Search PubMed⌕ Search

Biomedical subjects

J Schlegel

Publications and source records attributed to J Schlegel.

At least 19 recordsLinked to original sources
PubMed2006

[MRI of arthritis with the USPIO SH U 555 C: optimization of T1 enhancement].

PURPOSE: To optimize contrast agent dose and pulse sequence parameters in order to achieve a maximal T1 enhancement in arthritic knee joints with ultra small superparamagnetic iron oxides (USPIO)-enhanced MRI. MATERIALS AND METHODS: Antigen-mediated arthritis was induced in the right knee of nine Sprague Dawley rats. The arthritic knee joint as well as the contralateral normal knee were investigated in a 2 Tesla MR scanner before as well as in short intervals up to 2 h after USPIO injection, using T1-weighted gradient echo (GE) sequences. Three rats each received intravenous injections of the new USPIO SHU 555 C (SH U 555 C, Schering AG, Berlin) at doses of 40, 100 and 200 micromol Fe/kg. Pulse sequence parameters of the GE-sequence were optimized by varying flip angles (alpha) and echo times (TE). Changes in signal intensities (SI) of the arthritic knee and contralateral normal knee were quantified as DeltaSI (%) = /([SIpost - SIpre] / SIpre) x 100 %/ and compared with histopathology. RESULTS: Histology of the arthritic knees demonstrated a marked inflammatory proliferation of the synovium. The USPIO SH U 555 C caused a significant increase in signal intensity of the arthritic joints on T1-weighted MR images (p < 0.05). This effect was optimized using a flip angle of 60-70 degrees, a minimal TE and a dose of 200 micromol Fe/kg. Visually the contralateral normal knee did not show any USPIO enhancement. CONCLUSION: Inflammation can be depicted with marked T1 enhancement by the USPIO SH U 555 C using high contrast agent doses and optimized MR pulse sequence parameters.

Animals↗
PubMed2005

Regulation of mesenchymal stem cell and chondrocyte differentiation by MIA.

Melanoma inhibitory activity (MIA), also referred to as cartilage-derived retinoic acid-sensitive protein (CD-RAP), an 11-kDa secreted protein, is mainly expressed in cartilaginous tissue during embryogenesis and adulthood. Currently, the function of MIA in cartilage tissue is not understood. Here, we describe that MIA acts as a chemotactic factor on the mesenchymal stem cell line C3H10T1/2, stimulating cell migration significantly at concentrations from 0.24 to 240 ng/ml, while inhibiting cell migration at higher doses of 2.4 microg/ml. When analyzing the role of MIA during differentiation processes, we show that MIA by itself is not capable to induce the differentiation of murine or human mesenchymal stem cells. However, MIA influences the action of bone morphogenetic protein (BMP)-2 and transforming growth factor (TGF)-beta 3 during mesenchymal stem cell differentiation, supporting the chondrogenic phenotype while inhibiting osteogenic differentiation. Quantitative RT-PCR analysis revealed the up-regulation of the cartilage markers MIA, collagen type II and aggrecan in human mesenchymal stem cell (HMSC) cultures differentiated in the presence of MIA and TGF-beta 3 or BMP-2 when compared to HMSC cultures differentiated in the presence of TGF-beta 3 or BMP-2 alone. Further, MIA down-regulates gene expression of osteopontin and osteocalcin in BMP-2 treated HMSC cultures inhibiting the osteogenic potential of BMP-2. In the case of human primary chondrocytes MIA stimulates extracellular matrix deposition, increasing the glycosaminoglycan content. Therefore, we postulate that MIA is an important regulator during chondrogenic differentiation and maintenance of cartilage.

Adult↗
PubMed2004

Expression of epidermal growth factor receptor in neoplastic pituitary cells: evidence for a role in corticotropinoma cells.

The oncogenic effects of epidermal growth factor (EGF) have long been established. EGF receptor (EGFr) is overexpressed in many types of tumors and constitutes a target for cancer treatment. The pituitary gland is a target of EGF action and it is very likely that EGFr plays a role in pituitary tumor formation and progression. However, there is a controversy in the literature concerning EGFr expression in the different types of pituitary adenomas. In the present study we investigated the expression pattern of the wild type EGFr (EGFrWT) and the constitutively active variant III (EGFrvIII) at the mRNA and protein levels in a large series of pituitary tumors. EGFrWT was found in a high percentage of hormone-secreting tumors, but only in a small fraction of non-functioning pituitary adenomas, while no expression of the EGFrvIII could be detected by nested RT-PCR in any tumor. Among the hormone-secreting adenomas, the highest incidence of EGFr expression was found in Cushing's pituitary adenomas. Furthermore, immunohistochemistry for the phosphorylated EGFr revealed the presence of activated EGFr in most Cushing's adenomas, compared with most pituitary adenomas. Taking into account that downregulation of p27/Kip1 plays a significant role in corticotrope tumorigenesis and that EGFr mitogenic signaling results in decreased p27/Kip1, we searched for a correlation between EGFr expression and p27/Kip1 levels in corticotropinomas. Low p27/Kip1 immunoreactivity was observed in corticotropinomas expressing EGFr. On the other hand, somatotropinomas expressing EGFr had high p27/Kip1 immunoreactivity. These data suggest a corticotrope-specific phenomenon and indicate that EGFr may have a role in the unbalanced growth of corticotrope tumoral cells.

Adenoma↗
PubMed2003

Recurrent spinal cord astrocytoma with intraventricular seeding.

PATIENT: We report on an unusual case of a recurrent and progressive spinal pilocytic astrocytoma with metastatic spreading to the hypothalamus in a 14-year-old boy. TREATMENT AND RESULTS: The patient underwent resection of an intramedullary atypical pilocytic astrocytoma classified as WHO grade II at the level of Th11/12 in 1997 and received local photon beam irradiation. Three years later, a second operation was necessary for a recurrent tumour at the same level. Seventeen months later, a second recurrent tumour with spinal seeding as well as an intracranial tumour in the third ventricle and hypothalamus was detected. He was shunted for an occlusive hydrocephalus and a stereotactic biopsy of the hypothalamic lesion was performed. The tumour was classified as anaplastic pilocytic astrocytoma (WHO grade III). He received chemotherapy with ifosfamide, cisplatin and etoposide (HIT-GBM-C-protocol), craniospinal radiation, and is still alive 60 months after the first operative intervention without neurological deficits.

Adolescent↗
PubMed2003

Multiple progressive intracerebral hemorrhages due to an angiosarcoma: a case report.

Identification of intracerebral hemorrhage (ICH) and the underlying cause is a common clinical problem. Rare causes of ICH can be particularly difficult to diagnose. We describe a man on oral anticoagulation with multiple progressive ICHs, who initially showed no signs of a malignant disease. After normalisation of all coagulation tests, the ICHs continued to spread. Autopsy examination revealed an angiosarcoma. Multiple progressive ICHs caused by an angiosarcoma that mainly affects the brain have not yet been described. In the presence of normal coagulation tests, further progression of ICH should raise questions about common causes of ICH such as oral anticoagulation in our case.

Aged↗
PubMed2002

Dedifferentiation-associated changes in morphology and gene expression in primary human articular chondrocytes in cell culture.

OBJECTIVE: The aim of the present study was the investigation of differential gene expression in primary human articular chondrocytes (HACs) and in cultivated cells derived from HACs. DESIGN: Primary human articular chondrocytes (HACs) isolated from non-arthritic human articular cartilage and monolayer cultures of HACs were investigated by immunohistochemistry, Northern analysis, RT-PCR and cDNA arrays. RESULTS: By immunohistochemistry we detected expression of collagen II, protein S-100, chondroitin-4-sulphate and vimentin in freshly isolated HACs. Cultivated HACs, however, showed only collagen I and vimentin expression. These data were corroborated by the results of Northern analysis using specifc cDNA probes for collagens I, II and III and chondromodulin, respectively, demonstrating collagen II and chondromodulin expression in primary HACs but not in cultivated cells. Hybridization of mRNA from primary HACs and cultivated cells to cDNA arrays revealed additional transcriptional changes associated with dedifferentiation during propagation of chondrocytes in vitro. We found a more complex hybridization pattern for primary HACs than for cultivated cells. Of the genes expressed in primary HACs the early growth response (EGR1) transcription factor showed the strongest expression whereas D-type cyclin was expressed in proliferating cells. Other factors associated with differentiated HACs were the adhesion molecules ICAM-1 and VCAM-1, VEGF, TGFbeta2, and the monocyte chemotactic protein receptor. CONCLUSIONS: Our data support the hypothesis that HACs dedifferentiate when grown in monolayer cultures. Moreover, the expression patterns also show that proliferation and differentiation are exclusive features of human chondrocytes.

Aged↗
PubMed2002

[Validity of nonspecific bronchial provocation tests for the diagnosis of airway hyperresponsiveness--a comparison of different methods].

OBJECTIVE: To compare the validity of different methods for the assessment of bronchial hyperresponsiveness used by different centers. METHODS: Case series of 648 subjects referred to six pulmonary centers, all with a history of shortness of breath without airway obstruction, without use of medication that might influence the tests and without viral infections during the previous two weeks. All subjects answered a questionnaire of recent symptoms and underwent bronchial challenge with a chemical stimulus according to each center's protocol. Analysis was performed by receiver operating characteristic (ROC) plots using the questionnaire's answers as the gold standard. Diagnostic test sensitivities at the cut-offs for bronchial hyperresponsiveness indicated by each center were compared. RESULTS: ROC plots showed poor validity of all tests, i.e. both acceptable sensitivity and specificity were not observed with any test. There was no obvious difference of the slope of the ROC plots between the different centers. However, maximal sensitivity differed considerably: for "wheeze during the previous 12 months", sensitivity at each center's cut-off for the definition of bronchial hyperresponsiveness varied between 0.35 and 0.73. The choice of the question used as the standard had little influence on test validity. CONCLUSION: Although some of the differences between centers may be explained by subject characteristics, the large differences of the test sensitivities are unacceptable and underscore the need for standardization of these tests, primarily with respect to sufficient sensitivity.

Adolescent↗
PubMed2002

Signaling pathways mediate the neuroprotective effects of GDNF.

We show that the glial cell line-derived neurotrophic factor (GDNF) activates the PI3K/Akt-signaling pathway in human neuroblastoma cells that express functional Ret-receptor complexes. Consistent with this finding we show PI3K-dependent Bad-inactivation by binding to 14-3-3 proteins in response to GDNF. Using differential display techniques we detected several cDNA clones differentially expressed after treatment with GDNF or 6-OHDA.

14-3-3 Proteins↗
PubMed2001

Epidermal growth factor receptor, c-erbB2 and c-erbB3 receptor interaction, and related cell cycle kinetics of SK-BR-3 and BT474 breast carcinoma cells.

BACKGROUND: Receptors belonging to the epidermal growth factor receptor (EGFR) family transfer extracellular signals by homotypic and heterotypic receptor interaction and cross-activation. Cell differentiation, death, and proliferation are regulated via these receptor-tyrosine-kinases. However, the initial mechanisms that lead to signal specificity and diversity, which cause a defined cellular response, are incompletely understood. We investigated the recruitment of receptor complexes in two c-erbB2-overexpressing breast carcinoma cell lines, SK-BR-3 and BT474, after ligand binding and its effects on intracellular signal transduction and cell cycle regulation. METHODS: In order to analyze the coaggregation of receptors on the cell surface induced by specific growth factor treatment, we used the flow cytometric Foerster-type fluorescence resonance energy transfer (FRET) technique. Cell cycle kinetics were monitored flow cytometrically via the anti-BrdU technique and acitivation of intracellular signal cascades was analyzed by Western blotting. RESULTS: After stimulation with EGF BT474, but not SK-BR-3, cells formed EGFR/c-erbB2 receptor complexes. Neither EGF nor heregulin (HRG) induced c-erbB2/c-erbB3 receptor complexes in BT474. However, SK-BR-3 cells exhibited a high amount of c-erbB2/c-erbB3 heterodimers even without growth factor stimulation which could be elevated after prolonged EGF and HRG treatment. In both cell lines, mitogen-activated protein kinase (MAPK) phosphorylation was detectable after short-term and prolonged EGF and HRG treatment. However, only SK-BR-3 cells showed a constitutive activation of both protein kinase B (PKB)/Akt and MAPK signaling pathways. Growth factor treatment caused an amplified PKB/Akt activation in this cell line. The induction of EGFR/c-erbB2 complexes in BT474 was associated with shortening of the G1-phase of the cell cycle. In contrast, the concurrent activation of MAPK and PKB/Akt by EGF treatment led to an inhibition of proliferation in SK-BR-3 and can be attributed to missing EGFR/c-erbB2 heterodimers. HRG was a strong stimulator of proliferation in both cell lines. CONCLUSIONS: We show that in the presence of identical amounts of c-erbB2 receptors, the ligand-induced cellular response differs significantly. These differences were mediated by variances in signal transduction, most likely due to different recruitment of heterotypic receptor complexes. Overall, there is strong evidence that c-erbB2 receptor overexpression in breast cancer cells is an insufficient marker to determine cellular response in terms of cell proliferation. 2001.

Breast Neoplasms↗
PubMed2001

Extensive cerebral invasion of a basal cell carcinoma of the scalp.

Basal cell carcinomas (BCC) are the most common cutaneous malignant neoplasms affecting fair-skinned human beings. They may progressively enlarge and spread by peripheral extension. Intracranial invasion is very rare. A case of a giant BCC of the scalp invading directly into the left hemisphere through the frontal and parietal lobe and meninges is presented. Brain invasion along Virchow-Robin's spaces is demonstrated histopathologically. A review of literature failed to disclose a previous report of similar extensive and fatal cerebral invasion from a basal cell carcinoma of the scalp.

Brain Neoplasms↗
PubMed2001

Endothelial proliferation, neoangiogenesis, and potential de novo generation of cerebrovascular malformations.

OBJECT: To date, both arteriovenous malformations (AVMs) and cavernomas have been considered to be congenital malformations. A recent survey of the literature has shown the potential for de novo generation of both familial and sporadic cavernomas as well as AVMs. Therefore, it was of interest to determine the biological behavior of these lesions in detail. METHODS: The proliferative and angiogenic capacities of the endothelium of 13 cavernomas and 25 AVMs obtained in patients recently treated (1997-1998) at one institution were studied. Immunohistochemical staining for proliferating cell nuclear antigen (PCNA), MIB-1, and vascular endothelial growth factor (VEGF) and its receptor Flk-1 was performed using standard staining procedures. Positive immunostaining of the nuclei of endothelial cells was observed in specimens of both AVMs and cavernomas for PCNA (80% of AVMs and 85% of cavernomas), and Flk-1 (80% of AVMs and 31% of cavernomas). Endothelial expression of VEGF in the 18 incompletely embolized AVMs was found in 72% of cases but only in 28% of the seven cases in which patients did not undergo endovascular treatment: it was found in 38% of cavernomas. Endothelial expression of MIB-1 was found in 12% of AVMs but in no cavernomas. CONCLUSIONS: These results indicate that there is endothelial proliferation as well as neoangiogenesis in cerebral cavernomas and AVMs. The increased level of angiogenesis in only partially obliterated AVMs underscores the need for radical and complete occlusion of cerebral AVMs to avoid recurrences and further risks of morbidity.

Adult↗
PubMed2000

The Akt/protein kinase B-dependent anti-apoptotic pathway and the mitogen-activated protein kinase cascade are alternatively activated in human glioblastoma multiforme.

We investigated the activation of two important signal transduction pathways in human glioblastoma cells and found a constitutive phosphorylation of either Akt or mitogen-activated protein kinase (MAPK) under serum free conditions. In all but one cell line Wortmannin-sensitive activation of Akt could be attributed to the loss of functional PTEN protein. All cell lines with Akt activation exhibited only weak phosphorylation of the MAPK signal pathway, whereas those without constitutive Akt activation demonstrated high levels of phosphorylated MAPK under serum free conditions. Our data might indicate the presence of two functional subtypes of glioblastoma multiforme, since Akt and MAPK are involved in cellular survival and proliferation signalling, respectively.

Apoptosis↗
PubMed2000

Focal airtrapping at expiratory high-resolution CT: comparison with pulmonary function tests.

This study was undertaken to determine prevalence, extent, and severity of focal airtrapping at expiratory high-resolution CT, and to compare focal airtrapping with age, gender, pulmonary function tests, and blood gas analysis. Two-hundred seventeen patients with and without pulmonary disease underwent paired inspiratory/expiratory high-resolution CT. Six scan pairs with corresponding scan levels were visually assessed for focal--not diffuse--airtrapping using a four-point scale. Pulmonary function tests and blood gas analysis were available for correlation in all patients (mean interval 5 days). Focal airtrapping with lower lung predominance was observed in 80% of patients. Twenty-six of 26 patients with restrictive lung function impairment exhibited focal airtrapping (mean score 2.4), whereas only 72 of 98 (74%) patients with obstruction did (mean score 1.5; p < 0.05). Fifty-eight of 70 (83%) patients with normal lung function (mean score 1.8) and 19 of 23 (83%) patients with mixed impairment (mean score 1.8) had focal airtrapping. Focal airtrapping showed negative correlations with static lung volumes (-0.27 to -0.37; p < 0.001) in all patients and moderate positive correlations with dynamic parameters (0.3-0.4; p < 0.001) in patients with obstruction. No significant correlations were found with age, gender, and blood gas analysis. Visual assessment of focal--not diffuse--airtrapping at expiratory high-resolution CT does not correlate with physiological evidence of obstruction as derived from pulmonary function tests since the perception of focal airtrapping requires an adequate expiratory increase in lung density.

Adolescent↗
PubMed2000

[Self-expanding nitinol stents in proximal tracheal stenosis].

UNLABELLED: The use of silicone- or metal stents in stenosis of the distal trachea and the bronchial system is a customary procedure [1-4], for example after tumor invasion or cicatricial stenosis after transplantation. In the proximal part of the trachea, on smaller, short and soft strictures we try to stabilise the trachea by the implantation of rings. Other methods are tracheal plasty or transverse tracheal resectomy [5-7]. In the case of longer or nearer subglottal stenoses the positioning of self-expanding nitinol stents has proven a simple, gentle and well-tolerated alternative procedure even in very serious disorders [1, 8, 9]. METHOD: These stents can be placed in short narcosis under endoscopic control without great strain on the patient. RESULTS: We placed nitinol-stents in the proximal part of the trachea in eleven cases. In five cases dyspnoea caused by a tracheal collapse improved. In two further cases a tracheal stenosis with massive granulation tissue and cicatricial pull under an inlaid tracheal cannula was removed and the tracheostoma was closed. In four cases a solid, scarred and cartilaginous stenosis in the area of the cricoid and the upper tracheal rings was widened with laser and later on stented. CONCLUSION: Over an observation time of two years no complications showed safe one case in which a directly postoperative dislocation was repositioned quickly. The patients live without restrictions through the tracheal stenosis or a tracheostoma. In the best possible case epithelialization over the metal meshes develops so that a nearly normal mucus transportation is possible [1, 10-12].

Adult↗
PubMed2000

Aberrant p21 regulation in radioresistant primary glioblastoma multiforme cells bearing wild-type p53.

OBJECT: A clearer understanding of the cellular mechanisms involved in the response to ionizing radiation is pivotal to the development of new therapeutic strategies for glioblastoma multiforme (GBM). To gain insight into dynamic functional aspects of cell cycle regulation and the control of apoptosis in GBMs, the authors investigated the molecular changes induced by ionizing radiation in genetically characterized primary GBMs in vitro compared with secondary GBMs, Grades II and III gliomas, and three GBM cell lines. METHODS: Irradiation of primary GBMs bearing wild-type (wt) p53 invariably fails to invoke the G, checkpoint and apoptosis in vitro. In approximately half of these primary GBMs a defect lies at or above the level of p53 because transcriptional activation of p21 and bax after irradiation does not occur. The failure of a p21 response to irradiation is invariably accompanied by overexpression of p21 mRNA under nonirradiated conditions. In all remaining primary GBMs transcriptional activation of p21 after irradiation does occur, suggesting that a defect downstream from p21 prevents G, arrest. CONCLUSIONS: These results show that the G, checkpoint and the p53 pathway are dysfunctional in primary GBMs in vitro, despite the presence of an intact p53 gene. The data also suggest that primary GBMs may be divided into two categories on the basis of their p21 response to irradiation.

Adult↗
PubMed1999

Glial cell line-derived neurotrophic factor protects dopaminergic neurons from 6-hydroxydopamine toxicity in vitro.

Glial cell line-derived neurotrophic factor (GDNF) is a potent and specific neurotrophic factor for dopaminergic neurons. GDNF has been previously shown to protect dopaminergic neurons from lesion-induced degeneration in vivo. In this study we investigated the effect of GDNF on 6-hydroxydopamine (6-OHDA)-treated dopaminergic neurons in vitro. In dissociated cultures of embryonic rat mesencephalon, 6-OHDA exhibited a dose-dependent cytotoxicity on tyrosine hydroxylase (TH)-immunoreactive neurons. After pre-treatment with GDNF, however, 6-OHDA-induced loss of dopaminergic neurons was effectively reduced. It has been shown recently that GDNF signals through the receptor tyrosine kinase Ret and the GDNF receptor-alpha (GFR-alpha). By RT-PCR, we found both Ret- and GFR-alpha-genes to be expressed in the cultured mesencephalic cells. We propose that the neuroprotective effect of GDNF on 6-OHDA-treated dopaminergic neurons in vitro is most likely mediated by functional Ret receptor signaling pathways.

Animals↗
PubMed1999

[Electrophysiological brain-stem diagnosis in patients with a pronounced obstructive sleep apnea syndrome].

BACKGROUND AND OBJECTIVE: The pathophysiological basis of obstructive sleep apnoea syndrome (OSAS) is a loss of tone of the oropharyngeal muscles during sleep, leading to partial and/or total collapse of the oropharyngeal muscle tube. The normal inspiration-synchronous activation (ISA) of the tongue muscles is diminished or lost in patients with OSAS. Observations of OSAS in patients with ischaemic pontomedullary lesions, syringobulbia (syringomyelia), olivo-ponto-cerebellar atrophy or disseminated encephalopathy have indicated that it is due to impairment of ISA. In this study systematic electrophysiological studies (EPS) were undertaken in patients with severe OSAS, as demonstrated by polysomnography, to determine whether, in addition to the central abnormality of oropharyngeal muscular tone, one can demonstrate an increased incidence of subclinical, functional disorder in the brain stem as well as any pointers to a central localization of abnormalities in OSAS. PATIENTS AND METHODS: 19 patients with severe OSAS were examined for the presence of subclinical brain-stem lesions by means of acoustic evoked potentials, blinking reflex, masseter reflex, masseter silent period, electronystagmogram together with vestibular testing and magnetic evoked potentials of the tongue musculature. RESULTS: Findings were unremarkable in 15 of the 19 patients. EPS gave reproducible evidence of functional left pontine (blink reflex) brain-stem lesions in two of the patients and of bilateral pontomesencephalic (masseter reflex) brain-stem lesions in the other two. CONCLUSION: In the absence of systematic abnormalities our findings speak against relevant brain-stem lesions being the cause and/or consequence of OSAS.

Adult↗