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Biomedical subjects

Markus Schwarz

Publications and source records attributed to Markus Schwarz.

15 recordsLinked to original sources
PubMed2006

Metabolic activity and gene expression of osteoarthritic chondrocytes in correlation with radiological and histological characteristics.

The aim of this study was to analyze metabolic activity of osteoarthritic chondrocytes in correlation with radiographic, histologic and gene expression data. Six patients with osteoarthritis (OA) of the knee were analyzed clinically and radiographically (Kellgren and Lawrence, K&L). During total knee replacement surgery cartilage samples from the medial and lateral condyles and tibial plateaus were separately harvested. Specimen were analyzed histologically (Mankin Score) and total RNA was extracted. Steady state levels of stromelysin (MMP-3), aggrecan (AGG) and the house-keeping gene beta-actin were measured using quantitative PCR. In order to estimate metabolic activity chondrocytes were cultured in alginate beads and proteoglycan content was measured after 1 week. PG content in cultures was dependent from degradation status of cartilage (medial compartments 20.4 +/- 0.83 ng/ng, lateral compartments 29.9 +/- 3.0 ng/ng P < 0.01). We found a positive correlation of PG content in cultures with Mankin's grading (r = 0.79; P < 0.01) and with K&L scoring (r = 0.57; P = 0.05). There was a considerable variation of expression levels of MMP-3 and AGG. PG metabolism of cultured chondrocytes correlated only with the macroscopic and microscopic degradation status of cartilage. Gene expression showed a high variability and no correlation to PG metabolism indicating a more complex regulation.

Actins↗
PubMed2006

Differential effects of 5-HTTLPR genotypes on the behavioral and neural responses to tryptophan depletion in patients with major depression and controls.

CONTEXT: Tryptophan depletion (TD) is a model used to study the contribution of reduced serotonin transmission to the pathogenesis of major depressive disorder (MDD). Recent studies have not sufficiently addressed the relative contribution of a functional-length triallelic polymorphism in the promoter of the serotonin transporter, 5-HTTLPR, to the behavioral and neural responses to TD in individuals with remitted MDD (rMDD) and controls. OBJECTIVE: To determine the role of 5-HTTLPR on the behavioral and neural responses to TD in medication-free patients with rMDD and individually matched controls. DESIGN: Participants were stratified according to diagnosis and 5-HTTLPR genotypes and underwent TD on one test day and sham depletion on the other test day in a prospective, double-blind, randomized order. SETTING: Outpatient clinic. PARTICIPANTS: Twenty-seven medication-free patients with rMDD (18 women and 9 men) and 26 controls (17 women and 9 men). INTERVENTIONS: Tryptophan depletion was induced by administration of capsules containing an amino acid mixture without tryptophan. Sham depletion used identical capsules containing lactose. Fludeoxyglucose F 18 positron emission tomography was performed 6 hours after TD. Magnetic resonance images were obtained for each participant. MAIN OUTCOME MEASURES: Quantitative positron emission tomography of regional cerebral metabolic rates for glucose and measures of depression using the Hamilton Depression Rating Scale. RESULTS: Behavioral responses to TD are affected by 5-HTTLPR in patients with rMDD and controls. A direct effect of 5-HTTLPR on the regulation of regional cerebral metabolic rates for glucose was identified in patients with rMDD for the amygdala, hippocampus, and subgenual anterior cingulate cortex. CONCLUSIONS: Variations in 5-HTTLPR modulate the sensitivity of patients with rMDD and controls to the behavioral effects of TD. In patients with rMDD, variations in triallelic 5-HTTLPR have a direct effect on regulation of regional cerebral metabolic rates for glucose in a corticolimbic circuit that has been implicated in rMDD.

Adult↗
PubMed2006

Osseointegration of cementless implants with different bisphosphonate regimens.

Some evidence suggests a daily dose of bisphosphonates improves fixation of cementless metal implants by enhancing osseointegration. Because the necessity of daily administration may result in suboptimal adherence to therapy, single- dose administration is desirable. We examined whether a dose-equivalent single injection of the nitrogen-containing bisphosphonate ibandronate is as effective as a daily injection in improving the osseointegrated surface and enhancing periprosthetic bone mineralization (bone volume to tissue volume) of cementless metal implants. Uncoated titanium and hydroxyapatite-coated titanium implants were surgically inserted into the femoral medullary canal of 55 female Sprague Dawley rats. The animals were randomly assigned subcutaneous treatments with 25 microg/kg body weight ibandronate per day, a dose-equivalent single injection of 28 x 25 microg/kg body weight, or saline solution for control. Histomorphometric evaluation revealed an enhanced osseointegrated surface for hydroxyapatite-coated implants in both treatment groups, but only for daily injections for uncoated titanium implants. Bone volume to tissue volume was improved in both treatment groups. Our results suggest that an equivalent-dose single injection of ibandronate is as effective as a daily dose in improving osseointegration and stabilization of hydroxyapatite-coated titanium implants in this rat model.

Analysis of Variance↗
PubMed2006

No association between genetic variants at the ASCT1 gene and schizophrenia or bipolar disorder in a German sample.

Altered glutamatergic neurotransmission is considered a potential etiological factor of schizophrenia (SCZ) and affective disorders. The gene ASCT1 (SLC1A4) coding for a Na+-dependent neutral aminoacid transporter is a member of the glutamate transporter superfamily and is located on 2p13-14, a region showing linkage to both SCZ and bipolar disorder (BD). ASCT1 can thus be considered a candidate gene for both disorders. In a German sample, we tested for association between ASCT1 and both SCZ and BD. Allele and haplotype frequencies, however, did not differ between cases and controls. Recent findings on the associations between brainderived neurotrophic factor (BDNF) and SCZ and between G72/G30 and BD suggest that SCZ patients with a history of major depressive episodes (MDE) outside psychotic episodes and BD cases with a history of persecutory delusions constitute genetically distinct subgroups of these disorders. Thus, we hypothesized that restricting case definition to those 95 SCZ individuals with MDE and to those 107 BD patients with a history of persecutory delusions might clarify the relationship between BD, SCZ and ASCT1. However, these stratification approaches did not yield any significant association either. Allele and haplotype frequencies did not differ between cases and controls. Our results do not support an association of the ASCT1 gene with BD or SCZ in the German population.

Amino Acid Transport System ASC↗
PubMed2006

No association between genetic variants at the GRIN1 gene and bipolar disorder in a German sample.

Disturbed glutamatergic neurotransmission has been implicated in the pathogenesis of schizophrenia and bipolar disorder, with the N-methy-D-aspartate receptors being in the focus of research. The NR1 subunit, which is encoded by the gene GRIN1, plays a key role in the functionality of N-methy-D-aspartate receptors. We tested the association between GRIN1 and bipolar disorder in a sample of German descent, consisting of 306 bipolar disorder patients and 319 population-based controls. No significant association was found. In accordance with our recent findings, we hypothesized that restricting case definition to individuals with a history of persecutory delusions might clarify the relationship between bipolar disorder and GRIN1. This stratified analysis did not yield any significant association either. Our results do not support an association of the GRIN1 gene with bipolar disorder in the German population.

Bipolar Disorder↗
PubMed2005

Yeast oligosaccharyltransferase consists of two functionally distinct sub-complexes, specified by either the Ost3p or Ost6p subunit.

The key step of N-glycosylation of proteins in the endoplasmic reticulum is catalyzed by the hetero-oligomeric protein complex oligosaccharyltransferase (OST). It transfers the lipid-linked core-oligosaccharide to selected Asn-X-Ser/Thr-sequences of nascent polypeptide chains. Biochemical and genetic approaches have revealed that OST from Saccharomyces cerevisiae consists of nine subunits: Wbp1p, Swp1p, Stt3p, Ost1p, Ost2p, Ost4p, Ost5p, Ostp3 and Ost6p. By blue native polyacrylamide electrophoresis we show that yeast OST consists of two isoforms with distinct functions differing only in the presence of the two related Ost3 and Ost6p proteins. The OST6-complex was found to be important for cell wall integrity and temperature stress. Ost3p and Ost6p are not essential for OST activity, and can in part displace each other in the complex when overexpressed, suggesting a dynamic regulation of the complex formation.

Cell Wall↗
PubMed2005

Biosynthesis of lipid-linked oligosaccharides in Saccharomyces cerevisiae: Alg13p and Alg14p form a complex required for the formation of GlcNAc(2)-PP-dolichol.

N-Glycosylation in the endoplasmic reticulum is an essential protein modification and highly conserved in evolution from yeast to man. Here we identify and characterize two essential yeast proteins having homology to bacterial glycosyltransferases, designated Alg13p and Alg14p, as being required for the formation of GlcNAc(2)-PP-dolichol (Dol), the second step in the biosynthesis of the unique lipid-linked core oligosaccharide. Down-regulation of each gene led to a defect in protein N-glycosylation and an accumulation of GlcNAc(1)-PP-Dol in vivo as revealed by metabolic labeling with [(3)H]glucosamine. Microsomal membranes from cells repressed for ALG13 or ALG14, as well as detergent-solubilized extracts thereof, were unable to catalyze the transfer of N-acetylglucosamine from UDP-GlcNAc to [(14)C]GlcNAc(1)-PP-Dol, but did not impair the formation of GlcNAc(1)-PP-Dol or GlcNAc-GPI. Immunoprecipitating Alg13p from solubilized extracts resulted in the formation of GlcNAc(2)-PP-Dol but required Alg14p for activity, because an Alg13p immunoprecipitate obtained from cells in which ALG14 was down-regulated lacked this activity. In Western blot analysis it was demonstrated that Alg13p, for which no well defined transmembrane segment has been predicted, localizes both to the membrane and cytosol; the latter form, however, is enzymatically inactive. In contrast, Alg14p is exclusively membrane-bound. Repression of the ALG14 gene causes a depletion of Alg13p from the membrane. By affinity chromatography on IgG-Sepharose using Alg14-ZZ as bait, we demonstrate that Alg13-myc co-fractionates with Alg14-ZZ. The data suggest that Alg13p associates with Alg14p to a complex forming the active transferase catalyzing the biosynthesis of GlcNAc(2)-PP-Dol.

Blotting, Western↗
PubMed2005

The influence of 4-week treatment with sertraline on the combined T3/TRH test in depressed patients.

In the present study, the influence of a 4-week treatment with sertraline on the regulation of hypothalamic-pituitary-thyroid (HPT) axis activity in depression was investigated, in particular the impact of sertraline on the thyroid receptor (TR)-mediated negative feedback control as measured by the combined T3/TRH test. In 20 drug-free patients (8 men, 12 women) suffering from a major depressive episode according to DSM-IV criteria the single TRH-stimulation test (administration of 200 microg TRH at 09:00h) was carried out followed by a combined T3/TRH test (pre-treatment with 40 microg 3,5,3'-triiodothyronine [T3] the night before; administration of 200 microg TRH at 09:00h the next day). After 4 weeks of treatment with sertraline at a standard dosage of 50 mg/day, both the single TRH test and the combined T3/TRH test were repeated in the depressed patients. Using repeated-measures ANOVA for statistical analysis, antidepressant therapy with sertraline did not have any significant impact on the TRH-induced TSH and prolactin stimulation (deltaTSH, deltaPRL) during the single TRH test nor during the combined T3/TRH test, neither in responders (n = 10) nor in non-responders (n = 10). Moreover, the percentage suppression of TRH-induced TSH stimulation (deltaTSH) after pre-treatment with 40 microg T3 was comparable before (-61.07%) and after the 4-week treatment with sertraline (-58.92%). Apparently, the therapeutic efficacy of antidepressants such as sertraline is not related to the regulation of HPT axis activity in depressed patients.

Adult↗
PubMed2005

High dosage treatment of nitrogen-containing bisphosphonate ibandronate is required for osseointegration of cementless metal implants.

BACKGROUND: There is evidence that application of a bisphosphonate can improve fixation of cementless metal implants by enhancing the extent of osseointegration, but the required dose regimen is still under discussion. The current preclinical study was designed to determine the optimal treatment dose of the nitrogen-containing bisphosphonate ibandronate to improve osseointegration of cementless metal implants. METHODS: The study was conducted in 52 female Sprague-Dawley rats in which uncoated and hydroxyapatite-coated titanium implants were surgically inserted into the medullary canal of each femur. The animals were randomly assigned to receive subcutaneous treatment with ibandronate 1 microg/kg body weight (osteoporosis dose) or 25 microg/kg (tumor dose) per day or saline solution for control. RESULTS: Histomorphometric evaluation revealed a significant enhanced extent of osseointegrated implant surface in the high-dose treatment group for both implants compared to the low-dose group and the control group. No significant differences were observed between the two implants in any group. CONCLUSIONS: The results of the present study indicate that improved osseointegration of hydroxyapatite-coated and uncoated titanium implants is dose-dependent and requires high-dose application of bisphosphonate ibandronate equivalent to that needed to treat patients with tumor disease. Lower doses equivalent to those for treatment of osteoporosis showed no beneficial effect.

Animals↗
PubMed2005

Immunosuppression with FK506 has no influence on fracture healing in the rat.

Immunosuppressant drugs like cyclosporine A and FK506 are widely used for solid organ transplantation. They are accelerating bone remodeling but cause net bone loss. The aim of this study was to investigate the effect of FK506 on fracture healing in the rat. Eighty Lewis rats were divided into four groups, which received FK506 (1 mg/kg BW) or no treatment for 2 or 4 weeks, beginning after production of a closed, nondisplaced unilateral tibial fracture. Radiographic, histological, and biomechanical studies were used to evaluate fracture healing and histomorphometric analysis of the tibial metaphysis of the intact contralateral side was performed. Radiographs revealed no difference of the healing of the control fractures compared with the fractures in the FK506-treated group at 2 and 4 weeks. The mechanical parameters of the tested contralateral intact tibiae and of the fracture callus demonstrated no difference between control and immunosuppressed animals. Tibial bone histomorphometry revealed increased measures of bone formation and bone resorption, accompanied by a significant reduction of percent trabecular area. At 4 weeks, the fractures showed osseous healing with woven bone at the fracture site and only minimal amounts of cartilage. Histological grading was not different between the control and the FK506 group at both time points. We conclude that systemic application of FK506 has no biomechanical and histological effects of experimental fracture healing in the rat. However, resorption far in excess of formation leads to a net bone loss in the trabecular bone of the tibia that has no effect on the stability of the intact bone.

Animals↗
PubMed2004

Deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase causes congenital disorder of glycosylation type Ik.

The molecular nature of a severe multisystemic disorder with a recurrent nonimmune hydrops fetalis was identified as deficiency of GDP-Man:GlcNAc(2)-PP-dolichol mannosyltransferase, the human orthologue of the yeast ALG1 gene (MIM 605907). The disease belongs to the group of congenital disorders of glycosylation (CDG) and is designated as subtype CDG-Ik. In patient-derived serum, the total amount of the glycoprotein transferrin was reduced. Moreover, a partial loss of N-glycan chains was observed, a characteristic feature of CDG type I forms. Metabolic labeling with [6-(3)H]glucosamine revealed an accumulation of GlcNAc(2)-PP-dolichol and GlcNAc(1)-PP-dolichol in skin fibroblasts of the patient. Incubation of fibroblast extracts with [(14)C]GlcNAc(2)-PP-dolichol and GDP-mannose indicated a severely reduced activity of the beta 1,4-mannosyltransferase, elongating GlcNAc(2)-PP-dolichol to Man(1)GlcNAc(2)-PP-dolichol at the cytosolic side of the endoplasmic reticulum. Genetic analysis of the patient's hALG1 gene identified a homozygous mutation leading to the exchange of a serine residue to leucine at position 258 in the hALG1 protein. The disease-causing nature of the hALG1 mutation for the glycosylation defect was verified by a retroviral complementation approach in patient-derived primary fibroblasts and was confirmed by the expression of wild-type and mutant hALG1 in the Saccharomyces cerevisiae alg1-1 strain.

DNA Mutational Analysis↗
PubMed2004

Neural and behavioral responses to tryptophan depletion in unmedicated patients with remitted major depressive disorder and controls.

CONTEXT: An instructive paradigm for investigating the relationship between brain serotonin function and major depressive disorder (MDD) is the response to tryptophan depletion (TD) induced by oral loading with all essential amino acids except the serotonin precursor tryptophan. OBJECTIVE: To determine whether serotonin dysfunction represents a trait abnormality in MDD in the context of specific neural circuitry abnormalities involved in the pathogenesis of MDD. DESIGN: Randomized double-blind crossover study. SETTING: Outpatient clinic. PARTICIPANTS: Twenty-seven medication-free patients with remitted MDD (18 women and 9 men; mean +/- SD age, 39.8 +/- 12.7 years) and 19 controls (10 women and 9 men; mean +/- SD age, 34.4 +/- 11.5 years). INTERVENTIONS: We induced TD by administering capsules containing an amino acid mixture without tryptophan. Sham depletion used identical capsules containing hydrous lactose. Fluorodeoxyglucose F 18 positron emission tomography studies were performed 6 hours after TD. Magnetic resonance images were obtained for all participants. MAIN OUTCOME MEASURES: Quantitative positron emission tomography of regional cerebral glucose utilization to study the neural effects of sham depletion and TD. Behavioral assessments used a modified (24-item) version of the Hamilton Depression Rating Scale. RESULTS: Tryptophan depletion induced a transient return of depressive symptoms in patients with remitted MDD but not in controls (P<.001). Compared with sham depletion, TD was associated with an increase in regional cerebral glucose utilization in the orbitofrontal cortex, medial thalamus, anterior and posterior cingulate cortices, and ventral striatum in patients with remitted MDD but not in controls. CONCLUSION: The pattern of TD-induced regional cerebral glucose utilization changes in patients with remitted MDD suggests that TD unmasks a disease-specific, serotonin system-related trait dysfunction and identifies a circuit that probably plays a key role in the pathogenesis of MDD.

Adult↗
PubMed2003

A new type of congenital disorders of glycosylation (CDG-Ii) provides new insights into the early steps of dolichol-linked oligosaccharide biosynthesis.

Deficiency of GDP-Man:Man1GlcNAc2-PP-dolichol mannosyltransferase (hALG2), is the cause of a new type of congenital disorders of glycosylation (CDG) designated CDG-Ii. The patient presented normal at birth but developed in the 1st year of life a multisystemic disorder with mental retardation, seizures, coloboma of the iris, hypomyelination, hepatomegaly, and coagulation abnormalities. An accumulation of Man1GlcNAc2-PP-dolichol and Man2GlcNAc2-PP-dolichol was observed in skin fibroblasts of the patient. Incubation of patient fibroblast extracts with Man1GlcNAc2-PP-dolichol and GDP-mannose revealed a severely reduced activity of the mannosyltransferase elongating Man1GlcNAc2-PP dolichol. Because the Saccharomyces cerevisiae mutant alg2-1 was known to accumulate the same shortened dolichol-linked oligosaccharides as the patient, the yeast ALG2 sequence was used to identify the human ortholog. Genetic analysis revealed that the patient was heterozygous for a single nucleotide deletion and a single nucleotide substitution in the human ortholog of yeast ALG2. Expression of wild type but not of mutant hALG2 cDNA restored the mannosyltransferase activity and the biosynthesis of dolichol-linked oligosaccharides both in patient fibroblasts and in the alg2-1 yeast cells. hALG2 was shown to act as an alpha1,3-mannosyltransferase. The resulting Manalpha1,3-ManGlcNAc2-PP dolichol is further elongated by a yet unknown alpha1,6-mannosyltransferase.

Base Sequence↗
PubMed2002

Deficiency of dolichyl-P-Man:Man7GlcNAc2-PP-dolichyl mannosyltransferase causes congenital disorder of glycosylation type Ig.

Deficiency of the endoplasmic reticulum enzyme dolichyl-phosphate mannose (Dol-P-Man):Man(7)GlcNAc(2)-PP-dolichyl mannosyltransferase leads to a new type of congenital disorder of glycosylation, designated type Ig. The patient 1 presented with a multisystemic disorder with microcephaly, developmental retardation, convulsions and dysmorphic signs. The isoelectric focusing pattern of the patient's serum transferrin showed the partial loss of complete N-glycan side chains. In skin fibroblasts from the patient, the activity of Dol-P-Man:Man(7)GlcNAc(2)-PP-Dol mannosyltransferase was severely reduced leading to the accumulation of Man(7)GlcNAc(2)-PP-Dol, which was transferred to newly synthesized glycoproteins. Sequencing of the Dol-P-Man:Man(7)GlcNAc(2)-PP-Dol mannosyltransferase cDNA revealed a compound heterozygosity for two point mutations, leading to the exchange of leucine(158) for a proline residue and a premature translation stop with loss of the C-terminal 74 amino acids. The parents were heterozygous for one of the two mutations. Retroviral expression of the wild-type Dol-P-Man:Man(7)GlcNAc(2)-PP-Dol mannosyltransferase cDNA in patient's fibroblasts normalized the mannosyltransferase activity.

Chromatography, High Pressure Liquid↗