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Biomedical subjects

A Müller

Publications and source records attributed to A Müller.

At least 199 records · Page 11Linked to original sources
PubMed2000

IAA-synthase, an enzyme complex from Arabidopsis thaliana catalyzing the formation of indole-3-acetic acid from (S)-tryptophan.

An enzyme complex was isolated from Arabidopsis thaliana that catalyzes the entire pathway of biosynthesis of the major plant growth hormone, indole-3-acetic acid (IAA), from (S)-tryptophan. The 160-180 kDa, soluble complex catalyzes a strictly O2-dependent reaction which requires no further added factors and is stereospecific for the substrate (S)-tryptophan (app. Km = 120 microM). H2(18)O labeling proved that both oxygen atoms of IAA were delivered via H2O. This, as well as immunological evidence for the presence of a nitrilase-like protein in the complex, suggests the reaction to proceed via the intermediate indole-3-acetonitrile. IAA-synthase forms a tight metabolite channel committed to IAA production and occurs in shoots, roots and cell cultures of A. thaliana.

Arabidopsis↗
PubMed2000

Frequency of somatic MEN1 gene mutations in monoclonal parathyroid tumours of patients with primary hyperparathyroidism.

OBJECTIVES: Investigation of small numbers of parathyroid tumours by X-chromosome inactivation analysis suggests that the majority of them are monoclonal lesions most likely caused by a somatic mutation. Somatic mutations in the MEN1 gene located on chromosome 11q13 have recently been identified in 12-17% of solitary parathyroid tumours in patients with sporadic primary hyperparathyroidism, and they may be the precipitating genetic defect leading to monoclonal cell proliferation in these tumours. DESIGN: To determine the prevalence of MEN1 gene mutations in monoclonal parathyroid neoplasias we investigated 33 parathyroid tumours of patients with primary hyperparathyroidism for clonality and mutations in the MEN1 gene. METHODS: X-chromosome inactivation analysis was used to assess the clonal status of the tumours, direct sequencing of the complete coding region was applied to identify mutations in the MEN1 gene. RESULTS: Twenty-eight female patients (26 patients with solitary adenoma, 2 patients with hyperplasia) were informative for the polymorphism of the androgen receptor on the X-chromosome and could be tested for inactivation pattern. Nineteen of twenty-six (73%) solitary adenomas were monoclonal. Somatic mutations in the MEN1 gene were identified in nine cases. Six of them were found in the relatively large second exon of the MEN1 gene (A49D, 193del36, 402delC, 482del22, 547delT, W126X). One was found in exon 5 (904del9), one in exon 7 (Y327X) and one in exon 9 (R415X). Of the monoclonal tumours, 5 out of 19 (26%) harboured a somatic MEN1 gene mutation. CONCLUSIONS: In summary, 73% of the solitary parathyroid adenomas were monoclonal. In 26% of the monoclonal tumours a somatic MEN1 gene mutation has been identified. However, for 74% of monoclonal tumours of the parathyroids the underlying genetic defects are still not known.

Adenoma↗
PubMed2000

Influence of androgens and age on androgen receptor and 5 alpha-reductase II transcription.

OBJECTIVE: The regulation of the androgen receptor (AR) and 5 alpha-reductase II (5RII) gene in genital skin fibroblasts is of particular interest in understanding androgen-dependent embryonic formation of external male genitalia. DESIGN: Human genital skin fibroblasts from pre- and postpubertal male individuals (aged 5 months to 51 years) were incubated with testosterone and dihydrotestosterone under various conditions to study the regulation of AR and 5RII transcript concentrations dependent on androgen concentration and donor age. METHODS: A competitive reverse transcribed PCR (RT-PCR) protocol was designed to achieve simultaneous relative quantification (semi-quantification) of AR and 5RII mRNAs in standardized whole RNA samples from each donor. RESULTS: Concentrations of AR and 5RII mRNAs are not influenced by androgens in genital skin fibroblasts. Moreover, comparison of AR transcript concentrations in genital skin fibroblast cell lines revealed weak variations independent of donor age, while 5RII transcription exhibited clear individual differences with a declining tendency towards higher ages. CONCLUSIONS: The transcription of AR and 5RII is not directly regulated by testosterone or dihydrotestosterone in pre- or postpubertal human genital skin fibroblasts. However, donor age seems to play a role in gradual depression of 5RII transcription.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2000

Comparison of the efficacy and endometrial safety of two estradiol valerate/dienogest combinations and Kliogest for continuous combined hormone replacement therapy in postmenopausal women.

OBJECTIVE: To compare the efficacy and endometrial safety of two estradiol valerate/dienogest combinations with Kliogest in the treatment of postmenopausal symptoms. DESIGN: This was a double-blind, randomized, multicenter study. METHODS: Patients were randomized to estradiol valerate 2.0 mg/dienogest 2.0 mg (Climodien), estradiol valerate 2.0 mg/dienogest 3.0 mg (E2Val 2/DNG 3); or estradiol 2.0 mg/estriol 1.0 mg/norethisterone acetate 1.0 mg (Kliogest) once daily for 1 year. The primary efficacy variable was the Kupperman index. Endometrial safety was determined primarily by biopsy. RESULTS AND CONCLUSIONS: Climodien and E2Val 2/DNG 3 were therapeutically equivalent to Kliogest (mean changes in Kupperman index -20.1, -19.0 and -18.3, respectively). No statistically significant differences existed between treatment groups in the severity of postmenopausal symptoms. The incidences of endometrial atrophy were similar in all groups. Climodien appeared to be superior to Kliogest in terms of vaginal bleeding pattern, whereas E2Val 2/DNG 3 was associated with a slightly higher incidence and greater intensity of vaginal bleeding. The incidences of adverse events were similar in all groups. A greater proportion of women in the Kliogest and E2Val 2/DNG 3 groups experienced vaginal bleeding, whereas breast problems were more common with Climodien. Climodien and E2Val 2/DNG 3 induced desirable changes in insulin-like growth factor I (decrease) and sex hormone binding globulin (increase) that were not seen with Kliogest.

Biopsy↗
PubMed2000

Detection of MUC1-expressing mammary carcinoma cells in the peripheral blood of breast cancer patients by real-time polymerase chain reaction.

We have prospectively analyzed blood samples of 122 patients with breast disease for the presence of circulating expressing MUC1 cells before and after treatment. Among them, 28 patients had histologically confirmed benign breast disease (group 1), 34 patients had operable breast cancer (group 2), and 60 patients had advanced breast cancer (group 3). Circulating epithelial cells were isolated with BerEP4-coated immunomagnetic beads. Total RNA was extracted and reverse transcribed before analysis by real-time PCR of a MUC1-specific cDNA sequence. The sensitivity of the reverse transcription-PCR tested with blood spiked with MCF7 cells was one cell in 5 ml of blood. The immunomagnetic separation step was mandatory to obtain the maximum specificity. Control samples from healthy donors never displayed cycle threshold (Ct) values for MUC1 lower than 38. Circulating cells (Ct, <38) were detected in 3 of 28 (11%) cases in group 1, in 8 of 34 (24%) cases in group 2, and in 27 of 60 cases (45%) in group 3. A semiquantitative estimate of blood-borne cells could be derived from the Ct value when below 32 (the lowest was 28) or by the number of positive aliquots of the same blood sample. Thus, immunomagnetic separation, followed by MUC1-specific RT-PCR, allows the semiquantitative detection of circulating mammary cells. A significant correlation between the presence of MUC1-positive cells and the group of breast tumors was observed. The clinical significance of blood-borne cells in breast cancer, especially at the operable stage, may be investigated by following these patients.

Adult↗
PubMed2000

Herpesvirus homologues of cellular genes.

For millions of years viruses have adapted strategies to interfere with the immune defense of the host, which in turn has to deal with this challenge. In general the antiviral defense remains one step behind the pathogen. To achieve this strategic advantage large DNA-containing Viruses encode cellular homologues that mimic or counteract key molecules of the host immune system. Understanding how these cellular homologues enable the viruses to evade the antiviral defense and persist in the host for the lifetime will ultimatively lead also to a better understanding of the principle functions of the immune system. In this review we focused on cellular homologues encoded by human herpesviruses and discuss the functional consequences of their expression.

Amino Acid Sequence↗
PubMed1999

Vertebrate-type and plant-type ferredoxins: crystal structure comparison and electron transfer pathway modelling.

Crystallographic analysis of a fully functional, truncated bovine adrenodoxin, Adx(4-108), has revealed the structure of a vertebrate-type [2Fe-2S] ferredoxin at high resolution. Adrenodoxin is involved in steroid hormone biosythesis in adrenal gland mitochondria by transferring electrons from adrenodoxin reductase to different cytochromes P450. Plant-type [2Fe-2S] ferredoxins interact with photosystem I and a diverse set of reductases.A systematic structural comparison of Adx(4-108) with plant-type ferredoxins which share about 20 % sequence identity yields these results. (1) The ferredoxins of both types are partitioned into a large, strictly conserved core domain bearing the [2Fe-2S] cluster and a smaller interaction domain which is structurally different for both subfamilies. (2) In both types, residues involved in interactions with reductase are located at similar positions on the molecular surface and coupled to the [2Fe-2S] cluster via structurally equivalent hydrogen bonds. (3) The accessibility of the [2Fe-2S] cluster differs between Adx(4-108) and the plant-type ferredoxins where a solvent funnel leads from the surface to the cluster. (4) All ferredoxins are negative monopoles with a clear charge separation into two compartments, and all resulting dipoles but one point into a narrow cone located in between the interaction domain and the [2Fe-2S] cluster, possibly controlling predocking movements during interactions with redox partners. (5) Model calculations suggest that FE1 is the origin of electron transfer pathways to the surface in all analyzed [2Fe-2S] ferredoxins and that additional transfer probability for electrons tunneling from the more buried FE2 to the cysteine residue in position 92 of Adx is present in some.

Adrenodoxin↗
PubMed1999

Benchmarking PSI-BLAST in genome annotation.

The recognition of remote protein homologies is a major aspect of the structural and functional annotation of newly determined genomes. Here we benchmark the coverage and error rate of genome annotation using the widely used homology-searching program PSI-BLAST (position-specific iterated basic local alignment search tool). This study evaluates the one-to-many success rate for recognition, as often there are several homologues in the database and only one needs to be identified for annotating the sequence. In contrast, previous benchmarks considered one-to-one recognition in which a single query was required to find a particular target. The benchmark constructs a model genome from the full sequences of the structural classification of protein (SCOP) database and searches against a target library of remote homologous domains (<20 % identity). The structural benchmark provides a reliable list of correct and false homology assignments. PSI-BLAST successfully annotated 40 % of the domains in the model genome that had at least one homologue in the target library. This coverage is more than three times that if one-to-one recognition is evaluated (11 % coverage of domains). Although a structural benchmark was used, the results equally apply to just sequence homology searches. Accordingly, structural and sequence assignments were made to the sequences of Mycoplasma genitalium and Mycobacterium tuberculosis (see http://www.bmm.icnet. uk). The extent of missed assignments and of new superfamilies can be estimated for these genomes for both structural and functional annotations.

Algorithms↗
PubMed1999

Archimedean Synthesis and Magic Numbers: "Sizing" Giant Molybdenum-Oxide-Based Molecular Spheres of the Keplerate Type.

Pythagorean harmony can be found in the spherical polyoxometalate clusters described here (see illustration for an example of a structure), since there are interesting relationships between the so-called magic numbers (12, 32, 42, 72, 132) relevant for spherical viruses and the number of the building blocks in the cluster. The size of these Keplerate clusters can be tailored by varying the type of connections between the pentagons by means of different spacers.

Journal Article↗
PubMed1999

Herpes simplex virus type 1 infection of activated cytotoxic T cells: Induction of fratricide as a mechanism of viral immune evasion.

Herpes simplex virus type 1 (HSV1), a large DNA-containing virus, is endemic in all human populations investigated. After infection of mucocutaneous surfaces, HSV1 establishes a latent infection in nerve cells. Recently, it was demonstrated that HSV1 can also infect activated T lymphocytes. However, the consequences of T cell infection for viral pathogenesis and immunity are unknown. We have observed that in contrast to the situation in human fibroblasts, in human T cell lines antigen presentation by major histocompatibility complex class I molecules is not blocked after HSV1 infection. Moreover, HSV1 infection of T cells results in rapid elimination of antiviral T cells by fratricide. To dissect the underlying molecular events, we used a transgenic mouse model of HSV1 infection to demonstrate that CD95 (Apo-1, Fas)-triggered apoptosis is essential for HSV1-induced fratricide, whereas tumor necrosis factor (TNF) also contributes to this phenomenon but to a lesser extent. By contrast, neither TRAIL (TNF-related apoptosis-inducing ligand) nor perforin were involved. Finally, we defined two mechanisms associated with HSV1-associated fratricide of antiviral T cells: (a) T cell receptor-mediated upregulation of CD95 ligand and (b) a viral "competence-to-die" signal that renders activated T lymphocytes susceptible to CD95 signaling. We propose that induction of fratricide is an important immune evasion mechanism of HSV1, helping the virus to persist in the host organism throughout its lifetime.

Animals↗
PubMed1999

Is there a psoriatic osteopathy? -- the activity of bone resorption in psoriatics is related to inflammatory joint process.

The aim of this study was to examine former own histomorphological results by using biochemical markers of bone collagen catabolism in patients with psoriasis vulgaris and psoriatic arthritis and to compare these results with those from rheumatoid arthritis. - The diagnosis of PsA was made according to the diagnostic criteria of Moll and Wright modified by Bennet. Urine was collected from 99 patients with PsA, 21 patients suffering from PS without articular manifestations, 154 patients with RA fulfilling the ACR criteria of 1987, and 80 healthy controls. Pyridinoline and deoxypyridinoline in urine were analyzed by HPLC, levels of CrP and ESR were estimated using laboratory assessment. - Both crosslinks show a elevated excretion in PsA (particularly in active PsA / aPsA) as well as in RA. PS and Controls show no significant difference in the elimination of crosslinks. The levels of both crosslinks are higher in females than males in all groups. With the exception of Dpyd levels in urine which only show a tendency to correlate with ESR, there are positive correlations between measured crosslink-levels in urine and markers of inflammation. The Pyd/Dpyd ratio displays a significant correlation with ESR. - An increased breakdown of collagen I and II was found only in active forms of psoriatic arthritis and in rheumatoid arthritis. Our biochemical results do not demonstrate a complete agreement with former scintigraphic or histological investigations of other authors and own histomorphological results.

Adult↗
PubMed1999

Investigations of bone turnover in renal osteopathy.

The renal bone disease which develops in chronic renal failure (CRF) is not an uniform disorder. Histomorphometry is accepted to be the best method for characterising the state of disease. The purpose of this study was to evaluate the suitability of pyridinium crosslinks in serum and urine as indicators of bone degradation processes. Patients with CRF had significantly higher Pyridinoline (Pyd) and Deoxypyridinoline (Dpyd) levels in serum and urine compared to normal controls except the urinary excretion in the subgroup of glomerulonephritis. A correlation was found between the serum levels of crosslinks and those of both creatinine and parathormone. The Pyd and Dpyd serum levels in patients under dialysis treatment were significantly higher than those of normal controls. With regard to bone turnover urinary crosslink measurements are of minor importance in CRF. In contrast, serum measurements could be helpful in revealing bone resorption both in patients with CRF and those under dialysis treatment.

Adult↗
PubMed1999

Neisserial porin (PorB) causes rapid calcium influx in target cells and induces apoptosis by the activation of cysteine proteases.

The porin (PorB) of Neisseria gonorrhoeae is an intriguing bacterial factor owing to its ability to translocate from the outer bacterial membrane into host cell membranes where it modulates the infection process. Here we report on the induction of programmed cell death after prolonged infection of epithelial cells with pathogenic Neisseria species. The underlying mechanism we propose includes translocation of the porin, a transient increase in cytosolic Ca2+ and subsequent activation of the Ca2+ dependent protease calpain as well as proteases of the caspase family. Blocking the porin channel by ATP eliminates the Ca2+ signal and also abolishes its pro-apoptotic function. The neisserial porins share structural and functional homologies with the mitochondrial voltage-dependent anion channels (VDAC). The neisserial porin may be an analogue or precursor of the ancient permeability transition pore, the putative central regulator of apoptosis.

Adenosine Triphosphate↗
PubMed1999

Image-guided endoscopic ventriculostomy with a new frameless armless neuronavigation system.

OBJECTIVE: Complications resulting from imprecise placement of the ventriculoscope and reduced visibility through the endoscopic lens under certain conditions during third ventriculostomy have been reported in the literature. The following is a report of our first experience with image-guided endoscopic ventriculostomy. MATERIALS AND METHODS: Between September 1996 and October 1997, 11 patients diagnosed with aqueduct stenosis were found to be eligible for image-guided neuroendoscopy. The image-guided system (BrainLab, Heimstetten, Germany) links a freehand probe, tracked by a passive-marker sensor system, to a virtual computer image space. A 4-mm rigid ventriculoscope (Storz Instruments GMBH, Tuttlingen, Germany) was used. RESULTS: Eight patients improved clinically directly after surgery, two patients stabilized, and one patient improved only after insertion of an additional ventriculo-peritoneal shunt. The computer- calculated registration accuracy ranged from 1. 1 to 3.1 mm (median 1.4 mm) using 3-mm computed tomographic slices. The accuracy of the tool tip calibration for the endoscope was in the range of 0.35-0.9 mm (mean = 0.47 +/- 0.21). The described technique provided maximal flexibility for the surgeon and helped in performing a safe and accurate endoscopical procedure. CONCLUSIONS: Although not all cases of ventriculostomy require additional image guidance, we found the technique to be helpful in patients with atypical or large ventricles, in cases where orientation became difficult owing to bloody or blurry cerebrospinal fluid, and in patients with small foramina of Monroe, where the entrance angle of the endoscope needs precise definition for an atraumatic procedure to be performed.

Adolescent↗
PubMed1999

T cell stimulation upon long-term secretion of viral IL-10.

Viral IL-10 (vIL-10), the IL-10 homologue of Epstein-Barr virus, has so far been described as a cytokine that solely inhibits T cell function. Here we show in vivo and in vitro that after long-term secretion vIL-10 has a stimulatory effect on T cells. For this purpose we employed transfectants derived from a mastocytoma cell line (P815 cells, H-2(d)) constitutively secreting vIL-10 (P815-vIL-10) or expressing the co-stimulatory molecule B7-1 (P815-B7). After in vitro stimulation of splenocytes from syngeneic DBA/2 mice for 7 days in the presence of P815-vIL-10 cells we could detect a marked reduction of proliferation as well as cytotoxicity against P815 target cells. However, this inhibitory effect was reversed when stimulation with P815-vIL-10 cells was extended to 14 days. In vivo P815-vIL-10 cells were rejected whereas P815 cells transfected with a control plasmic were tumorigenic after injection into syngeneic DBA/2 mice. Furthermore, this stimulatory effect of constitutive vIL-10 secretion could be exploited to irradicate already established P815 tumors which were smaller than 5 x 5 mm. In contrast, paracrine vIL-10 secretion for a limited time period of 8 - 9 days was associated with inhibitory effects in vivo: P815-B7 cells, which are normally eliminated in DBA/2 mice, could grow if exposed to temporarily secreted vIL-10. These time-dependent immunomodulatory effects have to be considered in potential therapeutic applications of vIL-10.

Animals↗
PubMed1999

Cytokine profiles in Wegener's granulomatosis: predominance of type 1 (Th1) in the granulomatous inflammation.

OBJECTIVE: To determine whether a specific cytokine pattern (type 1 [Th1] or type 2 [Th2]) predominates in Wegener's granulomatosis (WG), by evaluating interferon-gamma (IFNgamma) and interleukin-4 (IL-4) expression in different compartments of the body (i.e., biopsied nasal mucosal tissue [NBS], bronchoalveolar lavage [BAL] fluid, and peripheral blood [PB]) and comparing the findings with those in disease and healthy control subjects. METHODS: Competitive reverse transcriptase-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay were used to assess IFNgamma and IL-4 expression in T cell clones (TCC), T cell lines (TCL), and polyclonal CD4+ and CD8+ cells derived from NBS, BAL, and PB. RESULTS: Patients with WG and chronic rhinitis were found to share in situ production of messenger RNA (mRNA) specific for IFNgamma (Th1). Only 2 patients with WG expressed IL-4, whereas IL-4 mRNA PCR products were found in inflamed tissues of the disease control patients. The granuloma-derived T cells of WG patients produced only IFNgamma, while TCC, TCL, and CD4+ and CD8+ T cells from BAL and PB produced mainly IFNgamma. CONCLUSION: Our data indicate that a Thl cytokine pattern predominates in the granulomatous inflammation in patients with WG.

Adult↗