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Biomedical subjects

E Schmitt

Publications and source records attributed to E Schmitt.

At least 19 recordsLinked to original sources
PubMed2002

Hormonal and genotoxic activity of resveratrol.

Resveratrol (RES) is a natural polyphenol present in red wines and various human food items. The estrogenic activity of RES was demonstrated in two in vitro assay systems, i.e. binding to human estrogen receptor alpha and stimulation of MCF-7 cell proliferation. To investigate the inhibition of cell proliferation observed at high concentrations of RES, we analyzed the compound for genotoxic potential. RES induced cellular toxicity, micronuclei, and metaphase chromosome displacement in L5178Y mouse lymphoma cells. Likewise, the induction of micronuclei was observed in Chinese hamster V79 cells. Determination of kinetochore signals in micronuclei and cell cycle analysis suggested that RES did not cause a direct disturbance of mitosis. In support of this notion, cell-free tubulin polymerization studies indicated no direct effect of RES on microtubule assembly. According to an estimation of daily intake and bioavailability, concentrations that were found genotoxic in vitro might be reached in human exposure. On the other side, the estrogenic acitivity might be beneficial. Therefore, further investigations of mechanisms, possibly including animal models, would be desirable to clarifiy a potential risk for humans.

Animals↗
PubMed2001

[Utilization of family practice by unemployed persons. Results of a survey of 250 family and primary care physicians].

The results of a questionnaire-based poll of 25 general practitioners from five German Länder show that providing medical care to the jobless confronts the family doctor with specific personal and health problems requiring more treatment time and more comprehensive medication--including antidepressants and tranquilizers--than age-matched working patients. Most practitioners had a skeptical attitude towards cooperation with institutions offering options to the jobless. Family doctors are faced with the dilemma of not being able to delegate the resolution of the patients' personal problems to others, while having no opportunity of obtaining remuneration from health insurance carriers for the time they spend counseling these patients.

Family Practice↗
PubMed2001

Structure of crystalline D-Tyr-tRNA(Tyr) deacylase. A representative of a new class of tRNA-dependent hydrolases.

Cell growth inhibition by several d-amino acids can be explained by an in vivo production of d-aminoacyl-tRNA molecules. Escherichia coli and yeast cells express an enzyme, d-Tyr-tRNA(Tyr) deacylase, capable of recycling such d-aminoacyl-tRNA molecules into free tRNA and d-amino acid. Accordingly, upon inactivation of the genes of the above deacylases, the toxicity of d-amino acids increases. Orthologs of the deacylase are found in many cells. In this study, the crystallographic structure of dimeric E. coli d-Tyr-tRNA(Tyr) deacylase at 1.55 A resolution is reported. The structure corresponds to a beta-barrel closed on one side by a beta-sheet lid. This barrel results from the assembly of the two subunits. Analysis of the structure in relation with sequence homologies in the orthologous family suggests the location of the active sites at the carboxy end of the beta-strands. The solved structure markedly differs from those of all other documented tRNA-dependent hydrolases.

Amino Acid Sequence↗
PubMed2001

Treatment of allergic airway inflammation and hyperresponsiveness by antisense-induced local blockade of GATA-3 expression.

Recent studies in transgenic mice have revealed that expression of a dominant negative form of the transcription factor GATA-3 in T cells can prevent T helper cell type 2 (Th2)-mediated allergic airway inflammation in mice. However, it remains unclear whether GATA-3 plays a role in the effector phase of allergic airway inflammation and whether antagonizing the expression and/or function of GATA-3 can be used for the therapy of allergic airway inflammation and hyperresponsiveness. Here, we analyzed the effects of locally antagonizing GATA-3 function in a murine model of asthma. We could suppress GATA-3 expression in interleukin (IL)-4-producing T cells in vitro and in vivo by an antisense phosphorothioate oligonucleotide overlapping the translation start site of GATA-3, whereas nonsense control oligonucleotides were virtually inactive. In a murine model of asthma associated with allergic pulmonary inflammation and hyperresponsiveness in ovalbumin (OVA)-sensitized mice, local intranasal administration of fluorescein isothiocyanate-labeled GATA-3 antisense oligonucleotides led to DNA uptake in lung cells associated with a reduction of intracellular GATA-3 expression. Such intrapulmonary blockade of GATA-3 expression caused an abrogation of signs of lung inflammation including infiltration of eosinophils and Th2 cytokine production. Furthermore, treatment with antisense but not nonsense oligonucleotides induced a significant reduction of airway hyperresponsiveness in OVA-sensitized mice to levels comparable to saline-treated control mice, as assessed by both enhanced pause (PenH) responses and pulmonary resistance determined by body plethysmography. These data indicate a critical role for GATA-3 in the effector phase of a murine asthma model and suggest that local delivery of GATA-3 antisense oligonucleotides may be a novel approach for the treatment of airway hyperresponsiveness such as in asthma. This approach has the potential advantage of suppressing the expression of various proinflammatory Th2 cytokines simultaneously rather than suppressing the activity of a single cytokine.

Animals↗
PubMed2001

Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood.

A subpopulation of peripheral human CD4(+)CD25(+) T cells that expresses CD45RO, histocompatibility leukocyte antigen DR, and intracellular cytotoxic T lymphocyte-associated antigen (CTLA) 4 does not expand after stimulation and markedly suppresses the expansion of conventional T cells in a contact-dependent manner. After activation, CD4(+)CD25(+) T cells express CTLA-4 on the surface detectable for several weeks. These cells show a G1/G0 cell cycle arrest and no production of interleukin (IL)-2, IL-4, or interferon (IFN)-gamma on either protein or mRNA levels. The anergic state of CD4(+)CD25(+) T cells is not reversible by the addition of anti-CD28, anti-CTLA-4, anti-transforming growth factor beta, or anti-IL-10 antibody. However, the refractory state of CD4(+)CD25(+) T cells was partially reversible by the addition of IL-2 or IL-4. These data demonstrate that human blood contains a resident T cell population with potent regulatory properties.

Abatacept↗
PubMed2001

IL-9 and IL-13 production by activated mast cells is strongly enhanced in the presence of lipopolysaccharide: NF-kappa B is decisively involved in the expression of IL-9.

Mast cells, due to their ability to produce a large panel of mediators and cytokines, participate in a variety of processes in adaptive and innate immunity. Herein we report that in primary murine bone marrow-derived mast cells activated with ionomycin or IgE-Ag the bacterial endotoxin LPS strongly enhances the expression of IL-9 and IL-13, but not IL-4. This costimulatory effect of LPS is absent in activated mast cells derived from the LPS-hyporesponsive mouse strain BALB/c-LPS(d), although in these cells the proinflammatory cytokine IL-1 can still substitute for LPS. The enhanced production of mast cell-derived IL-13 in the presence of IL-1 is a novel observation. Coactivation of mast cells with LPS leads to a synergistic activation of NF-kappa B, which is shown by an NF-kappa B-driven reporter gene construct. In the presence of an inhibitor of NF-kappa B activation, the production of IL-9 is strongly decreased, whereas the expression of IL-13 is hardly reduced, and that of IL-4 is not affected at all. NF-kappa B drives the expression of IL-9 via three NF-kappa B binding sites within the IL-9 promoter, which we characterize using gel shift analyses and reporter gene assays. In the light of recent reports that strongly support critical roles for IL-9 and IL-13 in allergic lung inflammation, our results emphasize the potential clinical importance of LPS as an enhancer of mast cell-derived IL-9 and IL-13 production in the course of inflammatory reactions and allergic diseases.

Adjuvants, Immunologic↗
PubMed2001

Recognition of tRNAs by Methionyl-tRNA transformylase from mammalian mitochondria.

Protein synthesis involves two methionine-isoaccepting tRNAs, an initiator and an elongator. In eubacteria, mitochondria, and chloroplasts, the addition of a formyl group gives its full functional identity to initiator Met-tRNA(Met). In Escherichia coli, it has been shown that the specific action of methionyl-tRNA transformylase on Met-tRNA(f)(Met) mainly involves a set of nucleotides in the acceptor stem, particularly a C(1)A(72) mismatch. In animal mitochondria, only one tRNA(Met) species has yet been described. It is admitted that this species can engage itself either in initiation or elongation of translation, depending on the presence or absence of a formyl group. In the present study, we searched for the identity elements of tRNA(Met) that govern its formylation by bovine mitochondrial transformylase. The main conclusion is that the mitochondrial formylase preferentially recognizes the methionyl moiety of its tRNA substrate. Moreover, the relatively small importance of the tRNA acceptor stem in the recognition process accounts for the protection against formylation of the mitochondrial tRNAs that share with tRNA(Met) an A(1)U(72) motif.

Amino Acid Sequence↗
PubMed2001

Preeclampsia, a pregnancy-specific disease, is associated with fetal monocyte activation.

The maternal syndrome of preeclampsia is an exclusively pregnancy-related illness involving multiple organs and severe forms may be complicated by HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome. Recently, it has been proposed that both normal pregnancy and preeclampsia are associated with a systemic activation of the nonspecific maternal immune system and that, in particular, monocytes have a central role in the adjustment of maternal immune functions in pregnancy. Here we have investigated the role of the fetal nonadaptive immune system in normal term delivery, uncontrollable preterm labor, and preeclampsia. We demonstrate that spontaneous delivery at term as well as preterm occurrence of preeclampsia or HELLP syndrome are accompanied by an increased intracellular production of IL-6 in fetal monocytes, indicating strong activation of this cell type. In contrast, we show that elective cesarean delivery at term in the absence of labor or preterm delivery due to uncontrollable labor are not accompanied by an increased production of IL-6 in these cells. These results suggest that increased IL-6 synthesis in fetal monocytes may be a process occurring in association with normal spontaneous term delivery and that this process obviously occurs in early pregnancy in case of preeclampsia. Therefore, we propose that the activation of fetal monocytes as effectors of the innate immunity may be involved in mechanisms inducing spontaneous term delivery and that the occurrence of preeclampsia may be based on dysfunctions of probably both the maternal and the fetal innate immune system.

Female↗
PubMed2001

Identification of a 55-bp deletion in the glucocerebrosidase gene in Gaucher disease: phenotypic presentation and implications for mutation detection assays.

A 55-bp deletion in exon 9 of the glucocerebrosidase gene was identified in a 28-year-old male affected with Gaucher disease. The diagnosis was established during an evaluation for mild pancytopenia and was confirmed by bone marrow histology and biochemical studies. The patient is of German ancestry. Initial DNA testing indicated homozygosity for the N370S mutation. However, subsequent testing of the patient's parents suggested that the patient and his mother carried a null allele by our assay for N370S. Further molecular studies identified a 55-bp deletion in exon 9 of the glucocerebrosidase gene (g.6767_6822del55). This deletion has been previously reported in a patient with severe Gaucher disease (1), and is present in the glucocerebrosidase pseudogene. In the previously reported case, initial DNA testing also suggested the genotype N370S/N370S, but further mutation studies were undertaken because clinical severity was greater than expected for that genotype. In contrast, our patient has an unusually mild clinical course. Thus, clinical severity cannot be reliably used to determine when to test for the presence of the 55-bp deletion. While the 55-bp deletion is not reported to be common, its actual frequency may be underestimated since it eludes detection by many standard clinical assays for Gaucher disease. This report points out the need to consider this deletion mutation which may cause erroneous interpretation of results in existing assays for the common mutations N370S and L444P. Furthermore, the importance of recommending parental analysis for individuals who test homozygous for autosomal mutations is highlighted.

Adult↗
PubMed2001

[Diagnostic imaging in liver cirrhosis].

For the diagnosis of liver cirrhosis ultrasound, computed tomography, magnetic resonance imaging, and angiography are recommended as imaging modalities. Ultrasound of the liver is used as a screening imaging tool in cases of patients suspicious for diffuse liver disease and is helpful in the term of follow-up examinations. Computed tomography is mainly performed to clarify the presence of liver disease detected by ultrasound. In this context, accurate examination of the vascular structures of the liver as well as extrahepatic situation, is of the essence. Diagnosis of diffuse liver disease and characterization of morphologic changes is improved using contrast-enhanced MR imaging with liver specific contrast media. Combined magnetic resonance imaging can provide comprehensive evaluation of cirrhosis. An improved detection rate and characterization of regenerating nodules can be achieved compared to imaging modalities such as ultrasound and computed tomography. MR imaging can be performed in a one-stop-technique using unenhanced and liver-specific-contrast-enhanced sequence protocols to evaluate the liver parenchyma itself, MR cholangiography to verify the bile duct system, and MR angiography to specify the vascular situation. This technique is the optimal protocol for diagnostic imaging in patients suffering from liver cirrhosis and the method of choice to reach the final diagnosis.

Diagnostic Imaging↗
PubMed2001

[Significance of employment and unemployment in middle and advanced adult age for subjective perception of aging and realization of potentials and barriers of a responsible life].

This contribution proceeds on the assumption that occupational activities in middle and upper adulthood do offer opportunities to use and extend competences and therefore to experience self-efficacy, social participation and acceptance, whereas unemployment is associated with a constriction of personal resources which have a negative impact on subjective perceptions of ones's own aging process, potentials and barriers of leading a productive and responsible life. First, employed and unemployed subjects are compared in their scores on three psychometric scales (perceptions of age-related losses, potentials and barriers of leading a productive and responsible life) and four aspects of the "Lebenslage" (Subjective health status, Perceived social integration, Income of the household, Education). In a further step the predictive power of employment and unemployment for subjective perceptions of one's own aging process, potentials and barriers of leading a productive and responsible life when aspects of the "Lebenslage" and sociostructural variables (Age, Sex, Eastern versus western part of Germany, Areas with high versus low unemployment) are also taken into account. Results, obtained in a stratified sample of 641 subjects between 45 and 57 years, show that employed and unemployed subjects differ in subjective perceptions of one's own aging process, potentials and barriers of leading a productive and responsible life as well as in aspects of the "Lebenslage". Employment and unemployment are significant predictors of subjective perceptions of one's own aging process, potentials and barriers of leading a productive and responsible life even when aspects of the "Lebenslage" and sociostructural variables are already taken into account. Results are interpreted as support for the hypothesis that occupational activities are not only instrumental for the realization of human necessities, but that in middle and upper adulthood employment is to be regarded as a human need in itself.

Activities of Daily Living↗
PubMed2001

Dendritic cells as a tool to induce anergic and regulatory T cells.

The induction of antigen-specific T-cell tolerance in the thymus and its maintenance in the periphery is crucial for the prevention of autoimmunity. As well as their stimulatory functions, there is growing evidence that dendritic cells, acting as professional antigen-presenting cells, also maintain and regulate T-cell tolerance in the periphery. This control function is exerted by certain maturation stages and subsets of different ontogeny, and can be influenced by immunomodulatory agents. What is the current state of knowledge of the "immunoregulatory" properties of dendritic cells and how might tolerance-inducing dendritic cells be relevant to therapeutic applications in humans?

Animals↗
PubMed2001

[Controlled dynamic weight training in patients with neuromuscular disorders].

The question posed was whether individually adapted, controlled dynamic weight training, in accordance with training principles and methods from sports science, applied for a limited time, can lead to an improvement in the stimulation and release of muscular strength in patients with neuromuscular disorders. The muscles of the pelvic girdle and the lower extremity of 10 patients (5 with dystrophic muscle disease and 5 with neurogenic muscular atrophy) were exercised provisionally for a period of 6 weeks on various weight training machines. The training routine was 3 sessions (TS) per week at an intensity range of 40-60% of the respective best performance for the exercise (One Repetition Maximum; ORM), at 8-12 repetitions/set and 2-4 sets/exercise. Body weight and ORM were determined before, during and after the training period (TP), the different load criteria/TS were documented. It was possible to train the patients in accordance with principles of training known from sports science. Over the entire TP it was possible to increase the load criteria significantly (p < 0.01). The ORM had increased considerably in all exercises after the TP (p < 0.01). The changes in strength lay between 11 and 95%. Correlation analyses demonstrated that the percentage changes in strength correlated significantly (p < 0.01) and positively (r = 0.87) with the training load in terms of quality. No significant changes in development of strength could be ascertained between the two groups of patients (dystrophic versus atrophic). The individually adjusted, controlled dynamic weight training described above, leads to an increase in the stimulation and release of strength and can be conducted according to principles of training science. Applied in clinical rehabilitation, it represents a supplementary form of therapy in the symptomatic treatment of neuromuscular disorders.

Adult↗
PubMed2001

Local administration of antisense phosphorothioate oligonucleotides to the c-kit ligand, stem cell factor, suppresses airway inflammation and IL-4 production in a murine model of asthma.

BACKGROUND: The c-kit ligand, stem cell factor (SCF), is an important activating and chemotactic factor for both mast cells and eosinophils. These cells are known to play a fundamental role in the pathogenesis of asthma. OBJECTIVE: Our goal was to analyze the functional role of SCF in the pathogenesis of asthma. METHODS: The expression of SCF was targeted in fibroblasts, epithelial cells, and locally in a murine model of asthma in mice induced by ovalbumin sensitization with an antisense DNA strategy. RESULTS: We could suppress SCF expression in NIH 3T3 fibroblasts and SP1 epithelial cells by a specific antisense phosphorothioate oligonucleotide overlapping the translation start site of SCF, whereas control oligonucleotides were virtually inactive. We then focused on the role of SCF in a murine model of asthma associated with late-phase allergic inflammation in ovalbumin-sensitized mice: Local intranasal administration of FITC-labeled SCF antisense oligonucleotides led to strong DNA uptake in interstitial lung cells associated with a striking reduction of intracellular SCF expression. Such intrapulmonary blockade of SCF expression after repeated allergen challenges suppressed various signs of lung inflammation including IL-4 production and infiltration of eosinophils. SCF antisense DNA treatment was at least as effective as corticosteroid treatment. CONCLUSION: These data indicate a critical role for SCF in a murine asthma model and suggest that local delivery of SCF antisense oligonucleotides may be a novel approach for the treatment of inflammatory lung disorders such as asthma.

3T3 Cells↗
PubMed2001

Estrogenic activity of naturally occurring anthocyanidins.

Anthocyanins, which are natural plant pigments from the flavonoid family, represent substantial constituents of the human diet. Because some other bioflavonoids are known to have estrogenic activity, the aim of this study was to determine the estrogenic activity of the anthocyanine aglycones. Binding affinity to the estrogen receptor-alpha was 10,000- to 20,000-fold lower than that of the endogenous estrogen estradiol. In the estrogen receptor-positive cell line MCF-7, the anthocyanidins induced expression of a reporter gene. The tested anthocyanidins showed estrogen-inducible cell proliferation in two cell lines (MCF-7 and BG-1), but not in the receptor-negative human breast cancer cell line MDA-MB-231. The phytoestrogen-induced cell proliferation could be blocked by addition of the receptor antagonist 4-hydroxytamoxifen. Combination treatments with the endogenous estrogen estradiol resulted in a reduction of estradiol-induced cell proliferation. Overall, the tested anthocyanidins exert estrogenic activity, which might play a role in altering the development of hormone-dependent adverse effects.

Anthocyanins↗
PubMed2001

Increased formation of micronuclei after hormonal stimulation of cell proliferation in human breast cancer cells.

The carcinogenicity of sex hormones is considered to be the result of a combination of genotoxic and epigenetic modes of action. For estrogens, genotoxic activities include DNA damage by reactive metabolites and indirect genotoxicity by redox cycling and production of reactive oxygen species. Here, we present data on the induction of micronuclei in estrogen receptor-positive (MCF-7) and -negative (MDA) human breast cancer cell lines treated with estradiol to support an additional mechanism of chromosomal damage. MCF-7 cells, but not MDA cells, treated with estradiol in the picomolar concentration range showed an increase in micronucleus formation which correlated with the estradiol-induced cell proliferation. Addition of the specific estradiol-receptor antagonist hydroxytamoxifen suppressed the estradiol-induced formation of micronuclei in MCF-7 cells. Increased frequencies were also seen after normalization of the data to the number of cell divisions by additional treatment of the cells with cytochalasin B. Thus, formation of micronuclei was not due to the chromosomal damaging activity of estradiol. The induced genomic damage may be explained by a hormone-specific forcing of responsive cells through the cell cycle, thereby overriding checkpoints operating under homeostatic control of the cell cycle.

Breast Neoplasms↗
PubMed2001

Vasospasm after subarachnoid hemorrhage: interest in diffusion-weighted MR imaging.

BACKGROUND AND PURPOSE: Vasospasm secondary to subarachnoid hemorrhage (SAH) is responsible for severe ischemic complications. Although effective, angioplasty must be performed at a very early stage to produce any clinical recovery. Diagnostic investigations to assess arterial narrowing (transcranial Doppler, angiography) or cerebral perfusion (xenon CT, single-photon emission CT) do not provide evidence of the extent of parenchymal ischemia. In stroke, diffusion-weighted MR imaging (DWI) appears to be the most sensitive procedure to detect cerebral ischemia. We studied asymptomatic vasospasm in patients with aneurysmal SAH to assess whether DWI provides predictive markers of silent ischemic lesions and/or progression toward symptomatic ischemia. METHODS: Seven asymptomatic vasospasm patients (average blood velocity rates >120 cm/s), 3 patients with symptomatic vasospasm, and 4 patients with SAH but without vasospasm were studied at regular intervals by DWI, and their apparent diffusion coefficients (ADCs) were calculated. RESULTS: All patients with vasospasm including those without symptoms presented abnormalities on DWI with a reduction of the ADC prevalently in the white matter. No such abnormalities were observed in patients without vasospasm. The abnormalities on DWI resolved completely in 4 of the 7 patients, with no parenchymal lesion. Resolution was partial in 3 patients whose white matter still presented residual round, focal ischemic lesions. CONCLUSIONS: Being able to correlate abnormalities on DWI with parenchymal involvement in asymptomatic patients would be of considerable clinical significance. It is hoped that larger studies will be undertaken to determine whether the ADC has a reversibility threshold, because this would facilitate patient management.

Adult↗