[Therapy of varicella zoster and herpes simplex virus-induced diseases. 1: Virustatic agents].
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Adult↗
Biomedical subjects
G Schuler
Publications and source records attributed to G Schuler.
[The anti-atherogenic mechanism of action of physical training in patients with coronary heart disease].
In randomized trials, moderate to aggressive lipid-lowering therapy as well as regular physical exercise have both been shown to restore endothelial function, slow progression and in some patients even lead to regression of coronary artery disease. Furthermore, a reduced rate of cardiac events, morbidity and mortality have been documented. Similarly, regular physical exercise training has been identified to contribute independently to beneficial changes in the risk factor profile, retardation of the progression of coronary lesions and has been associated with a reduced rate of mortality. Therefore, besides adhering to a low fat diet, patients with coronary artery disease should further be motivated to include physical exercise in their daily routine. Although it has been puzzling how exercise training exerts antiatherogenic effects, accumulating evidence has recently unraveled some of the underlying cellular and molecular pathomechanisms, which will be discussed in this review.
Combined Modality Therapy↗
[Rate of restenosis after coronary stent implantation depending on regional left ventricular function].
At present the rate of restenosis after PTCA and stent implantation is approximately 30% in clinical routine practice. The aim of the present study was to investigate the influence of regional disturbances of left ventricular contractility, e.g. due to scars, on the development of restenosis after PTCA and stent implantation. In 310 patients with single stent implantation in the LAD, quantitative coronary angiography and ventricular analysis with the centerline wall motion model (Cardiovascular measurement systems, Medis, The Netherlands) were performed before, immediately after stent implantation and at angiographic follow-up after 3 to 6 months. Thirty-nine percent of all patients (121 patients) showed regional dysfunction of the left ventricular anterior wall. Increase of percent stenosis (relative late lumen loss) between stent implantation and follow-up angiography showed no correlation to left ventricular wall motion abnormalities (r = 0.243). There was no significant difference in restenosis rates between patients with or without left ventricular wall motion abnormalities (28.9% vs. 30.7%, p = 0.74). In conclusion, this study provides evidence that kinetic disorders of the left ventricular wall have no significant influence on long-term results after PTCA and stent implantation.
Angioplasty, Balloon, Coronary↗
[Safety and efficacy of LK565--a new polymer ultrasound contrast medium].
We tested a newly developed ultrasound contrast agent (LK565) from poly-aspartic acid (PAA; particle size 3 microns; particle content: air) in 15 healthy male probands (20-38 years) in doses of 10, 30 and 100 mg intravenously. One day and immediately before the study a routine laboratory test, an ECG and an EEG were performed. The EEG was continued through the complete time period that the ultrasound contrast lasted, i.e., up to one hour after the injection. All probands were followed clinically for 24 hours when the routine laboratory and the ECG were repeated. All subjects tolerated the contrast agent well. There were no changes in either the EEG or in the ECGs performed throughout the study. There were no significant laboratory changes except for a small and transient increase in the neutrophil count in five probands receiving the highest dose. All injections with 10 mg led to a significant improvement in the color Doppler signal. All injections with 30 and 100 mg led to a very strong echo contrast lasting for 5 to 12 minutes in the harmonic B-mode. Using the latter, fragments of intramyocardial coronaries could be visualized. The tested ultrasound polymer contrast agent was safe, well tolerated and efficient in this acute study.
Adult↗
[Recommendations for an extensive risk decrease for patients with coronary disease, vascular diseases and diabetes. Issued by the Executive Committee of the German Society of Cardiology, Heart and Circulation Research, reviewed on behalf of the Clinical Cardiology Commission by the Prevention Project Group].
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Coronary Disease↗
Endothelial dysfunction in patients with chronic heart failure: systemic effects of lower-limb exercise training.
OBJECTIVES: We sought to analyze the systemic effects of lower-limb exercise training (ET) on radial artery endothelial function in patients with chronic heart failure (CHF). BACKGROUND: Local ET has the potential to improve local endothelial dysfunction in patients with CHF. However, it remains unclear whether the systemic effects can be achieved by local ET. METHODS: Twenty-two male patients with CHF were prospectively randomized to either ET on a bicycle ergometer (ET group, n = 11; left ventricular ejection fraction [LVEF] 26 +/- 3%) or an inactive control group (group C, n = 11; LVEF 24 +/- 2%). At the beginning of the study and after four weeks, endothelium-dependent and -independent vasodilation of the radial artery was determined by intra-arterial infusion of acetylcholine (ACh-7.5, 15 and 30 microg/min) and nitroglycerin (0.2 mg/min). The mean internal diameter (ID) of the radial artery was assessed using a high resolution ultrasound system (NIUS-02, Asulab Research Laboratories, Neuchâtel, Switzerland) with a 10-MHz probe. RESULTS: After four weeks of ET, patients showed a significant increase in the baseline-corrected mean ID in response to ACh (30 microg/min), from 33 +/- 10 to 127 +/- 25 microm (p < 0.001 vs. control group at four weeks). In the control group, the response to ACh (30 microg/min) remained unchanged. Endothelium-independent vasodilation was similar in both groups at the beginning of the study and at four weeks. In the training group, increases in agonist-mediated, endothelium-dependent vasodilation correlated to changes in functional work capacity (r = 0.63, p < 0.05). CONCLUSIONS: In patients with stable CHF, bicycle ergometer ET leads to a correction of endothelial dysfunction of the upper extremity, indicating a systemic effect of local ET on endothelial function.
Aged↗
Viral vectors for dendritic cell-based immunotherapy.
Transduction of dendritic cells (DCs) by viral vectors genetically engineered to express tumor-associated antigens (TAAs) or cytokines can produce a high level of transgene expression and is an attractive approach for DC-based immunotherapy. Ex vivo transduction allows the control of DC quality, antigen quantity and site of DC reinjection. This review evaluates the viral vectors currently being developed for use in DC-based immunotherapy.
Adjuvants, Immunologic↗
A radiation hybrid map of mouse genes.
A comprehensive gene-based map of a genome is a powerful tool for genetic studies and is especially useful for the positional cloning and positional candidate approaches. The availability of gene maps for multiple organisms provides the foundation for detailed conserved-orthology maps showing the correspondence between conserved genomic segments. These maps make it possible to use cross-species information in gene hunts and shed light on the evolutionary forces that shape the genome. Here we report a radiation hybrid map of mouse genes, a combined project of the Whitehead Institute/Massachusetts Institute of Technology Center for Genome Research, the Medical Research Council UK Mouse Genome Centre, and the National Center for Biotechnology Information. The map contains 11,109 genes, screened against the T31 RH panel and positioned relative to a reference map containing 2,280 mouse genetic markers. It includes 3,658 genes homologous to the human genome sequence and provides a framework for overlaying the human genome sequence to the mouse and for sequencing the mouse genome.
Animals↗
Treatment of psoriatic arthritis with antitumour necrosis factor-alpha antibody clears skin lesions of psoriasis resistant to treatment with methotrexate.
BACKGROUND: In inflamed skin, keratinocytes and inflammatory cells both produce large amounts of tumour necrosis factor (TNF) -alpha, a cytokine with broad effects that are relevant to inflammation. Blockade of this proinflammatory cytokine by a monoclonal anti-TNF-alpha antibody might be effectively used in the treatment of inflammatory skin diseases. OBJECTIVES: To gather information about the efficacy of an anti-TNF-alpha antibody (infliximab) in the treatment of skin lesions of psoriatic arthritis. METHODS: Six patients with progressive joint disease and psoriatic skin lesions unresponsive to methotrexate therapy were treated with anti-TNF-alpha antibody. The Psoriasis Area and Severity Index was determined before and 10 weeks after initiation of therapy. RESULTS: Improvement of psoriatic skin lesions was observed in all patients. In addition, a marked improvement of the joint disease was noted. CONCLUSIONS: Therapy with anti-TNF-alpha antibody may be an effective treatment regimen for both psoriatic arthritis and psoriatic skin lesions.
Antibodies, Monoclonal↗
A strikingly constant ratio exists between Langerhans cells and other epidermal cells in human skin. A stereologic study using the optical disector method and the confocal laser scanning microscope.
Langerhans cells play an important part in the immune surveillance of the human epidermis. Therefore, a certain distribution and numerical relationship to other epidermal cells can be expected. To quantify epidermal Langerhans cells population extensive studies have been performed using two-dimensional quantification methods on vertical sections or epidermal sheet preparations. Whereas methods using vertical sections were complicated considerably by the sampling procedure, the dendritic shape, and the suprabasal, nonrandom distribution of Langerhans cells, epidermal sheet preparations have their limitations regarding the numerical relationship of Langerhans cells to total epidermal cells and the epidermal morphology as such. In order to improve the validity of data the three-dimensional dissector method combined with confocal laser scanning microscopy has been applied to quantify the number of Langerhans cells and other epidermal cell nuclei per volume unit in cryosections of 24 punch biopsies of normal breast skin of eight women. Furthermore, the ratio of Langerhans cells to other epidermal cells, their number per biopsy, and per skin surface area were calculated. To minimize the bias by shrinkage the reference volume was estimated using Cavalieri's principle. A constant ratio of one Langerhans cells to 53 other epidermal cells was identified in breast skin (interindividual correlation coefficient: 0.952, p < 0.0001). Thus, Langerhans cells represent 1.86% of all epidermal cells; however, a wide interindividual range was found for the number of Langerhans cells per mm2 (912-1806; mean +/- SD 1394 +/- 321) and other epidermal cells per mm2 (47,315-104,588; mean +/- SD 73,952 +/- 19,426). This explains the conflicting results achieved by conventional morphometric assessments relating cell numbers to skin surface area, ignoring the varying thickness of the epidermis. The surprisingly constant relationship of Langerhans cells to other epidermal cells stresses the hypothesis of an epidermal Langerhans cells unit where one Langerhans cells seems to be responsible for the immune surveillance of 53 epidermal cells.
Adult↗
Investigations on the activity of bovine placental oestrogen sulfotransferase and -sulfatase from midgestation to parturition.
To gain further information on the biological role of the high amounts of conjugated estrone (E1S) secreted by the bovine placenta, an in vitro assay system was developed to measure oestrogen sulfotransferase (OST) and oestrogen sulfatase (OS) activities in caruncular and cotyledonary homogenates and the respective subcellular fractions. Placental tissue was obtained from 150 (n = 3), 220 (n = 4), 240 (n = 3) and 270 days (n = 3) pregnant and parturient cows (n = 4). 3H-E1 and 3H-E1S served as substrates and 4-nitrophenyl sulfate potassium salt was used as a competitive inhibitor to block OS when testing for OST activity. OST-activity did not change during pregnancy and parturition and was higher (p < 0.001) in cotyledonary than in caruncular tissue with mean conversions (median) of 61.8% and 41.6% after 30 min of homogenate incubation. On a subcellular level OST-activity was clearly associated with the cytosol. OS-activity was higher (p < 0.001) in caruncular than in cotyledonary homogenates; it was constant during pregnancy (median of conversion: 88.0% and 66.4%, resp.), but was significantly decreased (p < 0.05) at parturition (median of conversion: 48.1% and 30.6%, resp.). On a subcellular level in both the cotyledon and the caruncle highest OS-activities were detected in the microsomal and the mitochondrial fractions. The decreased placentomal OS-activities in parturient cows are inconsistent with a substantial role of OS in the prepartal increase of free oestrogens. These results also suggest that bovine placental oestrogens may largely exert their action locally within the placentomes during most time of gestation as the enzymes catalyzing sulfoconjugation (i.e. inactivation of free oestrogens) and desulfation (i.e. activation of conjugated oestrogens) are expressed in close proximity to each other. In this respect the finding of oestrogen receptors in caruncular stromal cells is of particular interest.
Animals↗
Three-dimensional visualization of coronary arteries in excised hearts.
OBJECTIVE: We sought to image coronary arteries in excised hearts. METHODS: Twelve excised pigs' hearts were imaged in a water bath. The aortic valve was closed surgically. A contrast agent (Echovist) was injected into the aortic root and selectively into single coronary arteries. Three-dimensional (3D) imaging was performed with TomTec Echoscan equipment. Mechanical rotations were performed at 1 degrees intervals. The hearts were visualized by InVivo software. Selective coloring of coronary arteries in 3D data sets was obtained by using color superpositioning, which differentiates information before and after injection of contrast. Distance measurements were performed in conventional 3D echocardiograms of coronary arteries and color-superimposed echocardiograms and compared with those from angiograms and casts. RESULTS: After a learning curve, during which optimal conditions for the visualization of coronary arteries were determined, a quick display of all major parts of the coronary tree was obtained. Distance measurements (n >400) revealed that fundamental contrast echocardiography overestimated angiography by 25% +/- 5% and casts by 28% +/- 6%. However, distances in color-superimposed echocardiograms (flow mode 4) were not significantly different from those obtained from angiograms and casts. In harmonic contrast echocardiograms, color super-positioning gave smaller distances compared with those from fundamental contrast echocardiograms, though they were still significantly larger than the reference diameters. CONCLUSIONS: The 3D imaging of epicardial coronary arteries under ideal conditions in a water bath seems feasible and provides insight into coronary visualization with the use of ultrasonography.
Animals↗
Bipartite regulation of different components of the MHC class I antigen-processing machinery during dendritic cell maturation.
Dendritic cells (DC) are professional antigen-presenting cells (APC) which proceed from immature to a mature stage during their final differentiation. Immature DC are highly effective in terms of antigen uptake and processing, whereas mature DC become potent immunostimulatory cells. Until now, the expression profiles of the major components of the MHC class I antigen-processing machinery (APM) during DC development have not been well characterized. In this study, the mRNA and protein expression levels of the IFN-gamma inducible proteasome subunits, of the proteasome activators PA28, and of key components required for peptide transport and MHC class I-peptide complex assembly have been evaluated in immature and mature stages of human monocyte-derived DC using semiquantitative RT-PCR and Western blot analyses. The IFN-gamma-responsive immunoproteasome subunits LMP2, LMP7 and MECL1 are up-regulated in immature DC, whereas the other components of the MHC class I presentation machinery, such as PA28, TAP, tapasin, and HLA heavy and light chains, were found to be more abundant in mature DC. These findings support the hypothesis that immature DC produced by the differentiation of monocytes in response to IL-4 and granulocyte macrophage colony stimulating factor first increase their capacity to capture antigens and process them into peptides, thereby switching from housekeeping to immunoproteasomes, while mature DC rather up-regulate the components required for peptide translocation and MHC class I-peptide complex formation, and thus specialize in antigen presentation. Our results establish that MHC class I, like MHC class II surface expression, is markedly regulated during DC development and maturation.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
A "new" coronary anomaly: origin of the right coronary artery below the aortic valve.
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Aortic Valve↗
Diagnostic value of intraoperative swabs of heart valves in infective endocarditis.
BACKGROUND AND AIM OF THE STUDY: Intraoperative swabs of heart valves are obtained regularly from patients undergoing heart valve surgery for infective endocarditis (IE) in order to confirm the preoperative diagnosis and to adjust the antibiotic regimen. The study aim was to assess the diagnostic value of intraoperative swabs of heart valves in IE. METHODS: A total of 83 patients was referred for surgical treatment of active IE between October 1994 and May 1999. Preoperatively, microorganisms were isolated using a minimum of two positive blood cultures; results were compared with those obtained from intraoperative heart valve swab cultures. RESULTS: Preoperatively, 73 patients (88%) had a positive blood culture, and 10 (12%) had culture-negative endocarditis. The intraoperative swab confirmed the preoperative diagnosis in 31 cases (37%). Bacteria were isolated in three of the ten patients with preoperative culture-negative IE. Despite positive histopathological findings in seven patients, no microorganisms were cultured either pre- or intraoperatively. Among the remaining 42 patients (51%) with active IE, 25 valve cultures were sterile and 17 valve swabs were presumed to be contaminated. CONCLUSION: In patients with active IE in whom the causative agent could be isolated and identified before surgery, intraoperative valve swabs did not contribute further to patient management. In isolating contaminants, the risk of inappropriate modification of the antibiotic regimen is imminent. The diagnostic validity in culture-negative IE appears negligible.
Adolescent↗
[Therapy of varicella zoster and herpes simplex virus-induced diseases. 2: References for implementing and indications for virustatic therapy].
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Antiviral Agents↗
Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells.
The functional properties of dendritic cells (DCs) are strictly dependent on their maturational state. To analyze the influence of the maturational state of DCs on priming and differentiation of T cells, immature CD83(-) and mature CD83(+) human DCs were used for stimulation of naive, allogeneic CD4(+) T cells. Repetitive stimulation with mature DCs resulted in a strong expansion of alloreactive T cells and the exclusive development of T helper type 1 (Th1) cells. In contrast, after repetitive stimulation with immature DCs the alloreactive T cells showed an irreversibly inhibited proliferation that could not be restored by restimulation with mature DCs or peripheral blood mononuclear cells, or by the addition of interleukin (IL)-2. Only stimulation of T cells with mature DCs resulted in an upregulation of CD154, CD69, and CD70, whereas T cells activated with immature DCs showed an early upregulation of the negative regulator cytotoxic T lymphocyte-associated molecule 4 (CTLA-4). These T cells lost their ability to produce interferon gamma, IL-2, or IL-4 after several stimulations with immature DCs and differentiated into nonproliferating, IL-10-producing T cells. Furthermore, in coculture experiments these T cells inhibited the antigen-driven proliferation of Th1 cells in a contact- and dose-dependent, but antigen-nonspecific manner. These data show that immature and mature DCs induce different types of T cell responses: inflammatory Th1 cells are induced by mature DCs, and IL-10-producing T cell regulatory 1-like cells by immature DCs.
Antigens↗
A method for the production of cryopreserved aliquots of antigen-preloaded, mature dendritic cells ready for clinical use.
Dendritic cells (DC) are increasingly used as a vaccine. Unfortunately, a satisfactory cryopreservation of DC in the absence of FCS is not yet available, so that laborious repeated generation of DC from fresh blood or frozen peripheral blood mononuclear cells for each vaccination has been required to date. We now aimed at developing an effective cryopreservation method, and by testing several variables found that it was crucial to combine the most advantageous maturation stimulus with an improved freezing procedure. We generated monocyte-derived DC from leukapheresis products by using GM-CSF and IL-4 and showed that amongst several known maturation stimuli the cocktail consisting of TNF-alpha+IL-1 beta+IL-6+PGE(2) achieved the highest survival of mature DC. We then systematically explored cryopreservation conditions, and found that freezing matured DC at 1 degrees C/min in pure autologous serum+10% DMSO+5% glucose at a cell density of 10x10(6) DC/ml gave the best results. Using this approach 85-100% of the frozen DC could be recovered in a viable state after thawing (Table 1). The morphology, phenotype, survival as well as functional properties (allogeneic mixed leukocyte reaction, induction of influenza matrix or melan A peptide-specific cytotoxic T cells) of these thawed DC were equivalent to freshly prepared ones. The addition of CD40L or TRANCE/RANKL further improved DC survival. Importantly, we demonstrate that DC can effectively be loaded with antigens (such as Tetanus Toxoid, influenza matrix and melan A peptides) before cryopreservation so that it is now possible to generate antigen-preloaded, frozen DC aliquots that after thawing can be used right away. This is an important advance as both the generation of a standardized DC vaccine under GMP conditions and the carrying out of clinical trials are greatly facilitated.
Antigens↗