[Indications for heart transplantation].
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Age Factors↗
Biomedical subjects
M Hummel
Publications and source records attributed to M Hummel.
Origin of nodular lymphocyte-predominant Hodgkin's disease from a clonal expansion of highly mutated germinal-center B cells.
BACKGROUND: The atypical cells of nodular lymphocyte-predominant Hodgkin's disease, designated lymphocytic and histiocytic (L&H) cells, have a B-cell phenotype. To clarify the clonality of these cells, we studied rearranged immunoglobulin genes for the variable region of the heavy chain (V[H] genes) in individual L&H cells from 11 patients with nodular lymphocyte-predominant Hodgkin's disease. We also studied the expression of immunoglobulin light chains by those cells in six of the same patients. METHODS: Single CD20+ L&H cells were isolated from frozen sections by a technique of micromanipulation. The rearranged V(H) genes of these cells were amplified by the polymerase chain reaction (PCR), sequenced, and compared with germ-line V(H) genes. Immunoglobulin light-chain messenger RNA (mRNA) was detected by in situ hybridization. RESULTS: Of 615 L&H cells isolated from all the frozen sections, 160 yielded PCR products. In each of the 11 patients, the L&H cells that could be evaluated had identically rearranged V(H) genes, whether they were isolated from the same nodule, different nodules, or different blocks of tissue. All the V(H) sequences derived from the L&H cells were highly mutated (7.5 to 27.2 percent). In two cases the coding capacity of the V(H) genes was completely or partially disrupted by mutations. Intraclonal diversity was found in six cases, and monotypic immunoglobulin light-chain mRNA was found in six. CONCLUSIONS: The L&H cells of nodular lymphocyte-predominant Hodgkin's disease represent a monoclonal expansion of B cells. The high load of V(H) gene mutations and signs of intraclonal diversity suggest a relation between L&H cells and germinal-center B cells at the centroblastic stage of differentiation.
B-Lymphocytes↗
Identification of naturally processed T cell epitopes from glutamic acid decarboxylase presented in the context of HLA-DR alleles by T lymphocytes of recent onset IDDM patients.
Glutamic acid decarboxylase (GAD) has been defined as a major target antigen in insulin-dependent diabetes mellitus (IDDM). To identify the molecular ligands triggering a T cell response to GAD, a panel of human GAD65-specific T lymphocyte lines was generated from peripheral blood of three recent onset IDDM patients. All lines derived from a patient expressing the high-risk-conferring HLA-DR*0301/ *0401 haplotypes recognized a single epitope localized between amino acid positions 270 and 283 of GAD65, a stretch that is located in close proximity to the homology region shared with Coxsackie virus P2-C protein. All lines with this specificity were restricted to the DRA, B1*0401 product of the DR4 haplotype. Analysis of the GAD-specific T cell response in a second patient homozygous for DR4 haplotypes demonstrated that the same DRA, B1*0401 allele selected T cells specific for a different determinant. The T cell response profile in a third patient showed that DR*1501/ *1601-encoding haplotypes could present at least three different epitopes to GAD65-specific T lymphocytes. One of these epitopes was presented by a DR allele associated with the resistance-conferring DRB1*1501 haplotype. GAD-specific T cell lines could not be isolated from HLA class II-matched normal individuals. Our data reveal that (a) the T cell response to GAD65 is quite heterogenous in recent onset IDDM patients; (b) HLA-DR, not DQ, seems to be the principal restriction element used by T cells present at the onset of the disease; and (c) T cells responding to epitopes containing identical sequences to Coxsackie virus P2-C protein were not detected.
Alleles↗
Elongation of N-acetyllactosamine repeats in diantennary oligosaccharides.
Glycosylated [Asn22]lysozyme has been shown to contain N-acetyllactosamine repeats when expressed in chinese hamster ovary (CHO) cells. We find that the major portion of N-acetyllactosamine repeats are associated with diantennary oligosaccharides. In Lec2 CHO cells, which are deficient in sialylation, glycosylated lysozyme is synthesized with increased contents of N-acetyllactosamine repeats terminating in beta-galactosyl residues. In the Lec2 cells and the parental CHO cell line, Pro 5, only a minor portion of the oligosaccharides in lysozyme are of the triantennary type. Previously, it has been shown that the synthesis of N-acetyllactosamine repeats in Asn-linked oligosaccharides is enhanced by an increase in the activity of the elongating beta-N-acetylglucosaminyl transferase and by the synthesis of beta-1,6-linked antennae. The results with glycosylated lysozyme suggest that glycoproteins bearing diantennary oligosaccharides can contain several N-acetyllactosamine repeats and that the number of the latter can be increased by decreasing the activity of the capping sialyl transferases.
Amino Sugars↗
Strict lymphotropism of Epstein-Barr virus during acute infectious mononucleosis in nonimmunocompromised individuals.
Previous investigations of exfoliated oropharyngeal cells from individuals suffering from infectious mononucleosis (IM) suggested that the oropharyngeal epithelia are the primary target and also the site of life-long persistence of the Epstein-Barr virus (EBV). This concept was widely accepted. However, the investigation of histological sections with more sensitive EBV detection techniques has drawn this concept into doubt since EBV proved to be constantly absent in normal epithelial cells. To elucidate the discrepancy, throat washings and peripheral mononuclear blood cells from 16 patients suffering from IM were investigated for EBV-DNA and EBV gene products employing highly sensitive in situ hybridization, immunocytochemistry, and polymerase chain reaction. Although all patients exhibited latently infected B lymphocytes in peripheral blood, samples of exfoliated oropharyngeal cells were constantly EBV-negative with the exception of three cases. In these cases, the patients additionally suffered from purulent ulcerating tonsillitis, EBV-infected B cells, but no EBV-infected epithelial cells were detectable. These findings support the view that recirculating lymphocytes of B-cell origin, but not epithelial cells are the initial target of EBV during primary infection and that B cells also represent the site of life-long viral persistence.
Adolescent↗
Plasmablastic lymphomas of the oral cavity: a new entity associated with the human immunodeficiency virus infection.
We report here a series of 16 highly malignant diffuse large B-cell lymphomas of the oral cavity with unique immunohistologic features. Fifteen of these developed in human immunodeficiency virus-positive patients. All cases displayed morphologic features of diffuse large-cell lymphomas but strikingly differed from them in that they showed a minimal or absent expression of the leukocyte common antigen as well as of the B-cell antigen CD20. Instead, the tumor cells showed a constant reaction with the plasma cell characteristic antibody VS38c and a frequent reaction with the CD79a antibody. This, in conjunction with a variable expression of cytoplasmic Ig and a monoclonal rearrangement of the Ig heavy chain gene in all of the three tested cases confirmed the B-cell nature, the clonal origin, and the plasmacellular differentiation of these neoplasms. The majority of these tumors were negative for the BCL-6 protein, with the remaining cases showing only a partial and weak expression of this antigen. An association with the Epstein-Barr virus (EBV) was found in 9 of 15 tested cases showing abundant EBV-encoded nuclear RNA transcripts in the absence of EBNA-2. Five of the EBV-positive cases variably expressed LMP-1. We propose to name these tumors plasmablastic lymphomas, in accordance with their morphologic and immunohistologic features. Knowledge of this lymphoma entity is important to avoid confusion with nonlymphoid malignancies due to the lack of commonly used lymphoid markers.
Adult↗
Epstein-Barr virus-associated Hodgkin's disease: epidemiologic characteristics in international data.
Hodgkin's disease (HD) has long been suspected to have an infectious precursor, and indirect evidence has implicated Epstein-Barr virus (EBV), a ubiquitous herpesvirus, as a causal agent. Recent molecular studies using EBER in situ hybridization or latency membrane protein-I (LMP-I) immunohistochemistry have identified EBV latent infection in up to 50% of HD tumors. However, the epidemiologic features of these cases have not been examined in detail. To explore the epidemiology of EBV-positive HD so as to understand the role of EBV in HD etiology more clearly, this project accumulated patient data from 14 studies that had applied these EBV assays to HD tumors. With information on age at diagnosis, sex, ethnicity, histologic subtype, country of residence, clinical stage and EBV tumor status from 1,546 HD patients, we examined risk for EBV-positive disease using logistic regression. Forty percent of subjects had EBV-positive tumors, and EBV prevalence varied significantly across groups defined by the study variables. Odds ratios (OR) for EBV-associated HD were significantly elevated for Hispanics vs. whites (OR = 4.1), mixed cellularity vs. nodular sclerosis histologic subtypes (OR = 7.3, 13.4, 4.9 for ages 0-14, 15-49, 50+ years), children from economically less-developed vs. more-developed regions and young adult males vs. females (OR = 2.5). These findings suggest that age, sex, ethnicity and the physiologic effects of poverty may represent biologic modifiers of the EBV association and confirm that this association is strongly but variably linked to histologic subtype. The data augment biologic evidence that EBV is actively involved in HD pathogenesis in some cases but describe epidemiologic complexity in this process.
Adolescent↗
Human papillomavirus infection is not associated with bronchial carcinoma: evaluation by in situ hybridization and the polymerase chain reaction.
While a strong association between human papillomaviruses (HPVs) and squamous cell cancers of the female genital tract is known to exist, there is substantial controversy regarding the relationship of HPV with other non-genital carcinomas. Recently there have been some reports focusing on a possible association of HPVs with bronchial carcinomas. These studies mostly used either in situ hybridization (ISH) or the polymerase chain reaction (PCR). In view of these reports, 32 squamous cell carcinomas (SCCs) and six small cell carcinomas of the bronchus were examined for the presence of HPV DNA by both techniques: ISH using 35S-labelled, type-specific probes (HPV 6, 11, 16, 18), and PCR with consensus primers coding for more than 25 different HPV subtypes performed on formalin-fixed, paraffin-embedded material. None of the 38 bronchial carcinomas analysed was positive for HPV DNA, either by ISH or by PCR. On the other hand, additionally examined specimens of 15 cervical carcinomas were positive for HPV 16 DNA in at least three cases by ISH (20 per cent) and in 12 cases by PCR (80 per cent). We conclude that common HPV types do not play an important role in the pathogenesis of bronchial carcinoma.
Female↗
Disappearance of the Epstein-Barr virus in a relapse of Hodgkin's disease.
Hodgkin's disease (HD) is associated with the Epstein-Barr virus (EBV) in approximately half of cases. This is a report of a case of nodular sclerosing HD of the B-cell type that was associated with EBV in the initial manifestation, but was found to be EBV-negative in the relapse of the tumour. Both tumours displayed similar clinical, pathological, and immunohistochemical features. This finding implies that in a given individual EBV can be lost from malignant tumours and therefore shows that the EBV infection is not required to maintain neoplastic growth of HD tumour cells.
Antigens, Viral↗
Expression of vascular endothelial growth factor in lymphomas and Castleman's disease.
Vascular endothelial growth factor (VEGF) is one of the main angiogenic cytokines in human solid tumours and inhibition of VEGF-induced angiogenesis suppresses tumour growth. Some groups of malignant lymphoma, including peripheral T-cell lymphomas and Hodgkin's disease, are characterized by a conspicuous proliferation of small vessels. To test the hypothesis that VEGF may also be involved in the angiogenesis in lymphomas and other lesions of the lymphoid system, VEGF expression was analysed in tissues, employing in situ hybridization with a 35S-labelled RNA probe specific for this cytokine. Significant expression of VEGF transcripts was observed in Hodgkin's disease and peripheral T-cell lymphomas, particularly of the angioimmunoblastic type. In contrast, expression of this cytokine was minimal or absent in follicle centre lymphoma and chronic lymphocytic leukemia of B-cell type. VEGF was mainly observed in reactive non-lymphoid CD68-negative cells, which probably represent fibroblasts or myofibroblasts. In normal and ulcerated tonsils, VEGF was expressed in the squamous epithelium but only rarely found in the lymphoid tissue. Although infectious mononucleosis tonsils contained high numbers of VEGF-positive cells in the interfollicular zone, expression of this cytokine was not found in Epstein-Barr virus (EBV)-infected cells, as determined by simultaneous in situ hybridization for VEGF and EBV-encoded small nuclear RNAs (EBER). In 5/8 cases of Castleman's disease, germinal centres containing small vessels also showed expression of VEGF, in contrast to normal tonsillar germinal centres which are devoid of both vessels and VEGF transcripts. It is concluded that VEGF may be involved in the induction of the angiogenesis of both peripheral T-cell lymphomas and Hodgkin's disease, but not in low-grade B-cell lymphomas. In contradistinction to solid tumours, in which this cytokine is commonly secreted by the tumour cells themselves, in malignant lymphoma VEGF is not a product of neoplastic cells. Vascularization of germinal centres in Castleman's disease may also be a consequence of abnormal local expression of VEGF.
Castleman Disease↗
[Temporary mechanical left heart support. Recovery of heart function in patients with end-stage idiopathic dilated cardiomyopathy].
BACKGROUND: Implantation of a mechanical cardiac support system (MCSS) in patients with idiopathic dilated cardiomyopathy (IDC) may improve cardiac function and allow explantation of the device. Our experience now includes 13 patients who have been "weaned" from MCSS and we report about the overall results of this treatment as well as the effects of ventricular unloading on cardiac function, anti-beta 1-adrenoceptor-autoantibody (A-beta 1-AAB) level and the degree of myocardial fibrosis. METHODS: 13 patients with non-ischemic IDC who had been admitted here in cardiogenic shock (CI < 1.61.min-1.m2, left ventricular ejection fraction [LVEF] < 16% and left ventricular internal diameter in diastole [LVIDd] > 68 mm) and who all tested positive for A-beta 1-AABs were implanted with an uni-(12 patients) or a biventricular (1 patient) mechanical assist device. Echocardiographic evaluation and A-beta 1-AAB-level-monitoring was routinely performed after implantation and explantation of the MCSS and the degree of myocardial fibrosis was assessed at the time of implantation and after explantation. RESULTS: During a mean duration of mechanical support of 236 +/- 201 days (range: 30 to 794 days), LV-EF improved to a mean of 46% and LVIDd decreased to a mean value of 56 mm in these 13 patients. A-beta 1-AABs decreased and disappeared 11.7 weeks after implantation of the device and did not reincrease thereafter. The highly pathologic degree of fibrosis at the time of implantation diminished to normal values about 1 year after explantation. One patient died of anesthesiologic complications and another patient shortly presented with a new episode of cardiac insufficiency 6 months after explantation. He was implanted again with an univentricular assist device was successfully transplanted 3 weeks later. Mean observation period of the remaining 11 patients now amounts to 12.6 +/- 9.77 (range: 3 to 26) months after explantation of the device--as of May, 31, 1997--with a cumulative observation period of 139 patient months. CONCLUSION: Temporary implantation of a MCSS may normalize cardiac function in selected patients with IDC. The striking degree of myocardial fibrosis can reduce to normal values after explantation of the device. A-beta 1-AABs disappear during ventricular unloading and do not increase thereafter. "Weaning" from mechanical device may constitute an alternative treatment to cardiac transplantation in selected patients.
Adult↗
[Acute graft versus host disease (GvHD) after heart-lung transplantation].
We report on a 28 year old woman with congenital ventricle-septum defect and Eisenmenger-reaction who developed acute GvHD on 10th postoperative day after successful heart-lung transplantation. The patient died on the 34th postoperative day of dissociated brain death after intracerebral bleeding.
Acute Disease↗
Status of patients presently living 9 to 13 years after orthotopic heart transplantation.
BACKGROUND: Heart transplantation has a dramatic impact on both life expectancy and quality of life in patients with terminal heart failure. The aim of the study was to evaluate psychologic, social, occupational, and somatic status of patients living long-term, 9 to 13 years after orthotopic heart transplantation. PATIENTS AND METHODS: Seventy-seven of 182 patients who received transplants between July 1983 and January 1988 in Hannover (1983-1985; n = 69 patients) and Berlin (1986-1988; n = 113 patients) have survived up to now, 9 to 13 years after transplantation (mean, 10 years 4 months). The patients and their medical records (eg, cardiac catheter studies, echocardiography) were examined to assess their somatic status. Psychologic, social, and occupational status and quality of life data were assessed by combination of self-rating questionnaires (the Short Form Health Survey Questionnaire, Giessener Beschwerdebogen [the Giessen Subjective Complaints List], the Sickness Impact Profile, and the Hospital Anxiety and Depression Scale) and semistructured interviews. RESULTS: Ninety-one percent of the patients were in New York Heart Association functional class I (70%) or II (21%). The results of the psychologic investigation revealed a definite impact of the side effects of chronic immunosuppression; however, overall, the quality of life rating was within the normal range. Sixty-seven (86%) patients were married, 51 (66%) patients were retired, 17 (22%) worked full-time or part-time, and 9 (12%) were housewife or houseman. Four male patients have fathered five healthy children 1 to 10 years after the transplantation. More than 75% of the patients had normal systolic ventricular function (mean left ventricular ejection fraction, 0.63). Coronary angiograms were normal or with minor wall irregularities in 86% (n = 66 patients), and revealed severe obstructions in 14% (n = 11). Normal function of all valves was found in one-third of the patients, tricuspid valve incompetence was not found or was insignificant in 87% (n = 67 patients) and severe in 8% (n = 10). Six patients had undergone tricuspid valve replacement, invariably for structural valve defects attributable to biopsy injuries. Fifty-eight patients (75%) exhibited various degrees of compensated renal insufficiency, 7 of them were on chronic hemodialysis, and 2 patients have undergone kidney transplantation. Hepatic function was normal in 68% (n = 52) of the patients, and 1 patient has developed liver cirrhosis. Osteoporosis was diagnosed of the discrete form in 7 (9%) and of a significant degree in 24 patients (31%); 38.5% (n = 30) complained of symptoms of polyneuropathy. CONCLUSIONS: The patients surviving 9 to 13 years after orthotopic heart transplantation are mostly in good physical status, the quality of life is comparable to the general population, and only a few of them have significantly limited in their life style. They do show the substantial chronic side effects of long-term immunosuppression, remaining treatment-dependent for a lifetime.
Adolescent↗
Acute graft-versus-host disease after human heart-lung transplantation: a case report.
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Acute Disease↗
Cutaneous involvement in prelymphomatous angioimmunoblastic lymphadenopathy.
We describe prelymphomatous angioimmunoblastic lymphadenopathy with cutaneous involvement in a 73-year-old female patient. A maculopapular skin eruption was the first sign of the disease. Skin histology showed extensive perivascular and periadnexal mixed lymphoid infiltrates including centroblasts and immunoblasts with a high proliferative index and with focal erythrocyte extravasation. Lymph node histology confirmed the diagnosis, showing nearly complete effacement of the follicular architecture, a mixed lymphoid infiltrate, and numberous high endothelial venules in an expanded T-cell zone. Immunohistochemistry, however, demonstrated preservation of at least some follicular structures. T-cell receptor gene rearrangement analysis revealed oligoclonal patterns in both lymph node and skin specimens. In contrast, immunoglobulin heavy-chain gene rearrangement analysis revealed a polyclonal pattern. Accordingly, the disease was classified as a prelymphomatous stage of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) with specific involvement of both lymph node and skin. The patient was treated with high-dose corticosteroids, and long-lasting remission was induced. In contrast to our case, most reported cases of AILD show a monoclonal T-cell pattern indicating AILD-type lymphoma. Therefore we discuss the concept of prelymphomatous AILD developing into AILD-type lymphoma. Persistence of some antigenic stimulus may induce the proliferation of a monoclonal population of lymphoid cells from a polyclonal background in a multistep fashion. Proper treatment of AILD at an early, prelymphomatous stage may protract or inhibit development of full-blown, fatal AILD-type lymphoma.
Aged↗
Intestinal taurine availability from synthetic amino acid-taurine conjugates: an in vitro perfusion study in rats.
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Journal Article↗
Uniform expression of cytotoxic molecules in anaplastic large cell lymphoma of null/T cell phenotype and in cell lines derived from anaplastic large cell lymphoma.
We recently provided ample evidence that anaplastic large cell lymphomas of T/null phenotype (T-/null-ALCL) genotypically represent peripheral T cell lymphomas which in up to 90% have a phenotype of cytotoxic cells with expression of granzyme B protein and perforin transcripts. However, the issue of granzyme B expression in T-/null-ALCL is still controversial due to differing results from another laboratory. To verify our earlier immunohistochemical stainings for granzyme B, we looked for granzyme B transcripts by in situ hybridization (ISH). In addition, we investigated our previously analyzed cases by immunohistology (IH) with another antibody (2G9), which reacts with two molecules known to be expressed in cytotoxic cells: T-cell-restricted intracellular antigen (TIA)-1 and granule membrane protein-17 (GMP-17). We also extended our studies to homogenous tumor cell populations provided by ALCL-derived cell lines. As evidenced by ISH, transcripts for perforin, TIA-1 and granzyme B were found in all ALCL-derived cell lines. Similarly, proteins of TIA-1/GMP-17, granzyme B and perforin were expressed in all of these lines as shown by IH. In biopsy specimens, TIA-1/GMP-17 were detected by IH in 14/16 cases of T-/null-ALCL, and granzyme B transcripts were found in 13/13 T-/null-ALCL cases, but not in 6 B-ALCL cases. The detection of granzyme B transcripts yielded results largely identical to those of IH for granzyme B protein, thus confirming our earlier data and suggesting that the regulation of the expression of this molecule largely occurs at the transcriptional level. Our data further confirm the almost uniform expression of cytotoxic molecules in both primary ALCL cases and ALCL-derived cell lines and therefore suggest that the derivation from cytotoxic T cells may be the unifying characteristic for T-/null-ALCL.
Cytotoxicity, Immunologic↗
Reappraisal of indispensable amino acids. Design of parenteral synthetic dipeptides: synthesis and characterization.
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Amino Acids↗