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U Fischer

Publications and source records attributed to U Fischer.

At least 19 recordsLinked to original sources
PubMed2007

Planar polarity of root hair positioning in Arabidopsis.

The co-ordinated polarity of cells within the plane of a single tissue layer (planar polarity) is intensively studied in animal epithelia but has only recently been systematically analysed in plants. The polar positioning of hairs in the root epidermis of Arabidopsis thaliana provides an easily accessible system for the functional dissection of a plant-specific planar polarity. Recently, mutants originally isolated in genetic screens for defects in root hair morphogenesis and changes in the sensitivity to or the production of the plant hormones auxin and ethylene have identified players that contribute to polar root hair placement. Here, we summarize and discuss recent progress in research on polar root hair positioning from studies in Arabidopsis.

Animals↗
PubMed2006

Apoptin is modified by SUMO conjugation and targeted to promyelocytic leukemia protein nuclear bodies.

Apoptin, a protein of the chicken anemia virus (CAV), represents a novel potential anticancer therapeutic, because it induces apoptotic death specifically in tumor but not normal cells. The cellular localization appears to be crucial for apoptin's selective toxicity. In normal cells apoptin remains in the cytoplasm, whereas in transformed cells it migrates into the nucleus and kills the cell. However, the manner by which apoptin is able to distinguish between tumor and normal cells is unknown. Here, we report for the first time that apoptin interacts directly with the promyelocytic leukemia protein (PML) in tumor cells and accumulates in PML nuclear bodies (NBs), which are involved in apoptosis induction and viral replication. We also demonstrate that apoptin is sumoylated and that a sumoylation-deficient apoptin mutant is no longer recruited to PML-NBs, but localizes in the nuclear matrix. This mutant fails to bind PML, but can still induce apoptosis as efficiently as wild-type apoptin. Moreover, apoptin kills also PML-/- cells and promyelocytic leukemia cells with defective PML expression. Our results therefore suggest that apoptin kills tumor cells independently of PML and sumoylation, however, the interaction of apoptin with PML and small ubiquitin-like modifier (SUMO) proteins might be relevant for CAV replication.

Capsid Proteins↗
PubMed2006

Pattern of invasion is of prognostic value in surgically treated cervical cancer patients.

OBJECTIVES: Different patterns of invasion (representing different grades of tumor cell dissociation) are associated with prognostic outcome in cancer. We evaluated the prognostic value of different patterns of invasion (PI) in cervical carcinomas (CX). METHODS: Six hundred eleven surgically treated CX (FIGO IB to IIB) were re-evaluated histologically regarding the PI, using a three-level scoring system. Closed PI was defined as cohesive growth with well-delineated (pushing) borders. In finger-like PI the tumor grows in solid cords/trabecles. Highly dissociative growth in small groups or single cells was defined as spray-like PI. Types of PI were correlated to tumor stage, histo-morphologic factors and prognostic outcome. RESULTS: Sixty percent of the tumors showed a spray-like PI, 30% a finger-like PI and only 7.4% were of the closed type. Spray-like PI showed a significant correlation with advanced stage disease, lymphovascular space involvement, poorly differentiated tumors and pelvic lymph node metastases. Spray-like PI was accompanied by a reduced 5-year overall survival when compared to the finger-like and closed PI (68.7% vs. 80.9% vs. 88.5%; P=0.0004). The prognostic impact of the PI disappeared in node-positive patients (P=0.06) but persisted in patients without pelvic lymph node disease (P=0.03). In multivariate analysis, using COX regression model, the PI represented as independent prognostic factor. CONCLUSIONS: Spray-like PI (i.e., highest degree of tumor cell dissociation) is associated with advanced tumor stages, increased rate of recurrency and a reduced overall survival. In separate analysis of patients with and without lymph node metastases, the impact of PI persisted only in node-negative cases as a prognostic factor.

Adult↗
PubMed2006

Staphylococcus aureus induces caspase-independent cell death in human peritoneal mesothelial cells.

Bacterial peritonitis remains a serious complication of peritoneal dialysis. Although Staphylococcus epidermidis is the most common pathogen involved, infections with Staphylococcus aureus lead to severe peritoneal damage and are often associated with a dramatic loss of mesothelial cells. Induction of cell death appears to be involved in peritoneal damage and mesothelial cell loss during bacterial infections. Using cultured human peritoneal mesothelial cells (HMCs), we investigated the ability of different S. epidermidis and S. aureus strains to damage the HMC monolayer and to trigger cell death. We show that only a subgroup of live S. aureus isolates, characterized by an invasive and alpha-hemolysin-producing phenotype, induces cell death. None of the tested S. epidermidis strains, which were not invasive or hemolytic, had a cytotoxic effect. After host cell invasion, S. aureus resided within phagocytic vacuoles, and HMCs were apparently able to degrade staphylococci. However, even after prolonged infection, a high percentage of S. aureus remained alive within HMCs and might be released after host cell death. Cell death induced by S. aureus was accompanied by apoptotic alterations, such as DNA fragmentation, but was independent of endogenous FasL and tumor necrosis factor-alpha death ligand expression. Moreover, caspases were not involved in S. aureus-induced mesothelial cell death. In conclusion, our data indicate that mesothelial cell death might represent a major mechanism of S. aureus-induced damage of the peritoneum during bacterial peritonitis.

Apoptosis↗
PubMed2006

Differences in protein and energy metabolism following portal versus systemic administration of insulin in diabetic dogs.

AIMS/HYPOTHESIS: In non-diabetic people, insulin levels in the liver are two-fold higher than those in the systemic circulation. In contrast, patients with type 1 diabetes have similar hepatic and systemic insulin levels because insulin is administered peripherally. The aim of this study was to compare the effects of systemic (SI) and pre-portal (PI) insulin administration on energy, glucose and protein metabolism in chronic insulin-dependent ketosis-prone diabetic dogs. MATERIALS AND METHODS: We applied glucose-controlled insulin infusion, indirect calorimetry and stable isotope and radioisotope techniques to measure energy, protein and glucose metabolism. We maintained near-normoglycaemia at identical levels under both study conditions for 20 h. RESULTS: SI was associated with lower oxygen consumption (130+/-13 vs 161+/-8 ml/min), CO(2) production (99+/-10 vs 130+/-8 ml/min), respiratory quotient (0.76+/-0.02 vs 0.81+/-0.01) and energy expenditure (870+/-90 vs 1089+/-60 kcal/24 h) (p<0.05 for all differences). PI increased the respiratory quotient from the insulin-deprived state, whereas SI did not. Glucose kinetics were similar for SI and PI, whereas leucine oxidation (36+/-4 vs 54+/-5 micromol kg(-1) min(-1)) and the fractional synthesis rates of liver tissue protein (0.68+/-0.6 vs 0.83+/-0.07%/h), albumin (0.55+/-0.06 vs 0.68+/-0.4%/h), and fibrinogen (1.73+/-0.23 vs 2.59+/-0.25%/h) were all lower during SI than PI (p<0.05). CONCLUSIONS/INTERPRETATION: The route of insulin administration did not alter glucose metabolism but did affect protein synthesis in the liver. The potential impact of this altered liver protein metabolism on chronic complications needs careful evaluation. A similar decrease in energy expenditure resulting from systemic insulin administration during tight glycaemic control is a potential cause of weight gain.

Amino Acids↗
PubMed2006

The tyrosine kinase Lck is a positive regulator of the mitochondrial apoptosis pathway by controlling Bak expression.

Tyrosine kinases of the Src family have been implicated in key biological processes. Here, we provide evidence that p56(Lck), a lymphoid-specific Src kinase, is involved in the activation of the mitochondrial apoptosis pathway. Lck-deficient T cells were completely resistant to anticancer drugs. In contrast, apoptosis sensitivity to death receptors was not altered, indicating a specific interference of Lck with the mitochondrial pathway. Re-expression of Lck restored sensitivity to drug-induced apoptosis and triggered mitochondrial cytochrome c release and caspase activation. Further analysis identified that the sensitization by Lck was independent of classical mediators of T-cell signaling, but essentially involved the Bcl-2 protein Bak. Expression of Bak was completely absent in Lck-deficient cells, while re-expression of Lck transcriptionally triggered Bak expression and conferred sensitivity to apoptosis, associated with a proapoptotic conformational change of Bak. Furthermore, in vitro the truncated fragment of Bid specifically activated Bak and cytochrome c release only from mitochondria of Lck-expressing cells. These results do not only demonstrate a sentinel role of Lck in drug resistance but also delineate a hitherto unknown pathway of Src kinases in regulation of Bcl-2 proteins.

Antineoplastic Agents↗
PubMed2006

Unique and overlapping substrate specificities of caspase-8 and caspase-10.

Although caspase-8 has an established role as an initiator of death receptor-mediated apoptosis, the function of its closest homolog, caspase-10, is almost completely unknown. To gain a closer insight into the physiological function of caspase-10, we compared the cleavage of known caspase-8 substrates by both initiator caspases. We demonstrate that caspase-10 and -8 have overlapping cleavage preferences for several substrates such as the kinases RIP and PAK2. Interestingly, in other substrates, such as the Bcl-2 protein Bid, we found additional and distinct cleavage sites for both caspases, which might have important consequences for mitochondrial targeting and propagation of the death signal. Caspase-8 and -10 also caused different interchain cleavage patterns of their enzyme precursors. Together, these results suggest that caspase-8 and -10, despite having overlapping functions, also have selective substrate cleavage specificities and might thereby exert nonredundant roles in apoptosis signaling.

Amino Acid Sequence↗
PubMed2006

Reasons to withhold intra-arterial thrombolysis in clinical practice.

BACKGROUND: In selected stroke centers intra-arterial thrombolysis (IAT) is used for the treatment of acute stroke patients presenting within 6 hours of symptom onset. However, data about eligibility of acute stroke patients for IAT in clinical practice are very scarce. METHODS: We collected prospectively data on indications advising for or against IAT of 230 consecutive stroke patients in a tertiary stroke center. RESULTS: 76 patients (33.0%) presented within 3 hours, 69 (30%) between 3 and 6 hours of symptom onset and 85 (37%) later than 6 hours. Arteriography was performed in 71 patients (31%) and IAT in 46 (20%). In 11 patients no or only peripheral branch occlusions were seen on arteriography and therefore IAT was not performed. In 9 patients the ICA was occluded and barred IAT and in five anatomical or technical difficulties made IAT impossible. 72 patients presenting within 6 hours did not undergo arteriography and thrombolysis, mostly because of mild (n=44) or rapidly improving neurological deficits (n=13). Other reasons to withhold IAT were CT and/or clinical findings suggesting lacunar stroke due to small vessel occlusion (n=7), limiting comorbidty (n=7) and baseline international normalized ratio>1.7 (n=1). CONCLUSIONS: A third of the patients underwent diagnostic arteriography and one fifth received IAT. The most important reasons to withhold thrombolysis were presentation beyond the 6 hours time window and mild or rapidly improving symptoms.

Adolescent↗
PubMed2006

Impact of comorbidity on ischemic stroke outcome.

OBJECTIVE: To evaluate the impact of comorbidity on stroke outcome of patients admitted to a general ward (GW) and a stroke unit (SU). METHODS: Data of 266 patients with acute ischemic stroke (GW: 103, SU: 163) were collected prospectively for 13 months. Clinical and radiological findings, and the Charlson Comorbidity Index (CCI) were recorded. Predictors of outcome 4 months after stroke were analyzed. Favorable outcome was defined as modified Rankin Scale (mRS) score of < or = 2, unfavorable as mRS >2. RESULTS: The mean age of the patients was 67.2 years (SD = 14.4), the mean CCI 1.2 (SD = 1.4). In univariate analysis, small artery disease predicted favorable outcome (P < 0.001) and age (P = 0.022), high National Institutes of Health Stroke Scale (NIHSS) score (P < 0.001), high CCI (P < 0.001), treatment in a GW (P = 0.004), coronary artery disease (P = 0.02), dementia (P = 0.009), diabetes (P = 0.005) and atrial fibrillation (P < 0.001) unfavorable outcome after 4 months. In multivariate analysis, high NIHSS score (P < 0.001), atrial fibrillation (P = 0.004), coronary artery disease (P = 0.012) and diabetes (P = 0.031) were predictors of unfavorable outcome. CONCLUSIONS: Comorbidity has a significant impact on stroke outcome. In addition to stroke severity, atrial fibrillation, coronary artery disease and diabetes were predictors of outcome after stroke, but not the sum of the CCI.

Adult↗
PubMed2006

Pellucid marginal corneal degeneration: evaluation of the corneal surface and contact lens fitting.

AIM: To quantify corneal irregularities, to describe the fitting with contact lenses, and to answer the question whether or not contact lenses with a special back surface design could improve visual acuity in patients with pellucid marginal corneal degeneration (PMCD). METHODS: 13 eyes were fitted with contact lenses with a special back surface. Videokeratographic data were assessed. The patients were followed up for an average period of 22.2 months. Lens tolerance and corrected visual acuity were evaluated. RESULTS: The mean eccentricity did not exceed 0.7 in all patients. Either the superior or the inferior eccentricity, or both, were negative in all patients. Using Fourier analysis all PMCD subjects showed an increased irregular astigmatism of the anterior cornea. Using Zernike coefficients seven eyes (53.8%) had a higher order aberration root mean square error (HOA RMS error) out of the normal range. The visual acuity with contact lenses improved in all eyes with an average increase of 2.7 lines (maximum eight lines). No serious complications were observed. CONCLUSIONS: Quantitative evaluation of videokeratographic data may help to diagnose PMCD and to distinguish PMCD from other ectatic corneal diseases. Contact lenses with a special back surface design can improve visual acuity and lens tolerance.

Adult↗
PubMed2005

Digital mammography: current state and future aspects.

The introduction of digital technique in mammography has been the last step in completing the process of digitalization in diagnostic imaging. Meanwhile, some different digital techniques as well as a couple of different digital mammography systems were developed and have already been available for some years. In this review article, the relevant data of key studies are reported, the current status is defined, and perspectives of digital mammography are described.

Breast Neoplasms↗
PubMed2005

CD44-v6 concentrations in carcinoma of the uterine cervix: lack of prognostic significance.

Several kinds of cellular adhesion molecules, like different splicing variants of CD 44, have gained important as prognostic or markers for metastatic disease. Fresh frozen samples from 64 cervical carcinoma (CX) were stored in liquid nitrogen and examined using ELISA-technique, testing the prognostic impact. Normal cervical tissue served as control. CD 44-v6 concentration, was significant elevated in tumor tissue, when compared to the controls (P=0.04). There was no correlation to tumor stage (P=0.61), lymphovascular space involvement (P=0.075) or pelvic lymph node involvement (P=0.81). The CD 44-v6 concentration was not informative regarding recurrence-free and overall survival. Contrary to immunohistochemistry, the quantification of CD 44-v6 using ELISA-technique does not provide any further information.

Cell Adhesion↗
PubMed2005

Molecular and functional analysis of intragenic SMN1 mutations in patients with spinal muscular atrophy.

The autosomal recessive spinal muscular atrophy (SMA), a neuromuscular disease and frequent cause of early death in childhood, is caused in 96% of patients by homozygous absence of the survival motor neuron gene (SMN1). The severity of the disease is mainly determined by the copy number of SMN2, a copy gene which predominantly produces exon 7-skipped transcripts and only low amount of full-length transcripts that encode for a protein identical to SMN1. Only about 4% of SMA patients bear one SMN1 copy with an intragenic mutation. A comprehensive molecular genetic analysis of 34 SMA patients who carry one SMN1 gene is presented, including 18 that were previously published. Haplotype analysis with the microsatellite markers Ag1-CA and C212 in these SMA families turned out to be a reliable accessory method in predicting known SMN1 mutations in SMA patients carrying one SMN1 copy. Five novel missense mutations were identified that are localized in: exon 2a c.88G>A (p.D30N) and c.131A>T (p.D44V); exon 3 c.283G>C (p.G95R) and c.332C>G (p.A111G); and exon 6 c.784A>G (p.S262G), respectively. The survival motor neuron (SMN) protein has been shown to be a component of a large complex (termed the SMN complex) that promotes the formation of spliceosomal U small nuclear ribonucleoproteins (snRNPs). Within this complex, SMN forms oligomers and directly interacts via its N-terminus with SMN-interacting protein 1 (SIP1) and via its central Tudor domain with spliceosomal (Sm) proteins. We performed in vitro interaction studies to test whether SMA-causing missense mutations identified in this study interfere with the reported interactions of SMN. Our results show that mutations p.G95R and p.A111G reduce SMN binding to Sm proteins, further confirming the previous finding that the Tudor domain is the essential binding site of SMN to Sm-proteins. However, all mutations, including those in exon 2a, a region shown to be important for the binding of SMN to SIP1, do not disturb the interaction of SMN to SIP1.

Adolescent↗
PubMed2005

Risk stratification models fail to predict hospital costs of cardiac surgery patients.

BACKGROUND: The aim of this prospective study was to determine if commonly used risk stratification models can predict total hospital costs in cardiac surgical patients. METHODS: Between October 1st and December 31st 2003, all consecutive adult patients undergoing cardiac surgery on CPB at our institution were classified using seven risk stratification scoring systems: EuroSCORE, Cleveland, Parsonnet, Ontario, French, Pons, and CABDEAL. Total hospital costs for each patient were calculated on a daily basis including preoperative diagnostic tests, operating room costs, disposable materials, drugs, blood components, costs for personnel, and hospital fixed-costs. Linear regression analysis was used to determine the correlation between costs and the seven risk stratifications models as well as length of stay (LOS) on ICU. The Spearman correlation coefficient was calculated from the regression line, and an analysis of residuals was performed to determine the quality of the regression. RESULTS: A total of 252 patients were operated for CABG (n=175), valve (n=39), CABG plus valve (n=21), thoracic aorta (n=13) and miscellaneous (2 myxoma, 1 ASD, 1 pulmonary embolism). Mean age of the patients was 66.0+/-11.4 years, 29.4% were female. LOS on ICU was 3.3+/-6.3 days and the 30-day mortality rate was 6.7%. Spearman correlation between the seven risk stratification models and hospital costs was below r=0.32 (p=0.0001), but was r=0.94 (p=0.0001) between ICU LOS and costs. CONCLUSIONS: Total hospital costs can be identified by length of ICU stay. None of the common risk stratification models accurately predicted total hospital costs in cardiac surgical patients.

Aged↗
PubMed2005

Apoptosis-based therapies and drug targets.

The pathogenesis of many diseases is most closely connected with aberrantly regulated apoptotic cell death. The past 15 years have witnessed an explosion in the basic knowledge of mechanisms that regulate apoptosis and the mediators that either trigger or inhibit cell death. Consequently, great interest has emerged in devising therapeutic strategies for modulating the key molecules of life-and-death decisions. Numerous novel approaches are currently being followed employing gene therapy and antisense strategies, recombinant biologics or classical organic and combinatorial chemistry in order to target specific apoptotic regulators. Although drug development is still in its infancy, several therapeutics have progressed to clinical testing or have even been approved in record time. This review outlines the recent advances in the field of apoptosis-based therapies and explores some highlights of a very active field of drug development.

Animals↗