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Biomedical subjects

T Müller

Publications and source records attributed to T Müller.

At least 127 records · Page 7Linked to original sources
PubMed2001

Plasmapheresis-induced remission in otherwise therapy-resistant FSGS.

We report an 8-year-old Caucasian boy who presented with steroid-resistant nephrotic syndrome. Renal biopsy showed the cellular variant of focal segmental glomerulosclerosis (FSGS). Within 1 year he received a series of therapies that have induced remission in other patients with this disease, all to no avail (conventional-dose cyclosporin A, methylprednisolone pulse therapy, high-dose cyclosporin A, and therapy with mycophenolate mofetil). He achieved remission after five sessions of plasma exchange. This case argues for aggressive therapy of resistant nephrotic syndrome in the native kidney. Plasma exchange should be considered as a possible rescue therapy arm in future study protocols.

Child↗
PubMed2001

Enhanced protein phosphorylation in hypertensive hypertrophy.

OBJECTIVE: Chronic pressure overload in spontaneously hypertensive rats (SHR) is accompanied by heart hypertrophy and signs of heart failure. Since there is growing evidence for a possible pathophysiological role of altered protein phosphorylation in heart hypertrophy and failure, we studied here cardiac regulatory phosphoproteins and the kinases and phosphatases which regulate their phosphorylation state. METHODS: The experiments were performed in ventricles of SHR (12-13 weeks old) and age-matched normotensive Wistar-Kyoto rats (WKY). RESULTS: Basal as well as isoproterenol (Iso)-stimulated force of contraction (FOC) was markedly decreased in isolated electrically driven papillary muscles of SHR. Iso (3 micromol/l, 10 min) increased FOC by 0.91+/-0.20 mN in SHR and by 3.88+/-0.52 mN in WKY, respectively. Ca(2+)-uptake by sarcoplasmic reticulum (SR) at low ionized Ca(2+)-concentration was increased in homogenates from SHR. This was not due to altered expression of phospholamban (PLB), SR-Ca(2+)-ATPase and calsequestrin. However, PLB-phosphorylation at threonine-17 (PLB-PT-17) and the activity of Ca(2+)/calmodulin dependent protein kinase (Ca(2+)/Cam-PK) was increased in SHR. In addition, we found an enhanced protein kinase A (PKA)-dependent phosphorylation of the inhibitory subunit of troponin (TnI). In contrast, there was no difference in the activity or expression (protein- and mRNA-level) of protein phosphatases type 1 or type 2A between SHR and WKY. CONCLUSIONS: It is suggested that increased Ca(2+)/Cam-PK-activity with resulting increase of PLB-PT-17 enhanced SR-Ca(2+)-uptake in SHR and might contribute to the pathophysiological changes in cardiac hypertrophy of SHR.

Adrenergic beta-Agonists↗
PubMed2001

Serological evidence for naturally occurring transmission of Neospora caninum among foxes (Vulpes vulpes).

The study describes the time course of the Neospora caninum-specific antibody response in experimentally infected foxes, in naturally N. caninum-seropositive vixens and their litters. An immunofluorescence test, a tachyzoite surface antigen based ELISA and an immunoblot assay were established for this purpose. The immunoblot patterns of naturally seropositive and experimentally infected foxes revealed a high degree of similarity and resembled those reported for other intermediate host species. Reactions against immunodominant antigens of Mr 56, 68 and >94 kDa were observed which could be linked with a period of 14 days-2 months post experimental infection with tachyzoites. Cubs born by naturally seropositive vixens were found to be persistently or transiently seropositive, in the latter case, specific antibodies were detected only up to 44 days after birth. These antibodies may thus be of maternal origin. Differences between the immunoblot patterns of persistently positive cubs, those of their mothers and of transiently positive cubs, in particular the differential response to antigens of Mr 56 and 68 kDa, prove that cubs with persistent antibodies had actively mounted an antibody response. This result provides the first evidence for the postnatal or vertical transmission of N. caninum among naturally seropositive foxes.

Animals↗
PubMed2001

Galactography and exfoliative cytology in women with abnormal nipple discharge.

OBJECTIVE: To evaluate galactography and cytology in women with nipple discharge without clinical or mammographic evidence of cancer. METHODS: During a 12.5-year period, 384 women (15-85 years, mean age 47.5 +/- 14 years) were referred for galactography and smear cytology for recent onset of spontaneous, non-milky nipple discharge. Patients with clinical or mammographic evidence of tumor underwent excisional biopsy directly. Among 314 galactograms, 189 [60.2%; 95% confidence interval (CI) 54.5%, 65.6%] biopsies were recommended. A further 11 patients were scheduled for biopsy because of mammography or cytology. RESULTS: Sixteen of 182 biopsied patients had malignancies (8.8%; CI 5.3%, 14.1%). Combined rate of papillomas, papillomatous proliferation, and malignant tumors was 59.9% (109 of 182; CI 52.4%, 67.0%). Biopsy was malignant in three of 56 women (5%) with nonhemorrhagic discharge and in 13 of 97 (13%) with hemorrhagic discharge (P =.26). Exfoliative cytology revealed 11 false-negatives, four false-positives, five true-positives, and 153 true-negatives (sensitivity 31.2%, CI 11%, 58%; specificity 97.4%, CI 93%, 99%). In ten of 158 patients (6.3%) with suspicious galactography, cancer was found by biopsy. Sensitivity of galactography for malignancy was 83% (CI 51.6%, 97.9%) and specificity was 41% (CI 35.2%, 46.5%). Galactographic sensitivity for any (benign or malignant) neoplasm was 94% (93 of 99; CI 87%, 98%) and specificity was 55% (119 of 215; CI 48%, 62%). Half of the cancers were detected exclusively by galactography. CONCLUSION: Cytology is helpful when positive and galactography localizes the source of discharge. Biopsy is indicated when palpation, mammography, cytology, or galactography is suspicious.

Adolescent↗
PubMed2001

Gemcitabine and vinorelbine as first-line chemotherapy for advanced non-small cell lung cancer: a phase II trial.

The purpose of this phase II study was to investigate the efficacy and safety of gemcitabine plus vinorelbine as first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Eligibility criteria included cytologically or histologically confirmed NSCLC (stage IIIB or IV), no previous chemotherapy, and bidimensionally measurable disease. Patients received 1000 mg/m(2) gemcitabine and 30 mg/m(2) vinorelbine on days 1, 8 and 15 every 4 weeks up to eight courses. From December 1997 to November 1998, 70 patients (59 stage IV and 11 stage IIIB disease), with a median age of 59 years (range 38-74 years) were enrolled. The intent-to-treat response rate was 41% (95% confidence interval (CI) 30-54%) with 1 complete responder (CR) and 28 partial responders (PRs), 15 patients had stable disease (SD) and 26 progressed (PD). Median survival was 8.3 months (95% CI 6.0-9.9 months), median progression-free survival (PFS) was 4.8 months (95% CI 3.9-5.5 months), and 1-year survival rate was 33.5% (95% CI 24.0-46.8%). Patients received a total of 229 cycles. Haematological and non-haematological toxicities were moderate. Transient World Health Organization (WHO)-grade IV leucopenia and thrombocytopenia occurred in 13 (6%) and two (1%) cycles, respectively. The predominant non-haematological toxicity was local reactions of the veins in 19 (27%) patients (WHO-grade II and III). Neurotoxicity was infrequent, non-cumulative, and reversible. The combination of gemcitabine and vinorelbine has demonstrated activity in metastatic NSCLC, with response and survival rates similar to those of cisplatin-based regimens and a more favourable toxicity profile that is well tolerated in an outpatient setting.

Adult↗
PubMed2001

Delay of simple reaction time after levodopa intake.

BACKGROUND: Parkinsonian patients (PP) have deficits in the preparation and execution of movements. It is generally accepted that PP show delayed performance of simple reaction time (SRT) paradigms due to impaired response preprogramming. To date, no trial considered putative effects of dopaminergic substitution on SRT performance in PP. OBJECTIVES: To determine short-term effects of acute levodopa intake and impact of long-term dopaminergic substitution on the results of a SRT task. METHODS: We repeatedly performed a SRT paradigm in previously untreated- and treated PP, taken off medication for at least 12 h, before and after intake of levodopa/benserazide and in PP, who received placebo. RESULTS: Reaction time significantly increased and movement time did not change after levodopa intake. Placebo application showed no effects. CONCLUSIONS: Levodopa delayed cognitive processing and/or behaviour. Sedative effects of levodopa and/or dopamine overflow in prefrontal regions with subsequent cholinergic dysfunction hypothetically caused this phenomenon.

Adult↗
PubMed2001

Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome.

The dystonias are a common clinically and genetically heterogeneous group of movement disorders. More than ten loci for inherited forms of dystonia have been mapped, but only three mutated genes have been identified so far. These are DYT1, encoding torsin A and mutant in the early-onset generalized form, GCH1 (formerly known as DYT5), encoding GTP-cyclohydrolase I and mutant in dominant dopa-responsive dystonia, and TH, encoding tyrosine hydroxylase and mutant in the recessive form of the disease. Myoclonus-dystonia syndrome (MDS; DYT11) is an autosomal dominant disorder characterized by bilateral, alcohol-sensitive myoclonic jerks involving mainly the arms and axial muscles. Dystonia, usually torticollis and/or writer's cramp, occurs in most but not all affected patients and may occasionally be the only symptom of the disease. In addition, patients often show prominent psychiatric abnormalities, including panic attacks and obsessive-compulsive behavior. In most MDS families, the disease is linked to a locus on chromosome 7q21 (refs. 11-13). Using a positional cloning approach, we have identified five different heterozygous loss-of-function mutations in the gene for epsilon-sarcoglycan (SGCE), which we mapped to a refined critical region of about 3.2 Mb. SGCE is expressed in all brain regions examined. Pedigree analysis shows a marked difference in penetrance depending on the parental origin of the disease allele. This is indicative of a maternal imprinting mechanism, which has been demonstrated in the mouse epsilon-sarcoglycan gene.

Adolescent↗
PubMed2001

Complement activation by recombinant adenoviruses.

Recombinant adenoviruses are currently the most important vector system in gene therapy. Adenoviruses frequently cause upper respiratory tract infections in humans and anti-adenoviral antibodies are found in 35-70% of the population. Therefore in the majority of potential patients receiving adenoviral gene therapy, the contact of virus particles and blood will lead to the formation of antigen-antibody complexes. These complexes have the ability to induce inflammatory reactions via an activation of the complement system. We have determined the level of C3a (the most reactive complement component) generated in isolated citrate plasma of healthy individuals after challenge with recombinant and wild-type adenoviruses in amounts corresponding to virus blood levels to be expected in patients during adenoviral gene therapy. All plasma samples containing anti-adenoviral antibodies showed a substantial, dose-dependent generation of C3a. A virus plasma level of about 7.5 x 10(9) particles/ml (which was calculated to be the highest blood level reached during clinical trials in the past) induced an average release of about 3000 ng/ml C3a (baseline levels <140 ng/ml). Analyzing the nature of anti-adenoviral antibodies showed, that not only antibodies with neutralizing properties (anti-Ad5), but also non-neutralizing anti-adenoviral antibodies are capable of complement activation. This study suggests that complement activation can be ignored in local low-dose applications of recombinant adenoviruses, but warrants attention after systemic application of large viral quantities. In clinical protocols aiming at systemic virus application, measures for monitoring and controlling the complement system should be included on a regular basis.

Adenoviridae↗
PubMed2001

Population dynamics and antagonistic potential of enterococci colonizing the phyllosphere of grasses.

AIMS: To investigate the spatial and temporal dynamics of enterococci colonizing forage grass and their ability to produce bacteriocins. METHODS AND RESULTS: Enterococci could be detected on above-ground plant parts throughout the growing season, with high continuity but low cell numbers (2.60 x 101-6.16 x 104 cfu g-1 fresh matter). A total of 750 strains were isolated and identified by their whole-cell protein patterns as Enterococcus faecalis (7.9%), Ent. mundtii (7.9%), Ent. casseliflavus (5.5%), Ent. faecium (5.2%) and Ent. sulfureus (0.1%). The vast majority of the strains (69.7%) formed a homogeneous 16S rDNA genotype that differed from those of known enterococci. A screening for antagonistic activity using an agar spot test revealed that 18.4% of all isolates were potential antagonists. Partially-purified proteins extracted from cell-free culture supernatant fluids of various species were characterized as pH- and heat-stable bacteriocins active against a wide range of lactic acid bacteria, clostridia and Listeria. The producing strains were antagonistically active even on 'phylloplane agar' at temperatures between 4 and 37 degrees C. CONCLUSION: Enterococci are a common part of the epiphytic microflora of grasses, displaying probably some antagonistic activity. SIGNIFICANCE AND IMPACT OF THE STUDY: The results provide new information on the distribution, species diversity and antagonistic potential of enterococci in the phyllosphere.

Antibiosis↗
PubMed2001

Identification of plant-associated enterococci.

AIMS: Enterococcus isolates from forage grass were subjected to taxonomical investigations and tested for antibiotic resistance. METHODS AND RESULTS: The identification procedure included phenotypic characterizations, restriction analyses of polymerase chain reaction-amplified 16S rDNA, whole-cell protein profile analyses and 16S rDNA sequence analyses. Agar diffusion tests were performed to detect antibiotic resistance. CONCLUSION: The isolates were identified as belonging to the species Enterococcus faecium, Ent. mundtii, Ent. casseliflavus, Ent. faecalis and Ent. sulfureus. However, the majority of isolates differed distinctly in their restriction patterns from those of known species. They formed a group of a homogeneous 16S rDNA genotype (VI). The 16S rDNA sequence of a representative isolate revealed the closest relationship to the species Ent. faecalis (similarity of 97.4%). All isolates were sensitive to vancomycin, but almost all were resistant to gentamycin and streptomycin. SIGNIFICANCE AND IMPACT OF THE STUDY: The taxonomical investigations suggest that the isolates of the 16S rDNA genotype VI represent a new plant-associated Enterococcus species.

Bacterial Typing Techniques↗
PubMed2001

Immunogenicity and efficacy of the oral rabies vaccine SAD B19 in foxes.

Studies on the immunogenicity and efficacy of SAD B19 attenuated rabies virus vaccine in foxes under laboratory conditions were conducted. Twenty-seven foxes (Vulpes vulpes) were offered a vaccine bait containing 10(6.3) FFU/ml SAD B19. Blood samples were collected 60, 110 and 190 days post-vaccination. On day 190 post vaccination the animals and 14 controls were challenged with a canid street rabies virus. Twenty-four of the 26 vaccinated foxes (92.3%) survived the challenge, whereas all the controls died from rabies. The two vaccinated foxes that did not survive the challenge did not show any detectable level of rabies neutralizing antibodies at any time after vaccination. The geometric mean titres (GMT) of foxes that seroconverted after vaccination were 43.5, 33.9 and 43.5 IU/ml 60, 110 and 190 days post-vaccination, respectively. Furthermore, to test the vaccine virus under sub-optimal conditions five naive and nine previously vaccinated vixens received 2 ml SAD B19 (10(6.7) FFU/ml) by direct administration of the vaccine virus into the oral cavity shortly before or during pregnancy. All vixens seroconverted above the threshold of 0.5 IU/ml. No booster effect was observed in the immune response of the previously vaccinated animals.

Administration, Oral↗
PubMed2001

Cloning and functional expression of GABA(B) receptors from Drosophila.

The neurotransmitter GABA (gamma-aminobutyric acid) functions as the major inhibitory neurotransmitter in the central nervous system of vertebrates and invertebrates. In vertebrates GABA signals both through ionotropic receptors (GABA(A), GABA(C)), which induce fast synaptic inhibitory responses, and through metabotropic receptors (GABA(B)), which play a fundamental role in the reduction of presynaptic transmitter release and postsynaptic inhibitory potentials. Whilst GABA(A) and GABA(C) receptors have been cloned from vertebrates as well as invertebrates, GABA(B) receptors have only been identified in vertebrate species to date, although indirect evidence suggests their existence in arthropods, too. Here we report the cloning of three putative invertebrate GABA(B) receptor subtypes (D-GABA(B)R1, R2 and R3) isolated from Drosophila melanogaster. Whilst D-GABA(B)R1 and R2 show high sequence identity to mammalian GABA(B)R1 and R2, respectively, the receptor D-GABA(B)R3 seems to be an insect-specific subtype with no known mammalian counterpart so far. All three D-GABA(B)R subtypes are expressed in the embryonic central nervous system. In situ hybridization of Drosophila melanogaster embryos shows that two of the D-GABA(B)Rs (D-GABA(B)R1 and R2) are expressed in similar regions, suggesting a coexpression of the two receptors, whilst the third D-GABA(B)R (D-GABA(B)R3) displays a unique expression pattern. In agreement with these results we have only been able to functionally characterize D-GABA(B)R1 and R2 when the two subtypes are coexpressed either in Xenopus laevis oocytes or mammalian cell lines, whilst D-GABA(B)R3 was inactive in any combination. The pharmacology of the coexpressed D-GABA(B)R1/2 receptor was different from the mammalian GABA(B)Rs: e.g. baclofen, an agonist of mammalian GABA(B)Rs, showed no effect.

Adenylyl Cyclase Inhibitors↗
PubMed2001

Vascular Parkinsonism: a case report and review of the literature.

Vascular Parkinsonism (VP) is characterised by sudden onset and rapid progression of clinical symptoms, absent or poor response to dopamine substitution therapy, and postural instability with shuffling gait and absence of tremor, making it a clinically distinct entity from idiopathic Parkinson's disease (IPD). Furthermore, it displays certain typical findings in neurological investigations. We report on a patient presenting features of VP associated with an intracerebral lesion not ascribed to VP to date, namely an isolated ischaemic focal lesion located in the left cerebral peduncle between the substantia nigra and nucleus ruber as evidenced by magnetic resonance imaging (MRI). The pathophysiological organic correlate for contralateral extrapyramidal symptoms in this patient may be an interruption of nigro-thalamic projection, interrupting the final subcortical station in the cortic-striato-pallido-nigro-thalamico-cortical loop central to the pathophysiology of parkinsonian syndromes. Non-response t o levodopa therapy could be a consequence of disruption of the cortico-basal ganglia-cortical loop on account of ischaemic destruction of subcortico-cortical axons, the underlying pathology, therefore, not being the result of a loss of nigral dopaminergic neurons or striatal dopamine deficiency pathogonomonic of IPD. To our knowledge, this is the first case of clinically manifest VP to be described with a single lesion in the contralateral cerebral peduncle between the substantia nigra and nucleus ruber, and suggests alternative intracerebral patterns for the distribution of disease-causing lesions in VP, and possibly new pathophysiological explanations for the nature of this disease.

Basal Ganglia Diseases↗
PubMed2001

[Heparin-induced type II thrombocytopenia as the etiology of severe recurrent pulmonary embolism].

Heparin-induced thrombocytopenia (HIT) is a rare complication of anticoagulative heparin therapy. The more severe HIT type II is defined by peripheral thrombocytopenia combined with thrombotic and thromboembolic events. We report the case of a 24 year old male patient who was admitted to our ICU with thromboembolic obstruction of the right central pulmonary artery, and deep venous thrombosis (DVT) of the right superficial femoral vein. Systemic thrombolytic therapy with urokinase for seven days resulted in nearly complete resolution of the thromboembolic material in the pulmonary arteries. Antithrombotic therapy with intravenous heparin and overlapping oral phenoprocoumon was continued on the regular ward. Six days later, the patient had to be readmitted to the ICU with evidence of hemodynamic compromise due to massive bilateral pulmonary thromboembolism that could be confirmed by CT scan--DVT had extended to the right iliacal vein. Additionally, peripheral thrombocyte counts had markedly declined from 112.000 to 35.000/microliter within 3 days, indicating the presence of a Hit type II. This was verified by positive ELISA testing for antibodies against platelet factor 4 (PF4)-heparin-complex. A filter device was temporarily implanted into the inferior vena cava. The patients condition stabilized upon reinitiated systemic thrombolysis and replacement of heparin therapy against recombinant hirudin. Pulmonary artery pressures normalized. Peripheral thrombocytopenia diminished within three days. HIT type II is a severe complication of anticoagulative therapy with heparin. Here we report a case, and discuss diagnostic procedures as well as differential diagnosis to HIT type I.

Adult↗
PubMed2001

Non-symmetric score matrices and the detection of homologous transmembrane proteins.

Given a transmembrane protein, we wish to find related ones by a database search. Due to the strongly hydrophobic amino acid composition of transmembrane domains, suboptimal results are obtained when general-purpose scoring matrices such as BLOSUM are used. Recently, a transmembrane-specific score matrix called PHAT was shown to perform much better than BLOSUM. In this article, we derive a transmembrane score matrix family, called SLIM, which has several distinguishing features. In contrast to currently used matrices, SLIM is non-symmetric. The asymmetry arises because different background compositions are assumed for the transmembrane query and the unknown database sequences. We describe the mathematical model behind SLIM in detail and show that SLIM outperforms PHAT both on simulated data and in a realistic setting. Since non-symmetric score matrices are a new concept in database search methods, we discuss some important theoretical and practical issues.

Computational Biology↗
PubMed2001

The activity of NF-kappaB in Swiss 3T3 cells exposed to aqueous extracts of cigarette smoke is dependent on thioredoxin.

Multiple studies in vitro have demonstrated that aqueous extracts of mainstream cigarette smoke (CS) [smoke-bubbled phosphate-buffered saline (PBS)] induce a distinct pattern of stress response in cultured cells, which may be related to the reported pro-inflammatory activities of CS in vitro and in vivo. Nuclear factor kappaB (NF-kappaB) is a transcription factor involved in both inflammatory and stress-dependent cell-signaling processes. Here we report on the activity of NF-kappaB in cells exposed to subcytotoxic concentrations of smoke-bubbled PBS. Using electrophoretic mobility shift assay (EMSA) techniques, we observed a decreased DNA binding of NF-kappaB during the first 2 h of exposure, which was followed by a more than 2-fold increase over controls after 4 to 6 h of exposure. This type of kinetics is not regulated by IkappaB-alpha, as evidenced by the lack of phosphorylation and degradation of IkappaB-alpha in CS-treated cells. However, as demonstrated in immuno-coprecipitation experiments, the kinetics of NF-kappaB DNA binding is strictly paralleled by decreased and increased complex formation between NF-kappaB and thioredoxin (Trx), the reducing catalyst of Cys-62 of NF-kappaB subunit p50, the reduced thiol function of which is essential for efficient NF-kappaB DNA binding. Monitoring the expression of the gene encoding thioredoxin reductase (TrxR), which is required to keep Trx in a functional reduced state, we observed a significant increase in TrxR mRNA after 2 to 6 h of exposure. Based on the correspondence between the kinetics of NF-kappaB DNA binding, NF-kappaB/Trx complex formation, and TrxR expression, along with a lack of IkappaB-alpha phosphorylation and degradation, these results suggest that the activity of NF-kappaB in CS-treated cells is subject mainly to a redox-controlled mechanism dependent on the availability of reduced Trx rather than being controlled by its normal regulator, IkappaB-alpha.

3T3 Cells↗
PubMed2001

Implant-supported denture in a patient with Huntington's disease: interdisciplinary aspects.

Patients with extrapyramidal diseases often cannot maintain independent, efficient oral hygiene due to restricted motor ability of the upper extremities and lack of coordination. The hermetic closure of the mouth and lips, and the associated ability to keep liquid and toothpaste in the mouth, can become so weak that effective oral hygiene cannot be maintained. Over a period of many years, this illness leads to loss of teeth and the need for complete prosthodontic care. Dyskinesia and hyperkinesia of the tongue and the peri-oral musculature, combined with xerostomia and pooling of saliva, make it impossible for the patient to wear a conventional complete denture, despite an anatomically-adequate bearing area. In such cases, an implant-supported prosthesis is a better therapeutic measure, although some aspects of oral hygiene must initially be disregarded. Two ITI implants were inserted into the anterior mandibular region of a patient with Huntington's chorea, because a complete denture could not be retained on the alveolar ridge, despite adequate vestibule depth, due to tongue dyskinesia. A bar joint was used to anchor this mucosal-borne denture. This implant-supported complete denture led to a clear improvement in the patient's chewing function when observed over a period of a year.

Anesthesia, Dental↗