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Biomedical subjects

G Scholz

Publications and source records attributed to G Scholz.

At least 19 recordsLinked to original sources
PubMed2005

[Diagnosis of endolymphatic hydrops using low frequency modulated distortion product otoacoustic emissions].

BACKGROUND: The low frequency modulation of distortion product otoacoustic emissions (DPOAEs) is an objective audiometric method that appears to be a useful tool for the diagnosis of endolymphatic hydrops (EH), e.g. in patients with Menière's disease, or in those who present only some of the symptoms of the disease. METHOD: Low-frequency modulated DPOAEs were registered in 20 patients with unilateral Menière's disease (13 women and 7 men, aged 40-66 years) and were compared to a control group matched in age and gender. As a diagnostic parameter, the 'modulation index' MI=1/2 MS/DM was used (MS or modulation span, being the difference between the maximal and the minimal DPOAE-amplitude, and DM, being the mean of the suppressed stationary DPOAE-amplitude). RESULTS: In the patients with unilateral Menière's disease, MI was lower than in the control group. This difference was highly significant. In 56% of the patients' contralateral ears MI was lower than the cut off-value and significantly lower than in the control group, but did not differ significantly from the patients' ipsilateral ears. CONCLUSION: The registration of low-frequency modulated DPOAEs is comparable to the generally applied transtympanic electrocochleography in its diagnostic validity. The method is fast and non-invasive and could be applied to monitor the course of the disease.

Acoustic Stimulation↗
PubMed2005

Human exposure and internal dose assessments of acrylamide in food.

This review provides a framework contributing to the risk assessment of acrylamide in food. It is based on the outcome of the ILSI Europe FOSIE process, a risk assessment framework for chemicals in foods and adds to the overall framework by focusing especially on exposure assessment and internal dose assessment of acrylamide in food. Since the finding that acrylamide is formed in food during heat processing and preparation of food, much effort has been (and still is being) put into understanding its mechanism of formation, on developing analytical methods and determination of levels in food, and on evaluation of its toxicity and potential toxicity and potential human health consequences. Although several exposure estimations have been proposed, a systematic review of key information relevant to exposure assessment is currently lacking. The European and North American branches of the International Life Sciences Institute, ILSI, discussed critical aspects of exposure assessment, parameters influencing the outcome of exposure assessment and summarised data relevant to the acrylamide exposure assessment to aid the risk characterisation process. This paper reviews the data on acrylamide levels in food including its formation and analytical methods, the determination of human consumption patterns, dietary intake of the general population, estimation of maximum intake levels and identification of groups of potentially high intakes. Possible options and consequences of mitigation efforts to reduce exposure are discussed. Furthermore the association of intake levels with biomarkers of exposure and internal dose, considering aspects of bioavailability, is reviewed, and a physiologically-based toxicokinetic (PBTK) model is described that provides a good description of the kinetics of acrylamide in the rat. Each of the sections concludes with a summary of remaining gaps and uncertainties.

Acrylamide↗
PubMed2004

c-fos mRNA expression in rat cortical neurons during glutamate-mediated excitotoxicity.

We have previously reported that exposure of mouse cerebellar granule cells (mCGCs) to excitotoxic concentrations of glutamate (Glu) induced a delayed, elevated, and sustained expression of c-fos mRNA, which was N-methyl-D-aspartic acid (NMDA) receptor mediated. In this study, the overstimulation of Glu receptors in primary rat cortical neurons by excitotoxins was used to study the cellular events triggering excitotoxic neuronal cell death, as the rat is the preferred species in regulatory and nonregulatory toxicological investigations. Exposure of rat cortical neurons to excitotoxins at high, toxic concentrations showed a change in the c-fos mRNA expression profile from a transient expression to one of sustained elevated levels. The excitotoxins induced much higher levels of c-fos mRNA in rat cortical neurons than in the mouse CGC system. Glu-induced c-fos mRNA expression, under excitotoxic conditions, was inhibited by D-2-amino-5-phosphonopentanoate (AP5) but not 6-cyano-7-nitro-quinoxaline-2,3-dione (CNQX), indicating an event mediated by the NMDA subtype of Glu receptors. Using 12 compounds, which covered a range of nontoxic, toxic, and excitotoxic effects on rat cortical neurons, excitotoxicity was paralleled by a sustained, elevated c-fos mRNA expression. Furthermore, on account of the high expression levels of c-fos mRNA under excitotoxic conditions, it is suggested that an unambiguous elevation in c-fos mRNA expression at a single time point of 60 min can be used to predict the excitotoxic properties of a range of functionally different chemical compounds. In view of the high levels of expression of c-fos mRNA, the rat cortical cell system may also be used as a more sensitive model than mCGCs for investigations into early markers of excitotoxicity.

Animals↗
PubMed2003

[Aural fullness and endolymphatic hydrops].

BACKGROUND: Low-frequency modulated DPOAEs were registrated to investigate whether the subjective symptom of aural fullness can indicate an endolymphatic hydrops. METHOD: The cochlear partition is periodically moved towards scala vestibuli and scala tympani by a low-frequency suppressor tone. The level of simultaneously registrated DPOAEs is modulated depending on the phase of the suppressor. This modulation may be reduced when the displacement of the organ of Corti is inhibited by mechanical stiffening of the basilar membrane (e. g. in endolymphatic hydrops). SUBJECTS: Low-frequency modulated DPOAEs were registrated in 15 patients with Menière's disease, in 8 patients with aural fullness and tinnitus, but without vertigo, and in 21 normal hearing adults. RESULTS: In both patient groups the modulation depth is high significantly lower than in the control group. The results do not differ significantly in the patients with and without vertigo. CONCLUSION: The reduction of the modulation depth can be interpreted as a sign of an endolymphatic hydrops. In the group of patients with aural fullness a cochlear hydrops can be assumed. The measurement of low-frequency modulated DPOAEs is a new tool to diagnose and monitor the course of endolymphatic hydrops and to evaluate the effectiveness of therapeutic methods.

Audiometry, Pure-Tone↗
PubMed2002

[Objective test of smell with cognitive potentials].

BACKGROUND: An objective smelling test is indicated for a reliable assessment of olfactory disorders. Usually olfactory evoked potentials (OEP) are registered. But the technique of this measurement is complicated and the generation of the OEP depends on the respiration of the subject. Alternatively, the contingent negative variation (CNV) can be used in the diagnosis of anosmia and parosmia, requiring only a simple olfactory stimulator. SUBJECTS AND METHOD: OEP and CNV were derived from 25 adults with normal smelling and from 16 patients with anosmia after head injury. First, the "direct" CNV was registered when the subjects expected a tone following a smell stimulus after 1.5 s. Using two different odors in a random order, the tone only followed one of them, so the "selective" CNV was scored. RESULTS: In both tests a distinct CNV was found in 21 and 23 normal smelling subjects, respectively. OEPs were absent in 4.3 % of this control group. No patient with anosmia showed an OEP or a CNV. The amplitudes of the "selective" CNV are significantly higher than those of the "direct" CNV. No gender dependency was found. CONCLUSION: The results show that an objective olfactometry can be realized by registration of CNV. Contrary to the measurement of OEP which depend on the physical parameters of olfactory stimuli, CNV correlates well with the cognitive identification of odor.

Adult↗
PubMed2002

Managing for river health--integrating watercourse management, environmental water requirements and community participation.

The Mid North Rivers Management Planning Project (MNRMPP) of the Environment Protection Agency, Department for Environment and Heritage began as a response to community concerns regarding watercourse related issues in the Mid North of South Australia. In response to these concerns the MNRMPP project team developed rapid, cost effective methods to collect and assess data, establish collaborative partnerships with stakeholder organisations, ensure community involvement, and initiate mechanisms to sustain local involvement past the life of the project. Environmental water requirements were identified, along with key watercourse management issues; the integration of these two components of the study enabled more informed decision making regarding watercourse management within the study area. The integration of these components and the involvement of the community and stakeholders through all components of the project has resulted in a sense of ownership and an increase in awareness of watercourse related issues. This has increased the prospect of individuals and organisations implementing the management options and priorities identified within the plan, and has promoted the long term involvement of these groups in better watercourse management.

Community-Institutional Relations↗
PubMed2001

[Electrocochleography and phase audiometry in diagnosis of Meniere disease].

The diagnosis of Menière's disease is uncertain when the typical symptoms do not occur completely and definitely. A reliable finding of an endolymphatic hydrops (EH) is the base for a correct prognosis and therapy. Electrocochleography is a proven diagnostic procedure but requires a lot of time and of technical know-how. The mobility of cochlear partition can be tested by low-frequency masking (LFM) recording the phase dependent subjective masked threshold of a short test tone. We performed electrocochleography and LFM in 29 patients with suspected Menière's disease at the same day. Both tests pointed at an EH in 62%, and in 24% the results showed correspondent negative results. In 14% the results were inconsistent. Both methods also showed in 59% of the contralateral ears without symptomatic signs the indication of an EH. Considering the good conformity of both tests the easier LFM can be recommended for detection of EH.

Adolescent↗
PubMed2001

Fe homeostasis in plant cells: does nicotianamine play multiple roles in the regulation of cytoplasmic Fe concentration?

The cellular and intracellular localization of the non-proteogenic amino acid nicotianamine (NA) in leaves and root elongation zones was immunochemically investigated in pea (Pisum sativum L.) and tomato (Lycopersicon esculentum Mill.) plants grown under various iron regimes and in three mutants defective in the regulation of iron uptake. Strongest immunostaining was observed in the over-accumulating pea mutants brz and dgl, and in iron-loaded wild-type plants. Fe concentration and NA level paralleled staining intensity, indicating that NA synthesis is induced by high iron availability. While label was mainly present in the cytoplasm under normal (10 microM) Fe supply and under Fe deprivation, most of the labeling was present in the vacuole in iron-loaded plants. This pattern resembled the distribution of NA in Fe over-accumulating mutants, indicating the possible importance of vacuolar sequestration in the detoxification of excess Fe. Based on the dependence of the cellular distribution of NA on the iron nutritional status of the plant, a possible role of NA in buffering free Fe in root and leaf cells was inferred. We show here for the first time that the NA concentration is increased in response to iron overload, indicating that, besides other classes of intracellular metal-binding ligands, NA may play an essential role in iron tolerance.

Adaptation, Physiological↗
PubMed2001

Melatonin reduces UV-induced reactive oxygen species in a dose-dependent manner in IL-3-stimulated leukocytes.

Reactive oxygen species (ROS) are presumed to be involved in inflammatory UV reactions of the skin. This in vitro study was performed to investigate the suppressive effect of melatonin in interleukin-3 (IL-3) stimulated leukocytes. Neutrophilic granulocytes were isolated from EDTA-treated whole blood and placed in a phosphate-buffered saline (PBS) containing IL-3. Cell suspensions were either treated with PBS (control) or with increasing doses of melatonin (0.1, 0.5, 1, 2, 3, 5, 7.5, 10 mmol). One PBS solution was left unirradiated and the other nine solutions (PBS and melatonin) were irradiated with 750 mJ/cm2 UVB light (280-360 nm, max: 310 nm). Radical formation was measured by the chemiluminescence technique. UV-irradiated leukocytes showed a 5-fold higher radical formation than unirradiated leukocytes. Melatonin, in increasing doses in powers of ten, led to a maximum suppression of free radicals at 10 nmol (P= 0.01) and 1 mmol melatonin (P= 0.001), showing a biphasic, non-linear, dose response relationship. Melatonin, given in amounts of 0.1-10 mmol, led to a direct dose-dependent suppression of ROS. Radical formation was suppressed significantly in a range from 0.5 to 10 mmol (P= 0.001). Melatonin is known to function as a radical scavenger and antioxidant; some of these melatonin effects may be receptor independent, while others may be receptor dependent.

Dose-Response Relationship, Drug↗
PubMed2000

Modulation of the catalytic activity of the Src family tyrosine kinase Hck by autophosphorylation at a novel site in the unique domain.

Autophosphorylation is a key event in the activation of protein kinases. In this study, we demonstrate that autophosphorylation of the recombinant Src family kinase Hck leads to a 20-fold increase in its specific enzymatic activity. Hck was found to autophosphorylate readily to a stoichiometry of 1.3 mol of phosphate per mol of enzyme, indicating that the kinase autophosphorylated at more than one site. Solid phase sequencing and two-dimensional mapping of the phosphopeptide fragments derived from the autophosphorylated enzyme revealed that the kinase can undergo autophosphorylation at the following two sites: (i) Tyr-388, which is located to the consensus autophosphorylation site commonly found in the activation loop of many protein kinases, and (ii) Tyr-29, which is located in the unique domain of Hck. Hck purified from mouse bone marrow-derived macrophages could also autophosphorylate in vitro at both Tyr-388 and Tyr-29, indicating that naturally occurring Hck can also autophosphorylate at Tyr-29. Furthermore, Hck transiently expressed in human embryonic kidney 293T cells was found to be phosphorylated at Tyr-29 and Tyr-388, proving that Hck can also undergo autophosphorylation at both sites in vivo. The recombinant enzyme carrying the mutation of Tyr-388 to Phe was also able to autophosphorylate at Tyr-29, albeit at a significantly slower rate. A 2-fold increase in the specific enzymatic activity was seen with this mutant despite the stoichiometry of autophosphorylation only approaching 0.2 mol of phosphate per mol of enzyme. This indicates that autophosphorylation of Tyr-29 contributes significantly to the activation of Hck. Regulation of the catalytic activity by phosphorylation of Tyr-29 in the unique domain may represent a new mechanism of regulation of Src family tyrosine kinases.

Amino Acid Sequence↗
PubMed2000

Hck enhances the adherence of lipopolysaccharide-stimulated macrophages via Cbl and phosphatidylinositol 3-kinase.

Src family tyrosine kinases have previously been proposed to mediate some of the biological effects of lipopolysaccharide on macrophages. Accordingly, we have sought to identify substrates of Src family kinases in lipopolysaccharide-stimulated macrophages. Stimulation of Bac1.2F5 macrophage cells with lipopolysaccharide was found to induce gradual and persistent tyrosine phosphorylation of Cbl in an Src family kinase-dependent manner. Immunoprecipitation experiments revealed that Cbl associates with Hck in Bac1.2F5 cells, while expression of an activated form of Hck in Bac1.2F5 cells induces tyrosine phosphorylation of Cbl in the absence of lipopolysaccharide stimulation. The Src homology 3 domain of Hck can directly bind Cbl, and this interaction is important for phosphorylation of Cbl. Association of the p85 subunit of phosphatidylinositol (PI) 3-kinase with Cbl is enhanced following lipopolysaccharide stimulation of Bac1.2F5 cells, and transient expression experiments indicate that phosphorylation of Cbl by Hck can facilitate the association of p85 with Cbl. Lipopolysaccharide treatment also stimulates the partial translocation of Hck to the cytoskeleton of Bac1.2F5 cells. Notably, lipopolysaccharide enhances the adherence of Bac1.2F5 cells, an effect that is dependent on the activity of Src family kinases and PI 3-kinase. Thus, we postulate that Hck enhances the adherence of lipopolysaccharide-stimulated macrophages, at least in part, via Cbl and PI 3-kinase.

Biological Transport↗
PubMed2000

Generation and characterization of monoclonal antibodies to the Src-family kinase Hck.

Hck, a member of the Src-family of protein tyrosine kinases, is expressed primarily in hematopoietic cells of the myeloid and B-lymphocyte lineages. Hybridoma cell lines were established that secrete monoclonal antibodies (MAbs) to Hck. Three of the MAbs were extensively characterized and designated H7, H34, and H42. The MAbs H7 and H34 recognized an epitope within the SH3 domain of Hck, while the epitope recognized by the H42 MAb resides within the Unique domain. All three MAbs specifically recognized the p59 and p56 isoforms of Hck in transiently transfected 293T cells and in a murine macrophage cell line. Notably, the antibodies did not cross-react with other Src-family kinases tested. Under native conditions, the MAbs H34 and H42 efficiently immunoprecipitated Hck from transfected cells. Both MAbs were also successfully used for the immunofluorescent staining of Hck in intact cells.Thus, the MAbs described herein should be useful in studies of Hck function and expression.

Animals↗
PubMed2000

p50(Cdc37) can buffer the temperature-sensitive properties of a mutant of Hck.

Genetic studies have previously revealed that Cdc37p is required for the catalytic competence of v-Src in yeast. We have reasoned that temperature-sensitive mutants of Src family kinases might be more sensitive to the cellular level of p50(Cdc37), the mammalian homolog of Cdc37p, than their wild-type counterpart, thus potentially providing a unique opportunity to elucidate the involvement of p50(Cdc37) in the folding and stabilization of Src family kinases. A temperature-sensitive mutant of a constitutively active form of Hck (i.e., tsHck499F) was created by mutating two amino acids within the kinase domain of Hck499F. Significantly, overexpression of p50(Cdc37) rescues the catalytic activity of tsHck499F at 33 degrees C, while partially buffering it against inactivation at higher temperatures (e.g., 37 and 39 degrees C). Hsp90 function is required for tsHck499F activity and its stabilization by p50(Cdc37), but overexpression of Hsp90 is not sufficient to stabilize tsHck499F. Overexpression of p50(Cdc37) promotes the association of tsHck499F with Hsp90, suggesting that the cellular level of p50(Cdc37) might be the rate-limiting step in the association of tsHck499F with Hsp90. A truncation mutant of p50(Cdc37) that cannot bind Hsp90 still has a limited capacity to rescue the catalytic activity of tsHck499F and promote its association with Hsp90. This is a particularly important observation, since it argues that rather than solely acting as a passive adapter protein to tether tsHck499F to Hsp90, p50(Cdc37) may also act allosterically to enhance the association of tsHck499F with Hsp90. The findings presented here might also have implications for our understanding of the evolution of protein kinases and tumor development.

Amino Acid Sequence↗
PubMed2000

Development of prediction models for three in vitro embryotoxicity tests in an ECVAM validation study.

Since 1997 the National Center for Documentation and Evaluation of Alternative Methods to Animal Experiments, ZEBET, in Berlin, has been coordinating a validation study aimed at prevalidation and validation of three in vitro embryotoxicity tests, funded by the European Center for the Validation of Alternative Methods (ECVAM) at the Joint Research Center (JRC, Ispra, Italy). The tests use the cultivation of postimplantation rat whole embryos (WEC test), cultures of primary limb bud cells of rat embryos (micromass or, MM, test), and cultures of a pluripotent mouse embryonic stem cell line (embryonic stem cell test or EST). Each of the tests was performed in four laboratories under blind conditions. In the preliminary phase of the validation study 6 out of 20 test chemicals comprising different embryotoxic potential (non, weakly, and strongly embryotoxic) were tested. The results were used to define biostatistically based prediction models (PMs) to identify the embryotoxic potential of test chemicals for the WEC test and the MM test. The PMs developed with the results of the preliminary phase of the validation study (training set) will be evaluated with the results of the remaining 14 test chemicals (definitive phase) by the end of the study. In addition, the existing, improved PM (iPM) for the EST, which had been defined previously, was evaluated using the results of the preliminary phase of this study. Applying the iPM of the EST to the results of this study, in 79% of the experiments, chemicals were classified correctly according to the embryotoxic potential defined by in vivo testing. For the MM and the WEC test, the PMs developed during the preliminary phase of this validation study provided 81% (MM test) and 72% (WEC test) correct classifications. Because the PM of the WEC test took into account only parameters of growth and development, but not cytotoxicity data, a second PM (PM2) was developed for the WEC test by incorporating cytotoxicity data of the differentiated mouse fibroblast cell line 3T3, which was derived from the EST. This approach, which has previously never been used, resulted in an increase to 84% correct classifications in the WEC test.

3T3 Cells↗
PubMed1999

Urokinase receptor-dependent and -independent p56/59(hck) activation state is a molecular switch between myelomonocytic cell motility and adherence.

Anchorage-independent myelomonocytic cells acquire adherence within minutes of differentiation stimuli, such as the proteolytically inactive N-terminal fragment of urokinase binding to its cognate glycosylphosphatidylinositol (GPI)-anchored receptor. Here, we report that urokinase-treated differentiating U937 monocyte-like cells exhibit a rapid and transient inhibition of p56/59(hck) and p55(fgr) whereas no changes in the activity of other Src family kinases, such as p53/56(lyn) and p59(fyn) were observed. U937 transfectants expressing a kinase-defective (Lys267 to Met) p56/59(hck) variant exhibit enhanced adhesiveness and a marked F-actin redistribution in thin protruding structures. Conversely, urokinase as well as expression of wild-type or constitutively active (Tyr499 to Phe) p56/59(hck) stimulates the directional migration of uninduced U937 cells. Accordingly, expression of constitutively active or kinase inactive p56/59(hck) selectively prevents urokinase receptor-dependent induction of either adhesion or motility, indicating that a specific activation state of p56/59(hck) is required for each cell response. In conclusion, modulation of the intracellular p56/59(hck) tyrosine kinase activity switches cell motility towards adherence, providing a mutually exclusive mechanism to regulate these properties during monocyte/macrophage differentiation in vivo.

Actins↗
PubMed1999

Low-frequency modulation of the 2f1-f2 distortion product otoacoustic emissions in the human ear.

Low-frequency masking is a recent clinical procedure for the differential diagnosis of sensory hearing loss. Currently this requires the recording of the phase-dependent masked subjective threshold, which is time consuming and not always accurate. As an objective method, the recording of modulated distortion product otoacoustic emissions (DPOAEs) can be performed continuously, and with better frequency specificity. Results of measurements of the low-frequency modulated two-tone DPOAE 2f1-f2 in the human ear, and its dependence on various acoustic parameters, are presented here for the first time. Similar to the masked hearing threshold, the pattern of the phase-dependent modulated DPOAEs displayed two minima, at the phases of maximal rarefaction and condensation, respectively, with a latency of about 4 ms (suppressor frequency 32.8 Hz). The smaller dip, at maximal condensation, appeared only for a high suppressor level, and for a low level of the primary tone f2. The modulating effect measured for the primary frequencies f1 = 2.5 kHz and f2 = 3 kHz, decreased for 4 and 4.8 kHz, and vanished for 5 and 6 kHz. The results are discussed using a cubic distortion model based on the Boltzmann function for mechano-electrical transduction of the hair cells. The saturation behavior of the increase of the DPOAE level at different phases is compared with the growth rates of the DPOAE level in normal hearing and in sensory hearing loss.

Acoustic Stimulation↗
PubMed1999

Embryotoxicity screening using embryonic stem cells in vitro: correlation to in vivo teratogenicity.

Blastocyst-derived pluripotent embryonic stem (ES) cells of the mouse can be induced to differentiate in culture into a variety of cell types, including cardiac muscle cells. The embryonic stem cell test that makes use of the differentiation of ES cells into cardiomyocytes in a standardized in vitro model was developed to offer an alternative method to comprehensive in vivo studies in reproductive toxicology about toxic effects of chemicals. ES cells of the mouse cell line D3 are investigated for their preserved capability to differentiate following drug exposure, and both ES cells and differentiated fibroblast cells of the mouse cell line 3T3 are comparatively analyzed for effects on viability. The following endpoints are used to classify the embryotoxic potential of chemicals into three classes of in vitro embryotoxicity (non-, weakly or strongly embryotoxic). These endpoints are: (1) the inhibition of differentiation of ES cells into cardiomyocytes after 10 days of treatment, and the decrease of viability (cytotoxicity) of (2) 3T3 cells and (3) ES cells after 10 days of treatment, determined by a 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide (MTT) test. 50% inhibition concentrations for differentiation (ID(50)) and cytotoxicity (IC(50)D3 and IC(50)3T3) are calculated from concentration-response curves. Applying linear analysis of discriminance, a biostatistical prediction model (PM) was developed. This procedure identified three variables, the lg(IC(50)D3), the lg(IC(50)3T3) and the relative distance between IC(50)3T3 and ID(50), that improved the separation of the three classes of embryotoxicity compared to the prediction model that was originally proposed after test development. Unlike the original PM, the improved PM incorporates as one variable the relative distance between IC(50)3T3 and ID(50), instead of the ratio ID(50)/IC(50)D3 that was used previously.

Animals↗