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Biomedical subjects

T Schwarz

Publications and source records attributed to T Schwarz.

At least 127 records · Page 7Linked to original sources
PubMed1998

[Therapy with implanted cardioverter-defibrillator: Is a replacement of the impulse generator due to battery depletion also necessary without the occurrence of a tachyarrhythmia episode?].

The aim of this retrospective study was to evaluate the necessity of the replacement of an implantable cardioverter/defibrillator (ICD) in patients with pulse generator battery depletion without an adequate, spontaneous arrhythmia episode during the life-time of the first implanted device. In this study 213 patients with implanted ICDs were enrolled. In 62 patients an elective generator replacement due to battery depletion was performed. Both patient groups (Group A: patients with generator replacement n = 62 and Group B: patients without replacement n = 151) were not different with regard to main clinical characteristics, such as underlying heart disease and left ventricular function. In both groups there was a predominance of male patients (Group A: 89%; Group B: 83%). The mean age was 58 +/- 11 years and 59 +/- 11 years in Group A and Group B, respectively. Coronary artery disease was present in 66% and 68% of the patients. There was a comparable left ventricular ejection fraction: Group A: 30.5 +/- 9% vs Group B: 31.9 +/- 9%. The follow-up time was much longer in Group A patients compared to Group B patients (50.5 +/- 14 vs. 16.5 +/- 11 months). For the total patient group there was a 5 year event-free probability of 23%, no differences were found between both groups. The subanalysis in Group A patients revealed no difference in the probability of ICD-shock occurrence prior to or after the replacement of the pulse generator. In 48/62 (77%) of Group A patients adequate ICD discharges were documented. In 15/62 (24%) patients shock occurred before and after generator replacement. In 6/62 (10%) of Group A patients, the first adequate ICD-therapy was documented after generator replacement. The results of this study indicate the necessity of an ICD-pulse generator replacement even in patients without an adequate device discharge during the life-time of the first implanted device.

Aged↗
PubMed1998

[Dysfunctions of transvenous cardioverter/defibrillator electrode systems: clinical significance of system integrated diagnosis and measurement function--possibilities of partially automated system control].

UNLABELLED: The aim of this study is the analysis of electrical failures in transvenous cardioverter/defibrillator (ICD) lead systems with regard to the importance of device implemented diagnostic and measurement functions and the potential role of an automated device-control in the detection of lead failures. METHODS: All consecutive ICD patients at our institution were enrolled in this retrospective investigation. The routine follow-up controls consisted in a complete evaluation of all diagnostic and measurement ICD features and additional controls in case of spontaneous arrhythmia episodes. RESULTS: Two hundred thirty patients, 193 male and 37 female, were enrolled in this study (mean age: 61.5 +/- 10.2 years; mean LVEF 32 +/- 9%). During a mean follow-up period of 29.5 +/- 18.4 (6-76) months, lead failure occurred in 19 patients (8%), 16 patients were implanted with an ICD, capable of diagnostic and measurement functions. All nonadequate device discharges could be classified as sensing-failure by stored electrograms. Device implemented measurement features revealed clinical important information in 13/16 patients (81%). In 14/16 patients, the lead defect could not be detected during routine follow-up. At the time of documented lead failure the safety of the implanted devices was already lost in 6/16 patients (38%). CONCLUSIONS: Device implemented diagnostic and measurement options are of great importance in the early detection of ICD lead failures. The implementation of automated measurements of lead related parameters in connection with a patient alert function may contribute to a further increase in the safety of ICD therapy.

Adult↗
PubMed1998

Evaluation of the Association Between Coronary Calcification Detected by Electron Beam Computed Tomography and Atherosclerosis of Extracranial Carotid Arteries In Vivo.

The aim of this study was to evaluate the association between carotid and coronary atherosclerosis and their diagnostic value for predicting angiographically significant coronary artery disease (CAD). We investigated 80 subjects (mean age 55 +/- 8 years) by electron beam computed tomography (EBT), the most sensitive technology for noninvasive detection of coronary calcification (a marker of coronary atherosclerosis); by carotid sonography; and by coronary angiography. Carotid ultrasound was performed with a 7.5 MHz Duplex probe, EBT was done with an EVOLUTION(R) scanner. In 47 subjects, coronary calcification as well as carotid atherosclerosis was present. Thirteen subjects showed isolated coronary calcification, 10 had isolated carotid atherosclerosis, and 10 showed neither coronary calcification nor carotid atheroscleroosis. The association between carotid atherosclerosis and CAD as well as the relationship between coronary calcification and CAD were statistically significant (p < 0.05), but the correlation between coronary calcification and CAD was higher than between carotid atherosclerosis and CAD (Pearson contingency coefficient: 0.34 vs 0.86). In subjects without carotid atherosclerosis, the mean area of coronary calcificiation was significantly (p < 0.01) lower (41 mm2) than in subjects with carotid atherosclerosis (113 mm2). For noninvasive detection of CAD, electron beam CT was superior to carotid sonography on sensitivity (95% vs 78%) and specificity (81% vs 48%). Former studies suggested that sonography of extracoronary vessels could aid in screening for CAD. In our study, the sonographic status of carotid arteries was associated with cardiovascular atherosclerosis but it did not allow us to make a judgment about the presence of CAD with sufficient reliability and it was inferior to electron beam CT as a noninvasive marker of CAD.

Journal Article↗
PubMed1998

Comparative cytokine gene expression: regulation and release by human mast cells.

Since data on the ability of human mast cells to produce various cytokines are scanty, we examined the mRNA expression, its modulation and the resulting protein expression of a number of well-characterized cytokines, using semi-quantitative reverse transcription-polymerase chain reaction of cell extracts and enzyme-linked immunosorbent assays for analysis of cell supernatants. One million cells/ml of the human mast cell line HMC-1 were stimulated with 25 ng/ml phorbol myristate acetate (PMA), 5 x 10(-7) M calcium ionophore A 23187 (ionophore) or both stimuli combined for various time periods. Constitutive expression in unstimulated cells was found for interleukin-1 beta (IL-1 beta) -3, -4, -8, tumour necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta). Maximal mRNA up-regulation was observed by 2-4 hr, with a second peak for TNF-alpha at 24 hr. After a 4-hr stimulation, IL-13 expression was detectable as well, whereas for IL-12, only the p35 but not the p40 chain was found, and IL-2, -5, -7 and interferon-gamma (IFN-gamma) were not expressed at all. Large quantities of IL-8, TNF-alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-3 were secreted time-dependently over a 72-hr period, with lower levels of IL-1 beta, -6, -10 and TGF-beta and no detectable IL-2, -4 and IFN-gamma protein. When IL-6 and IL-8 expression was compared in more detail, IL-6 mRNA was found to be up-regulated only with ionophore but not PMA, whereas both stimuli alone or combined increased IL-8 mRNA expression. Preincubation with cycloheximide inhibited IL-6 but not IL-8 transcription, and incubation of stimulated cells with actinomycin D stabilized IL-8 and also IL-6 mRNA. These data suggest a selective regulation of distinct cytokines in human mast cells at the transcriptional and post-transcriptional levels. Furthermore, the spectrum of cytokines produced by HMC-1 cells supports the well-recognized role of mast cells in immediate-type hypersensitivity reactions as well as their potential colony-stimulating and tissue-remodelling abilities.

Calcimycin↗
PubMed1998

Interleukin 12 breaks ultraviolet light induced immunosuppression by affecting CD8+ rather than CD4+ T cells.

Recent studies showed that injection of interleukin (IL)-12 prevents ultraviolet (UV) light mediated suppression of contact hypersensitivity and breaks UV-induced hapten specific tolerance. UV-mediated suppression can be adoptively transferred by injecting splenocytes from UV-irradiated mice; however, suppression is not transferable when donor mice are treated with IL-12 after UV-irradiation. This study was performed to elucidate the mechanisms by which IL-12 counteracts this immunosuppression. To characterize the cells transferring suppression, depletion studies were performed revealing that UV-induced suppression is transferred via CD8+ T cells. To investigate whether IL-12 counteracts UV-induced suppression by either inhibiting the development of CD8+ suppressor T cells or inducing CD4+ effector T cells, splenocytes from mice, which were IL-12 treated and sensitized through UV-exposed skin, were depleted from CD4+ T cells and transferred into naive mice that were subsequently sensitized. Whereas transfer of splenocytes from UV-irradiated mice inhibited sensitization of recipients, no inhibition was observed after transfer of splenocytes from UV-exposed and IL-12 treated mice. Recipients that received CD4 depleted spleen cells from UV-exposed and IL-12 treated donors, were still fully sensitizable. IL-12 also blocked transfer of UV-induced suppression when it was injected into UV-exposed donor animals at a time point when suppressor cells had already developed. CD4 depletion of such splenocytes did not result in a loss of the reconstitutive effect of IL-12. This suggests that IL-12 may break UV-induced tolerance not by inducing CD4+ effector T cells, but rather by inhibiting or inactivating suppressor T cells belonging to the CD8 subtype.

Adoptive Transfer↗
PubMed1998

Ultraviolet light and interleukin-10 modulate expression of cytokines by transformed human dermal microvascular endothelial cells (HMEC-1).

Exposure of the skin to ultraviolet (UV) light causes DNA damage, inflammation, and impairment of local as well as systemic immune responses. Dermal microvascular endothelial cells are key elements for the recruitment of inflammatory cells during the pathogenesis of inflammatory skin diseases via the expression of adhesion molecules and the release of cytokines. Because UVB may directly affect the function of dermal cells it was investigated whether UVB irradiation alters the production of proinflammatory and chemotactic cytokines by endothelial cells. UVB exposure of transformed human microvascular endothelial cells (HMEC-1) resulted in a dose dependently increased mRNA expression as well as release of interleukin (IL)-1beta, IL-6, IL-8, and growth-regulated oncogene alpha (GROalpha). Maximum cytokine production was observed 16-24 h after irradiation when 7.5-12.5 mJ UVB per cm2 were used. In addition, it was examined whether IL-10, which is upregulated in keratinocytes following UVB irradiation and accounts for UV mediated immunosuppression such as inhibition of contact hypersensitivity, also affects endothelial cell cytokine production. Treatment of HMEC-1 with IL-10 significantly enhanced IL-6 and IL-8 release and further upregulated UVB-induced IL-6 and IL-8 mRNA expression. These findings demonstrate that UVB both directly and indirectly via the release of IL-10 stimulates microvascular endothelial cells to produce proinflammatory cytokines and chemokines that are required for the migration and activation of inflammatory cells in UV-mediated inflammatory skin reactions.

Cells, Cultured↗
PubMed1998

Differential regulation of epidermal cell tumor-antigen presentation by IL-1alpha and IL-1beta.

IL-1 exists in two forms, termed IL-1alpha and IL-1beta, which exert similar effects in a number of biologic models. Recently, there have been reports of some differences in the activities of these two species in some systems. To address this issue with regard to Langerhans cells, Langerhans cell-enriched preparations of epidermal cells were treated with either IL-1alpha or IL-1beta before pulsing with S1509a tumor-associated antigens and subsequent use for immunization of naive mice to S1509a. While epidermal cells treated with 100 U IL-1beta per ml were able to induce protective tumor immunity (as indicated by the rejection of a subsequent tumor challenge with viable S1509a tumor cells), epidermal cells treated with 100 U IL-1alpha per ml failed to confer protective immunity. At 1000 U per ml, IL-1beta also inhibited the ability of epidermal cells to induce tumor immunity. To investigate the effects of the two IL-1 forms on elicitation of tumor immunity, naive mice were immunized against the S1509a tumor by s.c. injection of dead S1509a cells. Epidermal cells enriched for Langerhans cells were treated with either 100 U IL-1alpha or IL-1beta per ml before tumor-associated antigens-pulsing. Epidermal cells were then washed and injected into a hind footpad of tumor immune mice and 24 h footpad swelling was assessed as a measure of delayed-type hypersensitivity. Exposure to IL-1alpha led to suppressed elicitation of delayed-type hypersensitivity, whereas IL-1beta treated epidermal cells elicited a normal (100 U per ml) or enhanced (1000 U per ml) level of delayed-type hypersensitivity. Previous experiments indicated that the suppressive effects of IL-1alpha on induction of immunity may be mediated by TNF alpha. Therefore, the ability of IL-1alpha or IL-1beta to induce epidermal cell production of TNF alpha was assessed. IL-1alpha induced epidermal cells to secrete significantly higher amounts of TNF alpha protein compared with stimulation with IL-1beta. IL-1alpha and IL-1beta appear to differentially regulate epidermal cell antigen presenting capability.

Animals↗
PubMed1998

Effects of a standardized mistletoe preparation on metastatic B16 melanoma colonization in murine lungs.

The immune response-modifying drug Lektinol is a mistletoe preparation which is standardized with respect to bioactive viscum album agglutinin, the most active component of mistletoe. The present study was designed to evaluate the antimetastatic effects of this preparation following intravenous injection of B16 melanoma cells into mice. The standardized mistletoe extract was administered intravenously in doses of 100, 1000 or 5000 microliters/kg (equivalent to 3, 30 or 150 ng/kg of viscum album agglutinin) once daily for three weeks. An inhibition of mean pulmonary metastatic colonization of 58 to 95%, as measured by the number of melanoma cells on lung tissue slides, and a significant decrease of percentage of bronchoalveolar lavage pigmented cells were observed. In addition, a correlation of this antimetastatic activity with cellular immune parameters was investigated. In lavage fluids from the tumor-bearing mice, there was a 5 to 6-fold significant increase in the percentage of MAC-1+ (CD11b/CD18) immunocompetent macrophages in comparison with cells from vehicle-treated animals. The percentages of double-positive immature CD4+8+ thymocytes were significantly increased in animals treated with the standardized mistletoe extract. There were no signs of treatment-related toxicity. The results of this study indicate that the standardized mistletoe extract shows antimetastatic activity against B16 melanoma lung colonization.

Animals↗
PubMed1997

Down-regulation of interferon gamma-activated STAT1 by UV light.

STAT1 is a cytoplasmic transcription factor that is phosphorylated by Janus kinases (Jak) in response to interferon-gamma (IFNgamma). Phosphorylated STAT1 translocates to the nucleus, where it turns on specific sets of IFNgamma-inducible genes. Here, we show that UV light interferes with tyrosine phosphorylation of STAT1, thereby hindering IFNgamma from exerting its biological effects. This effect is not due to a down-regulation of the IFNgamma receptor because phosphorylation of upstream-located Jak1 and Jak2 was not suppressed by UV light. In contrast, UV light had no effect on the phosphorylation of STAT3, which is activated by the proinflammatory cytokine interleukin 6. The UV light effect on STAT1 phosphorylation could be antagonized by vanadate, indicating at least partial involvement of a protein tyrosine phosphatase. Therefore, this study indicates a mechanism by which UV light can inhibit gene activation and suggests STAT1 as a new extranuclear UV target closely located to the membrane.

Animals↗
PubMed1997

Human dermal microvascular endothelial cells express the melanocortin receptor type 1 and produce increased levels of IL-8 upon stimulation with alpha-melanocyte-stimulating hormone.

Pro-opiomelanocortin (POMC)-derived peptides such as alpha-melanocyte-stimulating hormone (alpha-MSH) recently have been recognized as mediators with potent immunomodulating and anti-inflammatory properties. Their effects are mediated via different protein G-coupled melanocortin (MC) receptors that are capable to bind one or more POMC-derived peptides. Among these receptors, MC-1 is specific for alpha-MSH and adrenocorticotropin. The purpose of the present study was to investigate whether MC receptors are expressed on normal human dermal microvascular endothelial cells (HDMEC) as well as transformed human dermal microvascular endothelial cells (HMEC-1). Using semiquantitative reverse transcriptase-PCR and MC receptor-specific primers, both HDMEC and HMEC-1 were found to express MC-1 constitutively. In addition, MC-1 expression was increased upon stimulation with IL-1beta or alpha-MSH itself. Other known MC receptors were neither detectable in unstimulated nor in IL-1beta- or alpha-MSH-stimulated cells. The binding of alpha-MSH by HMEC-1 was specific and saturable as demonstrated by competitive and saturation-binding studies with 125I-labeled alpha-MSH (Kd: 1.1 nM). To evaluate the physiologic relevance of MC-1 expression, HMEC-1 were treated with various concentrations of alpha-MSH (10(-15)-10(-6) M) and were investigated for their cytokine-producing capacity. Alpha-MSH (10(-10)-10(-8) M) significantly up-regulated IL-8 release and mRNA expression by HMEC-1. In contrast, the production of IL-1 or IL-6 by HMEC-1 was not affected upon treatment with alpha-MSH. These data provide first evidence that HDMEC express functional MC receptors. Therefore, alpha-MSH, which is released in the skin during cutaneous inflammation via inducing chemokines may represent an important signal required for leukocyte-endothelial cell interaction.

Binding Sites↗
PubMed1997

Ultraviolet light suppresses IFN-gamma-induced IL-7 gene expression in murine keratinocytes by interfering with IFN regulatory factors.

UV light is a potent stimulus for keratinocytes to release several cytokines. Recently, UV light was shown to inhibit keratinocyte release of IL-7, a growth factor for dendritic epidermal T cells. Since to date IL-7 is the only keratinocyte-derived cytokine down-regulated by UV light, we addressed the molecular mechanisms involved. IFN-gamma treatment of the murine keratinocyte cell line Pam 212 resulted in an up-regulation of IL-7 mRNA, while IL-7 transcripts were suppressed in cells exposed to UV before IFN-gamma. Because IFN-gamma induces IL-7 via activation of an IFN-stimulated response element (ISRE) located in the 5' upstream region of the IL-7 gene, bandshift assays were performed using the ISRE sequence from the IL-7 gene. Nuclear extracts from untreated cells revealed two bands, a slower migrating band identified by supershift analysis as IFN regulatory factor-2 (IRF-2), a transcriptional repressor, and a more rapidly migrating band identified as IRF-1, a transcriptional activator. IFN-gamma significantly induced IRF-1 binding, whereas UV treatment plus IFN-gamma decreased IRF-1 binding, suggesting that UV light suppresses IFN-gamma-induced expression of IL-7 by interfering with IRF-1. Chloramphenicol transferase assay confirmed functional relevance, showing that the minimal promoter sequence for the ISRE explicitly responded to IFN-gamma, which was suppressed by UV irradiation. Northern blot analysis using an IRF-1 cDNA probe revealed that UV light reduced IFN-gamma-induced IRF-1 mRNA. This study demonstrates that UV light can inhibit cytokine activities by interference with transcriptional activators. This newly described ability of UV light may contribute to its immunosuppressive properties.

Animals↗
PubMed1997

Multifunctional tryptophan-synthesizing enzyme. The molecular weight of the Euglena gracilis protein is unexpectedly low.

After developing a suitable procedure to produce large amounts of Euglena gracilis as well as a reliable protocol to purify the multifunctional tryptophan-synthesizing enzyme derived from it (Schwarz, T., Bartholmes, P., and Kaufmann, M. (1995) Biotechnol. Appl. Biochem. 22, 179-190), we here describe structural and catalytic properties of the multifunctional tryptophan-synthesizing enzyme. The kinetic parameters kcat of all five activities and Km for the main substrates were determined. The relative molecular weight under denaturing conditions as judged by SDS-polyacrylamide gel electrophoresis is 136,000. Cross-linking as well as gel filtration experiments revealed that the enzyme exists as a homodimer. Neither intersubunit disulfide linkages nor glycosylations were detected. On the other hand, the polypeptide chains are blocked N-terminally. Complete tryptic digestion of the protomer, high pressure liquid chromatography separation of the resulting peptides, and N-terminal sequence analysis of homogenous peaks as judged by matrix-assisted laser/desorption ionization time-of-flight mass spectrometry was performed. Depending on the sequenced peptides, alignments to all entries of the SwissProt data base resulted in both strong sequence homologies to known Trp sequences and no similarities at all. Proteolytic digestion under native conditions using endoproteinase Glu-C uncovered one major cleavage site yielding a semistable, N-terminally blocked fragment with a molecular weight of 119,000. In addition, an increase in beta-elimination accompanied by a decrease in beta-replacement activity of the beta-reaction during proteolysis was observed.

Amino Acid Sequence↗
PubMed1997

Evidence for the differential expression of the functional alpha-melanocyte-stimulating hormone receptor MC-1 on human monocytes.

alpha-Melanocyte-stimulating hormone (alpha-MSH) is released by immunocompetent cells as well as the pituitary gland and functions as a potent inhibitor of immune and inflammatory reactions. Therefore, it was investigated whether normal human monocytes express melanocortin (MC) receptors specific for alpha-MSH. Upon FACS analysis using biotin-labeled alpha-MSH, a low number of alpha-MSH binding sites was detectable on unstimulated monocytes. alpha-MSH receptor expression was up-regulated when monocytes were treated with endotoxin (LPS) or mitogen (PHA) for 3 to 5 days and was further augmented by the addition of cytokines such as IL-2, IFN-gamma, IL-4, and IL-10. Adrenocorticotropin, a precursor of alpha-MSH, but not the structurally unrelated beta-MSH, competitively inhibited alpha-MSH binding, suggesting that the receptor expressed on monocytes is specific for alpha-MSH. This was further confirmed by reverse transcription-PCR, which demonstrated that monocytes express mRNA specific for the MC receptor MC-1, which binds alpha-MSH and adrenocorticotropin, whereas mRNA specific for other known melanocortin receptors was not detectable. To investigate whether the immunosuppressing capacity of alpha-MSH is associated with the up-regulation of MC-1, its effect on the expression of costimulatory molecules (CD86 and CD80) on human monocytes was investigated. alpha-MSH significantly inhibited the expression of CD86 on LPS-treated monocytes, which exhibited a high density of MC-1, whereas CD80 expression was not altered. These findings indicate that human monocytes, depending on their activation and maturation state, are able to express MC-1, and up-regulation of MC-1 seems to be required to enable alpha-MSH to modulate immune responses in which costimulatory molecules play a decisive role.

Binding Sites↗