[Public health: where are we?].
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Germany↗
Biomedical subjects
U Walter
Publications and source records attributed to U Walter.
[Anticoagulation in stroke. Evidence-based and empirical indications].
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Administration, Oral↗
Pancreatic NOD beta cells express MHC class II protein and the frequency of I-A(g7) mRNA-expressing beta cells strongly increases during progression to autoimmune diabetes.
AIMS/HYPOTHESIS: In the NOD mouse model, attempts to show MHC class II expression by pancreatic beta cells were unsuccessful so far. We readdressed this question by analysing I-A(g7) expression in single pancreatic beta cells. METHODS: Single-cell multiplex RT PCR and single-cell immunofluorescence were used to study MHC class II expression in NOD and NOD/SCID beta cells. RESULTS: Pancreatic beta cells from NOD mice express the I-A(g7) protein as well as the corresponding mRNA. The frequency of MHC class II mRNA-expressing beta cells is drastically increased during the progression to overt diabetes. MHC class II protein is accumulated intracellularly, and invariant chain is co-expressed. Beta cells from 9- to 10-week-old NOD/SCID mice express MHC class II at the same low frequency as beta cells from 3-week-old NOD mice. CONCLUSION/INTERPRETATION: NOD beta cells express I-A(g7) and could be a direct target of autoreactive CD4+ T cells. This MHC class II expression is triggered by infiltrating lymphocytes.
Animals↗
Brain parenchyma sonography discriminates Parkinson's disease and atypical parkinsonian syndromes.
OBJECTIVE: To study the use of brain parenchyma sonography (BPS) in discriminating between patients with idiopathic PD (IPD) and atypical parkinsonian syndromes (APS). METHODS: Twenty-five patients with APS, 9 with progressive supranuclear palsy (PSP) and 16 with multiple-system atrophy (MSA), and 25 age-matched patients with IPD were prospectively studied with BPS according to a standardized protocol. RESULTS: Twenty-four of the 25 (96%) IPD patients exhibited hyperechogenicity of the substantia nigra (SN) but only 2 of 23 (9%) APS patients (Mann-Whitney U test, p < 0.001). In those two APS patients, SN hyperechogenicity was moderate only, whereas the remaining 21 APS patients had normal SN echogenicity. The specificity of SN hyperechogenicity in detection of clinically diagnosed IPD patients was 96%, and the sensitivity was 91%. If SN hyperechogenicity was marked, APS could be excluded because of a positive predictive value of 100% for IPD. Nucleus lentiformis hyperechogenicity was found in 17 of 22 (77%) APS patients but in only 5 of 22 (23%) IPD patients (Mann-Whitney U test, p < 0.001). Nucleus caudatus and thalamus echogenicity and widths of the third ventricle and of the frontal horns of the lateral ventricles did not discriminate between IPD and APS. Two patients with PSP could not be assessed because of an insufficient bone window. CONCLUSIONS: BPS is a novel and noninvasive method to differentiate highly specifically between IPD and APS. Therefore, BPS might become a standard investigation in parkinsonian disorders.
Aged↗
Substantia nigra echogenicity is normal in non-extrapyramidal cerebral disorders but increased in Parkinson's disease.
Transcranial sonography (TCS) revealed substantia nigra (SN) hyperechogenicity in idiopathic Parkinson's disease (IPD). To further evaluate specificity of this finding, we examined 30 IPD patients and 30 age-matched subjects with non-extrapyramidal cerebral disorders (NED). All IPD patients showed a SN hyperechogenicity, in 17 it was bilateral and in 13 unilateral. 7 NED patients had a SN hyperechogenicity, in all it was unilateral, confirming previous results in healthy subjects. Bilateral SN hyperechogenicity indicates IPD and normal SN echogenicity indicates NED. In 30% of patients TCS does not distinguish between IPD and NED. Data further support the assumption that bilateral SN hyperechogenicity is specific for IPD.
Aged↗
Genetic risk factors in young adults with 'cryptogenic' ischemic cerebrovascular disease.
Mutations such as factor V Leiden G1691A (FVL), prothrombin G20210A (FIIM), methylenetetrahydrofolate reductase (MTHFR) C677T, cystathionine beta-synthase (CBS) 844ins68 and endothelial cell protein C receptor (EPCR) 4031ins23 are risk factors for thromboembolism. To assess the role of these mutations in young adults with cerebral ischemia of otherwise undetermined etiology, 93 patients younger than 50 years old with thromboembolic strokes or transient ischemic attacks were studied. One hundred and eighty-six healthy age-matched and sex-matched blood donors served as controls. The FVL mutation was detected in 15/93 patients and 13/186 controls. After adjustment for smoking, arterial hypertension, and hyperlipidemia, the association of the FVL mutation with cerebral ischemia [odds ratio (OR), 3.19; 95% confidence interval (CI), 1.38-7.39] remained significant. One of 93 patients and 6/186 controls were carriers of FIIM (OR, 0.33; 95% CI, 0.04-2.75). We detected the MTHFR TT677 genotype in 9/93 patients and 26/186 controls (OR, 0.66; 95% CI, 0.30-1.47), a CBS 844ins68 mutation in 12/93 patients and 19/186 controls (OR, 1.30; 95% CI, 0.60-2.81), and an EPCR 4031ins23 mutation in 1/93 patients and in no control individual (P = 0.33). In conclusion, in younger adults the FVL mutation is a risk factor for cerebrovascular disease. FIIM, the MTHFR TT677 genotype and the CBS 844ins68 mutation did not contribute to the risk in this group of patients. The EPCR 4031ins23 mutation is very rare, its possible role needs further investigation.
Adolescent↗
Distribution, cellular localization, and postnatal development of VASP and Mena expression in mouse tissues.
Vasodilator-stimulated phosphoprotein (VASP) and mammalian Enabled (Mena) are members of the proline-rich Ena/VASP protein family that links the cell membrane proteins, signal transduction pathways, and the actin cytoskeleton. VASP and Mena, substrates of cyclic nucleotide-dependent protein kinases, are associated in different cell types with microfilaments, focal adhesions, cell-cell contacts, and highly dynamic membrane regions. Here, the analysis of mRNA and protein expression, cellular localization, and postnatal development of VASP in different mouse tissues is reported and compared with that of Mena. The expression levels of VASP and Mena differ markedly among various tissues and cell types. The highest levels of VASP are observed in platelets, but stomach, intestine, spleen, lung, and blood vessels are also rich sources of VASP. Mena is abundantly expressed in brain, whereas it is not detectable in platelets and spleen. In intestine and stomach, prominent VASP and Mena immunoreactivity is detected in intestinal smooth muscle cells and blood vessels and cellular membranes of epithelial cells. In kidney, VASP and Mena are abundantly expressed in glomerular mesangial cells and in papilla. VASP and Mena immunoreactivity in heart is associated with blood vessels and with the intercalated discs of cardiac myocytes, where they colocalize with connexin-43. During postnatal development of heart, the level of VASP and Mena expression gradually decreases from neonatal to adult animals. The data demonstrate a clear colocalization of VASP and Mena in cells of stomach, intestine, kidney, and heart. These data and other recent developments suggest that proteins of the Ena/VASP family exert similar functions and may compensate for each other in these tissues.
Animals↗
[Prevention in medical care: potentials, effectiveness and conversion].
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Adult↗
Taming platelets with cyclic nucleotides.
Cardiovascular diseases are often accompanied and aggravated by pathologic platelet activation. Tight regulation of platelet function is an essential prerequisite for intact vessel physiology or effective cardiovascular therapy. Physiological platelet antagonists as well as various pharmacological vasodilators inhibit platelet function by activating adenylyl and guanylyl cyclases and increasing intracellular cyclic AMP (cAMP) and cyclic GMP (cGMP) levels, respectively. Elevation of platelet cyclic nucleotides interferes with basically all known platelet activatory signaling pathways, and effectively blocks complex intracellular signaling networks, cytoskeletal rearrangements, fibrinogen receptor activation, degranulation, and expression of pro-inflammatory signaling molecules. The major target molecules of cyclic nucleotides in platelets are cyclic nucleotide-dependent protein kinases that mediate their effects through phosphorylation of specific substrates. They directly affect receptor/G-protein activation and interfere with a variety of signal transduction pathways, including the phospholipase C, protein kinase C, and mitogen-activated protein kinase pathways. Regulation of these pathways blocks several steps of cytosolic Ca(2+) elevation and controls a multitude of cytoskeleton-associated proteins that are directly involved in organization of the platelet cytoskeleton. Due to their multiple sites of action and strong inhibitory potencies, cyclic nucleotides and their regulatory pathways are of particular interest for developing new approaches for the treatment of thrombotic and cardiovascular disorders.
Adenylyl Cyclases↗
Effects of in vivo nitroglycerin treatment on activity and expression of the guanylyl cyclase and cGMP-dependent protein kinase and their downstream target vasodilator-stimulated phosphoprotein in aorta.
BACKGROUND: Chronic in vivo treatment with nitroglycerin (NTG) induces tolerance to nitrates and cross-tolerance to nitrovasodilators and endothelium-derived nitric oxide (NO). We previously identified increased vascular superoxide formation and reduced NO bioavailability as one causal mechanism. It is still controversial whether intracellular downstream signaling to nitrovasodilator-derived NO is affected as well. METHODS AND RESULTS: We therefore studied the effects of 3-day NTG treatment of rats and rabbits on activity and expression of the immediate NO target soluble guanylyl cyclase (sGC) and on the cGMP-activated protein kinase I (cGK-I). Tolerance was induced either by chronic NTG infusion via osmotic minipumps (rats) or by NTG patches (rabbits). Western blot analysis, semiquantitative reverse transcription-polymerase chain reaction, and Northern blot analysis revealed significant and comparable increases in the expression of sGC alpha(1) and beta(1) subunit protein and mRNA. Studies with the oxidative fluorescent dye hydroethidine revealed an increase in superoxide in the endothelium and smooth muscle. Stimulation with NADH increased superoxide signals in both layers. Although cGK-I expression in response to low-dose NTG was not changed, a strong reduction in vasodilator-stimulated phosphoprotein (VASP) serine239 phosphorylation (specific substrate of cGK-I) was observed in tolerant tissue from rats and rabbits. Concomitant in vivo and in vitro treatment with vitamin C improved tolerance, reduced oxidative stress, and improved P-VASP. CONCLUSIONS: We therefore conclude that increased expression of sGC in the setting of tolerance reflects a chronic inhibition rather than an induction of the sGC-cGK-I pathway and may be mediated at least in part by increased vascular superoxide.
Administration, Cutaneous↗
In vivo blockade of the Fas-Fas ligand pathway inhibits cyclophosphamide-induced diabetes in NOD mice.
There is compelling evidence to show that insulin dependent diabetes ensues from selective apoptosis of pancreatic beta-cells mediated by autoreactive T-lymphocytes. The respective implication in this phenomenon of the various apoptotic pathways driven by Fas, perforin, or tumor necrosis factor is still ill- defined. Here we took advantage of the cyclophosphamide-induced model of accelerated diabetes in NOD mice to explore the physiopathological role of the Fas-Fas Ligand pathway. A single injection of cyclophosphamide (200 mg/kg) to 7-8 week-old prediabetic NOD mice triggered diabetes within 10-15 days in 85-100% of the animals. Cyclophosphamide also induced a significant decrease in spleen T cells, that was most evident by days 6-10 after treatment, and selectively affected the CD3(+)CD62L(+)compartment that includes immunoregulatory T cells. To block the in vivo Fas-Fas ligand (Fas L) interaction we administered a biologically active recombinant fusion protein coupling mouse Fas to the Fc portion of human IgG1 (FAS-Fc). Mice treated with FAS-Fc (10 doses iv of 15 microg) starting on the day of cyclophosphamide injection up to day 22, were fully protected from disease. Unexpectedly this protective effect was not due to blockade of Fas-FasL-mediated beta-cell apoptosis but rather to the inhibition of the cyclophosphamide effect on T cells. Indeed FAS-Fc treatment prevented the drug-induced T cell depletion in general and that of immunoregulatory T cells in particular. Additionally, FAS-Fc administration limited to the phase of beta-cell destruction did not afford any protection.
Animals↗
Insulin fails to modulate the cardiac L-type Ca2+ current in Type II diabetes patients--a possible link to cardiac dysfunction in diabetes mellitus.
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Aged↗
Inhibition of rat cardiac fibroblast growth by cAMP--but not by cGMP-dependent protein kinase.
Cardiac fibroblasts play a critical role in the process of pathophysiological cardiac hypertrophy as the cell type responsible for fibrosis. Whereas many growth factors and hormones are thought to be involved, possible crosstalks between signal transduction pathways are not well defined. Therefore we investigated the influence of cAMP- and cGMP-dependent protein kinases (cAK, cGK) on platelet derived growth factor (PDGF) stimulated growth of primary cardiac fibroblasts from adult rats. We show here that PDGF-BB induced cell proliferation can be inhibited by activation of the endogenous cAK directly via the cAMP analog 5,6-DCL-cBIMPS as well as indirectly via the cAMP-elevating receptor agonist prostaglandin-E1 (PGE1). In contrast, activation of the endogenous cGK-I has no influence on cardiac fibroblast cell growth. The strength of the proliferation inhibition is dependent on the time course of cAK activation, i.e., longer activation with the cAMP analog results in stronger proliferation inhibition. No significant influence of cAK or cGK-I on Akt activation or on the short-term activation of the MAPK cascade was observed. In contrast, 5,6-DCI-cBIMPS treatment of cardiac fibroblasts causes an inhibition of long-term MAPK phosphorylation. A prolonged PGE1-dependent cAMP signal after addition of 3-isobutyl-1-methylxanthine (IBMX) blocks the second long-term MAPK phosphorylation as well. Therefore the suppression of MAPK long-term phosphorylation, four to eight hours after PDGF-BB stimulation, appears to play the major role in inhibition of cardiac fibroblast proliferation by cAK activators.
Animals↗
Actin-based motility: stop and go with Ena/VASP proteins.
Proteins of the Ena/VASP (Enabled/vasodilator-stimulated phosphoprotein) family are involved in Abl and/or cyclic nucleotide-dependent protein kinase signaling pathways. These proteins are also crucial factors in regulating actin dynamics and associated processes such as cell-cell adhesion, platelet function and actin-based motility of both cytopathogenic Listeria and their eukaryotic host cells. Although biochemical mechanisms have emerged depicting Ena/VASP proteins as enhancers of actin filament formation, increasing evidence also suggests that these proteins have inhibitory functions in integrin regulation, cell motility and axon guidance.
Actins↗
In vivo haemostatic effects of activated prothrombin complex concentrate and recombinant factor VIIa in a haemophilia A patient with inhibitors.
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Aged↗
[Effect of a back education program by the Lower Saxony AOK in response to the development of health related quality of life and occupational disability].
The statutory sickness fund AOK Lower Saxony developed a specific course program for a target group of up to 55-year old employees with common back pain in the early satge of chronification. Comparative evaluation of effects in study participants and controls was achieved by quality of life and performance data, i.e. days of sick leave (DSL). Medium and long-term change inquality of life (6 and 12 months after the course) was assessed by means of the SF-36 dimensions for cases and controls and compared in bivariate and multivariate test. 92 of 197 baseline participants (or 127 participants who completed the programme) and 483 controls were included in the medium term effect analysis. Significant medium and long-term net efffects could only be shown for pain dimensions. Anonymised DSL data for all 5409 insured persons who were initially selected as potiential participants for the regionally restricted course programme in the second quarter of 1997 were available for the period from 01-01-1996 to 30-06-1999. For controlling any selection bias and potential regional differences, the initial DSL trends of the 197 baseline course participants were compared with two control groups, namely other insured from the programme region and control regions. DSL trends in the three groups prior to the course program were identical. Subsequently DSL due to ICD-9 Codes 710-739 were reduced more substantially in course participants than in controls: 25.5 versus 33 or 32 days respectively. A covariance analysis model that also considered socio-economic factors and pre-intervention DSL levels yeilded a 14-day reduction in DSL (p value 0.023). This is a clear effect on DSL trends taht may be utilised for net savings for AOK. This is also the first proof of a backpain programme outside company settings taht permits net savings.
Curriculum↗
The impact of maternal education on intrauterine growth: a comparison of former West and East Germany.
BACKGROUND: Objective of this re-analysis of datasets from former East and West Germany was to examine the influence of maternal education on intrauterine growth in two different political and social systems. METHODS: Information on socio-demographic or lifestyle factors and pregnancy outcome was available for 3374 liveborn singletons from West Germany (1987/88) and 3070 from East Germany (1990/91). Multiple logistic regression was used to estimate the association between maternal education and the risk of delivering a small-for-gestational-age (SGA) newborn below the 10th percentile of birthweight. RESULTS: Women with the lowest education had a significantly elevated risk of SGA newborns compared to women with the highest education in West (odds ratio [OR] = 2.58, 95% CI : 1.17-5.67) and East Germany (OR = 2.77, 95% CI : 1.54- 5.00). The distribution of factors known to influence intrauterine growth varied with education in both states. After adjusting for these factors, women with the lowest educational level still had a higher risk of SGA birth: OR (West) = 2.02, 95% CI : 0.87-4.72; OR (East) = 1.95, 95% CI : 1.02-3.74. CONCLUSIONS: Our findings support the assumption that in former socialist countries health inequalities as a result of social inequalities existed.
Body Mass Index↗
A cGMP-dependent protein kinase assay for high throughput screening based on time-resolved fluorescence resonance energy transfer.
Activation of cyclic GMP-dependent protein kinase (cGK) is an important event in the regulation of blood pressure and platelet function. Upstream signals are the generation of nitric oxide (NO) by NO synthases and the subsequent rise in cyclic GMP levels mediated by NO-dependent guanylyl cyclases (GCs). The identification of new cGK activators by high throughput screening (HTS) may lead to the development of a novel class of therapeutics for the treatment of cardiovascular diseases. Therefore, a homogeneous, nonradioactive assay for cGK activity was developed using a biotinylated peptide derived from vasodilator-stimulated phosphoprotein (VASP), a well-characterized natural cGK substrate. The phosphorylated peptide could be detected by a VASP-specific monoclonal phosphoserine antibody and a fluorescent detection system consisting of a europium-labeled secondary antibody and allophycocyanin (APC)-labeled streptavidin. Fluorescence resonance energy transfer (FRET) from europium to APC was detected in a time-resolved fashion (TR-FRET). Activation and inhibition constants for known substances determined by this new fluorescence-based assay correlated well with published results obtained by conventional radioactive cGK activity assays. The assay proved to be sensitive, robust, highly specific for cGK, and suitable for HTS in 96- and 384-well formats. This assay is applicable to purified enzymes as well as to complex samples such as human platelet extracts.
Alkaloids↗