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Biomedical subjects

Hans Peter Schwarz

Publications and source records attributed to Hans Peter Schwarz.

At least 19 recordsLinked to original sources
PubMed2006

Early manifestation of type 1 diabetes in children is a risk factor for changed bone geometry: data using peripheral quantitative computed tomography.

OBJECTIVE: Normal to severely decreased bone mineral density has been reported in children with type 1 diabetes. To detect possible abnormalities in bone mineralization, geometry, and muscle bone unit, we measured selective parameters in children with type 1 diabetes using peripheral quantitative computed tomography. METHODS: Measurements of the radius by peripheral quantitative computed tomography were made to assess cortical and trabecular bone characteristics as well as muscle mass in 88 patients (42 girls, 46 boys) at a mean age of 11.7 +/- 3.0 years, a mean disease duration of 5.6 +/- 3.7 years, and a mean manifestation age of type 1 diabetes of 6.1 +/- 3.5 years. Height, weight, Tanner stage, insulin regimen, and glycosylated hemoglobin values were recorded. Bone metabolism was studied by measurement of bone formation and bone resorption parameters. Dynamic muscle force was measured using a grip strength device. RESULTS: Overall, cortical, trabecular, and total bone mineral density were within the reference range. Total and cortical bone cross-sectional area and muscle mass were low in prepubertal patients, and total cross-sectional area was low in early puberty. Adolescent patients showed normal bone and muscle parameters. Grip strength and recreational physical activity were normal in all in relation to a healthy reference population. In a subgroup of 18 patients, early manifestation of type 1 diabetes was detected as a risk factor for altered bone development with significantly reduced cortical bone mineral density and total, cortical, and muscle cross-sectional area (-0.9 +/- 1.3 SD, -2.1 +/- 1.3 SD, -1.6 +/- 0.7 SD, and -1.0 +/- 0.7 SD, respectively). Bone characteristics were not influenced by metabolic control, disease duration, or insulin regimen. CONCLUSIONS: Manifestation of type 1 diabetes at an early age may impair bone development. Longitudinal data are needed to determine whether this impairment persists into adolescence and adulthood.

Adolescent↗
PubMed2006

Removal of small nonenveloped viruses by antibody-enhanced nanofiltration during the manufacture of plasma derivatives.

BACKGROUND: Filters with nominal pore sizes in the nanometer range are well-established tools for enhancing the virus safety margins of plasma-derived products, yet intrinsically less successful for smaller viruses such as hepatitis A virus (HAV) and human parvovirus B19 (B19V). The formation of virus-antibody complexes increases the effective size of these smaller viruses and would thus improve their removal by nanofiltration. While the principle of virus removal by antibody-dependent nanofiltration has been demonstrated with animal antisera and viruses spiked into human plasma product intermediates, the significance of these results remains unclear due to the potential contributions of xenoanti-bodies and/or heteroagglutination in such heterologous systems. STUDY DESIGN AND METHODS: The current study investigated antibody-dependent virus removal by nanofiltration in a heterologous animal parvovirus system to establish the concentration dependence of the effect. In addition, the phenomenon was investigated in a homologous system with custom-made HAV and B19V antibody-free and -containing human immunoglobulin intermediates. Viruses were analyzed with infectivity assays and fully validated polymerase chain reaction assays that also circumvent the obscuring effects of neutralizing antibodies with infectivity assays. RESULTS: By use of the heterologous mice minute virus and the homologous HAV and B19V systems, viruses passed the 35-nm (Planova 35N) filter in the absence of specific antibodies. Beyond a threshold virus antibody concentration, nanofiltration resulted in effective virus removal of viruses smaller than the nominal pore size of the filter used. CONCLUSION: HAV and B19V are effectively removed by antibody-dependent 35N nanofiltration, already at intermediate antibody concentrations well below those comparable to human plasma pools for fractionation.

Animals↗
PubMed2006

Biochemical, molecular characterization, and glycoproteomic analyses of alpha(1)-proteinase inhibitor products used for replacement therapy.

BACKGROUND: Isoelectric focusing (IEF) of alpha(1)-proteinase inhibitor (A1PI) shows that commercial products and plasma have different glycoisoform band patterns. Those in Aralast (Grifols Biologicals) reflect an anodal shift of glycoisoforms, which has caused concern. The protein, including glycoproteomic analyses, and structural features of A1PI products were investigated by state-of-the-art techniques. STUDY DESIGN AND METHODS: Batches from Aralast, Prolastin (Bayer), and Zemaira (Aventis Behring LLC) were analyzed by high-resolution IEF and high-performance size-exclusion chromatography (HP-SEC). Preparative separated isoforms from IEF were further purified by chromatography and subjected to mass spectrometry for sequence analyses, peptide mapping, and glycosylation analysis. Deamidation was quantified by enzymatic isoaspartate detection. Multiple sequence alignments and structural bioinformatics analyses were performed. RESULTS: In HP-SEC, Prolastin had the highest aggregate content at approximately 30 percent. Isoforms from all products purified by high-resolution IEF were sequenced with an amino acid coverage of more than 98 percent. Deamidation of Asn116 and Asn314 in A1PI was to found to some extent in all products and confirmed quantitatively by enzymatic analysis. There were no signs of methionine oxidation. Cys232 was found to be cysteinylated in A1PI in Prolastin and Aralast as in plasma, but not in Zemaira. All products showed truncation of the C-terminal lysine. Intact A1PI concentrates contained mainly diantennary, disialylated and smaller amounts of triantennary, trisialylated N-glycans. The percentage of fucosylation was similar in all products. Site-specific glycan analysis revealed bands M6 contained only diantennary glycans, whereas the more acidic bands M4 and M2 also carried triantennary structures. The most acidic isoforms, M2 in Prolastin and Zemaira and M0 in Aralast, additionally exhibited tetraantennary N-glycans. CONCLUSION: Protein chemical characterization of A1PI showed that all A1PI products to some extent differ from A1PI circulating in human plasma. Bioinformatic analysis indicated that removal of C-terminal Lys394 and cysteinylation of Cys232 are unlikely to affect structure and/or function of A1PI but cysteinylation may influence interaction between A1PI and its physiologic ligands. Aralast, Prolastin, and Zemaira contain the same set of N-glycans in the same ratios as those in normal human plasma A1PI. Tri- and tetraantennary structures are responsible for the partitioning into IEF isoforms, with the migration shift of Aralast not being due to any difference in the N-glycosylation, but to the partial loss of the C-terminal lysine.

Chromatography, High Pressure Liquid↗
PubMed2006

Tolerance to factor VIII in a transgenic mouse expressing human factor VIII cDNA carrying an Arg(593) to Cys substitution.

Inhibitory antibodies develop in approximately 25% of patients with severe hemophilia. A following treatment with factorVIII. In E-16KO or E-17KO mice, in which the factor VIII gene has been inactivated by insertion of a neo cassette, inhibitors develop following administration of factor VIII. Here, we describe the generation of transgenic mice expressing human factor VIII-R593C (huFVIII-R593C). Human factor VIII-R593C cDNA under control of a mouse albumin enhancer/promoter was injected into fertilized oocytes. Analysis of transgenic mice revealed that human factor VIII-R593C was expressed in the liver. Transgenic mice were crossed with factor VIII-deficient mice (E-16KO mice). In plasma of E-16KO mice antibodies were detected after five serial intravenous injections of factor VIII, while plasma of huFVIII-R593C/E-16KO mice did not contain detectable levels of antibodies. No antibody secreting cells were observed in either spleen or bone marrow of huFVIII-R593C/E-16KO mice. Also, factor VIII-specific memory B cells were not observed in the spleen of huFVIII-R593C/E-16KO mice. Analysis of T cell responses revealed that splenocytes derived of E-16KO mice secreted IL-10 and IFN-gamma following restimulation with factor VIII in vitro. In contrast, no factor VIII-specific T cell responses were observed in huFVIII-R593C/E-16KO mice. These results indicate that huFVIII-R593C/E-16KO mice are tolerant to intravenously administered factor VIII. It is anticipated that this model may prove useful for studying immune responses in the context of factor VIII gene therapy.

Amino Acid Substitution↗
PubMed2006

Recombinant factor VIII and factor VIII-von Willebrand factor complex do not present danger signals for human dendritic cells.

Several lines of evidence have shown that antibody responses to coagulation factor VIII (FVIII) in patients with hemophilia A depend on the help of activated CD4(+) T cells. The primary activation of CD4(+) T cells requires interaction with mature dendritic cells (DCs) that present antigenic peptides in the context of MHC class II and express costimulatory molecules. Maturation of DCs requires danger signals provided by exogenous or endogenous stimuli such as pathogen-derived products or inflammatory cytokines. We asked the question whether FVIII itself, FVIII complexed with von Willebrand factor (VWF) or thrombin-activated FVIII contain danger signals for human DCs that induce the upregulation of costimulatory molecules or the expression of proinflammatory cytokines necessary for effective activation of CD4(+) T cells. Human peripheral monocytes were differentiated into DCs. FVIII, thrombin-activated FVIII, VWF, VWF-FVIII, lipopolysaccharide (LPS), LPS + FVIII, LPS + VWF or LPS + FVIII-VWF were added either on day 0 or on day 5 of differentiation cultures. Differentiation markers, cytokines in cell culture supernatants and the capacity of DCs to stimulate autologous and allogeneic T cells were analysed after seven days of differentiation cultures. Our results indicate that neither FVIII, thrombin-activated FVIII, VWF nor a complex of FVIII and VWF modulate the maturation of human DCs or their capacity to stimulate autologous or allogeneic T cells. We conclude that neither of these proteins present danger signals to human DCs.

Animals↗
PubMed2005

High-dose factor VIII inhibits factor VIII-specific memory B cells in hemophilia A with factor VIII inhibitors.

Hemophilia A in its severe form is a life-threatening hemorrhagic disease that is caused by mutations in the factor VIII (FVIII) gene (symbol F8). About 25% of patients who receive replacement therapy develop neutralizing antibodies that inhibit the function of substituted FVIII. Long-term application of high doses of FVIII has evolved as an effective therapy to eradicate the antibodies and to induce long-lasting immune tolerance. Little is known, however, about the immunologic mechanisms that cause the down-modulation of anti-FVIII antibodies by high doses of FVIII. We report that high doses of FVIII inhibit the restimulation of FVIII-specific memory B cells and their differentiation into antibody-secreting plasma cells in vitro and in vivo in a murine model of hemophilia A. The inhibition of memory B-cell responses is irreversible and not mediated by FVIII-specific T cells. Furthermore, it seems to involve the activation of caspases. We conclude that the inhibition of FVIII-specific memory B cells might be an early event in the down-modulation of anti-FVIII antibodies in patients with hemophilia A who receive high doses of FVIII.

Animals↗
PubMed2004

Preventing restimulation of memory B cells in hemophilia A: a potential new strategy for the treatment of antibody-dependent immune disorders.

Memory B cells are responsible for the rapidly emerging antibody response after antigen reexposure. The signals required for the restimulation of memory B cells have not been fully explained. We used a murine model of anti-factor VIII (FVIII) antibody responses in hemophilia A to study the requirements for the restimulation of FVIII-specific memory B cells and their differentiation into anti-FVIII antibody-producing cells. We were particularly interested in the significance of activated T cells and costimulatory interactions. Our results indicate that the restimulation of FVIII-specific memory B cells is strictly dependent on interactions with activated T cells. These activated T cells can be specific for either FVIII or third-party antigens. Restimulation by T cells specific for third-party antigens requires the presence of FVIII, indicating that signals induced by B-cell receptor (BCR) triggering and by interactions with activated T cells are important. The blockade of B7-1 or B7-2 as well as the blockade of CD40L inhibits the restimulation and differentiation of FVIII-specific memory B cells in vitro and in vivo. The interference with inducible costimulator-inducible costimulator ligand (ICOS-ICOSL) interactions, however, does not cause any modulation. As expected, the production of anti-FVIII antibodies by plasma cells is not dependent on any of the costimulatory interactions tested.

Animals↗
PubMed2004

Partial anomalous pulmonary vein connection: an underestimated cardiovascular defect in Ullrich-Turner syndrome.

UNLABELLED: Congenital cardiovascular defects, commonly affecting the aortic valve or the aortic arch (50% to 70%), are seen in ca. 17%-44% of patients with Ullrich-Turner syndrome (UTS). However, there are only 36 case reports worldwide on the coincidental finding of partial anomalous pulmonary vein connection (PAPVC) in UTS. In 4 out of 108 patients with UTS seen in our clinic, PAPVC was suspected echocardiographically and confirmed by angiography in three patients. Surgical correction was performed in one patient with right ventricular enlargement. PAPVC can lead to right ventricular volume load and hypertrophy in adolescence. Early diagnosis and when necessary treatment is recommended. CONCLUSION: cardiological evaluation in patients with Ullrich-Turner syndrome should pay special attention to partial anomalous pulmonary vein connection.

Adolescent↗
PubMed2004

Effects of alpha1-acid glycoprotein in combination with catecholamines on hemorrhagic hypovolemic shock in rats.

To determine whether the beneficial effects of catecholamines on the variables of hemorrhagic hypovolemic shock are augmented by coadministration of alpha1-acid glycoprotein during resuscitation, alpha1-acid glycoprotein (200 mg/kg), a placebo formulation or Ringer's solution was infused in a rat model of hemorrhagic hypovolemic shock for 1 h concomitantly with either norepinephrine (CAS 51-40-1; 0.1, 0.3, 1 microg x kg(-1) x min(-1)) or dopamine (CAS 62-31-7; 5, 10, 15 microg x kg(-1) x min(-1)). Resuscitation with norepinephrine or dopamine alone was continued for a further 4 h. Mean arterial blood pressure, cardiac output, stroke volume, heart rate and total peripheral vascular resistance were measured during the entire 5-h period. The combination of dopamine or norepinephrine with alpha1-acid glycoprotein more effectively restored mean arterial blood pressure and cardiac output than analogous combinations with placebo formulation or Ringer's solution. So co-administration with alpha1-acid glycoprotein considerably augments the beneficial effects of catecholamines on the main variables of hemorrhagic hypovolemic shock.

Animals↗
PubMed2004

Bone mass development and bone metabolism in juvenile idiopathic arthritis: treatment with growth hormone for 4 years.

OBJECTIVE: To study the acquisition of bone mass and changes in bone mineral density (BMD) related to age, bone age, pubertal status, and growth hormone (GH) therapy in 11 children with juvenile idiopathic arthritis (JIA) longitudinally over 4 years, in comparison to healthy children. METHODS: Bone mineral content (BMC), BMD, and vertebral area were measured by dual energy x-ray absorptiometry. Since BMC and BMD increase with size, BMD was converted to volumetric BMD (vBMD) after adjustment for vertebral size. RESULTS: At inclusion all patients (7 female, 4 male, mean age 10.3 +/- 2.1 yrs) had low BMD, with a mean z-score for area BMD (aBMD) of -2.04 +/- 0.8 SD. After adjustment for size, vBMD was 0.198 g/cm3, and after 4 years of GH treatment it increased significantly to 0.232 g/cm3 (p < 0.03), expressed as SD scores that increased from -2.97 +/- 0.81 SD to -2.83 +/- 0.67 SD. In relation to bone age, vBMD SD increased from -2.53 +/- 0.85 to -2.41 +/- 0.79. Compared to pretreatment values, bone formation and resorption markers increased significantly during treatment. CONCLUSION: Our results reflect an increase in bone turnover under GH therapy in these patients. Despite biochemical changes there was a stabilization of vBMD for age and bone age, with a percentage increase comparable to healthy children. Longterm GH treatment will be necessary to evaluate a potential positive effect of GH on bone density and metabolism in patients with JIA.

Adolescent↗
PubMed2004

Update on the mechanism of action and future of activated prothrombin complex concentrates.

Activated prothrombin complex concentrates (aPCCs) are an established treatment for bleeding in patients with inhibitors. These products are derived from prothrombin complex concentrates, purified from human plasma with dedicated activation steps included in their manufacturing process. Despite these activation steps, the majority of the prothrombin complex proteins remain as zymogens, with only a relatively small content of activated coagulation enzymes. Among these, the order of concentration based on activity units is the following: factor VIIa to factor Xa to thrombin to factor IXa. Studies in various in vitro and in vivo model systems indicate that the mechanism of action of aPCCs is primarily based on an enzyme-substrate complex consisting of factor Xa and prothrombin. These findings are complemented by others showing that prothrombin is a major procoagulant that is capable of triggering hemostasis under physiologic and pathophysiologic conditions. Despite the findings of the mechanism of action, aPCCs have a long history of successful clinical use, with established dosing regimens, and a relatively low risk of thromboembolic complications compared with other treatment options for patients with inhibitors.

Blood Coagulation Factors↗
PubMed2003

Evaluation of the haemostatic potential of factor VIII-heparin cofactor II hybrid proteins in a mouse model.

We constructed factor VIII-heparin cofactor II (FVIII-HCII) hybrid molecules, which are more readily activated by thrombin in vitro than the respective wild-type molecules. The hybrid proteins were tested in a murine model of haemophilia A to investigate their haemostatic efficacy in vivo. Bleeding characteristics, measured using standard tail-tip cutting techniques, were total blood loss, bleeding time and survival rate. FVIII-HCII hybrids were found to be effective in preventing bleeding in FVIII knockout mice. While in vitro experiments showed that the chimaeric molecules had higher haemostatic functions than the wild-type proteins, the variables analysed in vivo were similar for both proteins.

Animals↗