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Biomedical subjects

S Schmitz

Publications and source records attributed to S Schmitz.

At least 19 recordsLinked to original sources
PubMed2006

Influence of lysosomal acid lipase polymorphisms on chromosome 10 on the risk of Alzheimer's disease and cholesterol metabolism.

Linkage analyses have identified a possible hot spot for a late-onset Alzheimer's disease (LOAD) risk gene on chromosome 10q21-22 and 10q25. It was also shown that cholesterol metabolism is involved in the pathogenic mechanisms of AD. The gene of lysosomal acid lipase (LIPA) is located next to the putative hot spot on chromosome 10. Its protein is involved in cholesterol metabolism and responsible for catalysing the hydrolysis of cholesteryl esters and triglycerides inside the lysosome. Previous publications reported controversial results on the role of LIPA polymorphisms on the risk of LOAD. We investigated two LIPA polymorphisms (rs1051338 and rs2297472) for their putative effect on the risk of LOAD in a homogenous sample of German origin. Genotypes of the investigated polymorphisms in AD patients and controls were compared. Also the effect of the LIPA gene polymorphisms on plasma cholesterol levels and 24S-hydroxycholesterol/cholesterol ratios on AD patients were investigated. None of the observed polymorphisms showed a significant influence on the risk of AD. We found that LIPA exon 2 polymorphism (rs1051338) influenced plasma 24S-hydroxycholesterol/cholesterol ratios in AD patients where carriers of the C/C allele presented with higher ratios than heterozygote carriers of the LIPA allele. Even though the biological function and gene location of LIPA on chromosome 10 suggest that LIPA might be a candidate for an AD risk gene, our results revealed that polymorphisms in LIPA did not influence the risk of AD in our study.

Aged↗
PubMed2004

Short-term changes of mRNA expression of various inflammatory factors and milk proteins in mammary tissue during LPS-induced mastitis.

During mammary gland infection, non-specific responses are the predominant ones. The goal of this study was to investigate the mRNA expression of various soluble immune components and of the major milk proteins during the acute phase of mammary inflammation. Five healthy lactating cows were intramammary infused in one quarter with 100 microg Escherichia coli-endotoxin (lipopolysaccharide, LPS) and the contralateral quarter with saline (9 g/l) serving as control. Mammary biopsy samples of both quarters were taken immediately before and at 3, 6, 9 and 12 h after infusion and mRNA expression of various factors was quantified via real-time RT-PCR. Blood samples for determination of leukocyte number were taken simultaneously with the biopsy samples and rectal temperature was measured at 1-h intervals. Rectal temperature increased until 5h (P < 0.05) after LPS administration and remained elevated until 9 h after LPS inoculation. Blood leukocyte number decreased (P < 0.05) from 0 to 3 h from 7.7 +/- 1.1 x 10(9)l(-1) to 5.7 +/- 1.0 x 10(9)l(-1) and thereafter recovered to pre-treatment levels until 12 h after LPS challenge. In LPS-treated quarters, tumor necrosis factor-alpha and cyclooxygenase-2-mRNA expression increased (P < 0.05) to highest values at 3h after LPS challenge. Lactoferrin, lysozyme, inducible nitric oxide synthase increased (P < 0.05) and peaked at 6 h after challenge, and platelet-activating factor acetylhydrolase-mRNA expression tended to increase (P = 0.07). mRNA expression of insulin-like growth factor-I and of alphaS1-casein (CN), alphaS2-CN, beta-CN and beta-lactoglobulin did not change significantly, whereas mRNA expression of 5-lipoxygenase and alpha-lactalbumin decreased (P < 0.05) in both quarters and that of kappa-CN only in the LPS quarter. mRNA expression of some investigated factors (tumor necrosis factor-alpha, lysozyme, 5-lipoxygenase, alpha-lactalbumin) changed in control quarters, however in all respective factors less than in the LPS quarters (P < 0.05). In conclusion, mRNA expression of most inflammatory factors increased within hours, whereas that of most milk proteins remained unchanged.

Animals↗
PubMed2004

Myosin VI: a multifunctional motor.

Myosin VI moves towards the minus end of actin filaments unlike all the other myosins so far studied, suggesting that it has unique properties and functions. Myosin VI is present in clathrin-coated pits and vesicles, in membrane ruffles and in the Golgi complex, indicating that it has a wide variety of functions in the cell. To investigate the cellular roles of myosin VI, we have identified a variety of myosin VI-binding partners and characterized their interactions. As an alternative approach, we have studied the in vitro properties of intact myosin VI. Previous studies assumed that myosin VI existed as a dimer but our biochemical characterization and electron microscopy studies reveal that myosin VI is a monomer. Using an optical tweezers force transducer, we showed that monomeric myosin VI is a non-processive motor with a large working stroke of 18 nm. Potential roles for myosin VI in cells are discussed.

Actins↗
PubMed2003

[Superparamagnetic iron oxide particles: current state and future development].

A wide range of applications for superparamagnetic iron oxide (SPIO) particles as contrast media for MRI has emerged over the last 15 years. SPIO particles can be manufactured with different particle sizes and surface coatings. Large SPIO particles (50-150 nm) predominantly produce a signal decrease or T2 -shortening and are used as contrast media for MRI of the liver and spleen. They have a high accuracy, especially in detecting liver metastases (approved for clinical use: AMI-25 (Endorem or Ferridex), SHU-555A (Resovist)). Smaller particles (about 20 nm in diameter) show a different organ distribution and have a potential for improving noninvasive lymph node assessment or characterizing vulnerable atherosclerotic plaques (in clinical trials: AMI-227 [Sinerem or Combidex]). Particles with an optimized T1-relaxivity and prolonged intravascular circulation time can be used as blood pool contrast media for MR angiography. The currently investigated indications are MR angiography of the trunk, peripheral vessels, and coronary arteries (e.g., SHU-555 C (Supravist), VSOP-C 184). Other applications of small SPIO particles include MRI of the bone marrow and the determination of perfusion parameters in tumors or other tissues like the myocardium. SPIO particles with a modified coat can be used in so-called molecular imaging, such as receptor-directed imaging, cell labeling for in-vivo monitoring of cell migration, e.g., stem cell labeling, and labeling of gene constructs for localization in genetic therapy. In tumor therapy SPIO particles can serve as mediators for hyperthermia. SPIO is a powerful MR contrast medium with manifold applications ranging from diagnostic imaging to molecular medicine.

Animals↗
PubMed2003

[Organisation of studies].

Haemato-oncological studies in private practices for haematology and oncology have been identified as an important instrument for quality assurance in the treatment of haemato-oncological patients. As the organisational structures of private practices for haematology and oncology are usually highly complex the inclusion into studies needs a high motivation and binds resources. Workflow was observed in four private practices for haematology and oncology. With this data, suggestions for a common workflow model for study inclusion in private practices were elaborated and are discussed in this article. A common workflow-model of study inclusion for private practices is illustrated in two flow charts. If patients are to be successfully included in studies, additional structures and resources have to be implemented. Beyond this the necessary steps for study inclusion must be incorporated into the everyday routine of the practices.

Clinical Trials as Topic↗
PubMed2003

[Pharyngoesophagolaryngeal metastases of medullary thyroid carcinoma. A case report].

We report the case of a patient with medullary thyroid carcinoma (MTC) who presented multiple pharyngoesophagolaryngeal metastases detected by flexible laryngoscopy. Pathology confirmed the diagnosis after resection with CO2 laser under direct laryngoscopy. Because of worsening dyspnea, complete circular pharyngolaryngectomy was performed with reconstruction of the pharyngeal region with a major pectoralis musculocutaneous flap. The postoperative period was satisfactory. At 17 months, calcitonin level was elevated; subcutaneous cervical metastases of the MTC developed and were resected. At 27 months, oral nutrition and phonation remained satisfactory. We discuss the diagnostic and therapeutic strategies used for this very unusual form of locoregional spread of medullary carcinoma of the thyroid gland.

Biomarkers, Tumor↗
PubMed2002

Spatiotemporal imaging of electrical activity related to attention to somatosensory stimulation.

The aim of the present study was to localize the effects of spatial attention on somatosensory stimulation in EEG. Median and tibial nerve were stimulated at all four limbs in a random order. Subjects were instructed to count the events on either the right median or the right tibial nerve. Attention-induced changes in the somatosensory evoked potentials (SEP) were revealed by subtracting the median nerve SEPs recorded while subjects attended to stimuli applied to the tibial nerve from those obtained during attention to the stimulated hand. In a current density reconstruction approach source maxima in the time range from 30 to 260 ms after median nerve stimulation were localized and the time courses of activation were elaborated by dipole modeling. Six regions were identified which contribute significant source activity related to selective spatial attention: contralateral postcentral gyrus (Brodman area (BA) 3), contralateral mesial frontal gyrus (BA 6), right posterior parietal cortex (BA 7), anterior cingulate gyrus (BA 32), and bilateral middle temporal gyrus (BA 21). Activation started at the right posterior parietal cortex, followed by the contralateral middle temporal gyrus, probably representing SII activity, and the middle frontal and anterior cingulate gyrus. Similar regions of source activation were revealed by tibial nerve SEP, but the effect was less pronounced and restricted almost entirely to activation of the contralateral postcentral gyrus (BA 3), anterior cingulate gyrus (BA 32), and ipsilateral middle temporal gyrus (BA 21). Our data provide evidence for a spatially separated frontal generator within the anterior cingulum, dependent on selective attention in the somatosensory modality.

Adult↗
PubMed2002

[The relationship between retrobulbar blood flow velocity and glaucoma damage. An intraindividual comparison].

BACKGROUND: Glaucomatous optic nerve damage is thought to be influenced by ocular perfusion. The aim was to investigate if a difference in visual field and Heidelberg retinal tomography (HRT) between two eyes of an individual glaucoma patient is reflected in different blood flow velocities in retrobulbar vessels. METHODS: Data from 53 patients including 26 normal tension glaucoma patients (NTG) and 27 high tension glaucoma patients (HTG) were evaluated retrospectively. In 38 patients asymmetric glaucomatous damage (AGD) could be demonstrated by both structural (HRT) and functional measures (static or Goldmann perimetry). In 15 patients there was symmetric glaucomatous damage (SGD). To discriminate between AGD and SGD we used a score for HRT and visual field. Color Doppler imaging (CDI) was performed with a Siemens Quantum 2000. RESULTS: No significant differences were found when comparing group means of intraindividual deviation of CDI in patients with AGD vs. SGD. Overall analysis of CDI values in NTG vs. HTG eyes also showed no significant differences. Nevertheless we measured decreased blood flow velocities for NTG compared to HTG eyes especially in short posterior ciliary arteries, peak systolic and end diastolic velocities. CONCLUSIONS: A simple correlation between retrobulbar blood flow velocities and glaucomatous damage could not be found. However, color Doppler images can give important additional information in the diagnosis of glaucoma, especially normal tension glaucoma.

Adult↗
PubMed2001

Genetic and environmental influences on the associations between attention problems and other problem behaviors.

Problem behavior in children shows a high degree of co-occurrence, both within the domains of internalizing and externalizing behaviors and across domains. Maternal ratings of 207 same- and opposite-sex twin pairs on the Child Behavior Checklist (CBCL/4-18; Achenbach, 1991) were used to determine the etiology of these associations. In the current sample of 4- to 11-year-old children (mean age: 7.6 years) phenotypic correlations were .68 between Internalizing and Externalizing, between .41 and .66 within the internalizing scales, and between .58 and .71 within the externalizing scales. Correlations across domains on the scale level were of similar magnitude. Genetic and shared environmental correlations were generally high, with the exception of the somatic complaints scale which showed low genetic correlations with other scales. These findings of uniformly high shared etiology was seen within and across domains. For example, Attention Problems showed genetic correlations of .65 with Delinquent Behavior and .76 with Aggressive Behavior; the genetic correlations of Attention Problems with internalizing scales were .71 for Anxious/Depressed and .79 for Withdrawn; a low genetic correlation was only shown for the Somatic Complaints scale (r(g) = .16). Although the magnitude of shared environmental contributions was lower, the environmental correlations were close to unity, indicating that the same family environmental factors were involved in aspects of problem behavior when assessed across domains. Results for the Attention Problems scale were similar to other disruptive behavior, justifying its inclusion with the externalizing scales.

Attention Deficit Disorder with Hyperactivity↗
PubMed2001

[In vitro permeability studies as a substitute for in vivo studies--which requirements have to be met?].

In order to reduce costs and shorten time-to-market, the permeability of drug substances can be characterized by in vitro techniques including the use of cell and tissue models. It is required to apply appropriate quality standards similar to those used in animal or clinical studies. The Caco-2 cell model is a well-established and recognized in vitro technique in research, industry and in the drug discovery sector. However, the lack of standardized operating is reflected in the heterogeneity of the data acquired using this model. Using the Caco-2 cell model as an example, this paper demonstrates how to test the suitability of a cell culture model for conducting drug permeability studies. The procedures involve not only the characterization of cell morphology but also functional assessment of the model and the periodic testing of monolayer permeability. Both the useful comparison of permeability data and the reliable prediction of in vivo permeability require prior classification of the in vitro permeability in accordance with the FDA"s Biopharmaceutics Classification System (BCS).

Animal Testing Alternatives↗
PubMed2001

[Marker transport across biological barriers in vitro: comparison of cell culture models for the gastrointestinal barrier, the blood-brain barrier and the alveolar epithelium of the lung].

In order to respond to the flood of new active ingredients currently being generated by combinatorial chemistry or molecular biological synthesis, selection procedures able to filter out rapidly and economically those drug candidates with the highest development potential are required. This necessitates the measurement of fundamental biopharmaceutical parameters very early in the drug development process. Any pharmaceutically active agent must be able to overcome the body's natural protective mechanisms. A broad variety of biological barriers can be simulated in the laboratory by cell monolayer models. Apart from ethical aspects, the advantage of these in vitro test systems is that permeability studies can be performed at high throughput rates under controlled and reproducible conditions. The validity of such a model is ultimately reflected in its ability to accurately predict the behaviour of an active ingredient at the corresponding in vivo barrier.

Animal Testing Alternatives↗
PubMed2000

Identical distribution of the alpha 2-macroglobulin pentanucleotide deletion in subjects with Alzheimer disease and controls in a German population.

Recently, an association between a deletion polymorphism in the alpha 2-macroglobulin gene (A2M) and Alzheimer disease (AD) has been reported. The aim of the present study was to corroborate this association in a German population of 102 AD patients and two control samples of 191 healthy subject and 160 depressed patients. The frequency of the A2M genotype in AD patients was almost identical to that in both control samples. Logistic regression analysis revealed an effect of age and the APOE genotype on AD risk, but no effect of the A2M genotype. Our findings do not support the fact that the previously reported positive association between A2M deletion polymorphism and AD modifies the disease risk in the studied population. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:775-777, 2000.

Aged↗
PubMed2000

Familial association between allergic disorders and depression in adult Finnish twins.

Clinical studies have shown a relationship between allergic disorders and depression, panic disorder, attention deficit/hyperactivity disorder, and social anxiety for a significant subset of patients with these disorders. The nature of the relationship, whether due to shared environmental or biologic vulnerabilities or as a result of the stress of chronic illness, has been less clear. By examining the covariance of atopic disorders and depressive symptoms in a community sample of monozygotic (MZ) and dizygotic (DZ) twins, the contribution of genetic and/or shared environmental etiological factors can be established. A Finnish sample of 1337 MZ and 2506 DZ twin pairs, ages 33-60 years, was sent questionnaires inquiring about history of asthma, eczema, and atopic rhinitis, as well as the Beck Depression Inventory (BDI). The nature of the covariation between twins of these symptoms was investigated by fitting competing genetic and environmental models. Within-person correlation between atopic symptoms and BDI was 0.103 (P < 0.001) for the total sample. Using the Mx statistical modeling program to fit the data to competing quantitative genetic models, the best fitting model estimated that 64% of the association between atopy and BDI was due to shared familial vulnerability, primarily additive genetic influences. Although the measures for allergic disorders and depression are crude, this study supports the hypothesis that there is a small shared genetic risk for atopic and depressive symptoms, and if replicated, may open research for common mechanisms between allergic and depressive disorders. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:146-153, 2000.

Adult↗
PubMed2000

Drosophila ACT88F indirect flight muscle-specific actin is not N-terminally acetylated: a mutation in N-terminal processing affects actin function.

Many eukaryotic proteins are co and post-translationally modified at their N termini by removal of one or two amino acid residues and N(alpha)-acetylation. Actins show two different forms of N-terminal processing dependent on their N-terminal sequence. In class II actins, which include muscle actins, the common primary sequence of Met-Cys-Asp-actin is processed to acetyl-Asp-actin. The functional significance of this in vivo is unknown. We have studied the indirect flight muscle-specific actin, ACT88F, of Drosophila melanogaster. Our results show that ACT88F is N-terminally processed in vivo as a class II actin by removal of the first two amino acid residues (Met and Cys), but that uniquely the N terminus is not acetylated. In addition we show that ACT88F is methylated, probably at His73. Flies carrying the mod(-) mutation fail to complete post-translational processing of ACT88F. We propose that the mod gene product is normally responsible for removing N-acetyl-cysteine from actin. The biological significance of this process is demonstrated by observations that retention of the N-acetyl-cysteine in ACT88F affects the flight muscle function of mod(-) flies. This suggests that the extreme N terminus affects actomyosin interactions in vivo, a proposal we have examined by in vitro motility assays of ACT88F F-actin from mod(-) flies. The mod(-) actin only moves in the presence of methylcellulose, a viscosity-enhancing agent, where it moves at velocities slightly, but significantly, reduced compared to wild-type. These data confirm that N-acetyl-cysteine at the N terminus affects actomyosin interactions, probably by reducing formation of the initial actomyosin collision complex, a process known to involve the actin N terminus.

Acetylation↗
PubMed2000

Acute hematologic toxicity and practicability of dose-intensified BEACOPP chemotherapy for advanced stage Hodgkin's disease. German Hodgkin's Lymphoma Study Group (GHSG).

BACKGROUND: Evidence is recently accumulating that the novel BEACOPP (bleomycin (B), etoposide (E), adriamycin (A), cyclophosphamide (C), vincristine (O), procarbazine (P), prednisone (P)) chemotherapy is a highly effective treatment for advanced stage Hodgkin's disease. Two dose variants of BEACOPP are currently tested in a phase III randomized multicenter trial of the GHSG. To enable more extensive testing of BEACOPP we characterized its practicability regarding schedule adherence, acute hematotoxicity and need for supportive treatment. PATIENTS AND METHODS: Data of 858 patients (6592 therapy cycles) from 184 participating institutions were evaluated. Planned total drug doses of the baseline variant (arm 1) were 80, 2400, 200, 5200, 11.2, 5600 and 4480 mg/m2 for B, E, A, C, O, P and P, respectively. Compared to arm 1, the doses of E, A and C in the dose-intensified variant (arm 2) were escalated by factor 2.0, 1.4, 1.92, respectively, using G-CSF assistance. Stepwise dose reductions were specified in case of dose-limiting toxicities. Both variants are given in eight three-weekly courses. RESULTS: Median dose adherence (dose actually given relative to planned arm 1 dose) in arm 1 was 1.0 for all drugs. Relative dose escalation of E, A, and C actually maintained in arm 2 was 1.83, 1.37 and 1.77 (medians), respectively, and 70% of patients maintained elevated dose levels throughout the entire treatment. Dose-limiting toxicities occurred in 25% of cycles in arm 2, most frequently due to leukocytopenia and thrombocytopenia. Time courses of leukocytes in arm 2 showed more severe but not more prolonged leukocytopenia compared with arm 1. WHO grades 3-4 infections were documented in 2.1% (arm 1) and 3.1% (arm 2) of all cycles. Erythrocytes were transfused in 61% (arm 1) and 28% (arm 2), platelets in < 1% (arm 1) and 6% (arm 2) of all cycles. CONCLUSIONS: Both BEACOPP schemes are practicable in a large multicenter setting. Despite increased hematotoxicity, moderate dose escalation is safe for the majority of the patients with G-CSF assistance and standard supportive treatment.

Adolescent↗