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Biomedical subjects

R Schubert

Publications and source records attributed to R Schubert.

At least 37 records · Page 2Linked to original sources

[New aspects of the mechanics of the auditory tube].

The aim of the present article is to describe the mechanical components of the auditory tube and the role of these components in auditory tube function. Particular attention will be given to those aspects which have not been sufficiently dealt with in the past, such as the role of the isthmus region, the function of the lateral mucosal folds, the significance of the of the surfactant proteins and the pathophysiology of the patulous auditory tube. Special attention is given to the tensor veli palatini muscle and its physiology. Because of its isometric contraction, the function of this muscle depends on so-called hypomochlia changing the direction of its force. In the context of this article, the three hypomochlia involved are the pterygoid hamulus, Ostmann's fatty tissue and the medial pterygoid muscle. The so-called "Eppendorf-maneuver" is depicted for the first time.

Biomechanical Phenomena↗

Change in pharmacokinetic and pharmacodynamic behavior of gemcitabine in human tumor xenografts upon entrapment in vesicular phospholipid gels.

PURPOSE: The in vivo pharmacokinetics (PK), biodistribution and antitumor activity of a new liposomal formulation of gemcitabine (GemLip) were compared to the conventional (clinical) formulation of gemcitabine (GemConv). METHODS: Gemcitabine was entrapped in a vesicular phospholipid gel (VPG) consisting of densely packed liposomes. Redispersed VPG containing GemLip consisted of 33% liposomally entrapped and 67% free gemcitabine. The in vivo efficacies of GemLip and GemConv were compared using the subcutaneously growing human soft tissue sarcoma SXF 1301 and the orthotopically growing human bladder cancer BXF 1299T. PK and biodistribution were evaluated using radiolabeled drug and lipid in SXF 1301 tumor-bearing nude mice. RESULTS: GemLip was highly active in SXF 1301 at a gemcitabine dose of 6-9 mg/kg (days 1, 8 and 15; dose near the MTD). In the 6-mg/kg groups, complete tumor remissions were observed in seven of eight mice. Equimolar doses of GemConv resulted in only moderate tumor growth inhibition. Even at equitoxic doses (360 mg/kg given on days 1, 8 and 15, or 120 mg/kg on days 1, 5 and 8) GemConv was less active than GemLip. Furthermore, GemLip was active in the orthotopically growing BXF 1299T bladder cancer model at 6 mg/kg and prevented distant organ metastasis. In the PK study, GemLip achieved a 35-fold higher plasma AUC (1680 mg x h/ml) than GemConv (47.6 mg x h/ml). The serum half-lives were 0.15 h for free gemcitabine and 13.3 h for liposomal gemcitabine (6 mg/kg each i.v.). Moreover, gemcitabine levels in tumors were fourfold higher following injection of GemLip than following injection of GemConv. CONCLUSIONS: GemLip is a highly effective gemcitabine delivery system which results in superior gemcitabine pharmacodynamics and PK than GemConv. The enhanced in vivo efficacy might be explained by sustained release and passive tumor targeting.

Animals↗

Supernumerary marker chromosomes derived from chromosome 15: analysis of 32 new cases.

Small supernumerary marker chromosomes (SMC) are a heterogeneous group of chromosomes with an estimated frequency of approximately 0.14-0.72 per 1000 newborns and higher frequencies in particular populations such as the mentally retarded or infertile males. With a frequency of about 50%, derivatives of chromosome 15 represent the most common SMC. Here we present the results of a detailed analysis of 32 SMC(15) carriers who were ascertained in pre- or post-natal routine cytogenetic diagnostics. SMC(15) with euchromatic content led to mental and psychomotor retardation. In contrast, SMC(15) without euchromatin were found to have no influence on the carrier's phenotype but were detected with a high incidence among infertile males. The majority of SMC(15) are pseudodicentric homologous rearrangements. Based on our investigations a further characterization of der(15) was possible.

Chromosome Aberrations↗

Deficiencies in CD4+ and CD8+ T cell subsets in ataxia telangiectasia.

Chronic sinopulmonary infections that are associated with immunodeficiency are one of the leading causes of death in the multi-systemic disease ataxia telangiectasia (AT). Immunological investigations of AT patients revealed a broad spectrum of defects in the humoral and the cellular immune system. Based on their important role in host defence the aim of our study was an extensive analysis of cell distribution and function of CD4+ and CD8+ T lymphocytes and NK cells. We found that naive (CD45RA+) CD4+ lymphocytes, as well as CD8+/CD45RA+ lymphocytes, are decreased, whereas NK cells (CD3-/CD16+CD56+) are significantly elevated in AT patients. In our culture system proliferation and cytokine production was normal in purified memory (CD45RO+) lymphocytes after stimulation with phorbol-12,13-dibutyrate (PBu2) and after PHA activation, indicating that differences in proliferation and cytokine production are due solely to reduced numbers of CD45RA+ lymphocytes. However, activation, and especially intracellular interferon production of AT lymphocytes, seem to follow different kinetics compared to controls. In contrast to polyclonal activation, stimulation via the T cell receptor results consistently in a reduced immune response. Taken together, our results suggest that deficiency of immunocompetent cells and an intrinsic immune activation defect are responsible for the immunodeficiency in AT.

Adolescent↗

Familial ovarian dysgerminomas (Swyer syndrome) in females associated with 46 XY-karyotype.

An asymptomatic woman (age 38 years) with a family history of ovarian malignancies was referred for presymptomatic genetic testing of mutations in the BRCA genes. A familial Swyer syndrome with the occurrence of dysgerminomas is the most likely diagnosis. However, in our case, all known causes of this heterogeneous disorder have been excluded pointing to the existence of another yet unknown genetic locus. The family history revealed three affected paternal aunts. Two of them developed ovarian malignancies at 13 and 15 years of age, and died at ages 19 and 20. The third aunt, 82 years old, was affected by this disease at the age of 35. She underwent hormonal treatment for 3 years starting at the age of 15 because of primary amenorrhea. Under this treatment she developed nearly complete secondary sexual characteristics. Karyotype analysis revealed a normal male karyotype (46 XY, QFQ). Pelvic ultrasound showed an uterus of normal size, incompatible with an androgen resistance syndrome or a defect in testosterone biosynthesis. We excluded a mutation in the sex-determining region on chromosome Y (SRY) by direct sequencing of the SRY gene. An involvement of the subtelomeric region of chromosome 9p (9p 24.3) recently reported to be involved in XY-sex reversal phenotypes was excluded by molecular testing for loss of heterozygosity as well as fluorescence in situ hybridization studies. Analyses of the DAX1 gene in the dosage sensitive sex reversal locus on chromosome Xp21 by Southern blot analysis showed no duplications.

17-alpha-Hydroxyprogesterone↗

[Study of NO action on calcium-activated potassium channel of the rat artery smooth muscle cells].

Nitric oxide (NO) released from the endothelium or from NO-donors is a powerful vasodilator. Its effect is mediated partly by vascular smooth muscle high conductance calcium-activated potassium (Kca) channels. Contradictory data exist as to whether NO activated the KCa channel directly or indirectly via protein kinase G (PKG). Thus the hypothesis that NO-donors can activate the KCa directly was investigated using the patch-clamp technique and freshly isolated smooth muscle cells from the rat tail artery. In inside-out experiments, the activity of KCa-channels was increased 1.61 +/- 0.20-fold (n = 10) by 10 microM SNP and 1.45 +/- 0.17-fold (n = 8) by 10 microM SNAP. However, the activity of KCa channels was also increased 1.46 +/- 0.20-fold (n = 8) by addition of the experimental bath solution. Thus these results suggest that NO released from NO-donors cannot activate KCa channel of the rat tail artery smooth muscle cells directly.

Animals↗

Reconstitution of bactericidal activity in chronic granulomatous disease cells by glucose-oxidase-containing liposomes.

Chronic granulomatous disease (CGD) is an inherited primary immunodeficiency characterized by phagocytes devoid of a functioning nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The failure of CGD phagocytes to produce reactive oxygen species (ROS) results in a marked increase in the susceptibility of affected patients to life-threatening bacterial and fungal infections. This study investigated whether loading of CGD phagocytes with glucose oxidase (GO)-containing liposomes (GOLs) could restore cellular production of bactericidal ROS (eg, H2O2 and HOCl) in vitro. Results indicate that GO encapsulated in liposomes enabled NADPH oxidase-deficient phagocytes to use H2O2 for the production of highly bactericidal HOCl. The intracellular colocalization of bacteria and liposomes (or liposome-derived ferritin) was demonstrated by confocal laser microscopy and electron microscopy. After uptake of GOLs (approximately 0.2 U/mL at 1 mM total lipid concentration, size approximately 180 nm), CGD granulocytes produced HOCl levels comparable to those of normal phagocytes. Remarkably, after treatment with GOLs, CGD phagocytes killed Staphylococcus aureus as efficiently as normal granulocytes. Moreover, treated cells retained sufficient motility toward chemotactic stimuli as measured by chemotaxis assay. Side effects were evaluated by measuring the H2O2 concentrations and the production of methemoglobin in whole blood. These studies revealed that H2O2 produced by GOLs was degraded immediately by the antioxidative capacity of whole blood. Elevated methemoglobin levels were observed only after application of extremely high amounts of GOLs (2 U/mL). In summary, the application of negatively charged GOLs might provide a novel effective approach in the treatment of patients with CGD at high risk for life-threatening infections.

Blood↗

Filter extrusion of liposomes using different devices: comparison of liposome size, encapsulation efficiency, and process characteristics.

Liposomes were prepared by stepwise extrusion through 5, 1, 0.4, 0.2, 0.1 and 0.05 microm pore sizes using two different filter-extruders, the continuous high pressure device Dispex Maximator (CE) or alternatively the discontinuous Avestin LiposoFast (DE). The liposome dispersions obtained were compared in terms of particle size, lamellarity and encapsulation efficiency of calcein. The liposomes were smaller with CE than DE at all stages due to higher flow rates and pressure drops, except for final filter pore size (0.05 microm) where both preparations had similar sizes. The particle size analysis technique itself had a strong influence on the liposome sizes measured. For bigger liposomes (extruded through 0.4 microm filters) the Nicomp 370 revealed bigger volume-based mean particle sizes along with more stringent differences between volume-based and number-based diameters than the Malvern Zetasizer. In contrast, for small liposomes extruded through 0.05 microm filters, similar liposome sizes were found no matter which of the two PCS techniques or cryo-transmission electron microscopy was used. In congruence to the liposome sizes measured, encapsulation efficiencies were smaller for CE than DE at all filter stages except the final (0.05 microm). No lipid loss occurred and lyso-phosphatidylcholine formation was negligible irrespective of which extrusion technique was used.

Filtration↗

Liposomal gels for vaginal drug delivery.

The aim of our study was to develop a liposomal drug carrier system, able to provide sustained and controlled release of appropriate drug for local vaginal therapy. To optimise the preparation of liposomes with regards to size and entrapment efficiency, liposomes containing calcein were prepared by five different methods. Two optimal liposomal preparations (proliposomes and polyol dilution liposomes) were tested for their in vitro stability in media that simulate human vaginal conditions (buffer, pH 4.5). To be closer to in vivo application of liposomes and to achieve further improvement of their stability, liposomes were incorporated in vehicles suitable for vaginal self-administration. Gels of polyacrylate were chosen as vehicles for liposomal preparations. Due to their hydrophilic nature and bioadhesive properties, it was possible to achieve an adequate pH value corresponding to physiological conditions as well as desirable viscosity. In vitro release studies of liposomes incorporated in these gels (Carbopol 974P NF or Carbopol 980 NF) confirmed their applicability as a novel drug carrier system in vaginal delivery. Regardless of the gel used, even 24 h after the incubation of liposomal gel in the buffer pH 4.5 more than 80% of the originally entrapped substance was still retained.

Acrylic Resins↗

Whole-cell patch-clamp: true perforated or spontaneous conventional recordings?

Perforated whole-cell patch-clamp recordings obtained with nystatin are frequently used to preserve intracellular integrity. However, the perforated-patch configuration may sometimes undergo a spontaneous change into the conventional whole-cell configuration, especially when lymphocytes are investigated. The electrophysiological criteria-- previously described--for establishing the existence of the perforated whole-cell configuration have been shown to be insufficient. Thus, the dye eosin, applied to the pipette solution, was tested as a tool for discriminating between the perforated and the conventional whole-cell configurations on rat T-lymphocytes. The dye never entered the cell from the pipette during the entire measurement in the perforated whole-cell configuration. In contrast, all cells in the conventional whole-cell configuration became red immediately after membrane rupture. Eosin barely changed the currents studied. The results suggest that eosin is a dye of choice for verifying a true perforated-patch configuration.

Animals↗

Protein kinases: tuners of the BKCa channel in smooth muscle.

Large-conductance, Ca(2+)-activated K(+) (BK(Ca)) channels in smooth muscle cells are unique because they integrate changes in both intracellular Ca(2+) and membrane potential. Protein kinases such as cAMP-dependent protein kinase, cGMP-dependent protein kinase and protein kinase C can affect tissue function by 'tuning' the apparent Ca(2+)- and/or voltage-sensitivity of the BK(Ca) channel to physiological changes in both Ca(2+) concentrations and membrane potential. However, despite the central importance of kinase-mediated modulation of BK(Ca) channels in different smooth muscle tissues, many key issues, including the sites and mechanisms of actions of protein kinases, remain unresolved. In this article, the role of protein kinases in the regulation of BK(Ca) channels is discussed.

Animals↗

Creating a high-resolution spatial/symbolic model of the inner organs based on the Visible Human.

Computerized three-dimensional models of the human body, based on the Visible Human Project of the National Library of Medicine, so far do not reflect the rich anatomical detail of the original cross-sectional images. In this paper, a spatial/symbolic model of the inner organs is developed, which is based on more than 1000 cryosections and congruent fresh and frozen CT images of the male Visible Human. The spatial description is created using color-space segmentation, graphic modeling, and a matched volume visualization with subvoxel resolution. It is linked to a symbolic knowledge base, providing an ontology of anatomical terms. With over 650 three-dimensional anatomical constituents, this model offers an unsurpassed photorealistic presentation and level of detail. A three-dimensional atlas of anatomy and radiology based on this model is available as a PC-based program.

Anatomy, Cross-Sectional↗

Urocortin relaxes rat tail arteries by a PKA-mediated reduction of the sensitivity of the contractile apparatus for calcium.

1. Urocortin is an endogenous vasodilator although the mechanism of vasorelaxation is not completely understood. The hypothesis that an alteration of smooth muscle calcium concentration is involved was tested using isometric tension recording and calcium fluorimetry. The relationship between contraction and intracellular calcium was also estimated. 2. Urocortin produced a concentration dependent relaxation (pD(2) 8.59+/-0.06, n=6) of vessels pre-contracted with a physiological salt solution containing 42 mM KCl (42 mM K-PSS). 3. Removal of the endothelium did not alter the effect of urocortin, pD(2) was 8.49+/-0.11, n=5. 4. Corticotropin-releasing factor relaxed 42 mM K-PSS pre-contracted vessels with less potency compared to urocortin (pD(2) 6.99+/-0.28, n=5). 5. Urocortin at 100 nM relaxed vessels pre-contracted with 42 mM K-PSS by 59.6+/-4.6% (n=8) and vessels pre-contracted with 500 nM noradrenaline by 25.2+/-6.8% (n=6). Both effects were not accompanied by a change in the intracellular calcium concentration. 6. Urocortin at 100 nM produced a significant rightward shift of 0.33+/-0.07 units of normalized intracellular calcium (n=5) of the relationship between tension and intracellular calcium. 7. The urocortin-induced relaxation was considerably reduced in the presence of 0.3 mM Rp-8-CPT-cAMPS, a cyclic AMP-dependent protein kinase (PKA) inhibitor. 8. The PKA-activator Sp-5,6-DCl-cBIMPS relaxed 42 mM K-PSS pre-contracted vessels (pD(2) 4.98+/-0.07, n=6). Sp-5,6-DCl-cBIMPS at 0.1 mM relaxed vessels by 85.3+/-2.5% (n=5), but did not change the intracellular calcium concentration. 9. In conclusion, the data show that urocortin is a potent, endothelium-independent dilator of rat tail arteries and suggest that this effect is mediated by PKA causing a reduction of the sensitivity of the contractile apparatus for calcium.

Animals↗

[Legionellas in domestic warm water--effects on the health of residents].

Only few epidemiological data on legionella diseases are available in Germany and studies on the prevalence of legionella antibody response in the population are scarce. We report on an epidemiological study on immune response in residents of homes with heavy and with minor legionella contamination in their hot-water system. 53 inhabitants of houseblocks with central hot-water system and high legionella contamination (6,049 +/- 17,995 cfu/l; 40% > 1,000 cfu/l) were studied. 92 persons living in 1-2 family houses with decentral hot water systems (244 +/- 1,434 cfu/l; 3% > 1,000 cfu/l) served as controls. All persons filled in a questionnaire on bronchial and fever diseases etc; blood specimen were tested for legionella antibodies (different methods: immunofluorescence, and ELISA), and urine specimens were analysed for legionella antigen. During this investigation in the population exposed to Legionella no cases of legionellosis were reported. The prevalence of legionella antibodies was twice as high in the exposed versus the control persons. Significant correlation between cfu/l and legionella antibody titer in the inhabitants were found. One person with high antibody titer and with legionella-free hot-water system in his home had reported about pulmonary problems after having stayed in a hotel. The positive antibodies of the other persons are most likely the result of asymptomatic infections caused by permanent exposure in their home hot-water supply. In conclusion, with regard to the increased prevalence of antibody titers against legionellae in the exposed inhabitants and the significant correlation between antibody titers and cfu/l in hot-water samples, the necessity to control and redevelop hot-water systems in homes is confirmed--even though no cases of legionelloses in the exposed population were reported.

Adult↗

Properties of fujicalin, a new modified anhydrous dibasic calcium phosphate for direct compression: comparison with dicalcium phosphate dihydrate.

The novel, commercially available, free-flowing spherically granulated dicalcium phosphate anhydrous (SGDCPA) Fujicalin for direct tableting was compared with directly compressible dicalcium phosphate dihYdrate (DCPD), the properties of which are well known. The two excipients were investigated and compared with regard to their physical and powder properties, compressibility, and compactibility. As a consequence of the spherical shape of its particles, SGDCPA shows the same good flowability and even better compactibility. In contrast to DCPD, SGDCPA shows significant uptake of moisture when exposed to relative humidities (RHs) exceeding 70%. For both excipients, the main deformation mechanism is fragmentation, with SGDCPA yielding significantly stronger tablets.

Calcium Phosphates↗

Identification of human candidate genes for male infertility by digital differential display.

Evidence for the importance of genetic factors in male fertility is accumulating. In the literature and the Mendelian Cytogenetics Network database, 265 cases of infertile males with balanced reciprocal translocations have been described. The candidacy for infertility of 14 testis-expressed transcripts (TETs) were examined by comparing their chromosomal mapping position to the position of balanced reciprocal translocation breakpoints found in the 265 infertile males. The 14 TETs were selected by using digital differential display (electronic subtraction) to search for apparently testis-specific transcripts in the TIGR database. The testis specificity of the 14 TETs was further examined by reverse transcription-polymerase chain reaction (RT-PCR) on adult and fetal tissues showing that four TETs (TET1 to TET4) were testis-expressed only, six TETs (TET5 to TET10) appeared to be differentially expressed and the remaining four TETs (TET11 to TET14) were ubiquitously expressed. Interestingly, the two tesis expressed-only transcripts, TET1 and TET2, mapped to chromosomal regions where seven and six translocation breakpoints have been reported in infertile males respectively. Furthermore, one ubiquitously, but predominantly testis-expressed, transcript, TET11, mapped to 1p32-33, where 13 translocation breakpoints have been found in infertile males. Interestingly, the mouse mutation, skeletal fusions with sterility, sks, maps to the syntenic region in the mouse genome. Another transcript, TET7, was the human homologue of rat Tpx-1, which functions in the specific interaction of spermatogenic cells with Sertoli cells. TPX-1 maps to 6p21 where three cases of chromosomal breakpoints in infertile males have been reported. Finally, TET8 was a novel transcript which in the fetal stage is testis-specific, but in the adult is expressed in multiple tissues, including testis. We named this novel transcript fetal and adult testis-expressed transcript (FATE).

Chromosome Mapping↗

Scenario-based risk assessment of multi-use chemicals: application to solvents.

The risk through chemical exposure is commonly characterized by ratios of exposure concentrations and effect levels (risk quotients). For chemicals with many different applications such as solvents, however, in addition to the risk quotients of different exposure situations it is useful to determine the corresponding numbers of exposed individuals, that is, not only the magnitude but also the extent of the risk. To this end, the Scenario-Based Risk Assessment (SceBRA) method has been developed that makes use of a large set of scenarios, each of which describes a typical situation regarding handling a solvent or solvent-containing product. The scenarios cover the life-cycle steps of production, distribution, and use of solvents. For each scenario, SceBRA provides the risk quotient, r, and the number of exposed individuals, N. This study investigated seven solvents that are used in large amounts in Switzerland. For each solvent, characteristic distributions of r and N values were calculated, making it possible to compare different solvents with respect to their risk profile. Graphical representations of the r, N data provide an informative way for analyzing and communicating the results of SceBRA.

Acetone↗