Search PubMed⌕ Search

Biomedical subjects

C Mannhalter

Publications and source records attributed to C Mannhalter.

At least 19 recordsLinked to original sources
PubMed2002

Alternative end-joining in follicular lymphomas' t(14;18) translocation.

T(14;18) chromosomal translocation is assumed to result from illegitimate rearrangement between the BCL2 proto-oncogene and the IGH locus during the D(H) to J(H) joining phase of V(D)J recombination in early B cells. Analysis of the breakpoint junctions suggests that translocation derives from the fusion between normal V(D)J recombination intermediates at the IGH locus and non-V(D)J-mediated broken-ends at the BCL2 locus. So far, BCL2 broken-ends have only been observed fused to coding-ends, raising questions concerning the molecular constraints of the illegitimate joining process. Using a combination of genome walking and long-range PCR assays, we describe in this report that in 4.5% (2/44) of the t(14;18), one of the BCL2 broken-ends is fused to a signal-end. The formation of these J(H)RSS/BCL2 junctions provides direct evidence that BCL2 broken-ends are capable of joining to both products of V(D)J recombination, suggesting their presence in the RAG-mediated post-cleavage complex. In addition, junctions generated by this alternative end-joining do not involve deletion of the chromosome 14 intervening sequences generally lost in the standard translocation, providing a unique opportunity to investigate the rearrangement status of this region in the translocated IGH allele. In both cases, a DJ(H) rearrangement could be detected 5' of the J(H)-RSS/BCL2 junction. These findings, together with the previously reported bias towards the most external D(H) and J(H) segments in standard breakpoints, strongly suggest that t(14;18) preferentially occurs during an attempted secondary D(H) to J(H) rearrangement. This unusual and restricted window of differentiation opens intriguing questions concerning the etiology of the translocation.

Base Sequence↗
PubMed2001

Combined occurrence of a heterozygous missense mutation in the protein C gene and allelic exclusion of one protein S allele leading to severe venous thrombosis.

Individuals with more than one defect in the natural anticoagulant system exhibit an increased risk for thrombosis. We report on a family with two cases of combined protein C (PROC) and protein S (PROS) deficiency, five cases of isolated PROC deficiency Type I, and two cases of isolated PROS deficiency Type I. PROC and PROS deficiency were documented by functional and immunologic tests. The sequencing of all exons and splice junctions of the PROC gene led to the identification of a new, unpublished G-->A transition at nt 8490, leading to an exchange of alanine 259 by threonine. The mutation was present in all family members with PROC deficiency. The carriers of the isolated PROC mutation were asymptomatic at ages of 4, 7, 10, 11, and 80 years. The combination of the PROC mutation with a PROS deficiency in two family members triggered venous thromboembolism at age 31 and 6 years, respectively. The PROS deficiency was associated with complete exclusion of one PROS allele. Two family members with isolated PROS deficiency are still asymptomatic at age 21 and 9 years, respectively. Our findings in this family suggest that the heterozygous mutation at codon 259 of the PROC gene represents a mild thrombotic risk factor and only confers a high thrombotic risk in combination with a second defect, such as the complete exclusion of one PROS allele.

Adult↗
PubMed2001

A common C-->T polymorphism at nt 46 in the promoter region of coagulation factor XII is associated with decreased factor XII activity.

Coagulation factor XII (FXII) deficiency is rarely found to be associated with bleeding, but single reports demonstrated thromboembolic events in FXII-deficient patients. Currently, the biological role of FXII is still discussed controversially. It is well known that plasma levels of FXII show great interindividual variability. Recently, it has been demonstrated that a frequently occurring C-->T polymorphism in the FXII promoter region at nucleotide (nt) 46 is associated with lower plasma FXII activity levels in Orientals. In our study, we evaluated the frequency of this polymorphism in a randomly selected sample of newborns and investigated whether this C-->T polymorphism also contributes to the frequently observed moderate FXII deficiency in Europeans. We developed a new mutagenically separated polymerase chain reaction assay (MS PCR), which allows mutation detection without the use of restriction enzymes. Among 100 healthy newborns, we found 64% homozygous carriers of the wildtype FXII 46C allele, 29% were heterozygous for FXII C46T, and 7% homozygous for FXII 46T. Evaluation of plasma FXII activity and genotype in 80 randomly selected and unrelated individuals revealed a highly statistically significant (P<.001) association of the FXII 46T allele with reduced FXII plasma activity. Individuals carrying the homozygous FXII 46C genotype had a mean of 1.17 U/ml (+/-0.31 U/ml), individuals heterozygous for FXII C46T showed a mean of 0.70 U/ml (+/-0.31 U/ml), and subjects homozygous for FXII 46T had only 0.44 U/ml (+/-0.10 U/ml) plasma FXII activity.

Alleles↗
PubMed2001

Templated nucleotide addition and immunoglobulin JH-gene utilization in t(11;14) junctions: implications for the mechanism of translocation and the origin of mantle cell lymphoma.

The t(11;14)(q13;q32) between the BCL-1 and immunoglobulin heavy chain gene (IgH) loci in mantle cell lymphoma (MCL) are believed to be mediated by the mechanism of V(D)J recombination similar to the t(14; 18) in follicular lymphoma (FL). We have recently shown that the t(14;18) event creates staggered double-strand breaks in the BCL-2 locus, and that the t(14;18) junctions contain templated nucleotide insertions (T-nucleotides; U. Jäger et al., Blood, 95: 3520-3529, 2000). Reasoning that the earlier (pregerminal center) B-cell origin of MCL might be reflected in a different molecular structure of the chromosomal breakpoints, we PCR-amplified diagnostic samples from 93 patients. Thirty-six samples (39%) were positive for the direct (BCL-1/J(H)) and 23 for both direct and reciprocal (D(H)/BCL-1) junctions. The breaks on chromosome 14 exhibited features of V(D)J-mediated recombination as shown by D(H) and J(H) coding end processing. However, duplications of BCL-1 sequences in 39% of the 23 patients indicate staggered double-strand breaks in the major translocation cluster region (MTC). This is incompatible with V(D)J recombination and indicates a different mechanism of cleavage. The use of J(H)6 in the junctions (39%) was similar to that in the immunoglobulin genes of normal B cells and B-CLL, but considerably less than in FL. Only 2 of 36 samples contained a BCL-1/DJ(H) rearrangement, which was indicative of a previous DJ(H) rearrangement. Most importantly, 19% of the BCL-1/IgH junctions with inserts of > or =5 nucleotides contained error-prone copies (T-nucleotides) of 8-12 nucleotides originating from the surrounding BCL-1 or IgH regions, a lower rate than in FL. No correlation was found between the addition of T-nucleotides and the rate of somatic mutation in the immunoglobulin genes. We conclude that the t(11;14) and t(14;18) use the same basic mechanism of translocation including V(D)J-mediated recombination, double-strand staggered breaks, and template-dependent, error-prone DNA-synthesis. However, the distinct differences in the utilization of J(H) regions suggest that the t(11;14) occurs predominantly during an attempted primary D(H)-J(H) rearrangement in early B cells, whereas the t(14;18) mostly occurs during secondary rearrangement. This is in agreement with the pregerminal center B-cell origin of MCL.

Base Sequence↗
PubMed2001

Impact of the factor II: G20210A variant on the risk of venous thromboembolism in relatives from families with the factor V: R506Q mutation.

OBJECTIVES: Factor V: R506Q mutation and the prothrombin G20210A variant (factor II: G20210A variant) are associated with an increased risk of venous thromboembolism (VTE). In cohorts of unrelated patients a cosegregation of both mutations has been shown to be associated with an increased risk of developing VTE. The aim of this study was to investigate the impact of the coinheritance of both mutations on the risk of VTE in relatives of symptomatic carriers of the factor V: R506Q mutation and the factor II: G20210A variant. PATIENTS AND METHODS: Four families with 48 family members were investigated for the presence of the factor V: R506Q mutation and the factor II: G20210A mutation, and their clinical history was evaluated. RESULTS: VTE was more frequent in family members with a combined defect (3/10; 30%) compared to those with a single mutation (1/16; 6%) or without a defect (1/12; 8%). The probability for VTE for 40-yr-old individuals with both mutations, a single mutation and no mutation was 56%, 12% and 20%, respectively. CONCLUSIONS: These data suggest that the G to A transition at position 20210 of the prothrombin gene leads to an increase in the risk of VTE in carriers of the factor V: R506Q mutation. The determination of the factor II: G20210A variant in index patients carrying a factor V: R506Q mutation and, if present, in family members may help to identify individuals who are at high risk for VTE.

Adolescent↗
PubMed2001

Treatment of leukemic relapse after allogeneic stem cell transplantation with cytotoreductive chemotherapy and/or immunotherapy or second transplants.

We analyzed toxicity and efficacy of chemotherapy (CT) or second stem cell transplantation (SCT) and/or immunotherapy defined as stop of immunosuppression (IS) or donor leukocyte infusion (DLI) in 47 patients relapsing with acute leukemia. Ten patients received no treatment and 14 patients were treated with CT only. In 12 patients IS was stopped and three of them received additional CT. Five patients received DLI after CT as consolidation and one patient as frontline therapy. Five patients received a second SCT. Median overall survival after relapse was 2 months for the untreated patients, 2 months for patients receiving CT only, 2 months in patients after cessation of IS, 17 months in DLI treated patients and three months in patients receiving a second SCT. Fourteen patients achieved remission after relapse. Two with CT (2, 2 months), three with SI (3, 19, 19+ months), six with DLI (3, 8, 9, 14, 20, 36 months) and three with second SCT (2, 4, 6 months). Conventional CT was able do re-establish donor hematopoiesis and patients achieving remission showed a significantly better survival than patients with refractory disease. Patients who were brought into remission by DLI or cessation of IS had a significantly better survival than patients who achieved remission with CT alone or a second SCT. We conclude that a selected group of patients achieving remission with regeneration of donor hematopoiesis following CT might benefit from immunotherapy as consolidation.

Adult↗
PubMed2001

Long-term clinical and molecular remission after allogeneic stem cell transplantation (SCT) in patients with poor prognosis non-Hodgkin's lymphoma.

From 1987 to 1999 35 patients with poor prognosis non-Hodgkin's lymphoma (NHL) underwent allogeneic stem cell transplantation (SCT) at the University Hospitals of Vienna and Graz. Initial biopsy specimens were reclassified according to the Revised European-American Classification of Lymphoid Neoplasms (REAL). All patients surviving 28 days engrafted. Twenty-eight of them (93%) attained clinical remission. At the last follow-up 14 patients were alive and disease-free at a median of 5.0 (range, 2.3-12.9) years after allogeneic SCT. The actuarial overall survival is 35%. Five patients relapsed 1.8 to 27.6 months after transplant, the probability of relapse is 23%. Of the 21 deaths following SCT, seven were due to relapse/refractory disease and 14 due to transplant-related causes. The probability of treatment-related mortality is 48%. After SCT, minimal residual disease (MRD) was monitored by polymerase chain reaction (PCR) in seven patients with a BCL-2/IgH translocation and in 13 with a clonal immunoglobulin heavy chain (IgH) rearrangement. All 20 patients attained clinical remission rapidly and converted to PCR negativity. In the follow-up nine of these patients are in long-term clinical and molecular remission, six PCR-negative patients died of transplant-related causes and five patients relapsed. In summary, allogeneic stem cell transplantation has a curative potential for patients with refractory and recurrent non-Hodgkin's lymphoma. In our series long-term disease-free survival was associated with molecular disease eradication after SCT. Treatment-related mortality rate was high, thus earlier referral of selected patients to allogeneic SCT should be considered.

Adult↗
PubMed2001

Homozygosity for the C-->T polymorphism at nucleotide 46 in the 5' untranslated region of the factor XII gene protects from development of acute coronary syndrome.

Recently, a C-->T polymorphism at nucleotide 46 in the 5'-untranslated region of the factor XII (FXII) gene was shown to be associated with lower levels of FXII. To study the impact of this polymorphism on the development of an acute coronary syndrome (ACS), we compared 303 patients with ACS and 227 patients with stable coronary artery disease (CAD). In the latter group, 54.2% of individuals carried wild-type FXII:46C, 37.9% were heterozygous FXII:C46T and 7.9% were homozygous for FXII:46T. In contrast, in the ACS group (n = 303), 54.1% were wild-type FXII:46C, 42.6% were heterozygous FXII:C46T and only 3.3% carried the homozygous FXII:46T genotype. The 2.5-fold lower prevalence of the FXII:46T genotype in patients with ACS could indicate a protective effect on the development of ACS (odds ratio = 0.4, 95% CI 0.1-0.9) in patients with pre-existing CAD.

5' Untranslated Regions↗
PubMed2001

PBPC mobilization with chemotherapy and G-CSF in patients with chronic myeloid leukemia: quantification of bcr/abl-positive cells by interphase fluorescence in situ hybridization and competitive PCR.

BACKGROUND: Autografting of normal stem cells mobilized after chemotherapy is increasingly used in chronic myeloid leukemia (CML). Thus, quantification of possible contamination of progenitor cell apheresis with breakpoint cluster region (bcr)/Abelson murine leukemia (abl)-positive cells is of great clinical interest. STUDY DESIGN AND METHODS: Two molecular methods were compared to quantify bcr/abl positivity in leukapheresis components obtained after mobilizing chemotherapy in six patients with CML. To document the efficacy of in vivo purging, the leukapheresis procedures were monitored with interphase fluorescence in situ hybridization (FISH) and quantitative competitive PCR (QC-PCR) as a ratio of bcr/abl:abl. RESULTS: From the first to the last leukapheresis, bcr/abl positivity in FISH increased from a median of 11 percent to 33 percent. For bcr/abl transcripts, a simultaneous increase in consecutive leukapheresis procedures was seen. The median percentage of bcr cells in a bcr/abl:abl ratio was 3.1 percent in the first apheresis. In the last apheresis after the mobilization with mRNA, the QC-PCR showed a median of 19.5 percent. FISH and QC-PCR showed a statistical significant increase of bcr/abl positivity from the first to the last apheresis. CONCLUSIONS: Both FISH and QC-PCR were reliable methods of quantifying bcr/abl positivity, and they allowed selection of the optimal apheresis component for autologous transplantation. In both methods, a significant increase in bcr/abl positivity was seen from the first to the last leukapheresis. With FISH, results can be obtained within 24 hours. This method may prevent additional contaminated leukapheresis in case of increasing percentages of bcr/abl-positive cells.

Adult↗
PubMed2001

Preeclampsia and fetal loss in women with a history of venous thromboembolism.

A higher prevalence of risk factors for venous thromboembolism (VTE) has been found in women with preeclampsia and fetal loss. We investigated whether women with a history of VTE have a higher prevalence of pregnancy-associated complications compared with control subjects. In 395 patients with a history of VTE and in 313 control women, the prevalence of complications during pregnancy and the mean birth weight of viable infants were evaluated. The prevalence of pregnancy-induced hypertension and preeclampsia was higher in patients (5.1% and 3.0%, respectively) compared with control subjects (1.3% each). The odds ratio was 4.13 for pregnancy-induced hypertension (95% CI 1.4 to 12.22, P=0.0058) and 2.43 for preeclampsia (95% CI 0.78 to 7.6, P=0.133). Stillbirth was slightly more frequent in patients (4.3%) than in control subjects (3.2%); the difference was not statistically significant. Miscarriage was equally frequent in patients (21.8%) and control subjects (21.3%). The birth weight of viable infants born to patients was, on average, 109 g lower than that of the infants born to the control subjects (P=0.014) after adjustment for the mother's body mass index. Our study demonstrates that women with a predisposition to VTE have, overall, a good chance for a successful pregnancy outcome. However, the findings from our study support the assumption that a predisposition to venous thrombosis is associated with a higher risk for complications during pregnancy and lower infant birth weight.

Adolescent↗
PubMed2001

Heme oxygenase-1 gene promoter microsatellite polymorphism is associated with restenosis after percutaneous transluminal angioplasty.

PURPOSE: To determine if an association exists between postdilation restenosis and heme oxygenase-1 (HO-1), which is induced by balloon injury and inhibits neointimal formation through the action of endogenous carbon monoxide. A dinucleotide repeat in the promoter region of the HO-1 gene shows a length polymorphism that modulates the level of gene transcription. METHODS: This cohort study included 96 consecutive patients (64 men; median age 69 years, interquartile range 60-75) who underwent successful balloon dilation in the femoropopliteal segment. Six-month patency was evaluated using oscillography, ankle-brachial index, and duplex sonography. The association of patency and the length of (GT) repeats in the HO-1 gene promoter was assessed in univariate and multivariate analyses. RESULTS: Restenosis was found in 23 (24%) patients within the first 6 months. Patients with short (<25 GT) dinucleotide repeats in the HO-1 gene promoter on either allele had restenosis significantly less often than patients with longer (> or = 25 GT) dinucleotide repeats (p = 0.01). Multivariate analysis revealed a significantly reduced risk for restenosis in these patients compared to patients without the short allele (odds ratio 0.2, 95% Cl 0.06 to 0.70, p = 0.007). CONCLUSIONS: Genetic risk factors for restenosis after percutaneous transluminal angioplasty have not been investigated. In this patient population, short repeat alleles of the heme oxygenase-1 gene promoter polymorphism were associated with reduced postdilation restenosis at 6 months. Upregulation of HO-1 may be an important protective factor after balloon angioplasty by inhibition of vascular smooth muscle cell proliferation.

Aged↗
PubMed2001

CD5 expression in a lymphoma of the mucosa-associated lymphoid tissue (MALT)-type as a marker for early dissemination and aggressive clinical behaviour.

Mucosa associated lymphoid tissue (MALT) developing in response to chronic infection or autoimmune stimuli has been recognized as a possible site of origin for a distinct type of B-cell lymphoma. While preferentially occurring in the stomach, MALT-type lymphomas can be found in virtually all organs. MALT-type lymphomas normally follow an indolent course, with a tendency to remain localized at their site of origin for a prolonged period of time. Histologically, MALT-type lymphomas are heterogeneous covering a cytological spectrum ranging from centrocyte-like cells to smaller lymphoid cells or monocytoid B-cells. Usually a small number of transformed blasts are also present. Immunohistochemically, the malignant cells express markers of B-cell lineage, but are distinct from follicular lymphomas (which express CD10), mantle cell lymphomas (expressing cyclin D1 and CD5) and small lymphocytic lymphoma, which express CD5 and CD23. In contrast to the usual phenotype CD20+CD10-CD5-Cyclin D1-, scattered reports in the literature have documented expression of CD5 in marginal zone B-cell lymphomas of MALT-type. However, these cases are rare, and aberrant CD5-expression has been thought to be a marker for early dissemination and aggressive behavior in some patients, while other reports have also found CD5 expression in localized indolent MALT-type lymphomas. We report a patient with a CD5+ MALT-type lymphoma following an aggressive clinical course without histological progression who relapsed only 18 months after local radiotherapy at the initial localizations (conjunctiva of the right upper eye lid and hypopharynx), and showed a rapid generalization to the contralateral conjunctiva, mediastinal lymph nodes and the esophagogastric junction. Our case lends further support to the notion that CD5+ MALT-lymphomas arising in the head-and-neck area and/or the ocular adnexa might be characterised by an aggressive clinical course.

Aged↗
PubMed2000

Unusual peripheral T cell lymphoma presenting as acute liver failure and reappearing in the liver allograft.

A 25-year-old man presented with fulminant hepatic failure from an unusual peripheral T cell lymphoma involving the liver and spleen without lymphadenopathy. He underwent liver transplantation before establishing a definitive diagnosis and 21 days later, died from liver allograft failure because of recurrent lymphoma. In both the native liver and hepatic allograft, the lymphoma presented as a sparse cytologically atypical malignant infiltrate intermixed with numerous reactive macrophages, which showed marked angio- and epitheliotropism and irregular areas of coagulative necrosis. The malignant cells were CD3+/ granzyme B+/TIA1+/CD8-/CD56-/S100-- with variable staining for beta F1, CD5, and CD7. Multiplex polymerase chain reaction (PCR) showed rearrangement of the T cell receptor gamma chain gene in the native and transplanted liver and spleen. Even in the absence of a mass lesion or lymphadenopathy, peripheral T cell lymphoma should be included in the differential diagnosis of fulminant hepatic failure in young patients who show no evidence of viral or autoimmune diseases.

Adult↗