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Biomedical subjects

A Marx

Publications and source records attributed to A Marx.

At least 91 records · Page 5Linked to original sources
PubMed1999

Reversible monoclonal lymphadenopathy in autoimmune lymphoproliferative syndrome with functional FAS (CD95/APO-1) deficiency.

The FAS (CD95/APO-1) receptor and its ligand play an important role in the initiation of apoptosis under many physiologic conditions. Loss of function mutations of the FAS gene have been described in lpr mice and in humans with autoimmune phenomena, recurrent lymphadenopathies, and hepatosplenomegaly. This syndrome is now called autoimmune lymphoproliferative syndrome type I (ALPS I). Recently, patients with similar clinical symptoms due to a functional FAS deficiency without FAS gene mutations have been distinguished. This disease has been termed autoimmune lymphoproliferative syndrome type II (ALPS II) or autoimmune lymphoproliferative disease (ALD). This report is the first description of the lymph node pathology and immunohistochemistry in a patient with ALPS II. After recurrent bacterial infections, a 4-year-old child developed cervical giant lymphadenopathy suggesting lymphoma. Lymph node histology resembled the findings in Epstein Barr virus-associated posttransplant atypical lymphoproliferations. Confluent sheets of immunoblasts, however, showed a monoclonal expression of IgG/lambda and a monoclonal rearrangement of the JH chain. The same clone was also present in the peripheral blood. Although high-grade lymphoma could not be excluded, the patient's parents insisted on the patient's leaving the hospital with only antibiotic treatment. Surprisingly, the giant lymphadenopathy completely resolved within 7 weeks, and the clone was no longer detectable in the peripheral blood. Twelve months later the patient was still free from lymphoma and was doing well. Retrospectively, transient monoclonal B-cell populations could be identified in an archival frozen blood sample taken when the patient was 3 years old. Increased FAS-independent spontaneous apoptosis was a feature of the patient's lymphocytes and could be the molecular basis for self-elimination of B-cell clones. We conclude that the diagnosis of a FAS-FAS-L deficiency should be considered in children with an otherwise unexplained atypical lymphoproliferation and that a diagnosis of lymphoma in patients with functional FAS deficiency should be made with considerable reservation.

Anti-Bacterial Agents↗
PubMed1999

Recognition, diagnosis, and management of heparin-induced thrombocytopenia and thrombosis.

This case report describes a post-coronary artery bypass graft patient who developed arterial thrombosis and loss of a dominant hand as a result of the common and serious immune complication of heparin anticoagulation, heparin-induced thrombocytopenia and thrombosis. This report underscores the need for all surgeons who use heparin in the course of their practice to be aware of heparin-induced thrombocytopenia and the spectrum of its clinical presentations and management. Thrombocytopenia or thrombosis that occurs in a patient receiving heparin should prompt a surgeon to stop all heparin as soon as possible and seek appropriate hematologic consultation. Because heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis are mainly clinical diagnoses, one should not wait for objective test confirmation of heparin-induced thrombocytopenia before stopping all heparin treatment. Alternative anticoagulation, other than low molecular weight heparin, must be considered for the patient who develops either condition. For surgeons who perform hand surgery, it is necessary to be aware of the significance of upper extremity thrombosis in a patient who is receiving heparin when consulted for surgical management.

Angina, Unstable↗
PubMed1999

Patient discomfort following pectoral defibrillator implantation using conscious sedation.

BACKGROUND: The miniaturization of implantable cardioverter defibrillators (ICDs) has made pectoral implantation possible. However, postoperative pain following the procedure has not been systematically studied. The aim of the current study was to prospectively assess patient discomfort and identify factors influencing pain perception during follow-up. METHODS: Pain related to device implantation was quantified in 21 consecutive patients (age, 61 +/- 11 years; 17 men and 21 women; 16 of 21 had coronary artery disease; left ventricular ejection fraction, 32% +/- 15%) undergoing pectoral ICD implantation with conscious sedation (fentanyl 118 +/- 72 micrograms midazolam 14 +/- 9 mg). Patients completed the Visual Analogue Scale (VAS, 0-100) and the McGill Pain Questionnaire 24 hours and 1 month postoperatively. Regression analysis was used to define clinical and procedure related variables affecting patient discomfort and frequency of postoperative analgesic use. RESULTS: The mean VAS score was 34 +/- 20 24 hours postoperatively. A single (4.8%) patient described postoperative pain as severe. Pain was reported to be moderate by 10 (47.6%) patients and mild by 10 (47.6%) patients. Intraoperative fentanyl requirement was a predictor of postoperative pain (R = 0.51, P = 0.036), and procedural duration was a strong predictor of postoperative analgesic use (R = 0.75, P < 0.001). Pain at 1 month decreased to a VAS score of 19 +/- 18 (P = 0.002 vs 24 hours) and was rated to be severe, moderate, and mild by 1, 3, and 17 patients, respectively. Late pain was related to a VAS score at 24 hours (R = 0.67, P = 0.004). CONCLUSIONS: (1) Pectoral ICD implantation using conscious sedation is well tolerated. (2) Postoperative discomfort correlates with longer procedural times and larger intraoperative narcotic requirements.

Adult↗
PubMed1999

Pathological aspects of malignant and benign thymic disorders.

A WHO committee recently defined criteria for distinguishing between thymic epithelial tumours (TET) and classified them as type A, AB, B1-3 and C thymomas. As the terminology for each WHO type is still controversial, it is recommended to use also other names in addition to the WHO classification to allow comparability of future clinicopathological studies. We consider type A and AB thymomas (medullary and mixed thymomas) clinically benign, whereas type B1-3 thymomas (predominantly cortical and cortical thymomas and well-differentiated thymic carcinomas) are of low-grade malignant potential and most type C thymomas (category II malignant thymomas) are highly malignant. Not yet approved by the WHO are the recently described 'thymoma with pseudosarcomatous stroma' and the 'low-grade metaplastic carcinoma of the thymus', which are considered as benign or low-grade malignant tumours, respectively. Thymic pathology frequently occurs in myasthenia gravis (MG). Production of autoantibodies against the acetylcholine receptor results from an antigen-driven immune reaction that starts inside the thymus, is maintained there but spreads to extrathymic sites already during the early phase of MG. Paraneoplastic MG occurs only in type A, AB and B1-3 thymomas. Abnormal TET microenvironments trigger nontolerogenic T-cell selection by neoplastic epithelial cells. Only after export of substantial numbers of naive, potentially autoreactive T cells to extratumorous sites does T-cell activation outside the thymoma initiate the autoimmune process. Early surgery after onset of MG is essential in thymitis to prevent substantial export of autoreactive T cells from the inflamed thymus to extrathymic organs, and it usually alleviates MG symptoms. In thymoma, 'dissemination' of autoreactive T cells to extratumorous sites has already continued for many months or even years before emergence of symptoms of MG. Therefore, thymoma surgery is aimed against oncological and local cardiovascular complications and rarely succeeds in alleviating symptoms of MG.

Carcinoma↗
PubMed1998

4'-Acylated thymidine 5'-triphosphates: a tool to increase selectivity towards HIV-1 reverse transcriptase.

4'-Acylated thymidines represent a new class of DNA chain terminators, since they have been shown to act as post-incorporation chain-terminating nucleotides despite the presence of a free 3'-hydroxyl group. Here, we describe the action of the 4'-acetyl- (MeTTP) and 4'-propanoylthymidine 5'-triphosphate (EtTTP) on HIV-1 reverse transcriptase in RNA- and DNA-dependent DNA synthesis and on DNA synthesis catalyzed by the cellular DNA polymerases alpha, beta, delta and epsilon. MeTTP exhibits a high selectivity towards HIV-1 reverse transcriptase. By the use of the bulkier propanoyl group as the 4'-substituent of the nucleoside 5'-triphosphate, selectivity towards HIV-1 reverse transcriptase could be increased without affecting substrate efficiency. Thus, 4'-modifications may serve as a tool to increase selectivity towards HIV-1 reverse transcriptase.

Acylation↗
PubMed1998

Image reconstructions of microtubules decorated with monomeric and dimeric kinesins: comparison with x-ray structure and implications for motility.

We have decorated microtubules with monomeric and dimeric kinesin constructs, studied their structure by cryoelectron microscopy and three-dimensional image reconstruction, and compared the results with the x-ray crystal structure of monomeric and dimeric kinesin. A monomeric kinesin construct (rK354, containing only a short neck helix insufficient for coiled-coil formation) decorates microtubules with a stoichiometry of one kinesin head per tubulin subunit (alpha-beta-heterodimer). The orientation of the kinesin head (an anterograde motor) on the microtubule surface is similar to that of ncd (a retrograde motor). A longer kinesin construct (rK379) forms a dimer because of the longer neck helix forming a coiled-coil. Unexpectedly, this construct also decorates the microtubule with a stoichiometry of one head per tubulin subunit, and the orientation is similar to that of the monomeric construct. This means that the interaction with microtubules causes the two heads of a kinesin dimer to separate sufficiently so that they can bind to two different tubulin subunits. This result is in contrast to recent models and can be explained by assuming that the tubulin-kinesin interaction is antagonistic to the coiled-coil interaction within a kinesin dimer.

Animals↗
PubMed1998

13C tracer experiments and metabolite balancing for metabolic flux analysis: comparing two approaches

Conventional metabolic flux analysis uses the information gained from determination of measurable fluxes and a steady-state assumption for intracellular metabolites to calculate the metabolic fluxes in a given metabolic network. The determination of intracellular fluxes depends heavily on the correctness of the assumed stoichiometry including the presence of all reactions with a noticeable impact on the model metabolite balances. Determination of fluxes in complex metabolic networks often requires the inclusion of NADH and NADPH balances, which are subject to controversial debate. Transhydrogenation reactions that transfer reduction equivalents from NADH to NADPH or vice versa can usually not be included in the stoichiometric model, because they result in singularities in the stoichiometric matrix. However, it is the NADPH balance that, to a large extent, determines the calculated flux through the pentose phosphate pathway. Hence, wrong assumptions on the presence or activity of transhydrogenation reactions will result in wrong estimations of the intracellular flux distribution. Using 13C tracer experiments and NMR analysis, flux analysis can be performed on the basis of only well established stoichiometric equations and measurements of the labeling state of intracellular metabolites. Neither NADH/NADPH balancing nor assumptions on energy yields need to be included to determine the intracellular fluxes. Because metabolite balancing methods and the use of 13C labeling measurements are two different approaches to the determination of intracellular fluxes, both methods can be used to verify each other or to discuss the origin and significance of deviations in the results. Flux analysis based entirely on metabolite balancing and flux analysis, including labeling information, have been performed independently for a wild-type strain of Aspergillus oryzae producing alpha-amylase. Two different nitrogen sources, NH4+ and NO3-, have been used to investigate the influence of the NADPH requirements on the intracellular flux distribution. The two different approaches to the calculation of fluxes are compared and deviations in the results are discussed. Copyright 1998 John Wiley & Sons, Inc.

Journal Article↗
PubMed1998

Interaction of monomeric and dimeric kinesin with microtubules.

The binding stoichiometry of kinesin to microtubules was determined using several biochemical and biophysical approaches (chemical crosslinking, binding assays, scanning transmission electron microscopy (STEM), image reconstruction, and X-ray scattering). The results show that each tubulin dimer associates with one kinesin head, irrespective of whether kinesin occurs in a monomeric or dimeric form in solution. Moreover, these heads appear to align along the protofilament axis generating a 16 nm periodicity of successive kinesin dimers. This is consistent with a "tightrope" model of movement where the first head of the dimer provides a guiding signal for the following one.

Animals↗
PubMed1998

The coiled-coil helix in the neck of kinesin.

Kinesin is a microtubule-dependent motor protein. We have recently determined the X-ray structure of monomeric and dimeric kinesin from rat brain. The dimer consists of two motor domains, held together by their alpha-helical neck domains forming a coiled coil. Here we analyze the nature of the interactions in the neck domain (residues 339-370). Overall, the neck helix shows a heptad repeat (abcdefg)n typical of coiled coils, with mostly nonpolar residues in positions a and d. However, the first segment (339-355) contains several nonclassical residues in the a and d positions which tend to weaken the hydrophobic interaction along the common interface. Instead, stabilization is achieved by a hydrophobic "coat" formed by the a and d residues and the long aliphatic moieties of lysines and glutamates, extending away from the coiled-coil core. By contrast, the second segment of the kinesin neck (356-370) shows a classical leucine zipper pattern in which most of the hydrophobic residues are buried at the highly symmetrical dimer interface. The end of the neck reveals the structure of a potential coiled-coil "trigger" sequence.

Amino Acid Sequence↗
PubMed1998

Conformations of kinesin: solution vs. crystal structures and interactions with microtubules.

Recently, the molecular structures of monomeric and dimeric kinesin constructs in complex with ADP have been determined by X-ray crystallography (Kull et al. 1996; Kozielski et al. 1997 a; Sack et al. 1997). The "motor" or "head" domains have almost identical conformations in the known crystal structures, yet the kinesin dimer is asymmetric: the orientation of the two heads relative to the coiled-coil formed by their neck regions is different. We used small angle solution scattering of kinesin constructs and microtubules decorated with kinesin in order to find out whether these crystal structures are of relevance for kinesin's structure under natural conditions and for its interaction with microtubules. Our preliminary results indicate that the crystal structures of monomeric and dimeric kinesin are similar to their structures in solution, though in solution the center-of-mass distance between the motor domains of the dimer could be slightly greater. The crystal structure of dimeric kinesin can be interpreted as representing two equivalent conformations. Transitions between these or very similar conformational states may occur in solution. Binding of kinesin to microtubules has conformational effects on both, the kinesin and the microtubule. Solution scattering of kinesin decorated microtubules reveals a peak in intensity that is characteristic for the B-surface lattice and that can be used to monitor the axial repeat of the microtubules under various conditions. In decoration experiments, dimeric kinesin dissociates, at least partly, leading to a stoichiometry of 1:1 (one kinesin head per tubulin dimer; Thormählen et al. 1998a) in contrast to the stoichiometry of 2:1 reported for dimeric ncd. This discrepancy is possibly due to the effect of steric hindrance between kinesin dimers on adjacent binding sites.

Animals↗
PubMed1998

[Diagnostic value of stomach biopsy in comparison with surgical specimen in gastric B-cell lymphomas of the MALT type].

Diagnostic und therapeutic management of gastric lymphomas of the mucosa-associated lymphoid tissue type (MALT-type lymphomas) is often based exclusively on the evaluation of biopsy material. To evaluate the diagnostic value of gastric biopsies in gastric MALT-type lymphomas, biopsies--on average six per patient--and subsequent surgical specimens of 64 patients were compared at the Institute of Pathology, University of Würzburg. Tumor diagnosis and tumor gradind were assessed. Using biopsy specimens, primary gastric MALT-type lymphomas were correctly diagnosed by local pathologists in 69% of cases, but correctly graded as low-grade, high-grade or secondary high-grade lymphomas in only 41%. When immunohistochemistry and molecular biological techniques were applied in addition to conventional histology, diagnosis of gastric MALT-type lymphoma was achieved in biopsies in 95% of cases at the Institute of Pathology Würzburg, but correct grading in only 73%. In secondary high-grade MALT-type lymphomas, both components--the high-grade and the low-grade component--were identified in gastric biopsies in only 33% of cases. Diagnostic accuracy in gastric lymphomas based on biopsies is limited by biopsy artefacts, but improved by using immunohistochemistry and molecular biological techniques. Particularly in secondary high-grade MALT-type lymphomas the correct diagnosis is often missed when using biopsies, due to a low number of biopsy specimens.

Biomarkers, Tumor↗
PubMed1998

Epidemic Legionnaires' disease two decades later: old sources, new diagnostic methods.

In July 1995 we investigated a pneumonia outbreak in a Pennsylvania town. We conducted epidemiological and molecular microbiological studies to determine the outbreak source and interrupt transmission of disease. Legionnaires' disease (LD) was quickly identified by urine antigen testing, and a newly developed immunohistochemical stain confirmed nosocomial transmission to a hospital inpatient. LD was confirmed in 22 patients. Case-patients were more likely than controls to have been within 1,000 feet of the hospital (matched odds ratio, 21.0; 95% confidence interval, 2.9-368) during the 2 weeks prior to illness. Legionella pneumophila serogroup 1 (Lp-1) was isolated from hospital cooling towers (CTs) and rooftop air samples but not from hospital potable water or community CTs. Hospital CT and air Lp-1 isolates matched all five patient isolates by monoclonal antibody, arbitrarily primed polymerase chain reaction, and pulsed-field gel electrophoresis subtyping. Strategies to prevent LD must include minimizing transmission from CTs.

Adult↗
PubMed1998

Polymerase chain reaction-based diagnosis of rhabdomyosarcomas: comparison of fetal type acetylcholine receptor subunits and myogenin.

The diagnosis of rhabdomyosarcoma (RMS) is usually straight-forward when light microscopy and immunohistochemistry are used. However, tumors that exhibit a low degree of differentiation and small biopsies can lead to confusion. In such patients and for the detection of minimal (residual) disease, a polymerase chain reaction (PCR)-based approach would be a valuable diagnostic adjunct. This type of approach would be highly sensitive and should be free from the risk for contamination of the tumor sample with normal tissue. Because myogenin and the alpha and gamma subunit of the fetal type acetylcholine receptor (AChR) are specific immunohistochemical markers for RMS, their expression on the mRNA level in RMS, other childhood and adult tumors, and normal tissues was studied. Although the sensitivity of both approaches was 100% in embryonal and alveolar RMS, detection of myogenin mRNA was not specific for RMS but occurred in normal muscle and the majority of the other normal tissues and childhood tumors. Conversely, detection of fetal AChR mRNA as defined by an alpha/tau ratio of < 1 was encountered only in RMS and denervated muscle. The authors conclude that mRNA of the fetal type AChR but not myogenin is a highly specific and sensitive target for the PCR-based diagnosis of RMS.

Adolescent↗
PubMed1998

CD40 ligand and autoantigen are involved in the pathogenesis of low-grade B-cell lymphomas of mucosa-associated lymphoid tissue.

Low-grade MALT-type lymphomas are malignancies of mucosal marginal-zone B cells and preceded by reactive inflammatory lymphoid tissue. Experimental observations suggest that antigen and CD40 Ligand act during cognate T/B cell interaction and are crucial for germinal center B-cell maturation generating marginal-zone B cells. To investigate the mechanisms underlying the development of extranodal MALT-type lymphomas, the immunoglobulin receptor was sequenced and analyzed for antigen specificity using heterohybridoma technology. Furthermore, CD40 ligand expression was evaluated by immunohistochemistry and by semiquantitative RT-PCR, and ligand binding to the CD40 of tumor B cells was studied using the CD40 system. Hypermutations were found in low-grade lymphomas throughout CDR1-CDR3 suggestive of positive selection through their antigen receptor. Different VH families were used and more than 69% of tumor immunoglobulins bound different mucosal antigens. CD40L expression was found in the tumor marginal zone in substantial amounts. The in vitro proliferation response of all low-grade MALT-type lymphomas was dependent on anti-CD40-mediated signals and cytokines. Our data provide evidence that autoantigen as well as the CD40L expressed by activated nonneoplastic T cells may drive the evolution of low-grade MALT-type lymphomas either directly or by paracrine mechanisms and that antigen may contribute to lymphoma pathogenesis.

Animals↗
PubMed1998

Paraneoplastic autoimmunity in thymus tumors.

Autoimmune phenomena are more frequent in thymic epithelial tumors (TET) than in any other human tumor. Mysthenia gravis (MG) is by far the most common autoimmune disease in thymoma patients. MG is characterized by muscle weakness due to autoantibodies against the acetylcholine receptor (AChR), and CD4+ AChR-specific T cells play a pivotal role for the production of these autoantibodies. About 10% of MG patients have a thymoma and, interestingly, only such thymomas exhibit an MG association that maintains thymuslike morphological and functional features with respect to the homing and differentiation of immature T cells. Since AChR protein is not expressed in thymomas, the specificity of the autoimmunity in thymoma-associated MG is thought to be determined by nonreceptor proteins with AChR epitopes. Such proteins are overexpressed in cortical-type MG-associated thymomas, and medullary thymomas express these proteins at barely detectable levels. Aside from this quantitative difference, the pathogenesis of anti-AChR autoimmunity might be qualitatively different in these thymoma subtypes. Our findings suggest that an antigen-specific abnormal T-cell selection by cortical-type TET may contribute to the pathogenesis of paraneoplastic MG. In contrast, an abnormal (intratumorous) activation of autoreactive T cells may be operative in medullary thymomas.

Adolescent↗
PubMed1998

[Comparison of the transcription of the fetal type acetylcholine receptor and myogenin in rhabdomyosarcoma].

Myogenin and the fetal type acetylcholine receptor (AChR) subunits are specific immunohistochemical markers for the diagnosis of rhabdomyosarcomas. In spite of light microscopy and immunohistochemistry, the diagnosis of doubtful cases and small biopsies of rhabdomyosarcomas remains a challenge. Therefore, a PCR-based highly sensitive approach, would be a valuable diagnostic adjunct and should be free from the risk of contamination of the tumor sample with normal tissue. We studied the transcription of myogenin and fetal type AChR in rhabdomyosarcomas, other childhood and adult tumors and normal tissues. In all embryonal and alveolar rahbdomyosarcomas transcripts of both myogenin and fetal type AChR could be detected. The detection of myogenin mRNA however was not specific for rhabdomyosarcomas but occurred in normal muscle and the majority of other normal tissues and childhood tumors. In contrast the transcription of fetal type AChR, which is defined by an alpha subunit AChR/gamma subunit AChR ratio < 1 was encountered only in rhabdomyosarcomas and denervated muscle. Therefore we suggest, that mRNA of the fetal type AChR but not myogenin is a highly specific and sensitive target for the PCR-based diagnosis of rhabdomyosarcomas.

Adult↗
PubMed1998

The fetal form of the acetylcholine receptor distinguishes rhabdomyosarcomas from other childhood tumors.

The fetal nicotinic acetylcholine receptor (AChR) of muscle is an oligomeric membrane protein with subunit composition alpha2betadeltagamma. After birth, the adult form, in which an epsilon-subunit replaces the gamma-subunit, predominates, and expression of the fetal form is limited to thymic myoid cells, extraocular muscles, and denervated striated muscle. We looked for expression of AChR in rhabdomyosarcomas and other childhood tumors by reverse transcription polymerase chain reaction and immunohistochemistry. mRNA for the AChR gamma-subunit was detected in all embryonal and alveolar rhabdomyosarcomas tested (n = 16) and in some tumors with a rhabdomyomatous component (n = 2) but not in other nonrhabdomyomatous tumors of childhood and adults (n = 45). The fetal form of the AChR was detected immunohistochemically in five of eight embryonal and four of eight alveolar rhabdomyosarcomas and in two Wilms' tumors with a rhabdomyomatous component but not in other tumors or in normal muscle. We conclude that reverse transcription polymerase chain reaction for AChR gamma-subunit could be useful for the diagnosis of rhabdomyosarcoma of childhood and for the detection of micrometastases and minimal residual disease. In addition, the fetal AChR protein is the first extracellular tumor marker that can distinguish rhabdomyosarcomas from nonrhabdomyomatous tumors and from normal muscle. Our findings, therefore, imply that the fetal AChR may be a target for in vivo imaging and, as AChR internalization and degradation is increased by antibody-induced cross-linking, may also provide a sensitive and specific target for immunotherapeutic strategies.

Adolescent↗