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Biomedical subjects

M Hummel

Publications and source records attributed to M Hummel.

At least 199 records · Page 11Linked to original sources
PubMed1996

A novel interleukin-12 p40-related protein induced by latent Epstein-Barr virus infection in B lymphocytes.

We have isolated a cDNA encoding a novel hematopoietin receptor family member related to the p40 subunit of interleukin-12 and to the ciliary neurotrophic factor receptor, whose expression is induced in B lymphocytes by Epstein-Barr virus (EBV) infection. This gene, which we have designated EBV-induced gene 3 (EBI3), encodes a 34-kDa glycoprotein which lacks a membrane-anchoring motif and is secreted. Despite the absence of a membrane-anchoring motif and of cysteines likely to mediate covalent linkage to an integral membrane protein, EBI3 is also present on the plasma membrane of EBV-transformed B lymphocytes and of transfected cells. Most newly synthesized EBI3 is retained in the endoplasmic reticulum in an endoglycosidase H-sensitive form associated with the molecular chaperone calnexin and with a novel 60-kDa protein. EBI3 is expressed in vivo by scattered cells in interfollicular zones of tonsil tissue, by cells associated with sinusoids in perifollicular areas of spleen tissue, and at very high levels by placental syncytiotrophoblasts. EBI3 expression in vitro is induced in EBV-negative cell lines by expression of the EBV latent infection membrane protein-1 and in peripheral blood mononuclear cells by pokeweed mitogen stimulation. EBI3 maps to chromosome 19p13.2/3, near genes encoding the erythropoietin receptor and the cytokine receptor-associated kinase, Tyk2. EBI3 synthesis by trophoblasts and by EBV-transformed cells and similarities to interleukin-12 p40 are compatible with a role for EBI3 in regulating cell-mediated immune responses.

Amino Acid Sequence↗
PubMed1996

Cellular immune response to diverse islet cell antigens in IDDM.

In IDDM, T-cells are postulated to mediate the destruction of pancreatic beta-cells. We analyzed peripheral blood mononuclear cell (PBMC) responses to human insulin, glutamate decarboxylase GAD65, tyrosine phosphatase ICA512, glucagon, membrane preparations of RIN cells and human pancreas, and three control antigens (La = nuclear cell antigen, tetanus toxoid, and phytohemagglutinin). A total of 28 patients with newly diagnosed IDDM, 9 antibody-positive (Ab+) first-degree relatives, and 16 healthy control subjects were included. Increased proliferative responses to pancreatic islet cell antigens were observed in diabetic patients and in Ab+ relatives compared with control subjects, whereas T-cell reactivity to nonpancreatic control antigens was similar between the study groups. The highest differences in the magnitude of proliferative responses were seen for ICA512, followed by membrane preparations of RIN cells, GAD65, and human pancreas. Few subjects reacted with insulin or glucagon. Interestingly, Ab+ relatives showed higher T-cell reactivity with respect to stimulation indexes and prevalences than newly diagnosed diabetic patients, and as many as 89% of Ab+ relatives showed proliferation to more than one islet cell antigen preparation in comparison to 43% of newly diagnosed diabetic patients and none of the control subjects. Statistical analysis revealed significant positive correlation of insulin autoantibody levels with the levels of insulin-specific T-cells in Ab+ relatives, but no relation of PBMC responses to age, sex, or HLA-DR haplotypes. Our results demonstrate the simultaneous existence of various autoreactive T-cells specific for islet cell antigens in the prediabetic period. These T-cells may play a significant role in the pathogenesis of the disease.

Adolescent↗
PubMed1996

The structures of the bovine and porcine proacrosin genes and their conservation among mammals.

Sperm acrosin is a serine protease that is involved in the recognition, binding and penetration of the sperm of the zona pellucida of the ovum. The bovine and porcine genes were cloned and characterized. Alignment of the intron/exon structure of both genes with the previously characterized human, rat and mouse genes and with other serine protease genes reveals that the coded sequence of the mammalian proacrosin is distributed in 5 exons and the splice junction types are identical to the exons encoding the catalytic domain of other serine protease genes. A comparison of the bovine, porcine, human, guinea pig, rabbit, rat and mouse preproprotein sequences shows that the catalytic domain is highly conserved, while the sequence of the proline rich domain is very variable among the species, ranging from 28.9% to 68.8%.

Acrosin↗
PubMed1996

Low incidence of Epstein-Barr virus presence in primary cutaneous T-cell lymphoproliferations.

Multiple biopsies taken from 76 European human immunodeficiency virus (HIV)-negative patients with primary cutaneous T-cell lymphoproliferations, including mycosis fungoides (MF), pleomorphic T-cell lymphoma (PMTCL), anaplastic large cell lymphoma (ALCL) and lymphomatoid papulosis (LyP) were investigated for the presence of Epstein-Barr virus (EBV) through a combined approach. Polymerase chain reaction (PCR) was employed for EBV-DNA detection, in situ hybridization (ISH) for cellular localization of EBV-encoded nuclear RNAs (EBER1 and EBER2) and immediate early Bam H-fragment; lower frame (BHLF) RNA, and immunohistology (IH) for the identification of EBV-encoded latent membrane protein 1 (LMP1) and of nuclear antigen (EBNA) 2 expression. EBV-DNA was detectable by PCR in 15 of 76 cases (19.7%). EBER-ISH combined with IH identified a variable, usually very low, number of infected neoplastic cells in only seven of the 15 EBV-DNA-harbouring cases. This discrepancy between the results obtained with PCR and ISH is apparently caused by the low number of the infected cells per tissue section. The PMTCL entity produced the greatest number of positive cases, whilst ALCL and LyP cases were almost constantly devoid of the virus. BHLF transcripts were not detectable in any case, nor did any of the EBER-positive cells show an LMP1 or EBNA2 expression. These data show that primary cutaneous T-cell lymphoproliferations display an infrequent association with a latent EBV infection and that the pathogenic role of the virus in the positive cases remains obscure as the virus frequently infects only a minority of the atypical cells.

DNA, Viral↗
PubMed1996

Mycotic aortic aneurysms after orthotopic heart transplantation: a three-case report and review of the literature.

Mycotic aortic aneurysm is a rare yet life-threatening complication after orthotopic heart transplantation. This article reviews three cases of mycotic aortic aneurysm in heart transplant recipients developing in the first year after heart transplantation. Excision of the aneurysm and in situ reconstruction of the ascending aorta were performed with a patch of glutaraldehyde-fixed pericardium or cryopreserved aortic allograft material as a patch or conduit replacement. These cases show that early diagnosis by computed tomographic scanning, surgical treatment, high-dose parenteral antibiotics, and close follow-up are essential for successful treatment.

Adult↗
PubMed1996

Presence of clonal T-cell receptor gene rearrangements provides evidence of widespread intramucosal intestinal T-cell lymphoma.

Intestinal T-cell lymphoma (ITCL) is a rare type of extranodal lymphoma derived from intraepithelial T-cells and generally exhibits macroscopically evident ulcerated lesions of the bowel wall composed of pleomorphic tumor cells. We report immunophenotypic and molecular genetic findings in an unusual small-sized intramucosal type of ITCL observed in a 74-year-old man presenting with enteropathy. Biopsies obtained from duodenum and jejunum showed a conspicuous accumulation of small-sized lymphoid cells forming intraepithelial clusters. The predominantly intraepithelial spread was accompanied by a spilling over to the lamina propria but not to deeper layers of the duodenal and jejunal wall, thus resulting in a purely intramucosal manifestation. This growth pattern and the immunophenotypic profile (CD3+, CD4-, CD8+, CD103+) suggested that the lesion may fall in the spectrum of ITCL. However, since the lymphoid cells cytomorphologically lacked neoplastic features and showed a small growth fraction. a reliable diagnosis of malignant lymphoma could not be established by histological and immunohistochemical methods. In this case a tissue-based polymerase chain reaction (PCR) analysis of T-cell receptor (TCR) beta and gamma gene rearrangements proofed to be essential in confidently distinguishing multifocal monoclonal intramucosal T-cell lymphocytosis from an intense reactive inflammatory infiltrate in celiac disease (CD). Our observation highlights that detection of clonal rearrangements of TCR genes is particularly useful in detecting ITCL composed of cytomorphologically innocuous T-cells because histologic diagnosis in such cases is at best presumptive.

Aged↗
PubMed1996

Blood contact with artificial surfaces during BVAD support.

Persistently elevated levels of cytokines (IL-6, IL-8) during the course of mechanical circulatory support correlated well with fatal outcome. To determine the influence of blood/artificial surface interaction on the chronic inflammatory process, we studied the biocompatibility of silicone and polyurethane membranes in vitro. Cultures of isolated mononuclear cells or whole blood were incubated for 24 hours in tubes coated with silicone or polyurethane, both used in the construction of ventricular assist systems. Concentrations of several inflammatory mediators were measured in the supernatant. Our results can be summarized as follows: a) Monocytes were stimulated to release inflammatory cytokines like IL-8 and MIP-1 alpha, particularly when silicone was involved; b) Both silicone and polyurethane stimulated thrombocytes thus resulting in the release of P-Selectin and PDGF-AB, although polyurethane was a stronger stimulus; c) Moderate complement activation was triggered by contact with either of the artificial surfaces. However, the prevention of most of these effects by coating the artificial surface with protein and the lack of correlation between in vitro data and serum levels of IL-6 and IL-8 during the course of circulatory support suggest that the persistence of inflammatory cytokines during BVAD support is not caused by blood/surface interaction.

Adolescent↗
PubMed1996

[Inflammatory mediators in patients with biventricular assist device systems].

We studied the plasma levels of TNF-alpha, IL-6, IL-8 and soluble adhesion molecules (sE-Selectin, sL-Selectin, sVCAM-1) immediately before and during mechanical circulatory support with a Biventricular Assist Device System (BVAD-"Berlin Heart") in comparison to patients with chronic heart failure (NYHA classes II/III) and patients with coronary artery disease with normal ventricular function. Additionally, the biocompatibility of the membranes used in the "Berlin Heart" was tested in vitro. IL-6 and IL-8 but not TNF-alpha could only be detected in patients with cardiogenic shock immediately before starting circulatory support. Furthermore, plasma concentrations of soluble adhesion molecules were statistically significantly elevated in patients with cardiogenic shock compared to patients with coronary artery disease. This picture of a systemic inflammatory response syndrome without significant level of TNF-alpha looks quite similar to that seen in patients following trauma and severe operations. During mechanical circulatory support plasma levels of cytokines and soluble adhesion molecules dropped to low levels in patients, who were successfully maintained on BVAD. By contrast, we have found persistently elevated levels of these mediators in patients with fatal outcome. This seems not to be the result of individual distinct response of blood cells to contact with the artificial surfaces of the device. In summary, our data suggest the development of a systemic inflammatory response syndrome may be due to hypoxia during cardiogenic shock. Persistence of systemic inflammation suggests failing of the mechanical support. Therefore, the monitoring of inflammatory mediators may be relevant as a prognostic marker in these patients (disappearance of peripheral hypoxia).

Adult↗
PubMed1996

[Evaluating physical fitness after unilateral lung transplantation with ergometry and blood gas analysis].

7 patients aged 30-56 years with the perception of subjective increased fitness 4-22 months after single lung transplantation were tested for the objective benefit. Using a standardized ergometric test protocol cardiopulmonary parameters (ventilation, blood gases, gas exchange, blood pressure, ECG) were measured 5 males and 2 females. After transplantation in all patients the objective fitness was increased by 30-60 watts and the blood gases were markedly improved. The physical fitness of the subjects under study was probably limited by the reduced lung function of the native lung, the reduced mobility of the diaphragm in elderly patients and the impaired muscular strength and endurance.

Adult↗
PubMed1995

Hodgkin's disease with monoclonal and polyclonal populations of Reed-Sternberg cells.

BACKGROUND: There is strong evidence that Reed-Sternberg cells have a lymphoid phenotype, but clonally rearranged genes for B-cell and T-cell antigen receptors have not been demonstrable in tumor tissue from most patients with Hodgkin's disease. To elucidate this issue, we assayed single Reed-Sternberg cells from 12 patients with classic Hodgkin's disease of a B-cell immunophenotype to detect rearranged immunoglobulin variable-region heavy-chain (VH) genes. METHODS: We isolated single Reed-Sternberg cells from frozen sections that had been immunostained for CD30. The rearranged VH genes of these cells were amplified by the polymerase chain reaction and analyzed by gel electrophoresis and nucleotide sequencing. RESULTS: In all 12 patients, the Reed-Sternberg cells studied contained rearranged VH genes. Three patterns were observed: in three patients the rearrangements in each patient were identical, in six patients all the rearrangements were unrelated and unique, and in three patients both identical and unrelated rearrangements were detected. Apparently somatic mutations of VH genes were present in some Reed-Sternberg cells but absent in others. CONCLUSIONS: Reed-Sternberg cells with B-cell phenotypes have rearranged VH genes; therefore, these cells arise from B cells. The pattern of VH gene mutations suggests that Reed-Sternberg cells can correspond to either immunologically naive or memory B cells. In half our patients the population of Reed-Sternberg cells was polyclonal; in the other half, monoclonal or mixed cell populations were found. Correlation with the clinical stage suggests that polyclonal Hodgkin's disease can present as a widespread lymphoma.

Adolescent↗
PubMed1995

ALK gene products in anaplastic large cell lymphomas and Hodgkin's disease.

The translocation t(2;5)(p23;q35), discovered in CD30+ anaplastic large cell (ALC) lymphomas, creates a potentially oncogenic fusion gene, part of which is contributed by a novel tyrosine kinase, ALK. Absence of ALK expression from normal hematolymphoid cells provides a basis for the morphologic assessment of t(2;5). The distribution of the t(2;5) in ALC lymphomas and Hodgkin's disease (HD), as assayed by nonmorphologic methods, is controversial. We used in situ hybridization and/or immunohistology to show ALK gene products in 85 ALC lymphomas, 82 HD cases, 40 other lymphoproliferations, as well as in 6 HD- and 4 ALC lymphoma-derived cell lines. ALK gene products were restricted to t(2;5)-positive ALC lymphoma cell lines and tumor cells of 16 primary non-B cell, common-type ALC lymphomas. These were mainly from young patients with initial lymphonodal disease. ALK expression was not detectable in any other specimen, including all cases of HD and HD-like type ALC lymphoma as well as secondary ALC lymphomas. Full congruence was noted for labeling results obtained with both methods. In agreement with cytogenetic analyses, but at variance with recently published studies, ALK gene expression distinguishes a subset of ALC lymphomas from other CD30+ lymphomas, including HD. The results do not support concepts attributing a significant role to the t(2;5) in the development of HD.

Activin Receptors↗
PubMed1995

Association of kyphomelic dysplasia with severe combined immunodeficiency.

Kyphomelic dysplasia is a distinct, rare, skeletal dysplasia with short angulated femora, bowing of long bones, short ribs, narrow thorax, and metaphyseal abnormalities. While immune deficiency occurs in other short stature/short-limb skeletal dysplasias and cartilage-hair hypoplasia, it has not been described with kyphomelic dysplasia. We report on an infant with this disorder who had profound humoral and cellular immunologic abnormalities consistent with severe combined immune deficiency (SCID). The infant died at age 2 months of overwhelming cytomegalovirus pneumonia. Kyphomelic dysplasia, as with other short stature/short-limb skeletal dysplasias, can be associated with immune deficiency and immune function should be investigated when this disorder is identified.

Bone Diseases, Developmental↗
PubMed1995

Patterns of cytokine gene expression in peripheral T-cell lymphoma of angioimmunoblastic lymphadenopathy type.

Peripheral T-cell lymphoma of angioimmunoblastic lymph-adenopathy type (AILD-TCL) is histologically characterized by a mixed infiltrate of atypical T cells, B cells including B immunoblasts, and plasma cells, as well as eosinophilic granulocytes accompanied by proliferated high endothelial venules, while, clinically, fever and weight loss are often observed. These morphologic and clinical pecularities are widely believed to reflect abnormal patterns of cytokine expression. To evaluate this hypothesis, 11 lymph nodes with AILD-TCL were studied for the presence of tumor necrosis factor-alpha (TNF), lymphotoxin (LT), interleukin-6 (IL-6), and IL-1 beta transcripts by in situ hybridization (ISH) using [35S]-labeled cytokine-specific RNA probes in seven cases subsequent to immunohistology for cell type characteristic antigens. Expression of all four cytokines was strongly enhanced in AILD-TCL when compared with the control groups of lymphoblastic lymphomas and peripheral T-cell lymphomas, other than AILD-TCL. TNF and LT transcripts were present in atypical T cells and in a variable proportion of B immunoblasts in all AILD-TCL cases, whereas IL-6 and IL-1 beta specific transcripts were mainly found in nonlymphoid cells. To verify a possible cytokine expression by Epstein-Barr virus (EBV)-infected cells, which are frequently present in AILD-TCL, the detection of EBV-encoded nuclear RNAs (EBER) was combined with ISH for cytokine transcripts. It became evident that expression of LT and TNF by EBV-infected cells was largely restricted to B immunoblasts, which were only infrequently present in most AILD-TCL cases, whereas the expression of IL-6 was very rare, and IL-1 beta was not found in EBV-infected cells. These data suggest that expression of TNF and LT genes may contribute to the characteristic histologic and clinical features of AILD-TCL and that cytokine expression by EBV-infected cells does not, in most cases, contribute significantly to the overall cytokine expression. Because it has been shown that LT is an autocrine growth factor for EBV-infected B cells, expression of this cytokine could contribute to the proliferation of EBV-infected B cells in AILD-TCL and, in the setting of immunosuppression, may ultimately play a role in the development of B-immunoblastic lymphomas.

Cytokines↗
PubMed1995

Morphology, immunophenotype, and distribution of latently and/or productively Epstein-Barr virus-infected cells in acute infectious mononucleosis: implications for the interindividual infection route of Epstein-Barr virus.

The present study was undertaken to unequivocally demonstrate the morphology, immunophenotype, and localization of Epstein Barr virus (EBV)-infected cells as well as the type of infection (latent versus productive) in tonsils of acute infectious mononucleosis. Paraffin sections from nine cases with clinical, serologic, and morphologic evidence of EBV infection were analyzed for the detection of small transcripts, designated EBER1 & 2, and BHLF1 by in situ hybridization (ISH) using nonisotopically labeled probes. ISH was combined with immunohistology, employing a broad panel of antibodies against B-, T-, epithelial-, macrophage-, and follicular dendritic cell (FDC)-antigens. All EBER-positive cells could be identified as lymphocytes, as they did not exhibit any morphologic or immunologic characteristics of epithelial cells, macrophages, or FDCs. A preferential accumulation of EBER-positive cells was noted around crypts, within surface squamous epithelium, and in the surroundings of necrosis. The majority of these lymphocytes could be shown to be B cells, which morphologically included Reed-Sternberg (RS)-like cells, immunoblasts, medium-sized lymphoid cells, as well as cells with plasmacytoid differentiation. In all cases, a varying number of EBER-positive T cells could be identified. ISH for BHLF1-RNA detection showed that almost all cases contained single positive small lymphoid cells, indicating a transition from latent to productive infection cycle. Such cells could also be detected within the crypt epithelium reaching up to its surface. Additional screening of 123 oropharyngeal mucosa samples from patients without evidence of acute EBV-infection, using the polymerase chain reaction for EBV-DNA detection combined with EBER- and BHLF1-ISH showed single latently infected lymphocytes in only one case. Our data imply that infected lymphocytes and not epithelial cells are, in fact, the reservoir for EBV infection, and that these are the cells that participate in the interindividual virus transfer.

Adolescent↗
PubMed1995

Epstein-Barr virus in B-cell non-Hodgkin's lymphomas: unexpected infection patterns and different infection incidence in low- and high-grade types.

Two hundred and eight cases of B-cell non-Hodgkin's lymphoma (B-NHL) occurring in Europeans without any signs of HIV infection were investigated for their association with an Epstein-Barr virus (EBV) infection. The polymerase chain reaction (PCR) was applied for EBV-DNA detection, in situ hybridization (ISH) for the cellular localization of EBV-encoded small nuclear RNAs (EBER) and immediate-early RNAs (BHLF), and immunohistology (IH) for the detection of EBV-encoded latent membrane protein (LMP) and EBV nuclear antigen 2 (EBNA2) expression. PCR and EBER-ISH produced congruent results in those cases with amplifiable DNA. EBV was present overall in 26 per cent (54/208) of the B-NHL cases. Through EBER-ISH, the virus could be localized merely in rare non-neoplastic bystander lymphocytes in 27 and additionally in tumour cells of 27 cases. Unexpectedly, the proportion of EBV-infected tumour cells present in the different cases varied between 1 and 100 per cent. All but three of the cases with infected tumour cells were of high-grade malignancy. Correlation with the morphological and immunological tumour phenotype revealed that all cases with more than 80 per cent EBER-positive tumour cells were either B-anaplastic large cell lymphomas (B-ALCL), sporadic Burkitt's lymphomas, or B-NHLs with partial or full plasmacellular differentiation. LMP was consistently absent from Burkitt's lymphomas and constantly expressed in B-ALCLs with EBER-positive tumour cells, while in all other instances it varied greatly and was rarer than EBER expression.(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens, Viral↗
PubMed1995

[Urodilatin. Use of a new peptide in intensive care].

On the subject of natriuretic peptides there is a great deal of controversy, and intensive research efforts have been made studying their effects on electrolyte homeostasis. In the early 1980s, a peptide that caused diuresis, natriuresis, and had a relaxant effect on vascular smooth muscle was discovered independently by several groups. This was the breakthrough for the identification of natriuretic peptides, followed by the characterisation of the amino-acid sequences of several species. Synthesis of the peptide, cloning of the encoding gene, identification and characterisation of specific receptors, as well as the development of antibodies and radioimmuno-assays were rapidly accomplished. Research on the immunohistochemistry of cardiodilatin/atrial natriuretic peptide (CDD/ANP) and the regulation of CDD/ANP gene expression led to detection of the peptide in extra-atrial tissues. Later on, two new peptides were discovered brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). These peptides share structural features with CDD/ANP with regard to their 17-amino-acid-exhibiting loop bridged by a disulfide bond. Another recently discovered peptide is urodilatin (URO), a renal-borne new member of A-type natriuretic peptide. URO was isolated from human urine and consists of the same sequence as CDD/ANP, containing the 17-amino-acid residue loop of the circulating hormone with 4 additional amino acids located at the NH2-terminus of the peptide. Regarding physiological actions, data strongly support a close association between URO and urinary sodium excretion. The application of URO in animals revealed a stronger diuresis and natriuresis with a lower influence on arterial blood pressure compared to CDD/ANP-99-126. These results were encouraging for the use of URO in clinical trials as a tool to prevent acute renal failure (ARF) in patients following heart transplantation and for treatment of incipient ARF in patients following liver transplantation. Summarising the results of these two studies, URO represents a new approach for not only prevention, but also for treatment of ARF following organ transplantation. This opens up new possibilities for the treatment of ARF of other origins in intensive care medicine.

Acute Kidney Injury↗