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Biomedical subjects

A Friedl

Publications and source records attributed to A Friedl.

At least 19 recordsLinked to original sources
PubMed2006

Syndecan-1 expression by stromal fibroblasts promotes breast carcinoma growth in vivo and stimulates tumor angiogenesis.

The induction of the cell surface heparan sulfate proteoglycan syndecan-1 (Sdc1) in stromal fibroblasts is observed in more than 70% of human breast carcinomas. Using a coculture model, we have recently shown that stromal cell-derived Sdc1 stimulates carcinoma cell proliferation in vitro, and that this activity requires Sdc1 glycanation. In the present study, we investigated the effect of stromal cell Sdc1 on breast carcinoma growth in vivo. MDA-MB-231 human breast carcinoma cells were inoculated into the flanks of athymic nude mice either alone, or as mixed suspensions with Sdc1-transfected or mock-transfected 3T3 mouse fibroblasts. The mixed tumors showed an intimate association between carcinoma cells and stromal fibroblasts and histologically closely resembled poorly differentiated human breast carcinomas. The presence of fibroblasts led to significantly accelerated tumor growth, which was further augmented (88% increase) by forced expression of stromal Sdc1. The hyperemic macroscopic appearance of tumors containing Sdc1-positive stromal cells contrasted with pale tumors developing in the presence of mock-transfected fibroblasts, which prompted us to examine tumor microvessels. Stromal Sdc1 expression was associated with a significantly elevated microvessel density (36% increase) and a larger vessel area (153% increase). To evaluate the relevance of this finding in human breast cancer, the relationship between stromal Sdc1 and tumor vascularity was also examined in a tissue array containing 207 human breast carcinoma samples. Similar to the xenografts, stromal Sdc1 expression correlated with both vessel density (P=0.013) and total vessel area (P=0.0026). In conclusion, stromal fibroblast-derived Sdc1 stimulates breast carcinoma growth and angiogenesis in vivo.

Animals↗
PubMed2006

Successful surgical treatment of a combined abdominal and thoracic impalement injury.

Accidents do occur during the performance of different domestic chores in the garden. The resulting injuries can lead to serious morbidity and, in some cases, they can be fatal. We present a case of trauma, in a 69-year old man, caused by a fall from a tree on a vertical metal rod in his garden. The rod entered the abdominolumbal region on the right side making an exit above the left clavicle. On arrival, he was in a stable circulatory condition. A chest X-ray (Fig. ), thoracic and abdominal sonography followed by chest and abdominal CT scan (Figs. - , ) were performed and they showed no severe injury of the heart, lung, bronchi, liver and right kidney. He underwent an emergent surgical intervention by a team of cardiothoracic, vascular and abdominal surgeons. Longitudinal sternotomy and laparotomy allowed us to remove the metal rod carefully with no severe signs of injuries of abdominal and thoracic organs. There were no surgical postoperative complications.

Abdominal Injuries↗
PubMed2005

Replacement of a severe chronic post-traumatic aneurysm of the ascending aorta with aortic valve conduit--reconstruction of the anterior mitral valve ring and implantation of A-V sequential/biventricular pacemaker.

We present the case of a 23-year-old African professional footballer who was admitted on April 1, 1999 to the Cardiology Department of the University Hospital in Magdeburg, on an emergency basis, from a regional lung clinic. According to the history, he was involved in a collision with an opposing player during a football match in his country (in Africa). He lost consciousness for a short time, but continued playing to the end of the match. About two months later he was invited by a German football club for a check-up, with the view to ultimately playing for the club. The team did not find him physically fit enough to play professional football, so he decided to go to Paris by bus on March 31, 1999. During the journey he suddenly became cardio-pulmonary decompensated and had to undergo cardio-pulmonary resuscitation (CPR). He was intubated and placed on a respirator and immediately transferred to a nearby lung clinic. From the lung clinic he was transferred to the Intensive Care Unit of the Cardiology Department of the Magdeburg University Hospital, on April 1, 1999 as an emergency case. He was intensively treated with catecholamines, intravenous ACE inhibitors and diuretics. His clinical condition did not improve appreciably. His chest X-ray showed extreme dilatation of the right and left heart as well as extreme pulmonary congestion.

Adult↗
PubMed2002

Determinants of early carotid atherosclerosis progression in young patients with type 1 diabetes mellitus.

The results of cross-sectional studies addressing early preintrusive atherosclerosis in type 1 diabetic patients are conflicting. In an observational longitudinal study we determined the course of carotid artery intima-media thickness (IMT) over a period of 2.5 years in mean. A total of 102 patients with type 1 diabetes mellitus (age < or = 40 years, diabetes duration > or = 2 years at baseline examination) who were participants of the baseline examination was studied again in a follow-up. HbA1c, albumin excretion rate (AER), lipids, systolic and diastolic blood pressure, retinopathy, and current smoking status were assessed at baseline and follow-up. The IMT of the common carotid artery was measured by high-resolution ultrasound, the maximum IMT was evaluated. The annual progression rate (APR) was calculated from the difference between baseline and follow-up IMT reading and the time between both examinations. The follow-up IMT was significantly higher, compared to the baseline measurement: 0.65 +/- 0.18 vs. 0.57 +/- 0.14 mm (p < 0.001), the mean APR was 0.033 mm/year. The APR was correlated with age (r = 0.337, p < 0.01), diabetes duration (r = 0.252, p < 0.05), hypertension (r = 0.225, p < 0.05), and systolic blood pressure (r = 0.281, p < 0.05) at the baseline examination. Comparing subgroups, defined according to APR tertiles, with no IMT progression (first tertile, mean APR - 0.012 mm/year), mild progression (second tertile, mean APR 0.037 mm/year), and advanced progression (third tertile, mean APR 0.088 mm/year), patients with advanced progression significantly (p < 0.05) more often had hypertension and nephropathy than subjects with mild progression. In a multiple linear regression analysis, the changes of plaque frequency and of the nephropathy status between baseline and follow-up examinations were independent predictors of the APR.

Adult↗
PubMed2001

[Pacing therapies for congestive heart failure considering the results of the PATH-CHF study].

Optimized uni- or biventricular pacing therapy improves left ventricular function in 80% of patients (responders) with wide QRS in surface ECG. Immediate improvement could be shown by an increase of LV dP/dt up to 28% and aortic pulse pressure up to 16%. Chronic improvement was documented by prolongation of the 6-minute-walk-test by 60 meters, an improvement of O2 uptake by 23% at exercise, and improvement of quality of life score and NYHA classification. This controlled study has shown for the first time a significant clinical improvement of congestive heart failure by pacing therapy in a selected group of patients. Conventional right ventricular stimulation is insufficient in this group of patients characterized by LBBB. These results support the hypothesis that optimized ventricular stimulation is an effective chronic therapy of congestive heart failure by improvement of left ventricular hemodynamics. Epicardial placement of the left ventricular electrodes in 50 patients was possible without operative and with low (2%) early mortality.

Aged↗
PubMed2001

Pilot study of interferon-alpha with and without amantadine for the treatment of hepatitis C in HIV coinfected individuals on antiretroviral therapy.

BACKGROUND: Concurrent potent therapy of hepatitis C (HCV) and HIV includes at least five antiviral drugs. Drug interactions, toxicity, tolerance and acceptance by patients of such treatment regimens are unknown. STUDY DESIGN: A prospective open randomized pilot trial was conducted to test interferon-alpha (6 million units/day for the 1st month followed by 6 million thrice weekly) and amantadine versus interferon-alpha monotherapy for tolerability and feasibility among HIV and HCV co-infected patients on stable antiretroviral combination therapy. RESULTS: 1,013 HIV-infected patients were consecutively evaluated. 314 were anti-HCV antibody positive; only eight (2.4%) were eligible. Major reasons for exclusion were: normal transaminase levels (34%), ongoing intravenous drug use (33%), or recent change in antiretroviral therapy (31%). Study drugs were stopped in all of the seven patients enrolled because of side effects and/or failure of anti-HCV therapy. CD4 lymphocyte counts and HIV-1 RNA remained stable. CONCLUSION: Among patients on highly active antiretroviral therapy, the addition of interferon-alpha with or without amantadine was inefficient and poorly tolerated, but had no negative influence on HIV infection. Eligibility for the study was unexpectedly low.

Adult↗
PubMed2001

Tissue examination to monitor antiangiogenic therapy: a phase I clinical trial with endostatin.

PURPOSE: The purpose of this study was to determine the effect of the angiogenesis inhibitor endostatin on blood vessels in tumors and wound sites. EXPERIMENTAL DESIGN: In a Phase I dose escalation study, cancer patients were treated with daily infusions of human recombinant endostatin. Tumor biopsies were obtained prior to and 8 weeks after initiation of treatment. Blood vessel formation in nonneoplastic tissue was evaluated by creating a skin wound site on the arm with a punch biopsy device. The wound site was sampled with a second biopsy after a 7-day interval. This sequential biopsy procedure was performed prior to and 3 weeks after initiation of endostatin treatment. Vascular density, endothelial cell kinetics, and blood vessel maturity were determined in tumor and skin wound samples. The ultrastructure of tumor blood vessels was examined by electron microscopy. RESULTS: As expected, the tumors were of variable vascular density. Skin wounding induced a vascular granulation tissue containing a high percentage of proliferating endothelial cells. The proportion of immature blood vessels was high in tumors and in wound sites and low in normal skin. No statistically significant difference was detected between pretreatment and treatment samples of tumors and of skin wounds for any of the parameters tested. CONCLUSIONS: Endostatin treatment was not associated with any recognizable vascular changes in tumor samples and did not perturb wound healing at the doses and the treatment schedule used.

Angiogenesis Inhibitors↗
PubMed2000

Methylation of the androgen receptor minimal promoter silences transcription in human prostate cancer.

Advanced hormone-independent prostate cancer is characterized by a significant loss of androgen receptor (AR) expression in 20-30% of the tumors. The transcriptional block underlying this phenomenon is not known, but we have proposed that methylation of CpG sites in the AR promoter may reversibly inactivate transcription of the AR (D. F. Jarrard et al, Cancer Res., 58: 5310-5314, 1998). In this study, detailed methylation analysis using bisulfite sequencing was performed on a series of AR expression-positive and -negative prostate cancer cells. We found that methylation of several consensus sequences in the AR promoter (from -131 to -121 and +44 to +54) are tightly linked to the loss of AR expression in metastatic hormone-independent prostate cancer cell lines. These consensus sites of methylation correlate with the minimal promoter region critical for AR transcription. In human tissues, no methylation was demonstrated in normal or primary prostate cancers that express the AR. Four of 15 tumors obtained from men who had died from hormone-independent prostate cancer demonstrated a significant loss of AR expression immunohistochemically and two (50%) of these AR-negative tumors contained AR methylation. We conclude that the AR promoter contains specific CpG methylation hot spots that are markers for gene silencing. Furthermore, AR methylation may represent a phenotype important in the development of hormone independence in a subset of advanced prostate cancer in which AR expression is lost. The finding of AR methylation also represents the first report of aberrant methylation on an X-linked gene associated with a somatic male cancer.

3' Untranslated Regions↗
PubMed2000

Differential ability of heparan sulfate proteoglycans to assemble the fibroblast growth factor receptor complex in situ.

Fibroblast growth factors (FGFs) require heparan sulfate proteoglycans (HSPGs) as cofactors for signaling. The heparan sulfate chains (HS) mediate stable high affinity binding of FGFs to their receptor tyrosine kinases (FR) and may specifically regulate FGF activity. A novel in situ binding assay was developed to examine the ability of HSPGs to promote FGF/FR binding using a soluble FR fusion construct (FR1-AP). This fusion protein probe forms a dimer in solution, simulating the dimerization or oligomerization that is thought to occur at the cell surface physiologically. In frozen sections of human skin, FGF-2 binds to keratinocytes and basement membranes of epidermis and dermal blood vessels. In contrast, in skin preincubated with FGF-2, FR1-AP binds avidly to FGF-2 immobilized on keratinocyte cell surfaces, but fails to bind to basement membranes at the dermo-epidermal junction or dermal microvessels despite the fact that these structures bind large amounts of FGF-2. Apparently, basement membrane and cell surface HSPGs differ in their ability to mediate the assembly of a FGF/FR signaling complex presumably due to structural differences of the heparan sulfate chains.

Animals↗
PubMed2000

Pneumococcal vaccine in patients with absent or dysfunctional spleen.

Four patients (3 long-term Hodgkin disease survivors and 1 recipient of an allogeneic bone marrow transplant) developed severe infections with Streptococcus pneumoniae after staging splenectomy or due to functional hyposplenism after total body irradiation and bone marrow transplantation. Current guidelines for prevention of infection recommend pneumococcal immunization for patients with Hodgkin disease treated with splenectomy and others with functional hyposplenism. Booster vaccination after 5 years is also advised. Hospital- and community-based vaccination initiatives may help identify at-risk patients.

Acute Disease↗
PubMed1999

Endostatin binds to blood vessels in situ independent of heparan sulfate and does not compete for fibroblast growth factor-2 binding.

Endostatin is a carboxyl-terminal proteolytic fragment of collagen XVIII and a potent inhibitor of angiogenesis. The mechanism of action is unknown, but the crystal structure of endostatin predicts a prominent heparan sulfate binding site, suggesting that endostatin competitively inhibits heparin-binding angiogenic factors, such as basic fibroblast growth factor (FGF-2). The goal of the study was to map endostatin binding sites in intact human tissues and to determine whether this binding is heparan sulfate dependent. In situ binding was performed with recombinant epitope-tagged murine endostatin. Endostatin predominantly binds to blood vessels of different calibers in a saturable fashion. In addition, binding to some epithelial basement membranes is seen. The localization pattern is similar to that reported for collagen XVIII, endostatin's parent molecule. In breast carcinomas, endostatin co-localizes largely with FGF-2. In a surprising contrast to FGF-2, endostatin binding is resistant to treatment with heparitinase, demonstrating that binding is not mediated by heparan sulfate proteoglycans. Furthermore, FGF-2 and heparin do not compete for endostatin binding, providing additional evidence for the discreteness of endostatin and FGF-binding sites.

Basement Membrane↗
PubMed1999

Neutrophil gelatinase-associated lipocalin in normal and neoplastic human tissues. Cell type-specific pattern of expression.

Neutrophil gelatinase-associated lipocalin (NGAL) has recently been identified in myeloperoxidase-negative neutrophil granules. Members of the lipocalin family are thought to bind and transport small lipophilic molecules such as retinoids and roles in cell regulation have been proposed. Recently, NGAL has also been demonstrated in the colonic mucosa in certain pathologic conditions. The aim of this study was to examine the distribution of NGAL in normal and neoplastic tissues by immunohistochemistry. Interestingly, NGAL was found in a variety of normal and pathological human tissues. A cell type-specific pattern of expression was seen in bronchus, stomach, small intestine, pancreas, kidney, prostate gland, and thymus. The comparative analysis of the putative rat homologue neu-related lipocalin showed a very similar pattern of expression with the exception of pancreas and kidney. Neoplastic human tissues showed a very heterogeneous expression of NGAL protein. High NGAL levels were found in adenocarcinomas of lung, colon and pancreas. In contrast, renal cell carcinomas of various subtypes and prostate cancers contained low NGAL levels. Lymphomas and thymic tumours were negative for NGAL immuno-labeling. Knowledge about the location of NGAL in normal cells and in disease states provides the first clues towards understanding its biological function.

Acute-Phase Proteins↗
PubMed1998

Heterogeneous expression of the lipocalin NGAL in primary breast cancers.

We have previously shown that neu oncogene-initiated rat mammary carcinomas uniquely over-express neu-related lipocalin (NRL), a member of the calycin protein superfamily. Here, we characterize the putative human homolog of NRL, neutrophil gelatinase-associated lipocalin (NGAL). ngal gene expression was found at moderate levels in only 2 of 17 human tissues examined, breast and lung. When breast cancers were examined for NGAL mRNA and protein levels, they were found to exhibit heterogeneous expression. NGAL levels varied in these tumors from undetectable to exceeding those in normal breast parenchyma. Immuno-histochemical analysis confirmed the presence of NGAL within breast carcinoma cells but detected only low levels of this protein in normal ductal epithelium. In contrast, large amounts of the protein were localized to the lumen of normal breast ducts in the vicinity of NGAL-expressing tumors. Interestingly, unlike NRL in rat mammary carcinomas, no significant association between NGAL expression and HER-2/neu activation was found in human breast tumors. In contrast, a significant correlation between NGAL expression in breast cancer was found with several other markers of poor prognosis, including estrogen and progesterone receptor-negative status and high proliferation (S-phase fraction). NGAL levels were stratified as high or low in breast cancers from a cohort of node-positive patients with known outcome. No significant association between NGAL expression and disease-free or overall survival was observed.

Acute-Phase Proteins↗
PubMed1998

[Otogenic meningitis].

We present three patients with otogenic meningitis, whose illness varied in extent and clinical course. Meningitis and otitis media are associated in 19-22% of all meningitis-patients. Streptococcus pneumoniae is the predominant microorganism with hemophilus influenzae being the second most important. We discuss the importance and problems of spinal puncture, early CT-scan as well as further, more extensive and sophisticated examinations to exclude late complications or predisposing factors. We emphasize an early start of antibiotic treatment, which should not be delayed for diagnostic reasons. With the appearance of highly penicillin-resistant pneumococci antibiotic therapy may become more difficult in the future, but for the moment pneumococcal infections in Switzerland can initially still be treated with cephalosporins or high dose penicillin. The use of steroids, although of unproven efficacy, may be considered in some cases. An otolaryngologist should initially be consulted for diagnostic reasons as well as for possibly indicated early surgery.

Adult↗
PubMed1998

Genetic interactions between mutants of the 'error-prone' repair group of Saccharomyces cerevisiae and their effect on recombination and mutagenesis.

We have created an isogenic series of yeast strains that carry genetic systems to monitor different types of recombination and mutation [B. Liefshitz, A. Parket, R. Maya, M. Kupiec, The role of DNA repair genes in recombination between repeated sequences in yeast, Genetics 140 (1995) 1199-1211.]. In the present study we characterize the effect of mutations in genes of the 'error-prone' or postreplicative repair group on recombination and mutation. We show that rad5 and rad18 strains have elevated levels of spontaneous recombination, both of ectopic gene conversion and of recombination between direct repeats. The increase in recombination levels is similar in both mutants and in the rad5 rad18 double mutant, suggesting that the RAD5 and RAD18 gene products act together with respect to spontaneous recombination. In contrast, RAD5 and RAD18 play alternative roles in mutagenic repair: mutations in each of these genes elevate spontaneous forward mutation at the CAN1 locus, but when both genes are deleted, a low level of spontaneous mutagenesis is seen. The RAD5/RAD18 pathway of mutagenic repair is dependent on the REV3-encoded translesion polymerase. We analyze the interactions between the RAD5 and RAD18 gene products and other repair genes. The high recombination levels seen in rad5 and rad18 mutants is dependent on the RAD1, RAD51, RAD52, and RAD57 genes. The Srs2 helicase plays an important role in creating the recombinogenic substrate(s) processed by the RAD5 and RAD18 gene products.

Adenosine Triphosphatases↗
PubMed1998

[Determination of intima-media thickness of the carotid artery: influences of methods, proband and examination variables].

AIM: Comparison of two different methods for the measurement of the common carotid artery intima-media thickness (IMT) regarding results and reproducibility, and investigation of the influence of the subjects' characteristics on the results. METHOD: 20 healthy subjects were studied (6 men, 14 women, mean age 27.4 +/- 4.4 years). B-Mode pictures were taken of the carotid arteries on both sides (longitudinal sections from ventral and lateral) and stored for measurement either in systole or in diastole. Maximum IMT was measured conventionally by manual setting of calipers (method 1), the mean IMT over a length of 1 cm was calculated from the area of the intima plus media by means of a computer (method 2). 10 subjects were studied twice for the evaluation of intra- and interobserver variability. RESULTS: Mean IMT was between 0.48 +/- 0.07 mm (method 1/observer 1) and 0.55 +/- 0.07 mm (method 2/observer 2). IMT values resulting from method 2 had a better correlation in repeated measurements (coefficient 0.84/0.93 for inter-/intraobserver comparison) than those resulting from method 1 (0.79/0.67). Age and height were significantly correlated with IMT (coefficients 0.53 and 0.52 for method 2), no correlation was found for body weight, BMI, sex or years of smoking. There was a significant inverse correlation between blood pressure and IMT (-0.21 to -0.32). CONCLUSION: In younger healthy subjects, the results of IMT measurement are influenced by age, height and actual blood pressure. The values resulting from both methods are comparable, whereas method 2 has a better reproducibility.

Adult↗