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227 Publications visible to you, out of a total of 227
A pharmacokinetic model of filgrastim and pegfilgrastim application in normal mice and those with cyclophosphamide-induced granulocytopaenia
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVES\backslashr\backslashnRecombinant human granulocyte colony-stimulating factor (rhG-CSF) is widely used as treatment for granulocytopaenia during cytotoxic chemotherapy; however, optimal … scheduling of this pharmaceutical is unknown. Biomathematical models can help to pre-select optimal application schedules but precise pharmacokinetic properties of the pharmaceuticals are required at first. In this study, we have aimed to construct a pharmacokinetic model of G-CSF derivatives filgrastim and pegfilgrastim in mice.\backslashr\backslashnMETHODS\backslashr\backslashnHealthy CD-1 mice and those with cyclophosphamide-induced granulocytopaenia were studied after administration of filgrastim and pegfilgrastim in different dosing and timing schedules. Close meshed time series of granulocytes and G-CSF plasma concentrations were determined. An ordinary differential equations model of pharmacokinetics was constructed on the basis of known mechanisms of drug distribution and degradation.\backslashr\backslashnRESULTS\backslashr\backslashnPredictions of the model fit well with all experimental data for both filgrastim and pegfilgrastim. We obtained a unique parameter setting for all experimental scenarios. Differences in pharmacokinetics between filgrastim and pegfilgrastim can be explained by different estimates of model parameters rather than by different model mechanisms. Parameter estimates with respect to distribution and clearance of the drug derivatives are in agreement with qualitative experimental results.\backslashr\backslashnCONCLUSION\backslashr\backslashnDynamics of filgrastim and pegfilgrastim plasma levels can be explained by the same pharmacokinetic model but different model parameters. Beause of a strong clearance mechanism mediated by granulocytes, granulocytotic and granulocytopaenic conditions must be studied simultaneously to construct a reliable model. The pharmacokinetic model will be extended to a murine model of granulopoiesis under chemotherapy and G-CSF application.

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

Date Published: 1st Dec 2009

Publication Type: Journal article

Pharmacokinetic and pharmacodynamic modelling of the novel human granulocyte colony-stimulating factor derivative Maxy-G34 and pegfilgrastim in rats
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVES\backslashr\backslashnThis study aims to compare pharmacokinetics and pharmacodynamics of pegfilgrastim, a pharmaceutical recombinant human granulocyte colony-stimulating factor (rhG-CSF), … with that of a newly developed reagent, Maxy-G34. This comparison was performed using rat experiments and biomathematical modelling of granulopoiesis.\backslashr\backslashnMETHODS\backslashr\backslashnHealthy rats and those with cyclophosphamide-induced neutropenia were treated with either pegfilgrastim or Maxy-G34 under various schedules. Time courses of absolute neutrophil count (ANC) and G-CSF serum level were measured and we constructed a combined pharmacokinetic/pharmacodynamic model of both drugs. Neutropenic episodes were assessed by experimental data and model simulations.\backslashr\backslashnRESULTS\backslashr\backslashnBoth Pegfilgrastim and Maxy-G34 showed strong dose-dependent efficacy in reducing neutropenic episodes. However, time courses of ANC and G-CSF serum levels were markedly different. The biomathematical model showed good agreement with these data. We estimated that differences between the two drugs could be explained by lower bioavailability and reduced elimination of Maxy-G34. Based on the data and model interpolations, we estimated that Maxy-G34 is superior in reducing neutropenic episodes. Also, we predicted that G-CSF administration 48 h after cyclophosphamide would be superior to its administration after 2 or 24 h, for both derivatives.\backslashr\backslashnCONCLUSION\backslashr\backslashnMaxy-G34 is a highly potent drug for stimulation of neutrophil production in rats. By our modelling approach, we quantified differences between Maxy-G34 and pegfilgrastim, related to pharmacokinetic parameters. Model simulations can be used to estimate optimal dosing and timing options in the present preclinical rat model.

Authors: Markus Scholz, Christoph Engel, D. Apt, S. L. Sankar, E. Goldstein, Markus Loeffler

Date Published: 1st Dec 2009

Publication Type: Journal article

Genetic variation and recent positive selection in worldwide human populations: evidence from nearly 1 million SNPs
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND\backslashr\backslashnGenome-wide scans of hundreds of thousands of single-nucleotide polymorphisms (SNPs) have resulted in the identification of new susceptibility variants to common diseases … and are providing new insights into the genetic structure and relationships of human populations. Moreover, genome-wide data can be used to search for signals of recent positive selection, thereby providing new insights into the genetic adaptations that occurred as modern humans spread out of Africa and around the world.\backslashr\backslashnMETHODOLOGY\backslashr\backslashnWe genotyped approximately 500,000 SNPs in 255 individuals (5 individuals from each of 51 worldwide populations) from the Human Genome Diversity Panel (HGDP-CEPH). When merged with non-overlapping SNPs typed previously in 250 of these same individuals, the resulting data consist of over 950,000 SNPs. We then analyzed the genetic relationships and ancestry of individuals without assigning them to populations, and we also identified candidate regions of recent positive selection at both the population and regional (continental) level.\backslashr\backslashnCONCLUSIONS\backslashr\backslashnOur analyses both confirm and extend previous studies; in particular, we highlight the impact of various dispersals, and the role of substructure in Africa, on human genetic diversity. We also identified several novel candidate regions for recent positive selection, and a gene ontology (GO) analysis identified several GO groups that were significantly enriched for such candidate genes, including immunity and defense related genes, sensory perception genes, membrane proteins, signal receptors, lipid binding/metabolism genes, and genes involved in the nervous system. Among the novel candidate genes identified are two genes involved in the thyroid hormone pathway that show signals of selection in African Pygmies that may be related to their short stature.

Authors: David López Herráez, Marc Bauchet, Kun Tang, Christoph Theunert, Irina Pugach, Jing Li, Madhusudan R. Nandineni, Arnd Gross, Markus Scholz, Mark Stoneking

Date Published: 18th Nov 2009

Publication Type: Journal article

Association of the X-chromosomal genes TIMP1 and IL9R with rheumatoid arthritis
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVE\backslashr\backslashnRheumatoid arthritis (RA) is an inflammatory joint disease with features of an autoimmune disease with female predominance. Candidate genes located on the X-chromosome … were selected for a family trio-based association study.\backslashr\backslashnMETHODS\backslashr\backslashnA total of 1452 individuals belonging to 3 different sample sets were genotyped for 16 single-nucleotide polymorphisms (SNP) in 7 genes. The first 2 sets consisted of 100 family trios, each of French Caucasian origin, and the third of 284 additional family trios of European Caucasian origin. Subgroups were analyzed according to sex of patient and presence of anti-cyclic citrullinated peptide (anti-CCP) autoantibodies.\backslashr\backslashnRESULTS\backslashr\backslashnFour SNP were associated with RA in the first sample set and were genotyped in the second set. In combined analysis of sets 1 and 2, evidence remained for association of 3 SNP in the genes UBA1, TIMP1, and IL9R. These were again genotyped in the third sample set. Two SNP were associated with RA in the joint analysis of all samples: rs6520278 (TIMP1) was associated with RA in general (p = 0.035) and rs3093457 (IL9R) with anti-CCP-positive RA patients (p = 0.037) and male RA patients (p = 0.010). A comparison of the results with data from whole-genome association studies further supports an association of RA with TIMPL The sex-specific association of rs3093457 (IL9R) was supported by the observation that men homozygous for rs3093457-CC are at a significantly higher risk to develop RA than women (risk ratio male/female = 2.98; p = 0.048).\backslashr\backslashnCONCLUSION\backslashr\backslashnWe provide evidence for an association of at least 2 X-chromosomal genes with RA: TIMP1 (rs6520278) and IL9R (rs3093457).

Authors: Jana Burkhardt, Elisabeth Petit-Teixeira, Vitor Hugo Teixeira, Holger Kirsten, Sophie Garnier, Sandra Ruehle, Christian Oeser, Grit Wolfram, Markus Scholz, Paola Migliorini, Alejandro Balsa, Renè Westhovens, Pilar Barrera, Helena Alves, Dora Pascual-Salcedo, Stefano Bombardieri, Jan Dequeker, Timothy R. Radstake, Piet van Riel, Leo van de Putte, Thomas Bardin, Bernard Prum, Ulrike Buchegger-Podbielski, Frank Emmrich, Inga Melchers, François Cornelis, Peter Ahnert

Date Published: 8th Oct 2009

Publication Type: Journal article

A family-based study does not support the association of a functional polymorphism in the gene for endothelial nitric oxide synthase with risk for rheumatoid arthritis
Genetical Statistics and Systems Biology

Abstract

Not specified

Authors: Holger Kirsten, Elisabeth Petit-Teixeira, Helene Hantmann, J. Reichardt, Jana Burkhardt, Frank Emmrich, François Cornelis, Peter Ahnert

Date Published: 13th Aug 2009

Publication Type: Journal article

Anesthesia management for transapical transcatheter aortic valve implantation: a case series
Genetical Statistics and Systems Biology

Abstract (Expand)

OBJECTIVE\backslashr\backslashnThe purpose of this study was to review the management of anesthesia for transapical transcatheter aortic valve implantation.\backslashr\backslashnDESIGN\backslashr\backslashnRetrospective … review of collected data.\backslashr\backslashnSETTING\backslashr\backslashnUniversity-affiliated heart center.\backslashr\backslashnPARTICIPANTS\backslashr\backslashnOne hundred consecutive patients with severe aortic stenosis.\backslashr\backslashnINTERVENTIONS\backslashr\backslashnGeneral anesthesia followed by an established fast-track protocol.\backslashr\backslashnMATERIALS AND METHODS\backslashr\backslashnA total of 100 patients with significant AS received transapical transcatheter aortic valve implantation. The patients were treated following a fast-track protocol. The mean arterial pressure was maintained above 65 mmHg by volume and/or inotropes during the procedure. The mean arterial pressure was increased above 75 mmHg to avoid hemodynamic deterioration before starting rapid ventricular pacing for the balloon valvuloplasty and the valve implantation. Transesophageal echocardiography was used to assess valve size and for hemodynamic monitoring. Eighty-one patients were treated completely off pump. There was a significant decline in mean arterial pressure from pre- to postvalvuloplasty (74.7 +/- 9.1 mmHg v 63.6 +/- 11.3 mmHg, p \textless 0.001) and from pre- to postimplantation (76.5 +/- 12.6 mmHg v 67.2 +/- 12.7, p \textless 0.001). The first 10 patients in the study intentionally were placed on cardiopulmonary bypass, and 9 patients required cardiopulmonary bypass because of hemodynamic deterioration.\backslashr\backslashnCONCLUSION\backslashr\backslashnA well-designed anesthetic plan as well as an understanding of the surgical procedure and the hemodynamic effects of rapid ventricular pacing are required to ensure successful outcomes in this new surgical option for high-risk patients.

Authors: Jens Fassl, Thomas Walther, Heinrich Volker Groesdonk, Joerg Kempfert, Michael Andrew Borger, Markus Scholz, Chirojit Mukherjee, Axel Linke, Gerhard Schuler, Friedrich Wilhelm Mohr, Joerg Ender

Date Published: 1st Jun 2009

Publication Type: Journal article

The role of gene DCDC2 in German dyslexics
Genetical Statistics and Systems Biology

Abstract (Expand)

Dyslexia is a complex reading and writing disorder with a strong genetic component. In a German case-control cohort, we studied the influence of the suspected dyslexia-associated gene DCDC2. For the … first time in a German cohort, we describe association of a 2445 basepair deletion, first identified in an American study. Evidence of association for three DCDC2 single nucleotide polymorphisms (rs807724, rs793862, rs807701), previously identified in German or American cohorts, was replicated. A haplotype of these polymorphisms showed evidence for association as well. Thus, our data further corroborate association of DCDC2 with dyslexia. Analysis of functional subgroups suggests association of investigated DCDC2 variants mainly with nondysphonetic, nonsevere, but probably dyseidetic (surface) dyslexia. Based on the presumed function of DCDC2, our findings point to a role of impaired neuronal migration in the etiology of the disease. Dyslexia is a complex reading and writing disorder with a strong genetic component. In a German case-control cohort, we studied the influence of the suspected dyslexia-associated gene DCDC2. For the first time in a German cohort, we describe association of a 2445 basepair deletion, first identified in an American study. Evidence of association for three DCDC2 single nucleotide polymorphisms (rs807724, rs793862, rs807701), previously identified in German or American cohorts, was replicated. A haplotype of these polymorphisms showed evidence for association as well. Thus, our data further corroborate association of DCDC2 with dyslexia. Analysis of functional subgroups suggests association of investigated DCDC2 variants mainly with nondysphonetic, nonsevere, but probably dyseidetic (surface) dyslexia. Based on the presumed function of DCDC2, our findings point to a role of impaired neuronal migration in the etiology of the disease.

Authors: Arndt Wilcke, Jana Weissfuss, Holger Kirsten, Grit Wolfram, Johannes Boltze, Peter Ahnert

Date Published: 1st Jun 2009

Publication Type: Journal article

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