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251 Publications visible to you, out of a total of 251
Association of MICA with rheumatoid arthritis independent of known HLA-DRB1 risk alleles in a family-based and a case control study
Genetical Statistics and Systems Biology

Abstract (Expand)

INTRODUCTION\backslashr\backslashnThe gene MICA encodes the protein major histocompatibility complex class I polypeptide-related sequence A. It is expressed in synovium of patients with rheumatoid … arthritis (RA) and its implication in autoimmunity is discussed. We analyzed the association of genetic variants of MICA with susceptibility to RA.\backslashr\backslashnMETHODS\backslashr\backslashnInitially, 300 French Caucasian individuals belonging to 100 RA trio families were studied. An additional 100 independent RA trio families and a German Caucasian case-control cohort (90/182 individuals) were available for replication. As MICA is situated in proximity to known risk alleles of the HLA-DRB1 locus, our analysis accounted for linkage disequilibrium either by analyzing the subgroup consisting of parents not carrying HLA-DRB1 risk alleles with transmission disequilibrium test (TDT) or by implementing a regression model including all available data. Analysis included a microsatellite polymorphism (GCT)n and single-nucleotide polymorphisms (SNPs) rs3763288 and rs1051794.\backslashr\backslashnRESULTS\backslashr\backslashnIn contrast to the other investigated polymorphisms, the non-synonymously coding SNP MICA-250 (rs1051794, Lys196Glu) was strongly associated in the first family cohort (TDT: P = 0.014; regression model: odds ratio [OR] 0.46, 95% confidence interval [CI] 0.25 to 0.82, P = 0.007). Although the replication family sample showed only a trend, combined family data remained consistent with the hypothesis of MICA-250 association independent from shared epitope (SE) alleles (TDT: P = 0.027; regression model: OR 0.56, 95% CI 0.38 to 0.83, P = 0.003). We also replicated the protective association of MICA-250A within a German Caucasian cohort (OR 0.31, 95% CI 0.1 to 0.7, P = 0.005; regression model: OR 0.6, 95% CI 0.37 to 0.96, P = 0.032). We showed complete linkage disequilibrium of MICA-250 (D’ = 1, r2= 1) with the functional MICA variant rs1051792 (D’ = 1, r2= 1). As rs1051792 confers differential allelic affinity of MICA to the receptor NKG2D, this provides a possible functional explanation for the observed association.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnWe present evidence for linkage and association of MICA-250 (rs1051794) with RA independent of known HLA-DRB1 risk alleles, suggesting MICA as an RA susceptibility gene. However, more studies within other populations are necessary to prove the general relevance of this polymorphism for RA.

Authors: Holger Kirsten, Elisabeth Petit-Teixeira, Markus Scholz, Dirk Hasenclever, Helene Hantmann, Dirk Heider, Ulf Wagner, Ulrich Sack, Vitor Hugo Teixeira, Bernard Prum, Jana Burkhardt, Céline Pierlot, Frank Emmrich, François Cornelis, Peter Ahnert

Date Published: 2009

Publication Type: Journal article

Effectiveness of cytopenia prophylaxis for different filgrastim and pegfilgrastim schedules in a chemotherapy mouse model
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVES Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is widely used to treat neutropenia during cytotoxic chemotherapy. The optimal scheduling of rhG-CSF is unknown and can …n hardly be tested in clinical studies due to numerous therapy parameters affecting outcome (chemotherapeutic regimen, rhG-CSF schedules, individual covariables). Motivated by biomathematical model simulations, we aim to investigate different rhG-CSF schedules in a preclinical chemotherapy mouse model. METHODS The time course of hematotoxicity was studied in CD-1 mice after cyclophosphamide (CP) administration. Filgrastim was applied concomitantly in a 2 x 3-factorial design of two dosing options (2 x 20 mug and 4 x 10 mug) and three timing options (directly, one, and two days after CP). Alternatively, a single dose of 40 mug pegfilgrastim was applied at the three timing options. The resulting cytopenia was compared among the schedules. RESULTS Dosing and timing had a significant influence on the effectiveness of filgrastim schedules whereas for pegfilgrastim the timing effect was irrelevant. The best filgrastim and pegfilgrastim schedules exhibited equivalent toxicity. Monocytes dynamics performed analogously to granulocytes. All schedules showed roughly the same lymphotoxicity. CONCLUSION We conclude that effectiveness of filgrastim application depends heavily on its scheduling during chemotherapy. There is an optimum of timing. Dose splitting is better than concentrated applications. Effectiveness of pegfilgrastim is less dependent on timing. OBJECTIVES Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is widely used to treat neutropenia during cytotoxic chemotherapy. The optimal scheduling of rhG-CSF is unknown and can hardly be tested in clinical studies due to numerous therapy parameters affecting outcome (chemotherapeutic regimen, rhG-CSF schedules, individual covariables). Motivated by biomathematical model simulations, we aim to investigate different rhG-CSF schedules in a preclinical chemotherapy mouse model. METHODS The time course of hematotoxicity was studied in CD-1 mice after cyclophosphamide (CP) administration. Filgrastim was applied concomitantly in a 2 x 3-factorial design of two dosing options (2 x 20 mug and 4 x 10 mug) and three timing options (directly, one, and two days after CP). Alternatively, a single dose of 40 mug pegfilgrastim was applied at the three timing options. The resulting cytopenia was compared among the schedules. RESULTS Dosing and timing had a significant influence on the effectiveness of filgrastim schedules whereas for pegfilgrastim the timing effect was irrelevant. The best filgrastim and pegfilgrastim schedules exhibited equivalent toxicity. Monocytes dynamics performed analogously to granulocytes. All schedules showed roughly the same lymphotoxicity. CONCLUSION We conclude that effectiveness of filgrastim application depends heavily on its scheduling during chemotherapy. There is an optimum of timing. Dose splitting is better than concentrated applications. Effectiveness of pegfilgrastim is less dependent on timing.

Authors: Markus Scholz, Manuela Ackermann, Frank Emmrich, Markus Loeffler, Manja Kamprad

Date Published: 2009

Publication Type: Journal article

Neuronal hypoxia in vitro: investigation of therapeutic principles of HUCB-MNC and CD133+ stem cells
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnThe therapeutic capacity of human umbilical cord blood mononuclear cells (HUCB-MNC) and stem cells derived thereof is documented in animal models of focal cerebral … ischemia, while mechanisms behind the reduction of lesion size and the observed improvement of behavioral skills still remain poorly understood.\backslashr\backslashnMETHODS\backslashr\backslashnA human in vitro model of neuronal hypoxia was used to address the impact of total HUCB-MNC (tMNC), a stem cell enriched fraction (CD133+, 97.38% CD133-positive cells) and a stem cell depleted fraction (CD133-, 0.06% CD133-positive cells) of HUCB-MNC by either direct or indirect co-cultivation with post-hypoxic neuronal cells (differentiated SH-SY5Y). Over three days, development of apoptosis and necrosis of neuronal cells, chemotaxis of MNC and production of chemokines (CCL2, CCL3, CCL5, CXCL8, CXCL9) and growth factors (G-CSF, GM-CSF, VEGF, bFGF) were analyzed using fluorescence microscopy, FACS and cytometric bead array.\backslashr\backslashnRESULTS\backslashr\backslashntMNC, CD133+ and surprisingly CD133- reduced neuronal apoptosis in direct co-cultivations significantly to levels in the range of normoxic controls (7% +/- 3%). Untreated post-hypoxic control cultures showed apoptosis rates of 85% +/- 11%. tMNC actively migrated towards injured neuronal cells. Both co-cultivation types using tMNC or CD133- reduced apoptosis comparably. CD133- produced high concentrations of CCL3 and neuroprotective G-CSF within indirect co-cultures. Soluble factors produced by CD133+ cells were not detectable in direct co-cultures.\backslashr\backslashnCONCLUSION\backslashr\backslashnOur data show that heterogeneous tMNC and even CD133-depleted fractions have the capability not only to reduce apoptosis in neuronal cells but also to trigger the retaining of neuronal phenotypes. BACKGROUND The therapeutic capacity of human umbilical cord blood mononuclear cells (HUCB-MNC) and stem cells derived thereof is documented in animal models of focal cerebral ischemia, while mechanisms behind the reduction of lesion size and the observed improvement of behavioral skills still remain poorly understood. METHODS A human in vitro model of neuronal hypoxia was used to address the impact of total HUCB-MNC (tMNC), a stem cell enriched fraction (CD133+, 97.38% CD133-positive cells) and a stem cell depleted fraction (CD133-, 0.06% CD133-positive cells) of HUCB-MNC by either direct or indirect co-cultivation with post-hypoxic neuronal cells (differentiated SH-SY5Y). Over three days, development of apoptosis and necrosis of neuronal cells, chemotaxis of MNC and production of chemokines (CCL2, CCL3, CCL5, CXCL8, CXCL9) and growth factors (G-CSF, GM-CSF, VEGF, bFGF) were analyzed using fluorescence microscopy, FACS and cytometric bead array. RESULTS tMNC, CD133+ and surprisingly CD133- reduced neuronal apoptosis in direct co-cultivations significantly to levels in the range of normoxic controls (7% +/- 3%). Untreated post-hypoxic control cultures showed apoptosis rates of 85% +/- 11%. tMNC actively migrated towards injured neuronal cells. Both co-cultivation types using tMNC or CD133- reduced apoptosis comparably. CD133- produced high concentrations of CCL3 and neuroprotective G-CSF within indirect co-cultures. Soluble factors produced by CD133+ cells were not detectable in direct co-cultures. CONCLUSION Our data show that heterogeneous tMNC and even CD133-depleted fractions have the capability not only to reduce apoptosis in neuronal cells but also to trigger the retaining of neuronal phenotypes.

Authors: Doreen M. Reich, Susann Hau, Tobias Stahl, Markus Scholz, Wilfried Naumann, Frank Emmrich, Johannes Boltze, Manja Kamprad

Date Published: 1st Dec 2008

Publication Type: Journal article

Zur Bedeutung der Genvariante PTPN22 620W für die Rheumatologie
Genetical Statistics and Systems Biology

Abstract (Expand)

PTPN22 620W is regarded as the second most important risk factor for type 1 diabetes and rheumatoid arthritis. Here we describe aspects of the molecular biology of the enzyme and its function, the … geographical distribution of the 620W variant, as well as its importance in less frequent rheumatic diseases.

Authors: Inga Melchers, Peter Ahnert

Date Published: 1st Nov 2008

Publication Type: Journal article

Genome-wide genetic characterization of an atypical meningioma by single-nucleotide polymorphism array-based mapping and classical cytogenetics
Genetical Statistics and Systems Biology

Abstract (Expand)

Most meningiomas, accounting for about 20% of intracranial tumors, can be cured by surgical removal. Yet, 8-22% of these tumors are classified as atypical or anaplastic (WHO grade II or III, respectively) … presenting with a more aggressive behavior and a high relapse rate. We analyzed genomic alterations of an atypical meningioma using high-density single nucleotide polymorphism arrays (SNP-A) karyotyping combined with GTG-banding, multicolor fluorescence in situ hybridization (M-FISH), and locus-specific FISH. In accordance to recent studies applying SNP-A karyotyping in different malignancies we found that genomic lesions are present at a higher frequency than predicted by traditional cytogenetics. Most of these aberrations have not been described before. Additionally, we unveiled loss of heterozygosity (LOH) without copy number changes on chromosome regions 1p31.1, 2p16.1, 2q23.3, 6q14.1, 6q21, 9p21.1, 10q21.1, and 14q23.3, suggesting partial uniparental disomy (UPD). UPDs are currently considered to play an important role in the initiation and progression of different malignancies. Furthermore, we detected two de novo reciprocal translocations, t(8;19)(q24;q13) and t(10;16)(q22;q12.1). While GTG-banding and M-FISH data suggested balanced translocations, SNP-A analysis clearly demonstrated imbalances in the same region.

Authors: Wolfgang Krupp, Heidrun Holland, Ronald Koschny, Manfred Bauer, Ralf Schober, Holger Kirsten, Michela Livrea, Jürgen Meixensberger, Peter Ahnert

Date Published: 1st Jul 2008

Publication Type: Journal article

The prevalence of activated protein C (APC) resistance and factor V Leiden is significantly higher in patients with retinal vein occlusion without general risk factors. Case-control study and meta-analysis.
Genetical Statistics and Systems Biology

Abstract (Expand)

Several small case-control studies have investigated whether factor V Leiden (FVL) is a risk factor for retinal vein occlusion (RVO) and generated conflicting data. To clarify this question we performed … a large two-centre case-control study and a meta-analysis of published studies. Two hundred seven consecutive patients with RVO and a control group of 150 subjects were screened between 1996 and 2006. A systematic meta-analysis was done combining our study with further 17 published European case-control studies. APC resistance was detected in 16 out of 207 (7.7%) patients and eight out of 150 (5.3%) controls. The odds ratio (OR) estimated was 1.49 with a (non-significant) 95% confidence interval (CI) of 0.62-3.57. The meta-analysis including 18 studies with a total of 1,748 patients and 2,716 controls showed a significantly higher prevalence of FVL in patients with RVO compared to healthy controls (combined OR 1.66; 95% CI 1.19-2.32). All single studies combined in the meta-analysis were too small to reliably detect the effect individually. This explains the seemingly contradictory data in the literature. In conclusion, the prevalence of APC resistance (and FVL) is increased in patients with RVO compared to controls, but the effect is only moderate. Therefore, there is no indication for general screening of factor V mutation in all patients with RVO. We recommend this test to be performed in patients older than 50 years with an additional history of thromboembolic event and in younger patients without general risk factors like hypertension.

Authors: Matus Rehak, Jiri Rehak, Marc Müller, Susanne Faude, Frank Faude, Annelie Siegemund, Vera Krcova, Ludek Slavik, Dirk Hasenclever, Markus Scholz, Peter Wiedemann

Date Published: 9th Apr 2008

Publication Type: Journal article

Cardiac surgery fast-track treatment in a postanesthetic care unit: six-month results of the Leipzig fast-track concept
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnThe authors compared the safety and efficacy of a newly developed fast-track concept at their center, including implementation of a direct admission postanesthetic care … unit, to standard perioperative management.\backslashr\backslashnMETHODS\backslashr\backslashnAll fast-track patients treated within the first 6 months of implementation of our direct admission postanesthetic care unit were matched via propensity scores and compared with a historical control group of patients who underwent cardiac surgery prior to fast-track implementation.\backslashr\backslashnRESULTS\backslashr\backslashnA total of 421 fast-track patients were matched successfully to 421 control patients. The two groups of patients had a similar age (64 +/- 13 vs. 64 +/- 12 yr for fast-track vs. control, P = 0.45) and European System for Cardiac Operative Risk Evaluation-predicted risk of mortality (4.8 +/- 6.1% vs. 4.6 +/- 5.1%, P = 0.97). Fast-track patients had significantly shorter times to extubation (75 min [45-110] vs. 900 min [600-1140]), as well as shorter lengths of stay in the postanesthetic or intensive care unit (4 h [3.0-5] vs. 20 h [16-25]), intermediate care unit (21 h [17-39] vs. 26 h [19-49]), and hospital (10 days [8-12] vs. 11 days [9-14]) (expressed as median and interquartile range, all P \textless 0.01). Fast-track patients also had a lower risk of postoperative low cardiac output syndrome (0.5% vs. 2.9%, P \textless 0.05) and mortality (0.5% vs. 3.3%, P \textless 0.01).\backslashr\backslashnCONCLUSION\backslashr\backslashnThe Leipzig fast-track protocol is a safe and effective method to manage cardiac surgery patients after a variety of operations. BACKGROUND The authors compared the safety and efficacy of a newly developed fast-track concept at their center, including implementation of a direct admission postanesthetic care unit, to standard perioperative management. METHODS All fast-track patients treated within the first 6 months of implementation of our direct admission postanesthetic care unit were matched via propensity scores and compared with a historical control group of patients who underwent cardiac surgery prior to fast-track implementation. RESULTS A total of 421 fast-track patients were matched successfully to 421 control patients. The two groups of patients had a similar age (64 +/- 13 vs. 64 +/- 12 yr for fast-track vs. control, P = 0.45) and European System for Cardiac Operative Risk Evaluation-predicted risk of mortality (4.8 +/- 6.1% vs. 4.6 +/- 5.1%, P = 0.97). Fast-track patients had significantly shorter times to extubation (75 min [45-110] vs. 900 min [600-1140]), as well as shorter lengths of stay in the postanesthetic or intensive care unit (4 h [3.0-5] vs. 20 h [16-25]), intermediate care unit (21 h [17-39] vs. 26 h [19-49]), and hospital (10 days [8-12] vs. 11 days [9-14]) (expressed as median and interquartile range, all P \textless 0.01). Fast-track patients also had a lower risk of postoperative low cardiac output syndrome (0.5% vs. 2.9%, P \textless 0.05) and mortality (0.5% vs. 3.3%, P \textless 0.01). CONCLUSION The Leipzig fast-track protocol is a safe and effective method to manage cardiac surgery patients after a variety of operations.

Authors: Joerg Ender, Michael Andrew Borger, Markus Scholz, Anne-Kathrin Funkat, Nadeem Anwar, Marcus Sommer, Friedrich Wilhelm Mohr, Jens Fassl

Date Published: 2008

Publication Type: Journal article

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