Biomedical subjects

W Mueller

Publications and source records attributed to W Mueller.

At least 19 recordsLinked to original sources

PubMed2006

Downregulation of RUNX3 and TES by hypermethylation in glioblastoma.

Glioblastoma, the most aggressive and least treatable form of malignant glioma, is the most common human brain tumor. Although many regions of allelic loss occur in glioblastomas, relatively few tumor suppressor genes have been found mutated at such loci. To address the possibility that epigenetic alterations are an alternative means of glioblastoma gene inactivation, we coupled pharmacological manipulation of methylation with gene profiling to identify potential methylation-regulated, tumor-related genes. Duplicates of three short-term cultured glioblastomas were exposed to 5 microM 5-aza-dC for 96 h followed by cRNA hybridization to an oligonucleotide microarray (Affymetrix U133A). We based candidate gene selection on bioinformatics, reverse transcription-polymerase chain reaction (RT-PCR), bisulfite sequencing, methylation-specific PCR and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Two genes identified in this manner, RUNX3 and Testin (TES), were subsequently shown to harbor frequent tumor-specific epigenetic alterations in primary glioblastomas. This overall approach therefore provides a powerful means to identify candidate tumor-suppressor genes for subsequent evaluation and may lead to the identification of genes whose epigenetic dysregulation is integral to glioblastoma tumorigenesis.

Azacitidine↗

PubMed2006

[Wound botulism in heroin addicts in Germany].

HISTORY AND ADMISSION FINDINGS: 5 heroin addicts (aged 31-44 years; 1 female, 4 men) presented with a history of blurred vision and diplopia followed by dysarthria. 3 of the patients also developed respiratory failure requiring long-term ventilatory support. Physical examination revealed cranial nerve deficits and abscesses at injection sites in 3 of them. DIAGNOSIS: In 4 patients wound botulism was diagnosed on the basis of symptoms, course of the illness and response to specific treatment. Clostridium botulinum was grown from wound swab in one patient. TREATMENT AND COURSE: Two of the patients, having been injected with antitoxin immediately after admission, were discharged almost symptom-free after only a few days. Adjuvant antibiotics and, in 3 patients, surgical débridement of the abscesses were needed. CONCLUSIONS: Progressive cranial nerve pareses in addicts who inject drugs intravenously or intramuscularly should raise the suspicion of wound botulism and require hospitalization. While indirect demonstration of toxin supports the diagnosis, false-negative results are common.

Adult↗

PubMed2006

[Long-lasting, refractory headache after bilateral dissection of the internal carotid artery].

Headache is usually the first and the most frequent symptom of cervicocephalic arterial dissection. Besides headache ipsilateral Horner's syndrome, cranial nerve palsies, or pulsatile tinnitus are observed. Serious complications of arterial dissection are ischemic strokes, which mostly occur later in the course of time. We report on a patient with spontaneous bilateral carotid artery dissection, who suffered from atypically prolonged, severe, and refractory headache. High-dose administration of nonsteroidal anti-inflammatory drugs as well as opioids were ineffective. Pain relief was only achieved after a 3-day course of corticosteroids (100 mg methylprednisolone/day).

Adrenal Cortex Hormones↗

PubMed2004

Technique for the direct measurement of DC-like magnetic biosignals demonstrated by the cold reflex of the abdomen.

Very low frequency dc-like signals, such as the cold reflex, could only be measured up to now by moving the subject repeatedly, up to the magnetic detector. PTB's novel magnetically shielded room BMSR 2, together with a low noise 16 channel SQUID magnetometer, allow the recording of dc-like signals without moving the subject; these are direct measurements. The total observed magnetic drifts are limited by 1/f-noise and external disturbances to a value below 6 pT/h. The measurement is continuous in time, therefore provides frequency resolution from dc to several kHz. This allows us to also observe the changing pattern between two different static magnetic states. As an example, the measurement of the cold reflex of the abdomen is shown and discussed. Not only the expected cold reflex, but other periodic and spontaneous signals from the human body can be seen with this method.

Abdomen↗

PubMed2004

Minor neurological dysfunction, cognitive development, and somatic development at the age of 3 to 7 years after dexamethasone treatment in very-low birth-weight infants.

The objective of this study was to assess minor neurological dysfunction, cognitive development, and somatic development after dexamethasone therapy in very-low-birthweight infants. Thirty-three children after dexamethasone treatment were matched to 33 children without dexamethasone treatment. Data were assessed at the age of 3-7 years. Dexamethasone was started between the 7th and the 28th day of life over 7 days with a total dose of 2.35 mg/kg/day. Exclusion criteria were asphyxia, malformations, major surgical interventions, small for gestational age, intraventricular haemorrhage grades III and IV, periventricular leukomalacia, and severe psychomotor retardation. Each child was examined by a neuropediatrician for minor neurological dysfunctions and tested by a psychologist for cognitive development with a Kaufman Assessment Battery for Children and a Draw-a-Man Test. There were no differences in demographic data, growth, and socio-economic status between the two groups. Fine motor skills and gross motor function were significantly better in the control group (p<0.01). In the Draw-a-Man Test, the control group showed better results (p<0.001). There were no differences in development of speech, social development, and the Kaufman Assessment Battery for Children. After dexamethasone treatment, children showed a higher rate of minor neurological dysfunctions. Neurological development was affected even without neurological diagnosis. Further long-term follow-up studies will be necessary to fully evaluate the impact of dexamethasone on neurological and cognitive development.

Child↗

PubMed2004

[Molecular pathology in hereditary colorectal cancer. Recommendations of the Collaborative German Study Group on hereditary colorectal cancer funded by the German Cancer Aid (Deutsche Krebshilfe)].

Although twin studies indicate that inherited genetic factors contribute to about 35% of colorectal cancers (CRC), the exact genetic background has currently been elucidated in only 5-10% of cases. These comprise several hereditary cancer predisposition syndromes that present with a high number of syn- or metachronous neoplasms within an affected person and/or family. Many of these tumors exhibit typical histopathological changes. In general, one should discriminate between cancer syndromes associated with adenomatous and non-adenomatous (i.e., hamartomatous) polyps, the latter being quite rare. The patient's age often serves as a substantial hint to hereditary cancer. The next step of diagnostic work-up includes analysis of microsatellite instability (MSI) together with immunohistochemical detection of a loss of expression in one of the most frequently affected mismatch repair genes (MSH2, MSH6; MLH1, PMS2). Finally, the molecular demonstration of a gene mutation in the blood or germline is the most expensive and tedious procedure. This requires a signed informed consent from the patient after appropriate genetic counseling.

Colonic Neoplasms↗

PubMed2004

No evidence of hSNF5/INI1 point mutations in choroid plexus papilloma.

Choroid plexus carcinomas (CPC) have been shown to carry mutations in the hSNF5/INI1 gene on chromosomal arm 22q11.2. A recent study on choroid plexus papillomas (CPP) and CPC revealed frequent losses of chromosomal portions on the long arm of chromosome 22 (-22q). The region harbouring hSNF5/INI1 was affected in 47% of the CPP and 73% of the CPC, respectively. -22q occurred more frequently in adult than in infantile CPP suggesting different pathogenetic pathways for these tumours. These findings may indicate a potential tumour suppressor gene function of hSNF5/INI1 in a subset of choroid plexus tumours. In order to examine its potential role in the pathogenesis of choroid plexus tumours, we analysed exons 1-9 of hSNF5/INI1 by SSCP analysis in a series of 21 formalin-fixed and paraffin-embedded CPP. No alterations in migratory patterns were detected. These data indicate that somatic point mutations of hSNF5/INI1 do not play a role in the pathogenesis of CPP and that CPP and CPC may arise by two different molecular pathways.

Choroid Plexus Neoplasms↗

PubMed2003

Simple invasive fixation device for fractionated stereotactic LINAC based radiotherapy.

BACKGROUND: The aim of this study was to develop a relocatable fixation device for linear accelerator (LINAC) based fractionated stereotactic radiotherapy. METHOD: The device consists of a CT- and MRI-compatible stereotactic frame, monocortical titan bone screws, four frame-posts with a lock for the fixation pins and a modified head clamp with additional arms that allows the exact and rigid placement of the frame in the desired final position prior to the final placement of the bone screws. By simply disconnecting the lock from the posts, the frame can be dismounted after treatment planning and after each treatment session. The accuracy of reposition was assessed prospectively, using phantom studies and also by comparison of isocenter movements during fractionated radiotherapy in 10 patients with an intracranial lesion. FINDINGS: No adverse events were seen after the surgical procedure and the screws were well tolerated throughout the course of treatment. The mean isocenter shifts observed during phantom reposition studies were x=0.05 mm, y=-0.32 mm, z=0.18 mm and the mean isocenter shifts during fractionated treatment were x=0.67 mm, y=0.65 mm, z=0.44 mm. INTERPRETATION: This new fixation device provides excellent accuracy of reposition during stereotactic radiotherapy. It appears superior to non-invasive, mask fixation techniques. Safety margins as small as 1-1.5 mm may therefore be sufficient for this method of stereotactic radiotherapy.

Adult↗

PubMed2002

Investigation of bax, bcl-2, bcl-x and p53 gene polymorphisms in multiple sclerosis.

Clinical course, outcome, radiological features, severity, and histopathology are heterogenous in multiple sclerosis (MS). Since MS is considered to be a polygenic disease, the genetic background may at least partly be responsible for this variability. Some MS cases are histopathologically characterized by a dramatic oligodendrocyte loss that is in part caused by apoptosis. A dysregulated apoptotic elimination of self-reactive T cells may also contribute to disease susceptibility. To analyze genetic differences in the apoptosis regulating factors bcl-2, bax, bcl-x and p53 we investigated polymorphisms of these genes in 105 patients with a relapsing remitting disease course and 99 controls by PCR-SSCP and direct sequencing. We identified so far unpublished sequence alterations in the promotor region of the bxl-x gene, in exon 7 of the p53 gene, and in exon 1 of the bax gene. No differences were observed between MS patients and controls. Additional known polymorphisms were found in intron 3 of the bax gene and in exon 6 of the p53 gene. No significant differences in the frequency of gene sequence variations were found between MS patients and controls. The apoptosis genes studied here therefore appear less likely to be important effector genes in MS.

Apoptosis↗

PubMed2001

Different patterns of beta-catenin expression in gastric carcinomas: relationship with clinicopathological parameters and prognostic outcome.

AIMS: The cadherin-catenin complex is known to play a critical role in maintenance of cell adhesion. Additionally beta-catenin (beta-ct) can also take part in signal transduction and nuclear beta-ct expression could be correlated with poor prognosis in several malignancies. Since, in gastric cancer, this role of beta-ct is still uncertain, we investigated the expression pattern of beta-ct as well as the possible prognostic role. METHODS AND RESULTS: beta-catenin expression was immunohistochemically investigated in a retrospective series of 401 R0-resected gastric carcinomas. Out of these cases, 54 tumours (13.5%) revealed a preserved membranous beta-ct expression similar to that in normal gastric mucosa. In 80 tumours beta-ct expression was moderately reduced and in 117 tumours highly reduced. In 150 tumours (37.4%), no or only a weak membranous beta-ct expression was found. Additionally, in 53 tumours, a strong beta-ct expression could be observed in the cytoplasm with a simultaneous nuclear beta-ct immunoreactivity in 17 of these 53 tumours, while nine tumours only showed nuclear immunoreactivity without cytoplasmic staining. There were no significant correlations between the degree of membranous beta-ct expression or the different staining pattern (membranous vs. cytoplasmic/nuclear) and the grade of tumour differentiation, the histological tumour type according to Lauren, as well as with the prognostic parameters pT, pN category and vascular invasion. No associations could be found with tumour cell proliferation and the expression of E-cadherin, irrespectively of the different beta-ct staining pattern. Univariate analysis revealed no influence on survival, either for membranous or for cytoplasmic/nuclear beta-ct expression. CONCLUSION: Our data on 401 tumours suggest that activation of the Wnt/beta-catenin signalling does also occur in a subset of gastric carcinomas. However, in gastric cancer, neither the presence of cytoplasmic/nuclear beta-ct expression nor the reduction or loss of membranous beta-ct expression is correlated with a specific histological tumour type, tumour progression or prognosis.

Cell Division↗

PubMed2001

Articular cartilage repair using a tissue-engineered cartilage-like implant: an animal study.

OBJECTIVE: Because articular cartilage has limited ability to repair itself, treatment of (osteo)chondral lesions remains a clinical challenge. We aimed to evaluate how well a tissue-engineered cartilage-like implant, derived from chondrocytes cultured in a novel patented, scaffold-free bioreactor system, would perform in minipig knees with chondral, superficial osteochondral, and full-thickness articular defects. DESIGN: For in vitro implant preparation, we used full-thickness porcine articular cartilage and digested chondrocytes. Bioreactors were seeded with 20x10(6) cells and incubated for 3 weeks. Subsequent to culture, tissue cartilage-like implants were divided for assessment of viability, formaldehyde-fixed and processed by standard histological methods. Some samples were also prepared for electron microscopy (TEM). Proteoglycans and collagens were identified and quantified by SDS-PAGE gels. For in vivo studies in adult minipigs, medial parapatellar arthrotomy was performed unilaterally. Three types of defects were created mechanically in the patellar groove of the femoral condyle. Tissue-engineered cartilage-like implants were placed using press-fit fixation, without supplementary fixation devices. Control defects were not grafted. Animals could bear full weight with an unlimited range of motion. At 4 and 24 weeks postsurgery, explanted knees were assessed using the modified ICRS classification for cartilage repair. RESULTS: After 3-4 weeks of bioreactor incubation, cultured chondrocytes developed a 700-microm- to 1-mm-thick cartilage-like tissue. Cell density was similar to that of fetal cartilage, and cells stained strongly for Alcian blue and safranin O. The percentage of viable cells remained nearly constant (approximately 90%). Collagen content was similar to that of articular cartilage, as shown by SDS-PAGE. At explantation, the gross morphological appearance of grafted defects appeared like normal cartilage, whereas controls showed irregular fibrous tissue covering the defect. Improved histologic appearance was maintained for 6 months postoperatively. Although defects were not always perfectly level upon implantation at explanation the implant level matched native cartilage levels with no tissue hypertrophy. Once in place, implants remodelled to tissues with decreased cell density and a columnar organization. CONCLUSIONS: Repair of cartilage defects with a tissue-engineered implant yielded a consistent gross cartilage repair with a matrix predominantly composed of type II collagen up to 6 months after implantation. This initial result holds promise for the use of this unique bioreactor/tissue-engineered implant in humans.

Animals↗

PubMed2001

INI1 mutations in meningiomas at a potential hotspot in exon 9.

Rhabdoid tumours have been shown to carry somatic mutations in the INI1 (SMARCB1/hSNF5) gene. A considerable fraction of these tumours exhibit allelic losses on chromosome 22. Allelic loss on 22q also is characteristic for meningiomas, however most of these alterations are considered to be associated with mutations of the NF2 gene. We examined a series of 126 meningiomas for alterations in the INI1 gene. Four identical somatic mutations in exon 9 were detected resulting in an exchange of Arg to His in position 377 of INI1. Our observations were reproduced both by using DNA from a new round of extraction and by employing overlapping primers. This mutational hotspot therefore appears to be an important target in the formation of a fraction of meningiomas. In addition, 4 novel polymorphisms of INI1 were characterized. Our data indicate that the INI1 is a second tumour suppressor gene on chromosome 22 that may be important for the genesis of meningiomas.

Alleles↗

PubMed2001

Clonal analysis in glioblastoma with epithelial differentiation.

Epithelial differentiation in glioblastomas (GBM) may be associated with circumscribed growth and focal keratin expression resembling carcinoma metastasis. Therefore these rare lesions can pose a diagnostic problem suggesting coincidental occurrence of two separate neoplasms. However molecular analysis should succeed in establishing a common origin of seemingly unrelated tumor samples. Five GBMs exhibiting epithelial differentiation were microdissected and analyzed for mutations in the TP53 gene. SSCP analysis of exons 5-8 was followed by direct sequencing of aberrantly migrating fragments. TP53 mutations were identified in tumors from two of five patients. A G-->T transversion in codon 176 was detected in a tumor, initially diagnosed as metastases of unknown origin, however, a later autopsy revealed GBM. In this lesion, the mutation was observed in both, areas of astrocytic differentiation and areas of epithelial differentiation. One tumor diagnosed as GBM with epithelial differentiation carried C-->T transition in codon 211 in both, areas of astrocytic and epithelial differentiation. Thus, molecular analysis proved clonality in two GBMs with epithelial differentiation, thereby excluding a collision tumor. The present data support the concept of clonal origin of these morphologically heterogeneous lesions.

Astrocytes↗

PubMed2001

Chromosomal imbalances in gastric cancer. Correlation with histologic subtypes and tumor progression.

DNA copy number changes were analyzed by comparative genomic hybridization (CGH) in 38 gastric carcinomas and correlated with tumor histologic type and progression. Gains of copy numbers were observed in all tumors, affecting all chromosomes except chromosome 16. The average number of copy number gains was 7 (range, 1-13), most frequently located on chromosomes 11, 12, 15, 17, and 20 in 45% to 97% of tumors. High-level amplifications were found on chromosomes 12, 15, 17, and 20; the latter was affected most frequently (66%). Loss of DNA copy numbers was detected in 14 tumors affecting 7 chromosomes. No statistically significant differences in the frequency and pattern of chromosomal imbalances were observed in tumor histologic type (Lauren classification) and grade of differentiation, as well as the prognostic parameters depth of invasion (pT) and lymph node involvement (pN). Our results indicate that in gastric cancer there is no specific recurrent pattern of DNA aberrations to be correlated with tumor histologic type or stage. However, CGH analysis could reveal new, recurrent genetic changes in gastric cancer affecting chromosomes sites that harbor genes known to participate in tumorigenesis and progression of several human malignant neoplasms.

Carcinoma↗

PubMed2001

Secondary abscess formation in pituitary adenoma after tooth extraction. Case report.

The presence of an abscess in a pituitary tumor is a very rare finding. The authors report the case of a 69-year-old man with a pituitary adenoma confirmed by neuroimaging results, in whom a high fever, meningismus, and left-sided ophthalmoplegia developed 4 days after tooth extraction. The results of serial cranial magnetic resonance imaging were highly indicative of an abscess formation within the pituitary adenoma. During surgery the tumor was approached transsphenoidally and removed. Histological examination confirmed the presence of an abscess formation within the pituitary adenoma. It is most likely that the tooth extraction caused a bacteremia, which led to an inflammation with abscess formation within the pituitary adenoma. The authors conclude that invasive dental procedures should be avoided before planned resection of a pituitary adenoma.

Adenoma↗

PubMed2000

Beta7 integrins contribute to demyelinating disease of the central nervous system.

A role for alpha4 integrins in different forms of the multiple sclerosis-like disease experimental autoimmune encephalomyelitis (EAE) has been demonstrated, but the individual contributions of alpha4beta1, alpha4beta7, and the related alphaEbeta7 integrin have not been determined. The P7 integrins alpha4beta7 and alphaEbeta7 play a central role in chronic inflammation, mediating the trafficking, entry, and/or adhesion of lymphocytes in the inflamed pancreas and gut, and their ligands MAdCAM-1, VCAM-1 and E-cadherin are expressed on brain endothelial cells and/or on microvessels in the inflamed central nervous system. Here, we show that an antibody directed against the beta7 subunit greatly attenuates a non-remitting form of EAE, induced by adoptive transfer of myelin oligodendrocyte peptide (MOG35-55)-stimulated T cells. Combinational treatment with both anti-beta7 and alpha4 integrin subunit antibodies led to more rapid and complete remission than that obtained with anti-alpha4 antibody alone, potentially implicating a role for alphaEbeta7 in disease progression. Remission correlated with the down-regulation of the vascular addressins VCAM-1. MAdCAM-1, and ICAM-1 on cerebral blood vessels. Attenuated forms of disease were induced by adoptive transfer of either wild-type encephalitogenic T cells to beta7-deficient gene knockout mice, or of beta7-/-encephalitogenic T cells to wild-type recipients. The former finding indicates that beta7 + ve recruited cells contribute to disease progression. Thus alpha4beta1, alpha4beta7, and alphaEbeta7 integrins may all play a contributory role in the progression of chronic forms of demyelinating disease, and together with their ligands could represent potential targets for improved treatment of some forms of multiple sclerosis.

Adoptive Transfer↗

PubMed2000

ENVIRONMENTAL AUDITING: Environmental Auditing in Hospitals: First Results in a University Hospital.

/ While medical audit in infection control today is one important element in the quality assurance of health care, environmental auditing, approved in 1993 by the Council of the European Communities for the industrial sector, so far has not been used as a tool to control and reduce environmental pollution caused by medical care. The aim of this study was to investigate whether environmental auditing according to the European Eco-Management and Audit Scheme (EMAS) can be implemented in hospitals as a process of improvement in protection of the environment. In a prior publication the methodological issues and the organizational steps that had to be taken were described. An environmental review of the activities of the Freiburg University Hospital and an ecoanalysis of the input and output were performed. The results of this analysis, published in an environmental report, provide a fundamental data set for the consumption of energy, water, materials, and the burdens of major pollutants and waste. Regarding the organizational structure of the hospital, the first steps towards an integrating environmental management system as demanded by EMAS could be taken. Beside supporting advantages, e.g., improvement of environmental safety, public image and staff contentment, and potential economic benefits such as less cost to be paid for energy and water consumption, there are important restrictions of environmental auditing in hospitals. Examples are the lack of basic environmental data, staff motivation (especially of physicians), cooperation of the organizational substructures, and funds for prefinancing urgently needed improvements in ecology. Based on the study findings, a textbook on environmental auditing in hospitals, including checklists covering all important environmental objectives, has been published to support hospitals in their efforts to achieve an optimized and sustainable practice of providing health care.

Journal Article↗

PubMed2000

Discrimination between neoplastic and nonneoplastic brain lesions by use of proton MR spectroscopy: the limits of accuracy with a logistic regression model.

BACKGROUND AND PURPOSE: The most accurate method of clinical MR spectroscopy (MRS) interpretation remains an open question. We sought to construct a logistic regression (LR) pattern recognition model for the discrimination of neoplastic from nonneoplastic brain lesions with MR imaging-guided single-voxel proton MRS data. We compared the LR sensitivity, specificity, and receiver operator characteristic (ROC) curve area (Az) with the sensitivity and specificity of blinded and unblinded qualitative MRS interpretations and a choline (Cho)/N-acetylaspartate (NAA) amplitude ratio criterion. METHODS: Consecutive patients with suspected brain neoplasms or recurrent neoplasia referred for MRS were enrolled once final diagnoses were established by histopathologic examination or serial neurologic examinations, laboratory data, and imaging studies. Control spectra from healthy adult volunteers were included. An LR model was constructed with 10 input variables, including seven metabolite resonance amplitudes, unsuppressed brain water content, water line width, and the final diagnosis (neoplasm versus nonneoplasm). The LR model output was the probability of tumor, for which a cutoff value was chosen to obtain comparable sensitivity and specificity. The LR sensitivity and specificity were compared with those of qualitative blinded interpretations from two readers (designated A and B), qualitative unblinded interpretations (in aggregate) from a group of five staff neuroradiologists and a spectroscopist, and a quantitative Cho/NAA amplitude ratio > 1 threshold for tumor. Sensitivities and specificities for each method were compared with McNemar's chi square analysis for binary tests and matched data with a significance level of 5%. ROC analyses were performed where possible, and Az values were compared with Metz's method (CORROC2) with a 5% significance level. RESULTS: Of the 99 cases enrolled, 86 had neoplasms and 13 had nonneoplastic diagnoses. The discrimination of neoplastic from control spectra was trivial with the LR, reflecting high homogeneity among the control spectra. An LR cutoff probability for tumor of 0.8 yielded a specificity of 87%, a comparable sensitivity of 85%, and an area under the ROC curve of 0.96. Sensitivities, specificities, and ROC areas (where available) for the other methods were, on average, 82%, 74%, and 0.82, respectively, for readers A and B, 89% (sensitivity) and 92% (specificity) for the group of unblinded readers, and 79% (sensitivity), 77% (specificity), and 0.84 (Az) for the Cho/NAA > 1 criterion. McNemar's analysis yielded significant differences in sensitivity (n approximately 86 neoplasms) between the LR and reader A, and between the LR and the Cho/NAA > 1 criterion. The differences in specificity between the LR and all other methods were not significant (n approximately 13 nonneoplasms). Metz's analysis revealed a significant difference in Az between the LR and the Cho/NAA ratio criterion.

Adolescent↗