Biomedical subjects

Sabine Fischer

Publications and source records attributed to Sabine Fischer.

17 recordsLinked to original sources

PubMed2006

Association of the calpain-10 gene with type 2 diabetes in Europeans: results of pooled and meta-analyses.

We conducted pooled and meta-analyses of the association of the calpain-10 gene (CAPN10) polymorphisms SNP-43, Indel-19 and SNP-63 individually and as haplotypes with type 2 diabetes (T2D) in 3237 patients and 2935 controls of European ancestry. In the pooled analyses, the common SNP-43*G allele was associated with modest but statistically significant increased risk of T2D (odds ratio (OR)=1.11 (95% confidence interval (CI), 1.02-1.20), P=0.01). Two haplotype combinations were associated with increased risk of T2D (1-2-1/1-2-1, OR=1.20 (1.03-1.41), P=0.02; and 1-1-2/1-2-1, OR=1.26 (1.01-1.59), P=0.04) and one with decreased risk (1-1-1/2-2-1, OR=0.86 (0.75-0.99), P=0.03). The meta-analysis also showed a significant effect of the 1-2-1/1-2-1 haplogenotype on risk (OR=1.25 (1.05-1.50), P=0.01). However, there was evidence for heterogeneity with respect to this effect (P=0.06). The heterogeneity appeared to be due to data sets in which the cases were selected from samples used in linkage studies of T2D. Using only the population-based case-control samples removed the heterogeneity (P=0.89) and strengthened the evidence for association with T2D in both the pooled (SNP-43*G, OR=1.19 (1.07-1.32), P=0.001; 1-2-1/1-2-1 haplogenotype, OR=1.46 (1.19-1.78), P=0.0003; 1-1-2/1-2-1 haplogenotype, OR=1.52 (1.12-2.06), P=0.007; and 1-1-1/2-2-1 haplogenotype, OR=0.83 (0.70-0.99), P=0.03) and the meta-analysis (SNP-43*G, OR=1.18 (1.05-1.32), P=0.005; 1-2-1/1-2-1 haplogenotype, OR=1.68 (1.33-2.11), P=0.00001). The pooled and meta-analyses as well as the linkage disequilibrium and haplotype diversity studies suggest a role for genetic variation in CAPN10 affecting risk of T2D in Europeans.

Calpain↗

PubMed2006

Prdm1 acts downstream of a sequential RA, Wnt and Fgf signaling cascade during zebrafish forelimb induction.

Vertebrate limb induction is triggered in the lateral plate mesoderm (LPM) by a cascade of signaling events originating in the axial mesoderm. While it is known that Fgf, Wnt and retinoic acid (RA) signals are involved in this cascade, their precise regulatory hierarchy has not been determined in any species. tbx5 is the earliest gene expressed in the limb bud mesenchyme. Recently, another transcription factor, Prdm1, has been shown to be crucial for zebrafish forelimb development. Here, we show that Prdm1 is downstream of RA, Wnt2b and Tbx5 activity. We find that RA activity, but not Fgf signaling, is necessary for wnt2b expression. Fgf signaling is required for prdm1 expression in the fin bud, but is not necessary for the initiation of tbx5 expression. We propose a model in which RA signaling from the somitic mesoderm leads to activation of wnt2b expression in the intermediate mesoderm, which then signals to the LPM to trigger tbx5 expression. tbx5 is required for Fgf signaling in the limb bud leading to activation of prdm1 expression, which in turn is required for downstream activation of fgf10 expression.

Animals↗

PubMed2006

Effects of oxidative challenge and calcium on ATP-levels in neuronal cells.

BACKGROUND: Neurocellular overload with hydrogen peroxide (H2O2) induces oxidative stress and may initiate a cascade of intracellular toxic events leading to energy failure, increased lipid peroxidation and subsequently cell death. Studies suggest that hippocampal neurons may be more vulnerable to oxidative stress than cortical cells pointing to a differential vulnerability of neuronal cells. Since disturbed ATP- and calcium (Ca2+)-metabolism may be involved in this process, we here evaluated the effects of H2O2-induced oxidative stress and the involvement of Ca2+-regulation on neuronal energy metabolism. METHODS: Using primary cortical and hippocampal neurons as well as immortalized hippocampal HT22 cells, we determined ATP-levels and accompanying cell death after oxidative challenge with H2O2. Additionally, the combined effects of H2O2 and alterations in Ca2+-concentrations were pharmacologically characterized in more detail. RESULTS: H2O2-incubation decreased ATP-levels in a dose- and time-dependent manner in all neuronal cell systems tested. Such effects were most pronounced in primary hippocampal neurons. In cortical cells, increased ATP-levels were notable under low H2O2-concentrations. A dose-dependent decrease in ATP-concentrations was observed after treatment with Ca2+, which was further enhanced by additional H2O2-challenge. CONCLUSIONS: Our data underline that both, H2O2- and Ca2+-treatment, are able to disturb intracellular energy metabolism. Out of the different systems studied, the ATP-decrease is most pronounced in hippocampal primary neurons, suggesting that this mechanism contributes to the selective neuronal vulnerability to oxidative stress in these neurons.

Adenosine Triphosphate↗

PubMed2006

Zebrafish Trap230/Med12 is required as a coactivator for Sox9-dependent neural crest, cartilage and ear development.

The vertebrate Sox9 transcription factor directs the development of neural crest, otic placodes, cartilage and bone. In zebrafish, there are two Sox9 orthologs, Sox9a and Sox9b, which together perform the functions of the single-copy tetrapod Sox9. In a large-scale genetic screen, we have identified a novel zebrafish mutant that strongly resembles the Sox9a/Sox9b double mutant phenotype. We show that this mutation disrupts the zebrafish Trap230/Med12 ortholog, a member of the Mediator complex. Mediator is a coactivator complex transducing the interaction of DNA-binding transcription factors with RNA polymerase II, and our results reveal a critical function of the Trap230 subunit as a coactivator for Sox9.

Animals↗

PubMed2006

Hypoadiponectinemia is associated with progression toward type 2 diabetes and genetic variation in the ADIPOQ gene promoter.

OBJECTIVE: Adiponectin encoded by the ADIPOQ gene modulates insulin sensitivity and glucose homeostasis. The aim of the current study was to investigate whether ADIPOQ gene variants in the promoter region predict adiponectin levels and type 2 diabetes progression. RESEARCH DESIGN AND METHODS: A total of 550 subjects with increased risk of type 2 diabetes were investigated; they underwent a 75-g oral glucose tolerance test, repeated after 3 years. Adiponectin levels were analyzed, and two ADIPOQ promoter variant single nucleotide polymorphisms, -11391G>A and -11377C>G, were genotyped. RESULTS: Tertiles of the adjusted adiponectin levels were associated with single nucleotide polymorphism -11391G>A and -11377C>G haplotypes (P < 0.0001). Carriers of the intermediate/high-level haplotype combination showed a bisected diabetes risk at the 3-year follow-up and were characterized by a "regression" of glucose tolerance. Evolution of disease status correlates with preexisting low adiponectin levels at inclusion rather than with variation in adiponectin levels. CONCLUSIONS: We present data that gene variants in the ADIPOQ promoter region are associated with variations in adiponectin levels and thus with future type 2 diabetes and disease progression.

Adiponectin↗

PubMed2005

Histone deacetylase 1 is required for cell cycle exit and differentiation in the zebrafish retina.

Histone acetylation is an important epigenetic mechanism for the control of eukaryotic transcription. The histone deacetylase 1 (HDAC1) gene has been implicated in controlling the transcription of core cell cycle regulators, but the in vivo role of HDACs in cell cycle regulation is still poorly understood. Loss of HDAC1 activity causes underproliferation in several contexts during vertebrate development. In contrast, we show here that HDAC1 has the opposite effect in the zebrafish visual system, where loss of HDAC1 activity leads to failure of cells to exit the cell cycle in the retina and in the optic stalk. The effect of HDAC1 on cell cycle exit is cell-autonomous, and loss of HDAC1 in the retina leads to up-regulation of cyclin D and E transcripts. These results demonstrate that the in vivo role of HDAC1 in regulating cell cycle progression is region-specific, as HDAC1 promotes cell cycle exit in the retina but stimulates proliferation in other cellular contexts.

Alleles↗

PubMed2005

PPARgamma-agonist rosiglitazone increases number and migratory activity of cultured endothelial progenitor cells.

OBJECTIVE: Endothelial progenitor cells (EPC) are involved in the process of endothelial maintenance and angiogenesis and might be related to endothelial function. EPC function was shown to be impaired in type 2 diabetic patients. Since endothelial dysfunction of type 2 diabetic patients can be ameliorated by treatment with thiazolidinediones we asked whether this treatment might also influence number and function of EPC. METHODS AND RESULTS: We investigated 10 recently diagnosed type 2 diabetic patients and 10 age and sex matched healthy control subjects. After baseline examination of metabolic parameters and EPC, patients received 4 mg rosiglitazone b.i.d. for 12 weeks. We measured EPC number and migratory activity after 3 and 12 weeks of treatment. Migratory activity of EPCs obtained from type 2 diabetic patients at baseline was 40% lower compared to control (P<0.05). There was no significant difference of EPC number between patients (323+/-19) and controls (358+/-25) at baseline. Treatment of patients with rosiglitazone normalized impaired migratory activity of EPC and increased EPC number (464+/-33, P<0.01). In addition treatment improved glycemic control and insulin sensitivity. CONCLUSIONS: Twelve-week treatment with rosiglitazone improved EPC number and migratory activity of type 2 diabetic patients. The latter mechanism may contribute to the recently observed improvement of endothelial function by rosiglitazone in type 2 diabetes.

AC133 Antigen↗

PubMed2005

Rosiglitazone improves glomerular hyperfiltration, renal endothelial dysfunction, and microalbuminuria of incipient diabetic nephropathy in patients.

Microalbuminuria, an early feature of diabetic nephropathy, indicates intrarenal endothelial damage. In type 2 diabetes, microalbuminuria is strongly related to insulin resistance. We therefore investigated whether rosiglitazone, an insulin-sensitizing drug that is known to improve endothelial dysfunction, was able to improve intrarenal endothelial dysfunction and microalbuminuria. Nineteen type 2 diabetic patients participated in this double-blind cross-over trial. Nine patients with newly diagnosed disease without microalbuminuria were randomized to a treatment with rosiglitazone or nateglinide, each for 12 weeks. Ten patients with microalbuminuria were randomized to rosiglitazone or placebo, each for 12 weeks in addition to their previous antidiabetic medication. After each treatment, glomerular filtration rate (GFR), renal plasma flow, and filtration fraction were measured before and after blockade of nitric oxide (NO) by intravenous administration of N-monomethyl-L-arginine-acetate (L-NMMA). Ten healthy subjects served as control subjects. Type 2 diabetic patients at baseline showed glomerular hyperfiltration compared with healthy control subjects. Rosiglitazone reduced elevated GFR and filtration fraction toward control primarily in patients with microalbuminuria (GFR: 133.4 +/- 9.8 vs. 119.6 +/- 8.7 ml/min; filtration fraction: 23.2 +/- 1.7 vs. 20.5 +/- 1.6% before and after rosiglitazone, respectively; control subjects: GFR 111.7 +/- 8.6 ml/min, filtration fraction 20.4 +/- 1.5%). Rosiglitazone improved intrarenal NO bioavailability in type 2 diabetes toward control as shown by infusion of L-NMMA. Rosiglitazone reduced albumin excretion in type 2 diabetes with microalbuminuria from 116.5 +/- 31 to 40.4 +/- 12 mg/day. Rosiglitazone ameliorated glomerular hyperfiltration in early type 2 diabetes, improved NO bioavailability, and lessened renal end-organ damage in type 2 diabetes with microalbuminuria.

Aged↗

PubMed2004

Sonic hedgehog, secreted by amacrine cells, acts as a short-range signal to direct differentiation and lamination in the zebrafish retina.

Neurogenesis in the zebrafish retina occurs in several waves of differentiation. The first neurogenic wave generates ganglion cells and depends on hedgehog (hh) signaling activity. Using transgenic zebrafish embryos that express GFP under the control of the sonic hedgehog (shh) promoter, we imaged the differentiation wave in the retina and show that, in addition to the wave in the ganglion cell layer, shh expression also spreads in the inner nuclear layer. This second wave generates amacrine cells expressing shh, and although it overlaps temporally with the first wave, it does not depend on it, as it occurs in the absence of ganglion cells. We also show that differentiation of cell types found in the inner and outer nuclear layers, as well as lamination of the retina, depends on shh. By performing mosaic analysis, we demonstrate that Shh directs these events as a short-range signal within the neural retina.

Amacrine Cells↗

PubMed2004

Dephosphorylation of cofilin is regulated through Ras and requires the combined activities of the Ras-effectors MEK and PI3K.

Remodeling of the actin cytoskeleton is crucial for a multitude of cellular functions including cell movement, intracellular transport as well as signal transduction and gene expression processes. Cofilin has been identified as a key mediator of actin reorganization. Its activity is regulated via reversible phosphorylation of ser-3. In a variety of cell types stimulation through particular surface receptors fastly induces the dephosphorylation/activation of cofilin. Yet, the signal transduction cascades linking receptor stimulation with cofilin activation have not been identified so far. Here we show that the GTPase Ras acts as a central regulator of the cofilin dephosphorylation pathway. Thus, stimulation of Ras through platelet-derived growth factor (PDGF) or transient expression of activated Ras-proteins induces the dephosphorylation of cofilin. Importantly, the cooperation of two Ras-initiated signaling pathways is required to induce cofilin dephosphorylation: a Ras-Raf-MAPkinase/Erk-kinase (MEK)- and a Ras-phosphatidylinositol-3-kinase (PI3K)-effector cascade.

Actin Depolymerizing Factors↗

PubMed2004

In type 2 diabetes, rosiglitazone therapy for insulin resistance ameliorates endothelial dysfunction independent of glucose control.

OBJECTIVE: Insulin resistance is an independent risk factor for arteriosclerosis and cardiovascular mortality. However, the mechanism by which insulin resistance contributes to arteriosclerosis is unknown. Conceivably, endothelial dysfunction could be involved. Therefore, we asked whether therapy for insulin resistance ameliorates any endothelial dysfunction. RESEARCH DESIGN AND METHODS: We performed a double-blind cross-over trial of 12 patients with recently diagnosed type 2 diabetes. They received rosiglitazone 4 mg b.i.d. for 12 weeks and nateglinide 60 mg b.i.d. for the same number of weeks in random order. To assess the degree of endothelial dysfunction, we used venous occlusion plethysmography. We studied vasodilation in response to acetylcholine (ACh) with and without exogenous insulin. The agents were infused into the brachial artery. Furthermore, we determined insulin resistance by euglycemic clamp. RESULTS: Glycemic control was comparable under rosiglitazone and nateglinide. Rosiglitazone ameliorated insulin resistance by 60% compared with nateglinide. ACh response was significantly increased after rosiglitazone treatment (maximum forearm blood flow 12.8 +/- 1.3 vs. 8.8 +/- 1.3 ml/100 ml after rosiglitazone and nateglinide, respectively; P < 0.05) but did not attain the level of healthy control subjects (14.0 +/- 0.7 ml/100 ml). Coinfusion of exogenous insulin increased ACh response further in the rosiglitazone group. N-monomethyl-L-arginine-acetate (L-NMMA), an antagonist of nitric oxide synthase, largely prevented the increased vasodilation after rosiglitazone, regardless of the presence or absence of insulin. Insulin sensitivity and blood flow response were found to be correlated (P < 0.01). CONCLUSIONS: Insulin resistance is a major contributor toward endothelial dysfunction in type 2 diabetes. Both endothelial dysfunction and insulin resistance are amenable to treatment by rosiglitazone.

Acetylcholine↗

PubMed2003

The zebrafish fgf24 mutant identifies an additional level of Fgf signaling involved in vertebrate forelimb initiation.

The development of vertebrate limb buds is triggered in the lateral plate mesoderm by a cascade of genes, including members of the Fgf and Wnt families, as well as the transcription factor tbx5. Fgf8, which is expressed in the intermediate mesoderm, is thought to initiate forelimb formation by activating wnt2b, which then induces the expression of tbx5 in the adjacent lateral plate mesoderm. Tbx5, in turn, is required for the activation of fgf10, which relays the limb inducing signal to the overlying ectoderm. We show that the zebrafish fgf24 gene, which belongs to the Fgf8/17/18 subfamily of Fgf ligands, acts downstream of tbx5 to activate fgf10 expression in the lateral plate mesoderm. We also show that fgf24 activity is necessary for the migration of tbx5-expressing cells to the fin bud, and for the activation of shh, but not hand2, expression in the posterior fin bud.

Animals↗

PubMed2002

Joint protection and home hand exercises improve hand function in patients with hand osteoarthritis: a randomized controlled trial.

OBJECTIVE: To determine the effect of joint protection and home exercises on hand function of patients with hand osteoarthritis (OA). METHODS: Randomized, controlled, 3-month trial with a blinded assessor. Primary outcome parameter was grip strength; secondary parameters were Health Assessment Questionnaire and visual analog scales (VAS) for pain and global hand function. Forty patients with hand OA were randomly assigned to 2 groups: One group received instruction for joint protection and home hand exercises (JPE group), the control group received an information session about hand OA. RESULTS: Grip strength improved by 25% in the JPE group (right hand, P < 0.0001; left hand, P = 0.0005), but not in the control group. Global hand function (by VAS) improved in a larger proportion (65%) of patients in the JPE group (P < 0.05). CONCLUSIONS: Joint protection and hand home exercises, easily administered and readily acceptable interventions, were found to increase grip strength and global hand function.

Ambulatory Care↗

PubMed2002

["REGRATIO" - A vocational reintegration project for psychiatric patients].

OBJECTIVE: Theoretical background and first results of a vocational rehabilitation program for unemployed persons with chronic psychiatric disabilities will be presented. The aim of the program is job-placement in the regular labour market. METHODS: After a 3-month preparatory period the participants were given the possibility of "training on-the-job" in the areas of social services, catering, and care taking activities in 12-months' rehabilitation reintegration courses in co-operation with a social service centre. In addition, a 6-months aftercare period will be included. RESULTS: More than one third of 34 participants (38 %) were placed in a regular employment. CONCLUSIONS: The results support the importance of vocational rehabilitation programs as a supplementary component of the care system of chronic mentally ill patients.

Adult↗

PubMed2002

Brassinosteroid-regulated gene expression.

Major brassinosteroid (BR) effects such as BR-induced growth are mediated through genomic pathways because RNA synthesis inhibitors and protein synthesis inhibitors interfere with these processes. A limited number of BR-regulated genes have been identified hitherto. The majority of genes (such as BRU1, CycD3, Lin6, OPR3, and TRIP-1) were identified by comparisons of BR-treated versus control-treated plants. However, altered transcript levels after BR application may not reflect normal physiological events. A complementary approach is the comparison of BR-deficient plants versus wild-type plants. No artificial treatments interfere with endogenous signaling pathways, but a subset of phenotypic alterations of phytohormone-deficient plants most probably is secondary. To identify genes that are subject to direct BR regulation, we analyzed CPD antisense and dwf1-6 (cbb1) mutant plants. Both show a mild phenotype in comparison with BR-deficient mutants such as cpd/cbb3, det2, and dwf4. Plants were grown under two different environments to filter out BR deficiency effects that occur only at certain environmental conditions. Finally, we established expression patterns after BR treatment of wild-type and dwf1-6 (cbb1) plants. Ideally, a BR-regulated gene displays a dose-response relationship in such a way that a gene with decreased transcript levels in BR-deficient plants is BR inducible and vice versa. Expression profile analysis of above ground part of plants was performed by means of Affymetrix Arabidopsis Genome Arrays.

Arabidopsis↗

PubMed2002

[Non-insulin therapy in diabetes mellitus].

Changes to nutritional habits, including the reduction of weight, are basic therapy principles for the treatment of diabetes mellitus. With overweight patients a reduction of energy intake is important. Patients with diabetes mellitus should eat plenty of carbohydrates, the intake of fat should be limited to a maximum of 35%. Patients treated with insulin must be made to calculate carbohydrate exchange units. Unless there are contraindications, diabetic patients should be encouraged to engage in physical exercise. Educating the patients is of major importance in the treatment of diabetics; this must be undertaken by trained personnel. All diabetic patients treated with oral antidiabetic drugs or insulin should be encouraged to measure their blood glucose levels themselves, in cases of insulin therapy this is an absolutely necessity. If with the aid of basic therapy measures, which include the control of fasting blood glucose, postprandial blood glucose and HbA1c levels, the aims of the therapy are not reached, this is an indication for the use of oral antidiabetic drugs. The drug should be chosen with the dominant pathophysiological disturbance in mind. In the case of increased fasting blood glucose values (hepatic insulin resistance leading to increased glucose production by the liver), after contraindications have been excluded, the use of metformin is recommended. If there are significantly increased postprandial blood glucose values (due to an early-insulin-secretion deficiency or severe insulin resistance), the use of alpha-glucosidase-inhibitors, metformin, sulphonylureas or glinides is indicated. With obese patients alphaglucosidaseinhibitors and metformin are the drugs of choice, with patients with BMI < 25 kg/m2 these are sulfonylureas or glinides. In cases of severe insulin resistance the use of glitazones in conjunction with metformin or sulphonylureas may be indicated.

Diabetes Mellitus↗

PubMed1998

The Streptomyces reticuli alpha-chitin-binding protein CHB2 and its gene.

When co-cultivated with chitin-containing fungi, Streptomyces reticuli secretes the chitin-binding protein CHB2. Microscopical and immunological investigations revealed that CHB2 acts like a glue to mediate the contact between the fungal and the Streptomyces hyphae. CHB2 was purified to homogeneity, and the sequence of its N-terminal amino acids was determined and used to deduce an oligonucleotide, which was then used to probe a subgenomic library. The chb2 gene was cloned, sequenced and overexpressed. The deduced mature protein has a molecular mass of 18.6 kDa, and a large number of its amino acids are identical to those of CHB1 from Streptomyces olivaceoviridis. CHB2 effectively targets different types of alpha-chitin, but no other polysaccharide. The dissociation constant (Kd) for binding to purified crab shell chitin is 0.27 microM. Immunological studies suggest that homologues of CHB1 and CHB2 are secreted by streptomycetes while growing in the presence of alpha-chitin-containing substrates.

Amino Acid Sequence↗