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Biomedical subjects

M Hummel

Publications and source records attributed to M Hummel.

At least 109 records · Page 6Linked to original sources
PubMed2000

Medium-term results of heart transplantation using older donor organs.

BACKGROUND: Donor heart shortage has necessitated the expansion of the donor pool by the use of older hearts. PATIENTS AND METHODS: In a 13-year period, 1,070 heart transplants were performed in 1,035 adults at the German Heart Institute Berlin. We divided the patients into 3 groups: Group I, donor age <35 years (n = 524); Group II, donor age 35 to 50 years (n = 379); Group III, donor age >50 years (n = 167). We analyzed post-operative mortality (up to 30 days), cumulative survival rates, cardiac dependent morbidity, and changes in the left/right ventricular ejection fraction as well as freedom from cytomegalovirus infection and freedom from acute rejection episodes grade >/= 2 (International Society for Heart and Lung Transplantation). We also calculated the rate of cardiac interventions per patient in the groups. RESULTS: Recipients in Group III were significantly older, compared with Groups I and II. The post-operative mortality was 16.8% in Group I, 29.8% in Group II, and 23.4% in Group III. The differences were significant (p = 0. 00001) between Group I and Group II. The long-term cumulative survival rates were significantly better in Group I when compared with Groups II and III (p < 0.00001, p = 0.014), but it did not differ between Groups II and III (p = 0.18). However, cardiac morbidity in Groups I and II was significantly lower when compared with Group III (p = 0.0009, p = 0.037). Mean left and right ventricular ejection fraction was >55% and did not significantly change in groups for up to 10 years. Freedom from cytomegalovirus infection was not significantly different between Groups II and III (p = 0.09). Significantly fewer percutaneous transluminal coronary angioplasties were performed in Group I, but comparable numbers were carried out in Groups II and III (p = 0.53). For retransplantation a similar situation occurred. CONCLUSION: We did not find significant differences in the mid-term follow-up between patients who received hearts from 35- to 50-year-old donors and from those who had received hearts from donors >50 years, despite increased cardiac morbidity in Group III. Close monitoring of the coronary situation after heart transplantation and expanded indications for revascularization in Group III makes heart transplantation with older hearts a suitable option to save the lives of patients in end-stage heart failure.

Adult↗
PubMed2000

Clinical relevance of immunoglobulin mutation analysis.

The precise diagnosis of malignant B-cell lymphoproliferations is essential for their appropriate clinical management. Histologic and immunophenotypical features alone are often insufficient in discriminating between various lymphoma entities and subtypes. The analysis of clonally rearranged immunoglobulin chain genes of the tumor cells was therefore suggested as an additional parameter. This article reviews current knowledge and describes which conclusions can be drawn for lymphoma diagnosis based on the type of immunoglobulin chain gene rearrangement, as well as on the number and distribution of somatic immunoglobulin mutations. Although there are striking correlations between the clinical outcome and the immunoglobulin mutations in some entities, many additional studies are required in order to draw final conclusions for most types of lymphoma.

B-Lymphocytes↗
PubMed2000

Ring chromosome 1 in a newborn.

A newborn girl with ring chromosome 1 is described. The letter reports the chromosome analysis of peripheral blood lymphocytes with 46,XX,r(1)(p36.3q44) and evidence of ring instability in umbilical cord fibroblasts.

Abnormalities, Multiple↗
PubMed2000

The E8E2C protein, a negative regulator of viral transcription and replication, is required for extrachromosomal maintenance of human papillomavirus type 31 in keratinocytes.

The viral E2 protein is a major regulator of papillomavirus DNA replication. An important way to influence viral replication is through modulation of the activity of the E2 protein. This could occur through the action of truncated E2 proteins, called E2 repressors, whose role in the replication cycle of human papillomaviruses (HPVs) has not been determined. In this study, using cell lines that contain episomal copies of the "high-risk" HPV type 31 (HPV31), we have identified viral transcripts with a splice from nucleotide (nt) 1296 to 3295. These transcripts are similar to RNAs from other animal and human papillomaviruses and have the potential to fuse a small open reading frame (E8) to the C terminus of E2, resulting in an E8E2C fusion protein. E8E2C transcripts were present throughout the complete replication cycle of HPV31. A genetic analysis of E8E2C in the context of the HPV31 genome revealed that mutation of the single ATG of the E8 gene, introduction of a stop codon downstream of the ATG, or disruption of the splice donor site at nt 1296 led to a dramatic 30- to 40-fold increase in the transient DNA replication levels in both normal and immortalized human keratinocytes. High-level expression of E8E2C from heterologous vectors was found to inhibit E1-E2-dependent DNA replication of an HPV31 origin of replication construct as well as to interfere with E2's ability to transactivate reporter gene constructs. In addition, HPV31 E8E2C strongly repressed the basal activity of the major viral early promoter P97 independent of E2. E8E2C may therefore exert its negative effect on viral DNA replication through modulating E2's ability to enhance E1-dependent DNA replication as well as by regulating viral gene expression. Surprisingly, HPV31 genomes that were unable to express E8E2C could not be maintained extrachromosomally in human keratinocytes in long-term assays despite high transient DNA replication levels. This suggests that the E8E2C protein may play a role in copy number control as well as in the stable maintenance of HPV episomes.

Base Sequence↗
PubMed2000

Telomerase expression in uveal melanoma.

BACKGROUND/AIMS: Accumulating evidence indicates that telomerase activity is repressed in normal human somatic cells but reactivated in cancers and immortal cells, suggesting that activation of telomerase activity has a role in carcinogenesis and immortalisation. To date, telomerase in uveal melanoma and, whether, it may have a role in the development or progression of these tumours has not been described. The expression patterns and the activity of telomerase were investigated in 14 uveal melanoma and these results were correlated with histological and immunohistological features of these tumours. METHODS: A modified PCR based telomeric repeat amplification protocol (TRAP) assay was used to demonstrate telomerase activity in 14 uveal melanomas. In addition, in situ hybridisation was used to demonstrate the expression pattern of the telomerase RNA component (hTR) at the single cell level in eight of these globes. RESULTS: The TRAP assay revealed moderate telomerase activity in all uveal melanomas examined. In situ hybridisation visualised a moderate to high upregulation of hTR in the melanoma cells but not in the admixed reactive cells. There was no correlation among tumour location, cell type, or growth fraction and the amount of telomerase activity. In addition, the cells of the germinative zone of the lens demonstrated a strong hTR expression. CONCLUSION: Telomerase activity is upregulated in uveal melanomas. The expression of hTR was located to the tumour cells and not the reactive tumour infiltrating cells. Strong telomerase expression was also demonstrated in cells of the germinative zone of the lens.

Adult↗
PubMed2000

Refractory sprue syndrome with clonal intraepithelial lymphocytes evolving into overt enteropathy-type intestinal T-cell lymphoma.

INTRODUCTION: Recently, patients with refractory sprue have been shown to contain a clonal proliferation of phenotypically abnormal intraepithelial lymphocytes in their intestine. Whether this signifies early enteropathy-type intestinal T-cell lymphoma (EITCL) or a reactive condition is not clear. We report on a patient presenting with the findings of refractory sprue who subsequently developed overt EITCL. MATERIAL AND METHODS: Duodenal biopsies from 1997 (refractory sprue) and duodenal and jejunal biopsies from 1998 (intestinal T-cell lymphoma) were compared by immunohistochemistry and PCR for the detection of T-cell receptor (TCR)-gamma gene rearrangements. Clonal PCR products were sequenced. RESULTS: The duodenal biopsies from both 1997 and 1998 and the jejunal tumor biopsy showed villus atrophy and an increase of intraepithelial lymphocytes with an abnormal immunophenotype (CD3+, CD4-, CD8- and TCR-beta-). In all duodenal specimens including the one from 1997, and the jenunal tumor biopsy, an identical clonal amplificate was detected by enzymatic amplification of the TCR-gamma gene. CONCLUSION: These data suggest that refractory sprue containing a clonal proliferation of phenotypically abnormal intraepithelial lymphocytes may represent an early manifestation of EITCL. The detection of immunohistochemical negativity for several antigens normally found on intraepithelial lymphocytes such as CD8 or the TCR-beta chain in combination with clonal T-cell populations by PCR may be helpful in identifying refractory sprue with a malignant transformation.

CD3 Complex↗
PubMed2000

No major association of breast-feeding, vaccinations, and childhood viral diseases with early islet autoimmunity in the German BABYDIAB Study.

OBJECTIVE: Environmental factors have been suggested to play an important role in the pathogenesis of type 1 diabetes. The aim of this study was to assess the influence of breast-feeding, vaccinations, and childhood viral diseases on the initiation of islet autoimmunity in early childhood. RESEARCH DESIGN AND METHODS: Data were prospectively collected from questionnaires obtained at birth, at 9 months of age, and at 2 years of age in 823 offspring from parents with type 1 diabetes. By 2 years of age, 31 offspring had islet antibodies, and 10 developed overt diabetes by the time of follow-up. RESULTS: In offspring from mothers with type 1 diabetes, duration of exclusive and total breast-feeding did not differ between islet antibody-positive and -negative children, regardless of HLA genotype, and breast-feeding of 3 months or longer was not associated with protection from antibody development or diabetes onset. In offspring from diabetic fathers, non-statistically significant reductions in exclusive and total breast-feeding times were observed in the antibody-positive cohort. Neither type nor quantity of vaccinations (including Bacille Calmette-Guerin vaccine; haemophilus influenzae vaccine; diphtheria, tetanus, and pertussis vaccine; tick-born encephalitis vaccine; or measles, mumps, and rubella vaccine) were associated with the development of islet antibodies and diabetes. Measles, mumps, and rubella were not reported in children with islet antibodies or diabetes. CONCLUSIONS: This study showed no evidence that proposed environmental factors affect islet antibody development in the first 2 years of life in offspring from parents with type 1 diabetes.

Autoantibodies↗
PubMed2000

[Monocytic B-cells represent a new cell population that is mainly recruited from unmutated polyconal naive B-cells].

Monocytoid B-cells appear as a distinct B-cell population in a number of lymphadenopathies but above all in Piringer's lymphadenopathy. Up until now, their assignment to a recognised B-cell subpopulation has not been conclusively achieved. Immunohistological studies have shown characteristics in common with the tumour cells of hairy cell leukemia and also with so-called splenic marginal zone cells. In order to unequivocally clarify their B-cell differentiation stage we have isolated single monocytoid B-cells from immunostained frozen sections and have analysed their immunoglobulin chain gene rearrangements. In addition we have studied the Ig-expression of monocytoid B-cells at both the RNA and protein levels.

B-Lymphocytes↗
PubMed1999

Medium-term results of heart transplantation using donors over 63 years of age.

BACKGROUND: The continual shortage of hearts for transplantation (HTx) led to the expansion of the donor pool by accepting older donors. We compared the medium-term follow-up of patients after HTx with older hearts (over the age of 63 years) with those of patients after HTx with younger hearts. PATIENTS AND METHODS: Since April 1994 we have used hearts for HTx from donors older than the age of 63 years. Until November 1998, 309 HTx and 9 re-HTx were performed in 309 adults with a mean age of 50.7+/-10.9 years (range 17-68 years). There were 252 men and 57 women. The patients were divided into two groups: group I--donor age under 63 years (296 patients, mean age 50.4+/-11 years; mean donor age 38.1+/-13 years; mean follow-up 1.7+/-1.6 years); group II-donor age of more than 63 years (13 patients, mean age 57.4+/-5.6 years; mean donor age 65.1+/-2.1; mean follow-up 2.2+/-1.6 years). There were no differences in the etiology of heart failure, gender, or ischemia time between the groups. The patients in group II were significantly older (P = 0.008). Multiple factors were analyzed in the groups, which included changes in the left/right ventricle ejection fraction, early postoperative mortality (up to 30 days), cumulative survival rates and cardiac-dependent morbidity [myocardial infarction, malignant arrhythmias, coronary stenosis (>50% in one of the main coronary arteries) and transplant vasculopathy]. Additionally, freedom from cytomegalovirus infection (rise of titer or seroconversion) and freedom of acute rejection episodes grade > or =2 (International Society of Heart & Lung Transplantation [ISHLT]) were analyzed. RESULTS: After 1 year mean left and right ventricle ejection fraction were good in both groups and did not significantly change for up to 2 years. No Re-HTx was performed in group II. The early postoperative mortality was similar in both groups (P = 0.8). Also, the cumulative survival rates were similar in both groups (P = 0.87). Long-term cardiac morbidity was lower in group I (P = 0.03). The long-term freedom from cytomegalovirus infection in group I was significantly higher when compared with group II (P = 0.0002). The long-term freedom from severe rejection episodes was similar in both groups (P = 0.3) CONCLUSION: The study found a significant increase in long-term cardiac morbidity due to more focal coronary stenosis in group II, and freedom from cytomegalovirus infection, but did not find significant differences in the long-term survival between patients who received hearts from donors of up to 63 years of age and from those more than 63 years. The acceptance of donors older than 63 years old for HTx does not worsen the outcome of the recipients. The careful selection of older donors, with close monitoring of the coronary situation after HTx and expanded indications for revascularization of older hearts, could make HTx with older hearts, even in older recipients, a safe option.

Adolescent↗
PubMed1999

Frequent expression of the B-cell-specific activator protein in Reed-Sternberg cells of classical Hodgkin's disease provides further evidence for its B-cell origin.

The neoplastic cells of classical Hodgkin's disease (cHD), ie, Hodgkin and Reed-Sternberg cells (HRS cells), contain clonally rearranged Ig genes, but are dissimilar to normal B cells in that they mostly do not display B-cell antigens such as CD20 or CD19. The transcription factor B-cell-specific activator protein (BSAP) influences numerous B-cell functions such as B-cell antigen expression, Ig expression, and class switch. We analyzed the expression of BSAP in cHD and control tissues by isotopic in situ hybridization and immunohistochemistry to determine whether BSAP is expressed in HRS cells and, if so, whether it may be involved in the genesis of the abnormal phenotype of these cells. Both in normal lymphoid tissue and non-Hodgkin lymphomas, BSAP transcripts and protein were almost exclusively found in B cells and B-cell lymphomas (40 cases), but were absent from the tumor cells of T-cell neoplasms (41 cases), including 19 cases of anaplastic large cell lymphoma of T- and null-cell type. Among cHD, variable numbers of HRS cells exhibited BSAP transcripts (22 of 25 cases) and protein (28 of 31 cases). Our findings show that BSAP is sufficiently specific to serve as B-cell marker. BSAP expression in HRS cells provides further strong evidence for a frequent B-cell origin of cHD and helps distinguish this disease from anaplastic large cell lymphoma of T- and null-cell type. Because BSAP is much more frequently expressed in HRS cells than the conventional B-cell antigens, the abnormal immunophenotype of HRS cells with frequent absence of B-cell antigens does not appear to be due to absent BSAP expression.

B-Lymphocytes↗
PubMed1999

Overexpression of I kappa B alpha without inhibition of NF-kappaB activity and mutations in the I kappa B alpha gene in Reed-Sternberg cells.

The transcription factor NF kappa B (NF-kappaB) mediates the expression of numerous genes involved in diverse functions such as inflammation, immune response, apoptosis, and cell proliferation. We recently identified constitutive activation of NF-kappaB (p50/p65) as a common feature of Hodgkin/Reed-Sternberg (HRS) cells preventing these cells from undergoing apoptosis and triggering proliferation. To examine possible alterations in the NF-kappaB/IkappaB system, which might be responsible for constitutive NF-kappaB activity, we have analyzed the inhibitor I kappa B alpha (IkappaBalpha) in primary and cultured HRS cells on protein, mRNA, and genomic levels. In lymph node biopsy samples from Hodgkin's disease patients, IkappaBalpha mRNA proved to be strongly overexpressed in the HRS cells. In 2 cell lines (L428 and KM-H2), we detected mutations in the IkappaBalpha gene, resulting in C-terminally truncated proteins, which are presumably not able to inhibit NF-kappaB-DNA binding activity. Furthermore, an analysis of the IkappaBalpha gene in single HRS cells micromanipulated from frozen tissue sections showed a monoallelic mutation in 1 of 10 patients coding for a comparable C-terminally truncated IkappaBalpha protein. We suggest that the observed IkappaBalpha mutations contribute to constitutive NF-kappaB activity in cultured and primary HRS cells and are therefore involved in the pathogenesis of these Hodgkin's disease (HD) patients. The demonstrated constitutive overexpression of IkappaBalpha in HRS cells evidences a deregulation of the NF-kappaB/IkappaB system also in the remaining cases, probably due to defects in other members of the IkappaB family.

Base Sequence↗
PubMed1999

Monocytoid B cells are distinct from splenic marginal zone cells and commonly derive from unmutated naive B cells and less frequently from postgerminal center B cells by polyclonal transformation.

Monocytoid B cells represent a morphologically conspicuous B-cell population that constantly occurs in Toxoplasma gondii-induced Piringer's lymphadenopathy. Although widely believed to be closely related to splenic marginal zone B cells, neither this relationship, nor the B-cell differentiation stage of monocytoid B cells, nor their cellular precursors have been established. We have therefore examined monocytoid B cells for their expression of B-cell differentiation markers and the Ig isotypes at the RNA and protein level as well as for rearranged Ig heavy chain (H) genes and somatic mutations within the variable (V) region. The results obtained were compared with the corresponding features of other B-cell populations. The monocytoid B cells displayed immunophenotypical differences to all other B-cell populations. IgM and IgD expression was absent from most monocytoid B cells at the RNA and protein levels. Unrelated (polyclonal) Ig rearrangements were found in 85 of the 95 cells studied. Seventy-four percent of the rearranged VH genes were devoid of somatic mutations, whereas the remaining 26% carried a low number of somatic mutations. The majority of these showed no significant signs of antigen selection. This finding in conjunction with the predominantly unrelated Ig gene rearrangements indicates that most monocytoid B cells arise not by clonal proliferation but by transformation of polyclonal B cells. The B cells undergoing a monocytoid B-cell transformation are in the majority (74%) naive B cells, and only a minority are (26%) non-antigen-selected postgerminal center B cells. Thus, our data show that monocytoid B cells represent a distinct B-cell subpopulation.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1999

Frequent expansion of Epstein-Barr virus (EBV) infected cells in germinal centres of tonsils from an area with a high incidence of EBV-associated lymphoma.

Burkitt's lymphoma (BL) and Hodgkin's disease (HD) occurring in developing regions are frequently associated with Epstein-Barr virus (EBV) infection and have a high incidence in childhood. Recent genotyping studies indicate that the tumour cells of both neoplasms represent B cells that contain somatically mutated immunoglobulin heavy chain genes. This implies that the precursors of these neoplasms have participated in the germinal centre (GC) reaction. We therefore presumed that normal lymphoid tissues from children living in developing regions would harbour an increased number of EBV-infected cells within the GC, when compared with children living in industrialized nations. To test this hypothesis, hyperplastic tonsils from 40 children living in Bahia (Brazil) and 40 from German children were analysed for the presence of EBV-encoded small nuclear RNA (EBER) and EBV-encoded proteins by in situ hybridization and immunohistology, respectively. Although the overall EBV infection rate was similar in both groups (50 per cent of Bahian vs. 45 per cent of German cases), a significantly higher number of EBER-positive lymphoid cells were found in the GCs of 8/20 EBV-positive tonsils from Brazil (9-89 cells/GC; mean: 14.5 cells/GC per case), while only 3/18 tonsils from Germany displayed a few EBER positive cells (1-9 cells/GC; mean: 0.5 cell/GC per case) in this compartment (p < 0.007). In addition, the EBV-infected GC cells in Bahian samples resembled centroblasts, exhibited mitotic activity, and in two cases showed expression of EBV-encoded latent membrane protein (LMP)-1, findings not present in German samples. These data show that latently EBV-infected cells participate more frequently in GC reactions in developing regions than in industrialized countries and may abnormally express the oncogenic protein LMP-1. This could in part explain the higher incidence in this region of EBV association with lymphomas related to GC cells or their progeny, such as BL and HD.

Adolescent↗
PubMed1999

Common and HIV-related diffuse large B-cell lymphomas differ in their immunoglobulin gene mutation pattern.

HIV-infected patients are at high risk of developing diffuse large B-cell lymphomas (DLBCL). It is currently unclear whether these lymphomas represent Epstein-Barr virus (EBV)-driven lymphoproliferations that develop in the setting of immunodeficiency, or whether these tumours are more closely related to the DLBCL seen in the general population. To clarify this issue, 12 HIV-related DLBCL from 11 patients were analysed for the presence of clonally rearranged and somatically mutated immunoglobulin heavy chain (IgH) genes and their association with EBV was determined. Eleven of the 12 tumour samples displayed monoclonal rearrangements of the IgH genes, with or without a moderate number of somatic mutations in the CDRII and in the FWIII regions (average four mutations). One patient presented two successive lesions; whereas the initial tumour showed an oligoclonal IgH rearrangement, the lymphoma at relapse proved to harbour a monoclonal B-cell population. Ten of 12 tumour samples expressed the EBV encoded small RNAs (EBERs), and six of these EBV-positive cases displayed, in addition, an expression of the EBV encoded nuclear antigen 2 (EBNA-2). The results obtained from HIV-related DLBCL are at variance to those described for DLBCL occurring in the general population, since the latter contain significantly more somatic IgH mutations in the CDRII and in the FWIII regions and are only rarely associated with EBV. It is concluded from these findings that HIV-related DLBCL represent a distinct group of B-cell lymphomas, a significant fraction of which most likely originates from EBV-driven lymphoproliferations, and that half of the cases derive from pre-germinal centre B-cells.

Gene Rearrangement↗
PubMed1999

Hodgkin and Reed-Sternberg cells of classical Hodgkin's disease overexpress the telomerase RNA template (hTR).

There is accumulating evidence to suggest that Hodgkin and Reed-Sternberg (HRS) cells represent the malignant cell population in Hodgkin's disease (HD). A recent report that HD tissue is in most instances devoid of telomerase activity was therefore unexpected. Since telomerase activity was determined in whole tissue extracts and HRS cells comprise only a small minority of the cells in the affected tissue, the telomerase activity of the HRS cells might have escaped detection. To test this possibility and to clarify whether HRS cells contain the enzyme telomerase, 13 cases of classical HD were analysed by three different methods. The presence of telomerase was studied at the single cell level by a sensitive radioactive in situ hybridization method employing a probe specific for the telomerase RNA template (hTR). In addition, tissue extracts were studied for telomerase activity by a modified TRAP assay and for hTR by reverse transcription-polymerase chain reaction (RT-PCR). The extractive methods revealed telomerase activity in eight and hTR in all of the 13 HD cases studied. In situ hybridization located large amounts of hTR in the HRS cells of all 13 HD cases and low to medium amounts in some of the non-malignant lymphoid bystander cells. These results indicate that HRS cells constitutively overexpress telomerase and thus use this enzyme for stabilizing their telomeres. This substantiates the malignant nature of HRS cells. Furthermore, the results confirm that normal lymphoid cells can express telomerase. In consequence, methods of measuring telomerase in tissue extracts are not suitable for determining the presence of this molecule in lymphoma cells, since the vast majority of lymphoid neoplasms contain significant amounts of non-neoplastic lymphoid cells.

Hodgkin Disease↗