunodeficiency virus (HIV-1 RT). RESULTS: We have developed a methodology to monitor the interplay between HIV-1 RT and its DNA substrate. To probe the protein-DNA interactions, the sugar backbone of one nucleotide was modified by a substituent that influenced the efficiency of the chain elongation in a characteristic way. We found that strand elongation after incorporation of the modified nucleotide follows a discontinuous efficiency for the first four nucleotides. The reaction efficiencies could be correlated with the distance between the sugar substituent and the enzyme. The model was confirmed by kinetic experiments with HIV-1 RT mutants. CONCLUSIONS: Experiments with HIV-1 RT demonstrate that strand-elongation efficiency using a modified nucleotide correlates well with distances between the DNA substrate and the enzyme. The functional group at the modified nucleotides acts as an 'antenna' for steric interactions that changes the optimal transition state. Kinetic experiments in combination with backbone-modified nucleotides can therefore be used to gain structural information about reverse transcriptases and DNA polymerases.
Acetylation↗
A comparison of MyoD1 and fetal acetylcholine receptor expression in childhood tumors and normal tissues: implications for the molecular diagnosis of minimal disease in rhabdomyosarcomas.
Detection of minimal residual disease or micrometastases in rhabdomyosarcoma (RMS) has been an unresolved problem in 70 to 80% of RMS patients. In patients with alveolar type RMS, which harbors chromosomal translocations and produces tumor-specific fusion products, polymerase chain reaction (PCR)-based diagnosis is clear-cut. In the more frequent embryonal RMS, however, no such PCR-based marker has been described. Recently it has been suggested that the PCR-based detection of MyoD1 may be a valuable adjunct in the diagnosis of minimal disease in embryonal RMS. We report here that MyoD1 mRNA is not specific for RMS, but can be amplified from ex vivo samples of many other childhood tumors and some normal tissues. By contrast, simultaneous amplification of alpha and gamma subunit message of the fetal type acetylcholine receptor (AChR), by a novel duplex PCR, and the quantification of both transcripts resulting in a alpha/gammaAChR ratio <1 was 100% sensitive in alveolar (n = 8) and embryonal (n = 10) RMS. Moreover, gammaAChR was not detected in other childhood (n = 27) or adult tumors (n = 12), or normal tissues, except thymus. The high sensitivity and specificity of the method were confirmed by the successful detection of five cases of cytologically or molecularly verified RMS bone marrow micrometastases among 47 bone marrow samples from childhood tumor patients. By contrast, MyoD1 showed no amplification because of its low level of transcription. We conclude that mRNA of the fetal type AChR is a more specific and (about 100 times) more sensitive marker for the molecular detection of RMS than MyoD1, and thus appears to be a promising candidate for the detection of minimal disease in RMS lacking tumor-specific translocations.
Base Sequence↗
Low-grade metaplastic carcinoma of the thymus.
AIMS: Five cases of a characteristic low-grade thymic epithelial tumour are described that we suggest calling metaplastic carcinoma of the thymus. METHODS AND RESULTS: The patients' ages ranged from 44 to 71 (mean 56.2) years. Four of the patients were male. Three of five tumours showed invasion into mediastinal fat or pleura but, otherwise, all were well circumscribed. No metastases were present. Histologically, the tumours showed a biphasic pattern with solid carcinomatous areas merging gradually with a spindle cell component. Lymphocytes were rare. Cytological atypia and mitotic activity were variable in the solid areas, but slight or absent in the spindle cell component. On immunohistochemistry, the tumours showed expression of cytokeratin, vimentin and/or epithelial membrane antigen, both in the carcinomatous and spindle cell components. In two cases, actin expression was also present in both components. In one case, chromogranin, S100 protein, glial fibrillary acidic protein and neuron-specific enolase were expressed in at least some cells of both components. None of the patients had myasthenia gravis. All patients are alive without evidence of recurrence or metastasis. CONCLUSION: Metaplastic carcinoma of the thymus is a distinct clinicopathological entity that should be distinguished from the usually benign medullary thymomas and from the clinically aggressive carcinosarcomas and sarcomatoid carcinomas.
Aged↗
An outbreak of acute gastroenteritis in a geriatric long-term-care facility: combined application of epidemiological and molecular diagnostic methods.
OBJECTIVE: To assess possible transmission modes of, and risk factors for, gastroenteritis associated with Norwalk-like viruses (NLVs) in a geriatric long-term-care facility. METHODS: During a prolonged outbreak of acute gastroenteritis, epidemiological data on illness among residents and employees were collected in conjunction with stool, vomitus, and environmental specimens for viral testing. NLVs were identified by electron microscopy in stool and vomitus specimens, and further characterized by reverse-transcriptase polymerase chain reaction and nucleotide sequencing. Potential risk factors were examined through medical-record review, personal interview, and a self-administered questionnaire sent to all employees. RESULTS: During the outbreak period, 52 (57%) of 91 residents and 34 (35%) of 90 employees developed acute gastroenteritis. Four case-residents were hospitalized; three residents died at the facility shortly after onset of illness. A point source was not identified; no association between food or water consumption and gastroenteritis was identified. A single NLV strain genetically related to Toronto virus was the only pathogen identified. Residents were at significantly higher risk of gastroenteritis if they were physically debilitated (relative risk [RR], 3.5; 95% confidence interval [CI95], 1.0-12.9), as were employees exposed to residents with acute gastroenteritis (RR, 2.6; CI95, 1.1-6.5) or ill household members (RR, 2.3; CI95, 1.4-3.6). Adherence to infection control measures among the nursing staff may have reduced the risk of gastroenteritis, but the reduction did not reach statistical significance. CONCLUSIONS: In the absence of evidence for food-borne or waterborne transmission, NLVs likely spread among residents and employees of a long-term-care facility through person-to-person or airborne droplet transmission. Rapid notification of local health officials, collection of clinical specimens, and institution of infection control measures are necessary if viral gastroenteritis transmission is to be limited in institutional settings.
Adult↗
Parainfluenza virus infection among adults hospitalized for lower respiratory tract infection.
To better define the contribution of human parainfluenza viruses (HPIVs) to lower respiratory tract infection in adults, we tested acute- and convalescent-phase serum specimens from hospitalized adults participating in a population-based prospective study of lower respiratory tract infection during 1991-1992. We tested all available specimens from the epidemic seasons for each virus and approximately 300 randomly selected specimens from the corresponding off-seasons for antibodies to HPIV-1, HPIV-2, or HPIV-3. During the respective epidemic season, HPIV-1 infection was detected in 18 (2.5%) of 721 and HPIV-3 infection in 22 (3.1%) of 705 patients with lower respiratory tract infection. Only 2 (0.2%) of 1,057 patients tested positive for HPIV-2 infection. No HPIV-1 infections and only 2 (0.7% of 281 patients tested) HPIV-3 infections were detected during the off-seasons. HPIV-1 and HPIV-3 were among the four most frequently identified infections associated with lower respiratory tract infection during their respective outbreak seasons.
Adult↗
Thymoma and thymic carcinoma.
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Carcinoma↗