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Biomedical subjects

E Seifried

Publications and source records attributed to E Seifried.

At least 55 records · Page 3Linked to original sources
PubMed1999

An endogenous retroviral long terminal repeat at the HLA-DQB1 gene locus confers susceptibility to rheumatoid arthritis.

Human endogenous retrovirus (HERV) long terminal repeat (LTR) elements contain regulatory sequences that can influence the expression of adjacent cellular genes, which may contribute to breakdowns of the immune function leading to autoimmune disease. Rheumatoid arthritis (RA) is associated with particular HLA-DR/DQ haplotypes that modulate the pathogenesis of this autoimmune disease. We have therefore studied a solitary LTR element (DQ-LTR3) of the HERV-K family at the HLA-DQB1 locus for a possible disease association among 228 RA patients and 311 unrelated blood donors. The DQ-LTR3 was significantly more frequent among patients (76% vs 33%, OR = 5.07,p < 0.0001), with the majority of patients being heterozygous for the DQ-LTR3 (61% vs 22%, p < 0.0001). HLA-DRB1*04 positive patients did still differ for the presence of the DQ-LTR3 (88% vs 70%, OR = 3.03, p < 0.001), with an increase of both DQ-LTR3 homozygous and heterozygous patients, when compared to DRB1*04 positive controls (p = 0.0015). HLA-DR/DQ genotype analysis among HLA-DRB1*04 positive individuals revealed significantly more DQ-LTR3 homozygotes among HLA-DRB1*04-DQBI*03 homozygous patients (72% vs 27%, P = 0.015), and the number of DQ-LTR3 homozygous (23% vs 19%) and heterozygous (66% vs 53%) individuals was also increased among HLA-DRB1*04 heterozygous patients (p = 0.034). The presence of the DQ-LTR3 element increased both the relative risk and the positive predictive value for either DRB1*04-DQB1*03 positive/negative individuals when compared to the presence of HLA-DRB1*04-DQB1*03 alone. In conclusion, these data suggest that this DQ-LTR3 enhances susceptibility to RA.

Arthritis, Rheumatoid↗
PubMed1999

A second unrelated bone marrow transplant: successful quantitative monitoring of mixed chimerism using a highly discriminative PCR-STR system.

A second bone marrow transplant (BMT) might be considered as an option in patients with leukaemia with graft failure after BMT. We report the successful treatment of a patient with graft failure by a second stem cell transplant from another unrelated donor. We evaluated the usefulness of an unrelated donor as the source of the second BMT in this clinical setting. In addition to this, a penta PCR-STR system was tested and shown to be sensitive for monitoring of marrow engraftment. The conditioning regimen for the first transplantation consisted of busulfan and cyclophosphamide while anti-thymocyte globulin and CY were used for the second BMT. The patient successfully engrafted at day +11 after second BMT.

Adult↗
PubMed1999

HLA-DR/DQ interaction in patients with erosive rheumatoid arthritis presenting articular and extraarticular disease manifestations.

In the present study we have analysed the effect of HLA-DRB1 and -DQB1 alleles on disease progression and genetic predisposition among 201 RA patients. We clearly confirm the association of RA with HLA class II alleles sharing the (Q)R/KRAA amino acid (AA) cassette in the third hypervariable region (HVR3) of the DR beta-chain. The HVR3 (Q)R/KRAA motif was significantly overrepresented among RA patients (79% vs. 40%, P < 0.001), with one third of the patients homozygous (28% vs. 6.7%, P < 10(-9)) and the number of rheumatoid factor positive (RF+) patients was significantly increased among HVR3 (Q)R/KRAA homozygous in comparison to HVR3 (Q)R/KRAA negative individuals. Erosive disease defined by the Larsen Score and personal disability determined using the Health Assessment Questionnaire (HAQ) was significantly increased among patients positive for the HVR3 motif with the worst outcome among HVR3 (Q)R/KRAA homozygous patients. In contrast, there was no association of the shared HVR3 AA cassette and disease severity in the majority of patients presenting systemic (extraarticular) disease. Homozygosity for the shared HVR3 motif was only marginally increased among patients presenting 'severe' extraarticular disease in comparison to patients with articular disease (33% vs. 43%, P = ns). Similarly, patients with nodular disease were not more often homozygous for the HVR3 (Q)R/KRAA motif. Furthermore, we observed no HLA-DR independent association of DQB1 alleles among HVR3 (Q)R/KRAA positive patients and controls. Our analysis supports the predominant role of HLA-DR for genetic susceptibility to RA. In the clinical setting, however, HLA-DR typing may be limited to assess the individual risk of patients for disease progression.

Adult↗
PubMed1999

Endogenous serum levels of thrombopoietic cytokines in healthy whole-blood and platelet donors: implications for plateletpheresis.

Serum concentrations of the thrombopoiesis-enhancing cytokines thrombopoietin (TPO), erythropoietin (EPO), interleukin (IL)-6 and IL-11 were determined in 119 healthy whole-blood (WBD) and 101 platelet donors (PD) prior to donation. The 90% TPO reference interval in WBD of 64-867 pg/ml (median 163, 100% range 45-7572) was significantly higher than in PD of 56-524 (median 122, range 44-801, P = 0.004), whereas their platelet counts were lower (P < 0.001). EPO levels were not different (WBD 7.7 +/- 3.8, PD 8.0 +/- 4.9 IU/l), IL-6 and IL-11 were below the detection limit in >/=90% of cases (IL-6 < 3.2 pg/ml, IL-11 < 31.2 pg/ml). None of the cytokines correlated with platelet counts, other blood parameters, or in the PD group with the frequency of platelet donations within the last 6 months. We conclude that plateletpheresis does not lead to a lasting increase of thrombopoietic cytokines and provide reference data for potential platelet mobilization strategies with recombinant growth factors.

Adult↗
PubMed1999

Association of (Q)R/KRAA positive HLA-DRB1 alleles with disease progression in early active and severe rheumatoid arthritis.

OBJECTIVE: We have shown that HLA-DRB1 alleles influence inflammatory activity in patients with early active and severe rheumatoid arthritis (RA). Therefore, we analyzed the effect of HLA-DRB1 alleles on disease progression in patients with early RA during a clinical followup period of 18 months. METHODS: Disease progression was defined by the Larsen Score, the Ritchie Index (RI), and the Health Assessment Questionnaire (HAQ) score. RESULTS: Patients carrying arthritogenic HLA-DRB1 alleles on one or both haplotypes are characterized by increased radiological joint destruction (Larsen Score). Further, (Q)R/KRAA homozygous patients were characterized by worse overall disease course (higher RI and HAQ). However, analysis of changes in joint effects (delta-RI) and personal disability (delta-HAQ) did not reveal significant differences between patients with or without disease associated HLA-DRB1 alleles. CONCLUSION: The predisposing genetic pattern with disease associated HLA-DRB1 alleles did not profoundly influence the therapeutic outcome. Our data support the role of the HLA-DRB1 gene locus in disease modulation of RA. The genetic predisposition due to HLA-DRB1, however, may have only a limited influence on the therapeutic outcome in clinically severe cases of RA.

Adult↗
PubMed1998

Effect of reteplase on hemostasis variables: analysis of fibrin specificity, relation to bleeding complications and coronary patency.

UNLABELLED: The first aim of the present study was to characterize the systemic and fibrin-specific lytic effect of reteplase in the treatment of patients with acute myocardial infarction. The second aim was to investigate the relation of hemostasis variables to risk of bleeding complications and to coronary patency. The present study is a hemostatic substudy of the German Recombinant Activator Study. Forty two patients have been treated with 10 MU of reteplase (Group A) and 100 patients with 15 MU of reteplase (Group B), given as a single bolus. Blood samples for assessment of fibrinogen, plasminogen, alpha-2-antiplasmin, fibrinogen degradation products (FDP) and D-dimers were obtained before and at 2, 4, 8, and 24 h after thrombolytic therapy. The median fibrinogen concentration was decreased from 279 to 169 mg/dl in Group A and from 254 to 92 mg/dl in Group B four hours after administration of reteplase. The decrease in fibrinogen was significantly more pronounced in Group B (P=0.0004). The median plasminogen concentration was decreased to 53% in Group A and to 33% in Group B two hours after administration of reteplase (P=0.0001). Alpha-2-antiplasmin was reduced to 27% and 17,5%, respectively (P=0.0007). D-Dimer levels were increased to 5.2 microg/ml in Group A and 11,6 microg/ml in Group B (P=0.02) and FDP levels to 3.0 microg/ml in Group A and 12,6 microg/ml in Group B (P=0.04). Patients with bleeding complications revealed significant lower nadir levels of fibrinogen than patients without bleeding complications (54 mg/dl versus 125.5 mg/dl, P=0.02). There was no significant difference in any hemostatic parameter between patients with patent and nonpatent infarct related arteries. CONCLUSIONS: Reteplase causes a moderate systemic lytic effect comparable with other relative fibrin specific thrombolytic agents. An increase in the dose from 10 to 15 MU is associated with a marked increase in both fibrin specific and systemic lytic effect. Patients with bleeding complications reveal significant lower nadir levels of fibrinogen than patients without bleeding complications. Determination of any hemostatic parameter seems to be no useful method to predict efficacy of thrombolysis in terms of coronary patency in the individual patient.

Clinical Trials, Phase II as Topic↗
PubMed1998

CTLA4 codon 17 dimorphism in patients with rheumatoid arthritis.

The genetic susceptibility to rheumatoid arthritis is conferred by genes in the human leukocyte antigen (HLA) region on chromosome 6, but additional genes may be involved to determine disease susceptibility. We have studied the distribution of the CTLA4 exon 1 polymorphism (49 A/G) in rheumatoid arthritis. This dimorphism at codon 17 results in an amino acid exchange (Thr/Ala) in the leader peptide of the expressed protein and was analyzed by PCR, SSCP and RFLP in 258 Caucasian rheumatoid arthritis patients and 456 controls. Rheumatoid arthritis patients were characterized by a decreased frequency of homozygotes for the Thr-17 substitution (32% versus 39%) and an overrepresentation of patients heterozygous for the Thr/Ala substitution (54% versus 46%). Gene frequencies for the Ala/Thr substitution differed only marginally from controls. In contrast, analyses of the CTLA4 exon 1 polymorphism with respect to HLA-DRB1*04 revealed significantly more patients with Ala in the homozygous (19% versus 15% controls) or heterozygous state (54% versus 39% controls) and less homozygous for Thr (27% versus 46% controls), with a particular increase of Ala/Ala genotypes among rheumatoid arthritis patients carrying the HLA-DRB1*0401 subtype. Among HLA-DRB1*04 negative rheumatoid arthritis patients, we observed no difference between the allele frequencies of the Ala-17 or Thr-17 substitution.

Abatacept↗
PubMed1998

HFE codon 63/282 (H63D/C282Y) dimorphism in German patients with genetic hemochromatosis.

Genetic hemochromatosis (GH) is closely associated with genes of the major histocompatibility complex (MHC) on chromosome 6. Recently, a candidate gene for GH, with structural similarities to MHC class I genes, designated HLA-H and presently named HFE, has been cloned. The HFE gene is localized telomeric to the MHC and several reports have indicated that the HFE gene is mutated in GH patients. In the present study we have analyzed the relationship of HFE gene variants and disease manifestation in GH patients and family members. Fifty-seven patients with GH, 73 family members and 153 healthy blood donors were studied for the amino acid dimorphism at codon 63 (His63Asp=H63D) and codon 282 (Cys282Tyr= C282Y) of the HFE gene. The codon 63 and 282 dimorphism were defined by PCR amplification of genomic DNA samples and restriction enzyme digestion using RsaI/SnaBI for C282Y and BclI/MboI for H63D. Ferritin, transferrin serum levels and total iron-binding capacity were determined prior to therapeutic intervention. The Tyr-282 substitution occurred in 53 (93%) of patients compared with 8 (5.2%) of controls (OR=169, P<0.0001). Fifty-one (90%) patients were Tyr-282 homozygous. In contrast, the Asp-63 substitution was present in 5 (8.8%) of the patients compared with 34 (22%) of controls (OR=0.39, P=NS) with none of the patients being homozygous. In Tyr-282 homozygous GH patients serum ferritin levels, transferrin saturation, liver iron and liver iron index were elevated significantly compared to Tyr-282-negative patients, whereas no difference was observed between Tyr/Cys-282 heterozygous and Tyr-282-negative patients.

Aspartic Acid↗
PubMed1998

Soluble HLA class I and class II antigens in patients with multiple sclerosis.

Soluble HLA class I (sHLA-I) and soluble HLA class II (sHLA-II) antigen levels during different stages of disease were investigated in paired serum and cerebrospinal fluid (CSF) samples from 37 patients with multiple sclerosis (MS) using ELISA and Western blot analysis. Soluble HLA-II antigens in the serum of untreated patients with the relapsing-remitting type of MS (RRMS) were found to be significantly elevated in acute relapse as compared to values obtained from patients under steroid treatment, in remission or healthy controls. No significant differences in circulating sHLA-I levels could be detected. In contrast, a trend towards increased intrathecal production of sHLA-I molecules in the CSF was observed in untreated RRMS patients in acute relapse, whereas the levels of soluble HLA-II antigens in the CSF were below the detection limit of the ELISA method. Our observations underline the presence of systemic immune activation in MS patients, as reflected in elevated serum sHLA-II antigen levels, and reveal a dichotomy between sHLA class I and II antigen production in the peripheral blood versus CSF in acute MS. Serial measurements of sHLA-II antigen levels might represent a non-invasive method to assess disease activity in MS patients.

Enzyme-Linked Immunosorbent Assay↗
PubMed1997

HLA-DR/DQ/DP interactions in rheumatoid arthritis.

Rheumatoid arthritis (RA) is associated with the presence of particular HLA-DRB1 alleles. In order to characterize HLA-DQB1 and/or-DPB1 alleles that contribute to disease susceptibility besides HLA-DRB1 alleles, we have analysed the HLA-DRB1, -DQB1 and -DPB1 polymorphism in 84 RA patients and 135 controls. HLA typing for HLA-DRB1 and -DQB1 alleles was performed using sequence-specific primers in combination with sequence-based typing. HLA-DPB1 alleles were characterized by reverse dot-blot hybridization. Our data confirm the predominant role of the (Q)R/KRAA sequence from AA position 70-74 of the HLA-DRB chain for disease susceptibility. In particular, the lysine (K) substitution at position 71 was highly significantly associated with RA. Analysis of the DQB1 locus revealed no association with RA when linkage disequilibrium between HLA-DRB1 and -DQB1 alleles was considered. In contrast, we observed an increased frequency of HLA-DPB1*0401 among (Q)R/KRAA-positive patients. (Q)R/KRAA-negative RA patients exhibited an overrepresentation of HLA-DPB1*0201 and HLA-DPB1*0601. Rheumatoid factor (RF) production correlated with the presence of the disease-associated (Q)R/KRAA amino acid cassette of the HLA-DRB chain. When HLA-DPB1 allele frequencies were compared between RF-positive and RF-negative RA patients, we observed an increased frequency of HLA-DPB1*0401 among RF-positive RA patients and HLA-DPB1*0201 among RF-negative patients. These results suggest that besides the predominent role of HLA-DR molecules in RA, HLA-DP molecules may have an influence on disease susceptibility and could modulate disease progression. HLA-DPB1*0401 may function in addition to HLA-DRB1*04, whereas HLA-DPB1*0201 and -DPB1*0601 may represent additional risk factors among (Q)R/KRAA-negative RA patients.

Adult↗
PubMed1997

Sensitive determination of the RhD genotype in mixed samples using fluorescence-based polymerase chain reaction.

OBJECTIVES: Prenatal determination of the fetal RhD status in pregnancies of Rh-negative (Rh-neg) women by polymerase chain reaction (PCR) on DNA has become of increasing importance. Since determination of the RhD genotype in these cases is usually performed in samples containing both maternal Rh-neg and fetal Rh-neg or Rh-positive (Rh-pos) DNA, the sensitivity and specificity of PCR-based DNA detection are of crucial importance in the diagnosis of the fetal RhD status. METHODS: We developed a method for RhD typing using the PCR and a fluorescence-based detection method that allows us to determine RhD-pos DNA even if it is mixed with large amounts of Rh-neg DNA. RESULTS: Using this approach, Rh-pos DNA could be detected in dilutions with Rh-neg DNA of as high as 1 in 10,000 (Rh-pos/Rh-neg). Furthermore PCR amplification could also be carried out on DNA samples from persons with weak (Dweak) or partial (Dcat) RhD antigens. CONCLUSION: This method will be valuable in prenatal RhD typing after amniocentesis or after the isolation of fetal cells from maternal peripheral blood.

Alleles↗
PubMed1997

Prevalence of hepatitis G virus and its strain variant, the GB agent, in blood donations and their transmission to recipients.

BACKGROUND: Hepatitis G virus (HGV) and its strain variant, the GB agent (GBV-C) are independent isolates of a recently identified non-A through -E hepatitis virus. Prevalence in United States volunteer blood donors is 1.5 to 1.9 percent, but no data on European blood donors are available. Epidemiologic data suggest a preferred parenteral transmission route. The prevalence of HGV/GBV-C in European blood donors and the efficiency of transmission to transfusion recipients were investigated. STUDY DESIGN AND METHODS: Plasma samples from unpaid volunteer German blood donors were tested for HGV/GBV-C by in-house reverse transcription-polymerase chain reaction. Positive donors were independently retested and interviewed for parenteral transmission risks. Amplification products were sequenced and subjected to phylogenetic analysis. Recipients of reverse transcription-polymerase chain reaction-positive donations were traced and tested for HGV/GBV-C infection. RESULTS: A total of 14 (1.34%) of 1048 donors (alanine aminotransferase < 45 IU/L) were repeatedly positive for HGV/GBV-C with 9 (2.18%) of 413 urban and 5 (0.78%) of 635 rural donors (chi 2-test; p = 0.04). Isolates differed in nucleotide sequence homology over a range of 12.5 to 19.6 percent. All but one positive donor reported parenteral transmission risks. Transmission of HGV/GBV-C was detected in 4 of 9 transfusion recipients. The prevalence of HGV/GBV-C in donors with an alanine aminotransferase level > 45 IU per L was 3 percent (3/100). Two mother/child pairs were identified with highly homologous isolates. CONCLUSION: A significantly greater prevalence of HGV/GBV-C was detected in urban volunteer blood donors than in rural donors. The high prevalence in urban donors (2.18%) suggests specific transmission risks for this group. The less than 50-percent efficiency of HGV/GBV-C transmission via blood components may indicate the presence of defective viruses with reduced infectivity. There is evidence for vertical transmission.

Adult↗
PubMed1997

HLA-DRB1*04 subtypes are associated with increased inflammatory activity in early rheumatoid arthritis.

The sequence polymorphism of HLA-DRB1 molecules in 84 rheumatoid arthritis (RA) patients with early RA has been analysed to evaluate whether particular HLA-DR alleles influence disease progression in the early stage of the disease. Clinical data were analysed by grouping the patients according to disease-associated haplotype combinations (DRB1*04,04/DRB1*04,01/DRB1*04,X/DRB1*01,X) in comparison to patients who did not carry these haplotypes (DRB1*X,X). Our results indicate that patients with early RA who are homozygous for DRB1*04 exhibit an elevated inflammatory activity and an increase of joint affections. In addition, the amino acid polymorphism (QR/KRAA) at position 70-74 seems to affect the production of rheumatoid factors. These results support the role of HLA-DRB1 alleles in the pathogenesis of RA and indicate that patients with particular HLA-DRB1*04 haplotype combinations may require intensified therapeutic interventions in the early stage of the disease to prevent disease progression.

Adult↗
PubMed1997

Frequencies of GB virus C/hepatitis G virus genomes and of specific antibodies in German risk and non-risk populations.

The prevalence of the new flavivirus GB virus C/hepatitis virus G (GBV-C/HGV) in different German populations was investigated by detection of viral genomes and anti-E2 antibodies. While blood donors had an overall prevalence of 10.4% there were increased rates for hemophiliacs (54.7%), hemodialysis patients (30.2%), male homosexuals (30.2%) and intravenous drug users (74.4). Most GBV-C/HGV positive samples were either viral genome positive or antibody positive, exclusively. Samples with the rare constellation "positive for both GBV-C/HGV genome and specific antibody" originated in almost all cases from patients who were additionally infected with HIV or HCV. Probable transmission of GBV-C/HGV by PCR-positive blood transfusions was observed in 5 of 6 cases approximately six months after transfusion.

Blood Donors↗
PubMed1997

[Prevalence of hepatitis G virus genome in blood donors].

The relevance of the GB virus C/hepatitis G virus (GBV-C/HGV) in blood banking results from its high prevalence in blood donors and the fact that it is present at a very high percentage (18%) in polytransfused and hemophiliac patients. Since there is no assay available for serological testing, we developed a sensitive PCR utilizing newly designed NS3 primers to investigate the prevalence in blood donors in Hessia. Testing 1,143 accepted blood donors with alaninaminotransferase (ALT) concentrations < 45 U/l we found 15 (1.3%) positive for GBV-C/HGV RNA. From 507 donors settling in urban Frankfurt areas, 10 (2.0%) were positive. Of those donors settling in rural hessian areas only 5/635 (0.8%) tested positive. By testing 100 excluded donors with ALT values > 45 U/l, 3% turned out to be positive. In 4 out of 9 recipients of GBV-C/HGV-positive blood products we detected the donor viral RNA as proved by sequencing and phylogenetic analysis. The virus was transmitted to 3 recipients by erythrocytes and to 1 recipient by platelets. Testing family members of the GBV-C/HGV-positive blood donors we could not detect any intrafamilial transmission.

Blood Banks↗