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Biomedical subjects

M Mueller

Publications and source records attributed to M Mueller.

At least 19 recordsLinked to original sources
PubMed2006

Prognostic relevance of Tiam1 protein expression in prostate carcinomas.

The Rac-specific guanine nucleotide exchange factor, Tiam1, plays a major role in oncogenicity, tumour invasion and metastasis but its usefulness as a prognostic marker in human cancer has not been tested yet. In the present study, Tiam1 expression was analysed in benign secretory epithelium, pre-neoplastic high-grade prostatic intraepithelium neoplasia (HG-PIN) and prostate carcinomas of 60 R0-resected radical prostatectomy specimens by semiquantitative immunohistochemistry. Tiam1 proved significantly overexpressed in both HG-PIN (P<0.001) and prostate carcinomas (P<0.001) when compared to benign secretory epithelium. Strong Tiam1 overexpression (i.e. > or =3.5-fold) in prostate carcinomas relative to the respective benign prostatic epithelium was statistically significantly associated with disease recurrence (P=0.016), the presence of lymph vessel invasion (P=0.031) and high Gleason scores (GS) (i.e. > or =7) (P=0.044). Univariate analysis showed a statistically significant association of strong Tiam1 overexpression with decreased disease-free survival (DFS) (P=0.03). This prognostic effect of strong Tiam1 overexpression remained significant in multivariate analysis including preoperative prostate-specific antigen levels, pT stage, and GS (relative risk= 3.75, 95% confidence interval=1.06-13.16; P=0.04). Together, our data suggest that strong Tiam1 overexpression relative to the corresponding benign epithelial cells is a new and independent predictor of decreased DFS for patients with prostate cancer.

Aged↗
PubMed2006

Retropatellar chondromalacia associated with medial osteoarthritis after meniscus injury. One year of observations in sheep.

BACKGROUND/AIMS: In an ovine meniscal repair model, the patellofemoral (PF) osteoarthritis due to a non-sutured tear or failed repair was investigated. METHODS: A radial meniscus tear was either sutured with polydioxanone (PDS), with a slow degrading polylactide long-term suture(LTS) or left without treatment. Knee joint cartilage in the PF and medial compartment was evaluated compared to normal knees (healthy controls). RESULTS: Retropatellar osteoarthritis in the non-sutured and sutured animals was intense in contrast to the control knees after 6 months in all groups (p < 0.001), and after 12 months in the PDS group (p < 0.001), LTS group and non-sutured animals (p < 0.05). CONCLUSION: Non-sutured meniscus tears and failed repair lead fast to intense PF osteoarthritis corresponding with tibial damage of the injured compartment.

Animals↗
PubMed2005

Enhanced acetylcholine-induced dilation in afferent arterioles in simvastatin-fed rats.

OBJECTIVE: 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to increase renal blood flow and glomerular filtration rate independent of their lipid lowering effects. The purpose of this study was to determine the effect of simvastatin on acetylcholine-induced vasodilation in the renal microcirculation. The hypothesis of the study was that simvastatin would increase acetylcholine-induced vasodilation in the renal microcirculation. METHODS: The hydronephrotic kidney preparation was used. On the day of the experiment the kidney was prepared for videomicroscopy and dose-response curves were done with acetylcholine and sodium nitroprusside (10(-10) M to 10(-5) M) in simvastatin-fed rats ??(n=8) and control rats (n=13). The vasodilator responses of afferent and efferent arterioles were directly quantitated using videomicroscopy. L-NAME; (N(omega)-nitro-L-arginine methyl ester) was also given in a group of simvastatin-fed rats (10(-5) M) to determine if it would block the acetylcholine (Ach)-induced vasodilation. RESULTS: Simvastatin enhanced Ach-induced vasodilation in the afferent arteriole compared to control rat responses to Ach. At 10(-7) M, ACH caused a 31.6+/-7.2% increase from baseline diameter in the afferent arteriole in the simvastatin-fed rats compared to a 23+/-8.1% vasodilation in the control rats (p<0.05). There were no differences in the response to ACH in the efferent arteriole between the two groups. L-NAME completely abolished the ACH response in the simvastatin-fed rats. CONCLUSIONS: The increase in renal blood flow and glomerular filtration rate observed with simvastatin may be due to its preglomerular vasodilator effects. This may be due to an increase in nitric oxide production.

Acetylcholine↗
PubMed2005

Dendritic cell-based cancer immunotherapy targeting MUC-1.

Vaccination therapy using dendritic cells (DC) as antigen presenting cells (APC) has shown significant promise in laboratory and animal studies as a potential treatment for malignant diseases. Pulsing of autologous DCs with tumor-associated antigens (TAA) is a method often used for antigen delivery and choice of suitable antigens plays an important role in designing an effective vaccine. We identified two HLA-A2 binding novel 9-mer peptides of the TAA MUC1, which is overexpressed on various hematological and epithelial malignancies. Cytotoxic T cells generated after pulsing DC with these peptides were able to induce lysis of tumor cells expressing MUC1 in an antigen-specific and HLA-restricted fashion. Within two clinical studies, we demonstrated that vaccination of patients with advanced cancer using DCs pulsed with MUC1 derived peptides is well tolerated without serious side effects and can induce immunological responses. Of 20 patients with metastatic renal cell carcinoma, 6 patients showed regression of metastases with 3 objective responses (1 CR, 2 PR). Furthermore, we found that in patients responding to treatment T cell responses for antigens not used for treatment occurred suggesting that antigen spreading in vivo might be a possible mechanism of mediating antitumor effects. These results demonstrate that immunotherapy in patients with advanced malignancies using autologous DCs pulsed with MUC1 derived peptides can induce immunological and clinical responses. However, further clinical studies are needed to identify the most potent treatment regimen that can consistently mediate an antitumor immune response in vivo.

Antigen-Presenting Cells↗
PubMed2005

Influence of immunisation with Mycobacterium bovis bacillus Calmette-Guérin on the sensitisation to inhaled allergens after infection with respiratory syncytial virus.

Respiratory syncytial virus (RSV) may play an important role in allergic diathesis by creating a Th2-type immune response. Mycobacterium bovis bacillus Calmette-Guérin (BCG) is known to induce a Th1-type immune response, but the association of BCG vaccination and the suppression of allergy development remain controversial. We investigated the influence of BCG vaccination on the immune response to RSV in a mouse model. Balb/c mice were BCG vaccinated, RSV infected and ovalbumin (OVA) challenged. Mice were sacrificed one, two and four weeks after allergen exposure. Bronchoalveolar lavage was performed. Alveolar macrophages and lymphocytes from spleens and lung-associated lymph nodes were investigated for cytokine production and cell proliferation. Serum was tested for allergen-specific immunoglobulin-E (IgE). Lung eosinophilia was diminished by BCG immunisation. OVA-specific serum IgE was increased regardless of prior BCG vaccination. Interleukin-4 secretion of spleen lymphocytes increased in BCG-vaccinated mice only one week after allergen exposure but was comparable to non-vaccinated mice at four weeks. The reactivity of spleen lymphocytes towards concanavalin-A to secrete interferon-gamma was increased in the vaccinated group at the end of the observation period. Interleukin-6 and tumour necrosis factor-alpha secretion of alveolar macrophages as well as proliferation of stimulated thoracic lymph node cells were increased and prolonged in vaccinated mice. BCG immunisation led to a local suppression of the allergic reaction within the lung. No reduction of systemic IgE production was observed. Further studies are necessary to determine a possible time dependence of BCG immunisation.

Allergens↗
PubMed2005

In vivo culture of IVM/IVF embryos in bovine oviducts by transvaginal endoscopy.

This study was conducted to establish a new approach for in vivo culture of in vitro produced embryos in the bovine oviduct by transvaginal endoscopy. Embryos were in vitro matured, fertilized and cultured for 1-4 days and assigned to groups consisting of 10-30 embryos. Embryos were transferred unilaterally into oviducts of 24 heifers by the means of transvaginal endoscopy. After 3-6 days of in vivo incubation embryos were re-collected. Experiment I aimed to evaluate the capability of embryos to migrate to the uterus. The uterine horns of four animals were flushed first, followed by a combined flushing of both oviducts and uterine horns resulting in collection rates of 31 and 34%, respectively. In experiment II, the transfer of embryos into the oviduct close to ovulation (day 1-2--experiment IIA) or at a more advanced cyclic stage (day 3--experiment IIB) succeeded in the collection of 46 and 34% of the transferred complexes, of which 13 and 37% showed the blastocyst stage. This is the first report of successful recovery of transferable blastocysts by transvaginal endoscopy after tubal in vivo culture in the homologous species of originally in vitro produced embryos.

Animals↗
PubMed2005

Endotoxin: physical requirements for cell activation.

Lipopolysaccharide (LPS) is the eminent lipid component of the outer leaflet of the outer membrane of Gram-negative bacteria and the major initiator of innate immune response to bacterial infection. Below the critical micellar concentration (CMC), LPS is exclusively present as a monomer. Above this concentration, aggregates are formed. Increasing the concentration beyond the CMC leads to an increase in aggregate concentration, whereas the concentration of monomers remains constant or even decreases. The question how LPS activates immune cells and whether the aggregate or the monomer is the biologically active unit has been and still is controversial. To prepare clearly defined monomeric solutions, we utilized a dialysis set-up consisting of a donor and an acceptor chamber, separated by a dialysis diaphragm with a cut-off of 5 kDa, thus allowing only monomers to pass. Human mononuclear cells (MNCs) were then stimulated with equal concentrations of aggregates and monomers, respectively, of deep rough mutant LPS from Escherichia coli strain F515 (Re LPS) and TNF-alpha release was determined. In contrast to earlier and very recent work of others, we started with a preparation of aggregate-suspensions and pure monomer-solutions and show that monomers are significantly less active than aggregates in the absence and presence of serum proteins at identical concentrations. In our model, we propose that LPS aggregates are detected by membrane-associated LBP and intercalated into the cell membrane to bring LPS into close proximity to signaling proteins in the membrane, thus finally leading to cell activation. To support this model, we present data showing that LBP is indeed present in or at the cell membrane of human macrophages.

Cell Membrane↗
PubMed2004

Ortho- and heterotopic bone grafts in bifocal transport osteogenesis for craniofacial reconstruction--an experimental study in sheep.

Bifocal transport osteogenesis (BTO) is a promising technique for the reconstruction of extended osseous craniofacial defects. Aim of this study was to determine the potential of this technique related to various donor sites of the transport segment. In 10 adult sheep critical size defects of the calvaria were treated by gradual movement of a transport segment consisting either of autogenous regional free calvarial bone grafts (n=5) or autogenous illiac free bone grafts (n=5). Latency period was 5 days; the rate of distraction was 1mm per day and extended approximately 40 days. The consolidation period was 28 days. After harvesting, specimens were investigated by conventional radiography, CT-scans, histologically and by fluorescence. In both groups transport osteogenesis resulted in a complete closure of the critical size defect. Membranous bone formation and remodeling occurred during the entire period of distraction and consolidation. The volumes and thickness of newly formed bone at the defect site were increased significantly when calvarial bone grafts were used (P<0.05). Iliac bone grafts became progrediently smaller during distraction, while the volume of calvarial grafts remained relatively constant (P<0.05). In conclusion, transport segments consisting of calvarial and iliac bone resulted in a reliable closure of craniofacial critical size defects in adult organisms; the application of calvarial bone grafts resulted in an increased extend of bone formation.

Animals↗
PubMed2003

Penetration of capecitabine and its metabolites into malignant and healthy tissues of patients with advanced breast cancer.

Capecitabine is an oral prodrug of 5-fluorouracil (FU). Since FU concentrations achieved in malignant lesions are an important determinant of efficacy, we investigated the intratumoral transcapillary transfer of capecitabine and its metabolites in vivo. A total of 10 patients with skin metastases from breast cancer received a daily dose of 2500 mg m(-2) capecitabine administered orally in two divided doses for 2 weeks. Microdialysis probes were inserted into a cutaneous metastasis and subcutaneous connective tissue to evaluate the interstitial tissue pharmacokinetics of capecitabine and its metabolites 5'-deoxy-5-fluorocytidine (DFCR), 5'-deoxy-5-fluorouridine (DFUR), and FU by capillary electrophoresis. As intended with the prodrug design of capecitabine, FU was present in low concentrations in tumour interstitium (median c(max): 0.26 microg ml(-1)) when compared with capecitabine, DFCR, and DFUR (median c(max): 2.66, 4.22, and 2.13 microg ml(-1), respectively). Capecitabine and its metabolites easily penetrated malignant and healthy tissue and equilibrated within 45 min between plasma and tissue interstitium. Considering tissue exposure at the extracellular level, no significant differences between healthy and malignant tissues were observed. Our data show that absorption and metabolism determined the tissue pharmacokinetics of capecitabine. There was no evidence of drug tolerance, which may be attributed to impaired transcapillary transfer into tissue, even after repeated administration as shown for three patients.

Adult↗
PubMed2003

Stenting of the ductus arteriosus and banding of the pulmonary arteries: basis for various surgical strategies in newborns with multiple left heart obstructive lesions.

OBJECTIVE: To present an institutional experience with stent placement in the arterial duct combined with bilateral banding of the pulmonary artery branches as a basis for various surgical strategies in newborns with hypoplastic left heart obstructive lesions. DESIGN: Observational study. SETTING: Paediatric heart centre in a university hospital. PATIENTS: 20 newborns with various forms of left heart obstructive lesions and duct dependent systemic blood flow. INTERVENTIONS: Patients underwent percutaneous ductal stenting and surgical bilateral pulmonary artery banding. Atrial septotomy by balloon dilatation was performed as required, in one premature baby by the transhepatic approach. MAIN OUTCOME MEASURES: Survival; numbers of and reasons for palliative and corrective cardiac surgery. RESULTS: One patient died immediately after percutaneous ductal stenting. One patient died in connection with the surgical approach of bilateral pulmonary banding. Stent and ductal patency were achieved for up to 331 days. Two patients underwent heart transplantation and two patients died on the waiting list. Ten patients had a palliative one stage procedure with reconstruction of the aortic arch and bidirectional cavopulmonary connection at the age of 3.5-6 months. There was one death. One patient is still awaiting this approach. Two patients received biventricular repair. In one, biventricular repair will soon be provided. CONCLUSIONS: Stenting the arterial duct combined with bilateral pulmonary artery banding in newborns with hypoplastic left heart or multiple left heart obstructive lesions allows a broad variation of surgical strategies depending on morphological findings, postnatal clinical conditions, and potential ventricular growth.

Cardiac Catheterization↗
PubMed2003

Peritoneal tuberculosis with negative polymerase chain reaction results: report of two cases.

Peritoneal tuberculosis is rarely observed in European countries. We report on peritoneal tuberculosis in two female immigrants from Somalia and Columbia who presented with diffuse abdominal pain, fever, weight loss and exudative, lymphocytic ascites. Laboratory investigations showed an increase in C-reactive protein and carcinoma antigen 125 serum levels. Nodular peritoneal lesions and adhesions were detected by ultrasound and computed tomography. In both patients, peritoneal biopsy from laparoscopy revealed epitheloid granulomas with central necrosis and multinucleate giant cells. Microscopy and PCR analysis were, however, negative for Mycobacterium tuberculosis in both patients. Despite repeated testing, ascites culture became positive for M. tuberculosis in only one patient. Shortly after starting antituberculous drug treatment, both patients improved, ascitic fluid disappeared and C-reactive protein and carcinoma antigen 125 serum levels returned to normal. Even in Western countries, peritoneal tuberculosis should be considered in any febrile patient with abdominal signs and symptoms, particularly if ascites is present. Empirical antituberculous treatment is justified in patients with clinical and histological features highly suggestive of peritoneal tuberculosis, even in cases with negative results from microscopy, culture and PCR analysis.

Adult↗
PubMed2002

Predictors of treatment failure during highly active antiretroviral therapy (racing trial).

PURPOSE: To determine factors associated with virological failure during long-term treatment with the triple combination of saquinavir soft gel capsule, zalcitabine and zidovudine. METHOD: Open-label, prospective, multicentre study undertaken in private practices and the outpatient department of the Auguste-Viktoria-Hospital. A total of 95 patients with plasma HIV RNA > 5000 copies/ml who had received no more than 6 months pre-treatment with NRTIs and no prior PI therapy received saquinavir soft gel, zalcitabine and zidovudine for 52 weeks, before being randomly assigned to either remain on therapy or switch to nelfinavir, lamivudine and zidovudine for further 52 weeks. RESULTS: Combination therapy with saquinavir, zalcitabine and zidovudine was found to be effective and well tolerated, with virological response to therapy maintained for up to 2 years. In patients responding to therapy, switching to a novel triple regimen did not result in a virological or immunological worsening, but it did not confer an additional clinical benefit. Factors predictive of early treatment failure (virological failure within 16 weeks of treatment initiation) included high viral load and presence of RT mutations at baseline (OR: 0.30, 95% CI 0.11 0.83 and OR 0.13, 95% CI 0.03 0.52, respectively), with baseline viral load and the development of genotypic mutations on therapy being predictive of late treatment failure (16 52 weeks; OR: 0.15, 95% 0.05 0.46 and OR: 0.26, 95% CI < 0.001 1.16, respectively). Plasma saquinavir concentration < 50 mg/ml at 4 weeks was also found to be an independent risk factor for both early and late treatment failure (OR: 1.80, 95% CI 1.23 2.64 and OR: 1.16, 95% CI 0.84 1.60, respectively). CONCLUSIONS: While antiretroviral drug resistance appears to be a principal cause of treatment failure, other factors such as inadequate drug plasma concentrations also play a role.

Adult↗
PubMed2002

Low-temperature electron microscopy for the study of polysaccharide ultrastructures in hydrogels. I. Theoretical and technical considerations.

The high-pressure freezing (HPF) technique was applied to the cryo-immobilization of alginate gels and the quality of the freezing analyzed on a TEM by comparison of the segregation pattern of samples of decreasing thickness. Dynamic simulations of heat transfer within an idealized slab of pure water surrounded by two walls of aluminium were performed to illustrate the effect of the heat-transfer coefficient by convection on the cooling rate of the sample. Heat-transfer coefficients in liquid nitrogen and liquid propane at ambient pressure were measured using a carefully characterized thermocouple and the values incorporated as parameters in heat-transfer simulations to compare the efficiency of the plunge-freezing technique with the high-pressure freezing technique. Values of the heat-transfer coefficient in liquid nitrogen and liquid propane, calculated between 273 K and 173 K were 670 and 18420 W/m(2)/K, respectively. Based on TEM observations and the results of heat-transfer simulations, the HPF technique was adapted to the cryo-fixation of 50-microm-thick alginate gels. The occurrence of artifacts was rejected because no differences were observed in the pattern of cryo-fixed and freeze-substituted samples of various thickness, with and without ethanol as cryo-protectant. A sample thickness of 50 microm was found to ensure an adequate preservation of structures as small as a few nanometers, as verified by TEM and SEM observations. Finally, DSC measurements on alginate solutions and alginate beads revealed that under the experimental conditions (0-3%), alginate cannot be considered to be an efficient cryo-protectant.

Alginates↗
PubMed2002

Low-temperature electron microscopy for the study of polysaccharide ultrastructures in hydrogels. II. Effect of temperature on the structure of Ca2+-alginate beads.

Calcium alginate beads were thermally treated at temperatures ranging from 25 degrees C to 130 degrees C for periods of up to 30 minutes. Important modifications to the structure of the alginate beads were shown to be a function of the temperature and period of incubation at each temperature. Modifications to the alginate beads included reduction in size, mechanical resistance, and molecular weight cut-off with increasing temperature and incubation period. Thus, heating 700 microm calcium alginate beads for 20 min at 130 degrees C resulted in a 23% reduction in diameter, 70% increase in mechanical resistance, and 67% reduction in molecular weight cut-off. Incubation of calcium alginate beads containing 2 x 10(6) kDa blue dextran for 20 min at 130 degrees C resulted in no detectable loss of either dye or alginate. This indicates the shrinkage of the beads was due to re-arrangement of the alginate chains within the beads, coupled with loss of water. This hypothesis was verified by direct visual observation of calcium alginate beads before and after thermal treatment using cryo-scanning electron microscopy (cryo-SEM). Unlike other microscopy methods cryo-SEM offers the advantage of extremely rapid freezing which preserves the original structure of the alginate network. As a result cryo-SEM is a powerful tool for studies of hydrogel and capsule structure and formation. Differential scanning calorimetry (DSC) showed that the water entrapped in 2% alginate beads was present in a single state, irrespective of the thermal treatment. This result is attributed to the low alginate concentration used to form the beads.

Alginates↗