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Biomedical subjects

T Schwarz

Publications and source records attributed to T Schwarz.

At least 19 recordsLinked to original sources
PubMed2001

Overexpression of CD40 ligand in murine epidermis results in chronic skin inflammation and systemic autoimmunity.

CD40-CD40 ligand (L) interactions play a pivotal role in immune-mediated inflammatory responses via the activation of antigen-presenting cells (APCs). To investigate the effects of continuous activation of resident tissue APCs, in this case the Langerhans cells (LCs) of the skin, CD40L expression was targeted to the basal keratinocytes of the epidermis of mice using the keratin-14 promoter. Approximately 80% of the transgenic (Tg) mice spontaneously developed dermatitis on the ears, face, tail, and/or paws. Compared with littermates, Tgs had a >90% decrease in epidermal LCs yet increased numbers within the dermis suggestive of enhanced emigration of CD40-activated LCs. Tgs also displayed massive regional lymphadenopathy with increased numbers of dendritic cells and B cells. Moreover, a decrease in IgM and an increase in IgG1/IgG2a/IgG2b/IgE serum concentrations was detectable. Screening for autoantibodies revealed the presence of antinuclear antibodies and anti-dsDNA antibodies implicative of systemic autoimmunity. Accordingly, renal Ig deposits, proteinuria, and lung fibrosis were observed. Adoptive transfer of T cells from Tgs to nonTg recipients evoked the development of skin lesions similar to those found in the Tgs. Dermatitis also developed in B cell-deficient CD40L Tg mice. These findings suggest that in situ activation of LCs by CD40L in the skin not only leads to chronic inflammatory dermatitis but also to systemic mixed-connective-tissue-like autoimmune disorders, possibly by breaking immune tolerance against the skin.

Animals↗
PubMed2001

Osteodystrophia fibrosa in two guinea pigs.

Two adult guinea pigs were examined because they were lethargic and reluctant to walk. Additionally, I guinea pig had otitis media, and the other had dental malocclusion. Both guinea pigs had been fed a commercially available diet of cereals and pellets enriched with vitamin C and formulated for this species. Radiographically, the guinea pigs had coarse trabecular bone patterns, skeletal deformations, pathologic fractures, and polyarthritic degenerative joint disease. A double cortical line was also evident on several long bones, the pelvis, and the vertebrae. A diagnosis of osteopenia was confirmed by use of dual-energy x-ray absorptiometry. Analysis of a food sample fed to 1 guinea pig revealed calcium and phosphorus contents of 0.524 and 0.425%, respectively (Ca:P ratio, 1.23:1). Microscopic examination of bone tissue from both guinea pigs revealed severe fibrous osteodystrophy. Nutritional secondary hyperparathyroidism caused by calcium-phosphorus imbalance was considered to be the underlying cause of osteodystrophia fibrosa in both guinea pigs.

Animal Feed↗
PubMed2001

Intracellular persistence of Staphylococcus aureus small-colony variants within keratinocytes: a cause for antibiotic treatment failure in a patient with darier's disease.

Intracellular persistence assays were performed with small-colony variants (SCVs) derived from a patient with Darier's disease from whom different phenotypes and genotypes of Staphylococcus aureus were isolated over a 28-month period; the assays revealed that >100-fold more SCV cells persisted intracellularly relative to the normal phenotype. The presence of intracellular S. aureus SCVs may protect against host defenses and antibiotic therapy and thus may have contributed to this patient's very prolonged skin infection.

DNA, Bacterial↗
PubMed2001

Ultraviolet radiation inhibits interleukin-2-induced tyrosine phosphorylation and the activation of STAT5 in T lymphocytes.

UV radiation was recently found to hinder interferon-gamma from exerting its biological effects by inhibiting the phosphorylation of signal transducer and activator of transcription (STAT)-1, a crucial signal transducing protein in the interferon-gamma pathway. Because this activity by UV may contribute to its immunosuppressive properties we studied whether this is specific for STAT1 or whether UV also affects other members of the STAT family. STAT5 is crucially involved in signaling of interleukin (IL)-2, enabling up-regulation of the IL-2 receptor alpha chain, an essential component of the high affinity IL-2 receptor. Exposure of the murine T cell line CTLL to IL-2 caused tyrosine phosphorylation of STAT5 that was remarkably reduced when cells were exposed to UV. Accordingly, STAT5 binding activity was significantly impaired in UV-exposed cells. In contrast, IL-2-induced tyrosine phosphorylation of the kinases Jak1 and Jak3 located upstream of STAT5 was not affected by UV. The effect of UV on STAT5 phosphorylation was antagonized by orthovanadate, implying involvement of a phosphatase in this process. Accordingly, up-regulation of the IL-2 receptor alpha chain was reduced in cells that were treated with IL-2 plus UV. Because STAT5-mediated IL-2 effects are vital for normal immune functions, inhibition of STAT5 signaling by UV may contribute to its well known immunosuppressive properties.

Animals↗
PubMed2001

Pyodera gangrenosum after aortic valve replacement.

A 68-year-old male patient developed pyoderma gangrenosum after elective aortic valve replacement. Treatment with steroids and clofazimine was initiated, which resulted in rapid cessation of the necrotic process. Due to thoracic instability, stabilization of the sternum was performed followed by surgical debridement and atraumatic wound closure. Postoperatively, immunosuppression with cyclosporine A was added; the patient recovered completely. Pyoderma gangrenosum is a potential life-threatening complication that must be considered in patients with severely impaired wound healing after cardiac operation.

Aged↗
PubMed2001

Patients with persistent APC-resistance without factor V Leiden mutation.

BACKGROUND: Activated protein C (APC) resistance and factor V Leiden mutation are major risk factors for deep venous thrombosis. Previous work has led to the view that the coagulation phenotype and the genetic defect are associated in almost all patients. It has been reported about single APC-resistant patients without associated factor V Leiden, but significance and thrombotic risk of this constellation have not yet been established. PATIENTS AND METHODS: We tested 486 consecutive patients with deep venous thrombosis, arterial disease or other than vascular disease for APC-resistance with a factor VIII based assay. RESULTS: 149 patients (31%) showed a pathological APC-ratio. Sensitivity and specificity for detection of factor V Leiden were 100% and 40%, respectively. At 6 months follow-up APC-ratio returned to normal in 55% of the patients with initial pathological APC-resistance. At 12 months follow-up 91% of the patients with persistent APC-resistance showed a pathological ratio as well. CONCLUSIONS: Patients with APC-resistance not due to factor V Leiden can be attributed to one subset with reversible APC-resistance--possibly due to a hypercoagulable state in an acute thrombotic situation, and to another with persistent APC-resistance.

Activated Protein C Resistance↗
PubMed2001

The molecular determinants of sunburn cell formation.

Sunburn cell (SBC) formation in the epidermis is a characteristic consequence of ultraviolet radiation (UVR) exposure at doses around or above the minimum erythema dose. SBC have been identified morphologically and biologically as keratinocytes undergoing apoptosis. There is evidence that SBC formation is a protective mechanism to eliminate cells at risk of malignant transformation. The level of DNA photodamage is a major determinant of SBC induction by a process controlled by the tumor suppressor gene p53. However, extra-nuclear events also contribute to SBC formation, such as the activation of death receptors including CD95/Fas. UVR triggers death receptors either by direct activation of these surface molecules or by inducing the release of their ligands such as CD95 ligand or tumor necrosis factor. Oxidative stress also appears to be involved, probably via mitochondrial pathways, resulting in the release of cytochrome C. Pathways which modify SBC formation are now extensively studied given the importance of apoptosis in eliminating irreparably damaged cells. A greater understanding of the mechanisms that induce and prevent UVR-induced apoptosis will contribute to our understanding of mechanisms relevant in genomic integrity.

Animals↗
PubMed2001

Interleukin-6-resistant melanoma cells exhibit reduced activation of STAT3 and lack of inhibition of cyclin E-associated kinase activity.

Development of cytokine resistance is an important feature of melanoma cells during tumor progression. To study the mechanisms of interleukin-6 resistance, we examined an interleukin-6 sensitive (WM35) and an interleukin-6 unresponsive cell line (WM9). Interleukin-6 treatment resulted in rapid inhibition of cyclin-dependent kinase 2/cyclin E activity and accumulation of the hypophosphorylated retinoblastoma protein in WM35 but not in WM9 cells. In contrast to previous reports, no differences in the expression of the cyclin-dependent kinase 2 inhibitor p21Cip1/WAF1 upon interleukin-6 treatment were found in both cell lines. Interleukin-6-induced inhibition of cyclin-dependent kinase 2 was also not due to changes in protein expression of cyclin-dependent kinase 2, cyclin E, p27Kip1 and cdc25A, a phosphatase positively regulating cyclin-dependent kinase 2 activity. As it is established that interleukin-6 resistance of WM9 cells is not caused by differential interleukin-6 receptor expression, we studied whether this is due to defective interleukin-6 signaling in which activation of signal transducer and activator of transcription 3 is a critical step. WM9 cells showed reduced tyrosine phosphorylation, DNA binding, and delayed nuclear translocation of signal transducer and activator of transcription 3 as compared with WM35 cells. The kinase upstream of signal transducer and activator of transcription 3, Janus kinase 1, was constitutively tyrosine-phosphorylated in WM9 cells and did not respond to interleukin-6 with increased phosphorylation. As compared with WM35 cells, interleukin-6 treatment of WM9 cells was not paralleled by reduced activity of the mitogen-activated protein kinase kinase-1, which suppresses activation of signal transducer and activator of transcription 3. Our data suggest that resistance of advanced melanoma cells to interleukin-6 is associated with reduced inhibition of cyclin-dependent kinase 2, which appears to be a consequence of a complex alteration in interleukin-6 signal transduction.

CDC2-CDC28 Kinases↗
PubMed2001

A directed approach to the selection of bacteria with enhanced catabolic activity.

AIMS: This study was aimed at selecting catabolicly-improved bacteria by in vitro evolution using a specially designed fermentor system. METHODS AND RESULTS: To facilitate this objective, genetic variation was induced by ultraviolet irradiation, and a selective pressure was subsequently exerted by gradual increases in the concentration of organic toxins. During a pilot experiment, a culture was forced to tolerate and catabolize a mixture of phenol and formaldehyde. The population developed a high resistance against formaldehyde and the specific degradation rate increased rapidly. Biochemical analysis of the mutants revealed an increase in the expression of enzymes involved in the pathway oxidizing formaldehyde. CONCLUSIONS: The fermentor system described is, in general, suitable for the selection of bacteria with enhanced catabolic activities. SIGNIFICANCE AND IMPACT OF THE STUDY: The procedure is an alternative to conventional genetic engineering, providing efficient and genetically stable strains suitable for applications in the field of environmental biotechnology.

Bacteria↗
PubMed2001

Dual-coil vs single-coil active pectoral implantable defibrillator lead systems: defibrillation energy requirements and probability of defibrillation success at multiples of the defibrillation energy requirements.

AIMS: The aim of the study was to compare the defibrillation energy requirements and the probability of successful defibrillation at multiples of the minimum defibrillation energy requirements in active pectoral implantable defibrillators with single- and dual-coil lead systems. METHODS AND RESULTS: Eighty-three consecutive patients undergoing implantation of an active pectoral cardioverter-defibrillator were randomized to receive a dual- or single-coil lead system. Defibrillators of two manufacturers with a fixed tilt biphasic defibrillation waveform were used. Defibrillation energy requirements were determined using a step-down defibrillation testing protocol. According to the randomization protocol, the patients were assigned to three additional consecutive defibrillation attempts during device implantation and during pre-discharge testing of either 1.0, 1.5 or 2.0 times the determined defibrillation energy requirement. Patients presenting defibrillation energy requirements > 15 J were excluded from analysis. Eighty of 83 patients (96%) completed the study protocol. Three patients were excluded due to elevated defibrillation energy requirements. The defibrillation energy requirements in the dual- and single-coil patient groups were 8.0 +/- 3.6 J and 8.4 +/- 3.7 J (ns), respectively. A comparable percentage of study patients showed defibrillation energy requirements <10 J (dual-coil: 88% vs single-coil: 83%). Defibrillation impedance was significantly different (dual-coil: 50 +/- 5.8 Ohm; single-coil: 39.8 +/- 4.2 Ohm). Regarding the probabilities of successful defibrillation, there were no significant differences between the two patient groups. The probabilities of defibrillation at the three multiples of the defibrillation energy requirement using a dual- and single-coil lead system were 82, 89.7 and 93.6 and 77.8, 94.1 and 95.8%, respectively (P=0.88, P=0.42, P=0.62, respectively). CONCLUSIONS: Dual- and single-coil active pectoral defibrillator systems show no difference in defibrillation energy requirements and no difference in the probability of successful defibrillation at multiples of the minimum defibrillation energy requirement. The use of more simplified defibrillator lead systems may contribute to a future lead design focusing on improvement in lead durability.

Aged↗
PubMed2001

[Breast cancer recurrence versus scar. Ultrasonographic differentiation using Levovist as the contrast medium].

AIM: To determine the scope of improving the distinction between a postoperative scar and the recurrence of a breast carcinoma through the use of the ultrasound echo enhancer Levovist? METHOD: In 23 patients with 26 lesions a colour-coded duplex sonography examination before and after administration of Levovist was performed. The parameters investigated were: degree of enhancement, number of tumour vessels and the pattern of vascular morphology and anatomy. RESULTS: Recurrences (n = 15) demonstrated a greater number of vessels and a stronger enhancement after administration of Levovist. Individual vessels were also visible in scars (n = 11). Further evaluations with respect to the pattern of the tumour vascularization are therefore necessary with the exception of one false positive and one negative result a clear distinction was possible. CONCLUSION: The administration of the ultrasound echo enhancer clearly improved the otherwise difficult distinction between a scar and a tumour recurrence through sonography and mammography. Further studies with larger number of patients are necessary to establish the value of the method.

Adult↗
PubMed2001

Activation of Gi-coupled receptors releases a tonic state of inhibited platelet aggregation.

Single-receptor pharmacology does not satisfactorily explain the physiology of the ADP-induced platelet aggregation response. It has been shown that, in addition to Gq-coupled receptor activation, one Gi-coupled receptor, either the ADP P2T or the alpha2-adrenoceptor, is required for elicitation of aggregation. The underlying mechanism of this action, however, has not been elucidated. By systematically assaying the entire time course of the aggregation and its fade using two methods of aggregometry, we have investigated the role of graded activation of these two Gi-coupled receptors. We demonstrate that constant activation of either of two Gq-coupled receptors, the ADP P2Y1 or the 5-HT2A, and incremental activation of either of the two Gi-coupled receptors, tightly regulates the aggregation response in vitro, through the apparent release of a tonic inhibition of platelet aggregation. This tightly regulated release of inhibition, which appears analogous to the phenomena of disinhibition observed in the central nervous system, may be instrumental for the continuous adaptation of the aggregation response to variable physiological conditions.

Adaptation, Physiological↗
PubMed2001

The balance of concurrent aggregation and deaggregation processes in platelets is linked to differential occupancy of ADP receptor subtypes.

Deaggregation, the partial reversal of the initial aggregation of platelets is observed following low, but not higher, micromolar ADP concentrations. This study tested the hypothesis that deaggregation results from a balance between concurrent, opposing, aggregation and deaggregation processes which are ADP (adenosine 5'-diphosphate) receptor occupancy-dependent. Aggregation of human platelet-rich plasma (PRP) prepared in r-hirudin was assayed in a 96-well plate reader over 20 min by measurement of the optical density (OD) at 580 nm. Aggregation and the time to reach peak aggregation were directly proportional to ADP receptor occupancy. The magnitude and time course of the response to ADP were comparable to those previously reported with standard aggregometry. The rate constant of platelet deaggregation, as assessed by a four-compartment kinetic model, was inversely proportional to agonist concentration. The ratio of the rate constants of aggregation and deaggregation was receptor occupancy-dependent and directly proportional to aggregation. Consequently, platelet aggregation was proportional, and deaggregation inversely proportional, to ADP receptor occupancy. We propose that the response of PRP to ADP and to 2-MeS-ADP (2-methylthioadenosine-diphosphate), in vitro, consists of at least two active, concurrent processes, aggregation and deaggregation. Incremental occupancy of the P2T ADP receptor subtype attenuates deaggregation and governs the balance between these two processes.

Adenosine Diphosphate↗
PubMed2001

Deaggregation is an integral component of the response of platelets to ADP in vitro: kinetic studies of literature and original data.

Adenosine diphosphate (ADP) is recognized as an important mediator of platelet aggregation. Transient aggregation at low (< or =1 microM), and sustained aggregation at higher ADP concentrations are consistently observed. Dissociation of platelet aggregates has been described and may explain the reversible component of the aggregation response. We hypothesized that the net aggregation response to ADP in vitro results from the concurrent activation of two opposing processes, aggregation and deaggregation. Different purinergic receptor subtypes may mediate these effects. To test this hypothesis and its generalizability, we performed a kinetic analysis of representative published ADP-induced aggregation responses supplemented with original data from our laboratory. A four-compartment kinetic model was used to estimate k(3), a rate constant of deaggregation. Two model-independent parameters, the magnitude of the aggregation response (DeltaOD) and the time to reach maximal aggregation (t(peak)) were also assessed. Greater sustained aggregation at higher ADP concentrations was consistently associated with increased DeltaOD and t(peak) but decreased k(3) values. These relationships were independent of type of platelet preparation or experimental conditions and not due to ADP receptor desensitization. Conversely, blockade of the P2Y(12) receptor subtype (ticlopidine, clopidogrel or 2-MeS-AMP) decreased DeltaOD and t(peak) but increased k(3) values. This supports the presence of active deaggregation which is decelerated by activation of the P2Y(12) receptor subtype.

Adenosine Diphosphate↗