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Biomedical subjects

M Schön

Publications and source records attributed to M Schön.

At least 19 recordsLinked to original sources
PubMed2004

Prognostic significance of detecting micrometastases by tyrosinase RT/PCR in sentinel lymph node biopsies: lessons from 322 consecutive melanoma patients.

This prospective study was performed to determine the prognostic value of tyrosinase mRNA detection in sentinel lymph nodes (SLN) of melanoma patients. About 847 SLNs from 322 consecutive patients were assessed by histopathology and immunohistochemistry as well as tyrosinase-reverse transcriptase-polymerase chain reaction (RT/PCR) for the presence of micrometastases. The results were correlated with the prognostic parameters employing a multivariate analysis after a median follow-up of 37 months. Histopathological analysis revealed metastases in 34/322 patients (10.6%). Among the 288 patients with histopathologically negative SLN, tyrosinase-mRNA was detected in 39 patients. A relapse of the tumour occurred in 44.1% of the patients with histopathologically positive SLN, in 25.6% with histopathologically negative, but tyrosinase-RT/PCR-positive SLN, and 8.0% with "double-negative" SLN. A multivariate analysis identified tumour thickness, the histopathological SLN status, and the ulceration of the primary tumour as independent prognostic factors. Thus, by assessing tyrosinase mRNA in the SLN of melanoma patients, we identified a subgroup with histopathologically negative, but Tyr-RT-PCR-positive SLN who have a high risk of disease relapse.

Adolescent↗
PubMed2004

Immune modulation and apoptosis induction: two sides of the antitumoral activity of imiquimod.

Imiquimod, the first member of the imidazoquinoline family of immune response modifiers, has proven good clinical efficacy against basal cell carcinomas and actinic keratoses in several independent studies. In addition, there is recent evidence that imiquimod is also efficacious against other tumors such as cutaneous metastases of malignant melanoma or vascular tumors. Imiquimod exerts its antitumoral effect, at least in part, through binding to TLR-7 and TLR-8 on dendritic cells followed by secretion of a multitude of proinflammatory cytokines. The net result of this proinflammatory activity is a profound tumor-directed cellular immune response. However, recent experimental and clinical data indicate that imiquimod also possesses considerable direct pro-apoptotic activity against tumor cells both in vitro and in vivo. This novel mode of action appears to be independent of membrane bound death receptors, but involves caspase activation. Induction of apoptosis by imiquimod is, at least in part, presumably mediated through Bcl-2-dependent release of mitochondrial cytochrome c and subsequent activation of caspase-9. The structural analogue, resiquimod, exhibited very limited, if any, such pro-apoptotic activity, possibly due to its lacking ability to enter the cell. Bypassing molecular mechanisms of apoptosis deficiency by a topical compound may be of great utility for treating certain cutaneous tumors.

Adjuvants, Immunologic↗
PubMed2001

Simultaneous carotid artery reconstruction in patients undergoing other surgical interventions.

Abstract. We performed 343 vascular reconstructions of the supraaortal arteries from April 1996 to April 2000. Of these patients, 30 underwent combined vascular reconstructions - 22 combined extrathoracal and 8 combined transthoracal reconstructions. In 15 patients, carotid endarterectomy was combined with other cervical surgical interventions. In 10 patients, the vascular operation was combined with surgical interventions in other regions. No permanent complications were observed 8-52 months postoperatively, with the exception of one hemiparesis in the complex vascular operations. Consequently, we recommend the simultaneous surgical approach after careful individual assessment.

Adult↗
PubMed2001

Role of integrin alphaE(CD103)beta7 for tissue-specific epidermal localization of CD8+ T lymphocytes.

Tissue-specific T cell localization is crucial for immune surveillance of normal tissues and the pathogenesis of inflammatory disorders. In psoriatic skin, CD8+ lymphocytes predominantly reside within the epidermis, whereas CD4+ T cells are most abundant within the dermis. Molecular mechanisms guiding this spatial compartmentalization are not completely understood, however. Here, we demonstrate that 55% (+/-9.7%, n = 14) of the epidermal T cells, predominantly of the CD8+ phenotype, expressed the integrin alphaE(CD103)beta7. In contrast, only 5% (+/-2.0%) of the dermal T cells were alphaE(CD103)beta7+. Integrin alphaE(CD103)beta7 was not detected in normal skin (n = 10), and less than 1% of peripheral blood lymphocytes derived from normal (n = 11) or psoriatic (n = 10) donors expressed alphaE(CD103). When cultured T lymphoblasts (n = 12 donors) were stimulated with transforming growth factor beta1, expression of integrin alphaE(CD103)beta7 was induced on 52.8% (+/-16.2%) of CD8+ cells, but only on 6.1% (+/-2.3%) of CD4+ cells, suggesting selective inducibility on CD8+ lymphocytes. Whereas similar overall expression of transforming-growth-factor-beta1-specific mRNA was detected in normal and psoriatic skin by real-time quantitative polymerase chain reaction, immunohistochemistry revealed focal overexpression of transforming growth factor beta1 underneath psoriatic, but not normal, epidermis. This heterogenous transforming growth factor beta1 expression may contribute to induction of alphaE(CD103) in vivo. Adhesion of transforming-growth-factor-beta1-stimulated CD8+, but not CD4+, T cells to cultured keratinocytes and psoriatic epidermis in frozen sections could be significantly inhibited by antibodies that blocked the alphaE(CD103)/E-cadherin interaction. Co-culture of lymphoblasts and keratinocytes resulted in marginal enhancement of alphaE(CD103)beta7 expression in some cases. Overall, integrin alphaE(CD103)beta7 appears to contribute to tissue-specific epidermal localization of CD8+ T lymphocytes.

Antigens, CD↗
PubMed2001

Pathogenic function of IL-1 beta in psoriasiform skin lesions of flaky skin (fsn/fsn) mice.

IL-1 acts on many cells as an inflammatory mediator. Its two forms, IL-1 alpha and IL-1 beta, are regulated differentially within hyperproliferative inflammatory skin conditions, such as psoriasis. While IL-1 alpha is down-regulated within psoriatic lesions, the levels of IL-1 beta are increased. However, some investigators have described an inactive form of IL-1 beta in psoriasis, while others have detected increased IL-1 beta activity within these lesions. Thus, its in vivo role remains unclear. We have assessed expression and function of IL-1 beta within psoriasiform skin lesions of the spontaneous mouse mutation flaky skin (fsn/fsn ). It was found that IL-1 beta was increased by 357% within psoriasiform lesions of fsn/fsn mice compared with their wild-type or heterozygous (+/?) littermates (P < 0.00001). When the IL-1 beta function was inhibited by i.p. injection with a neutralizing MoAb, no effects were seen in +/? mice. In contrast, psoriasiform features in fsn/fsn mice were alleviated dramatically, as demonstrated by a 40% decrease of the epidermal thickness and a diminished number of intra-epidermal microabscesses. In addition, infiltrating epidermal CD4(+) and CD8(+) T cells were decreased by 68% and 81%, respectively (P < 0.05), and epidermal Langerhans cells also were reduced by 36% (P < 0.005). In contrast, mast cells were not affected, suggesting differential responses of various cutaneous cell types. Our results demonstrate an important in vivo role of IL-1 beta for the generation of hyperproliferative inflammatory skin lesions in the fsn/fsn model.

Animals↗
PubMed2001

Experimental evaluation of a cell module for hybrid liver support.

Aim of the study was to evaluate a hybrid liver support system in a porcine model of acute liver failure, after hepatectomy. Pigs with a body weight of 70+/-18 kg underwent total hepatectomy and porto-cavo-caval shunting as well as ligation of the bile duct and the hepatic artery. Control animals were connected to the system (including capillary membrane plasma separation) containing a four compartment bioreactor with integral oxygenation and decentralized mass exchange but without liver cells. The treatment group received hybrid liver support with the same system including 370+/-42 g primary isolated porcine parenchymal liver cells in co-culture with hepatocyte nursing cells, tissue engineered to liver- like structures at high density. Treatment started after complete recovery from anesthesia and was performed continuously. A positive influence on peripheral vascular resistance and a reduced need of catecholamine dosage was observed in the treatment group. Hybrid liver support with a cell module upscaled for clinical application significantly prolonged survival time in animals after hepatectomy with the longest survival being 26 hours in the control group an 57 hours in the treatment group.

Animals↗
PubMed2000

Cutaneous inflammatory disorder in integrin alphaE (CD103)-deficient mice.

The integrin alpha(E)beta(7) is thought to play an important role in the localization of mucosal, but not of cutaneous T lymphocytes. Thus, it was surprising that 89% of adult alpha(E)(-/-) mice on the 129/Sv x BALB/c background developed inflammatory skin lesions without an apparent infectious etiology. Skin inflammation correlated with alpha(E) deficiency in mice with a mixed 129/Sv x BALB/c background, but not in mice further backcrossed to BALB/c and housed in a second animal facility. These studies suggested that alpha(E) deficiency, in combination with other genetic and/or environmental factors, is involved in lesion development. The lesions were infiltrated by CD4(+) T cells and neutrophils, and associated with increased expression of inflammatory cytokines. Furthermore, skin inflammation resulted from transfer of unfractionated alpha(E)(-/-) splenocytes into scid/scid mice, but not from transfer of wild-type splenocytes, suggesting that the lesions resulted from immune dysregulation. We also studied the role of alpha(E)beta(7) in a murine model of hyperproliferative inflammatory skin disorders that is induced by transfer of minor histocompatibility-mismatched CD4(+)/CD45RB(high) T cells into scid/scid mice under specific environmental conditions. Under housing conditions that were permissive for lesion development, transfer of alpha(E)-deficient CD4(+)/CD45RB(high) T cells significantly exacerbated the cutaneous lesions as compared with lesions observed in mice reconstituted with wild-type donor cells. These experiments suggested that alpha(E)-expressing cells play an important role during the course of cutaneous inflammation. In addition, they suggest that alpha(E)beta(7) deficiency, in combination with other genetic or environmental factors, is a risk factor for inflammatory skin disease.

Adoptive Transfer↗
PubMed2000

Reduced gut intraepithelial lymphocytes in VLA1 null mice.

Very late antigen 1 (VLA1) is an integrin collagen receptor that is expressed by lymphocytes in several disease states. VLA1 blockade has been shown to ameliorate gut disease in experimental graft-versus-host disease. Here we show that in the VLA1 null mouse, which is generally healthy, there is a 50% reduction in gut intraepithelial lymphocytes (IELs) despite an otherwise normal lymphocyte distribution in peripheral blood and lymphoid organs. The gammadelta to alphabeta ratios of IELs are unchanged. We also find that IL2-stimulated splenocytes from VLA1 null animals show a deficiency in adhesion to fibrillar and basement membrane collagen as well as reduced proliferation in response to collagen substratum. These results suggest that some, but not all, intraepithelial lymphocytes require VLA1 to survive or proliferate within the gut epithelium or possibly to traverse the basement membrane.

Animals↗
PubMed2000

Basal-cell adhesion molecule (B-CAM) is induced in epithelial skin tumors and inflammatory epidermis, and is expressed at cell-cell and cell-substrate contact sites.

Basal-cell adhesion molecule (B-CAM) is a 90 kDa cell surface glycoprotein of the immunoglobulin superfamily that functions as a laminin-binding receptor. B-CAM is upregulated following malignant transformation of some cell types in vivo and in vitro, thus being a candidate molecule involved in tumor progression. As cutaneous distribution and function of B-CAM are largely unknown, we have studied its expression and regulation in normal and diseased human skin. In normal skin, B-CAM was expressed by endothelial cells of dermal blood vessels. In contrast, B-CAM was strongly upregulated within the tumor tissue of both malignant and benign epithelial skin tumors, including basal cell carcinomas, squamous cell carcinomas, keratoacanthomas, and common warts. Transformation-associated upregulation was confirmed in vitro, but normal keratinocytes also expressed B-CAM under culture conditions. Interestingly, the basal epidermal layer of normal-appearing skin surrounding the tumors also expressed B-CAM, and B-CAM were induced on the basal and apicolateral surfaces of basal keratinocytes in inflammatory skin disorders suggesting transformation-independent mechanisms of epidermal induction of the B-CAM. Immunoelectron microscopy studies of cultured transformed keratinocytes revealed that B-CAM was expressed at cell-cell and cell-substrate contact sites. Halting proliferation of transformed keratinocytes through cytostatic drugs resulted in decreased B-CAM synthesis. Likewise, inducing terminal differentiation in keratinocyte cultures by increasing the Ca(2+) concentration in the medium decreased B-CAM expression. In contrast, both ultraviolet A and B irradiation of cultured human keratinocytes resulted in significantly increased expression of the B-CAM. Overall, it appears that B-CAM expression in human skin is associated with activated states of keratinocytes, and that B-CAM may be involved in cell-cell adhesion or migration, in addition to its known function as a laminin receptor. J Invest Dermatol 115:1047-1053 2000

Carcinoma↗
PubMed2000

Critical role of neutrophils for the generation of psoriasiform skin lesions in flaky skin mice.

Although T cell dysregulation is thought to underlie the pathogenesis of psoriasis, prominent infiltration and microabscess formation by neutrophils is a distinctive hallmark feature of this common disorder. The exact role of neutrophils in the pathogenesis of psoriasiform alterations in vivo, however, is unknown. Similar to human psoriasis, flaky skin mice (fsn/fsn) revealed a prominent infiltrate of neutrophils, and microabscesses within the hyperproliferative epidermis were associated with de novo expression of intercellular adhesion molecule-1. Intraperitoneal injection with the neutrophil-depleting RB6-8C5 monoclonal antibody (anti-Ly-6G) resulted in a dramatic reduction of the epidermal thickness by 58% compared with isotype-treated animals (p < 0.001). In addition, epidermal microabscesses were conspicuously absent (p < 0.001), and cutaneous neutrophils and T cells, but not mast cells or dendritic cells, were markedly reduced in anti-Ly-6G-treated mice. Proinflammatory cytokines, including tumor necrosis factor alpha and interleukin-1, were also downregulated. Therapeutic effects occurred as early as 4 d after beginning of treatment. Wildtype skin was not affected. When the integrin alphaMbeta2 (CD11b/CD18), which mediates neutrophil localization through binding to intercellular adhesion molecule-1, was blocked in vivo with the M1/70 monoclonal antibody, the epidermal thickness was reduced by 31% (p < 0.002), and neutrophil and T cell accumulation was diminished compared with control animals. Likewise, treatment of fsn/fsn mice with the MP1-22E9 monoclonal antibody neutralizing granulocyte macrophage-colony stimulating factor, a cytokine stimulating neutrophils by upregulating alphaMbeta2, resulted in significant reduction of inflammation and acanthosis by 30% (p < 0.003). These results demonstrate a critical pathogenic role of neutrophils for hyperproliferative inflammatory lesions in fsn/fsn mice, suggesting that blocking neutrophil function may have therapeutic benefit in some human skin disorders.

Abscess↗
PubMed1999

Tension and bending, but not compression alone determine the functional adaptation of subchondral bone in incongruous joints.

In the present study, we tested the hypothesis that tension and bending, rather than compression alone, determine the functional adaptation of subchondral bone in incongruous joints. We investigated whether tensile stresses in the subchondral bone of the humero-ulnar articulation are affected by the direction of muscle and joint forces, and whether the tensile stresses are large enough to cause microstructural adaptation, specifically a preferential alignment of the trabeculae and the subchondral collagen fibres. Using a previously validated finite element model of the human humero-ulnar joint, we calculated the contact pressure, the principal compressive and tensile stresses, and the strain energy density in the subchondral bone for various flexion angles. A bicentric (ventro-dorsal) pressure distribution was found in the joint at 30 degrees to 120 degrees of flexion, with contact pressures of up to between 2.5 and 3 MPa in the ventral and dorsal aspects of the ulnar joint surface, but less than 0.5 MPa in the centre. The principal tensile stress in the subchondral bone of the trochlear notch quantitatively exceeded the principal compressive stress at low flexion angles (maximum 8.2 MPa), and the distribution of subchondral strain energy density differed substantially from that of the contact stress (r=-0.72 at 30 degrees and r=+0.58 at 90 degrees of flexion). No important tensile stress was computed in the trochlea humeri. On contact radiography, we found sagittally orientated subarticular trabeculae in the notch, running tangential to the surface. Furthermore, we observed sagittally orientated split lines in the subchondral bone of the notch of 20 cadaver joints, suggesting a ventro-dorsal orientation of the collagen fibres. The trochlea humeri, on the other hand, did not show a preferential direction of the subchondral split lines, these findings confirming the predictions of tensile stresses in the model. We conclude that, due to the important contribution of tension to subchondral bone stress, the distribution of subchondral density cannot be directly employed for assessing the long term distribution of joint pressure at the cartilage surface. The magnitude of the tensional stress varies considerably with the direction of the muscle and joint forces, and it appears large enough to cause functional adaptation of the subchondral bone on a microstructural level.

Adaptation, Physiological↗
PubMed1999

[Preferential direction of collagen fibrils in the sub-chondral bone bone and the hip and shoulder joint].

We hypothesised that--due to bending and tension--there should exist a preferential direction of the collagen fibrils in the subchondral bone of the concave components of the hip and shoulder joint that results from bicentric or eccentric loading, but there should be no preferential direction in the convex joint partners. We therefore examined 25 human hip and 27 shoulder joints, these being decalcified after maceration. To analyse the preferential direction of the collagen fibrils, we used the split line method. The subchondral plate was pierced at regular intervals with needles that had been previously dipped in diluted ink. In the acetabulum, we found a predominantly transverse direction of the split lines in the ventral and dorsal horn of the lunatic surface, and these usually continued through the acetabular fossa. In the ventral part of the acetabular roof, arch-like orientations of the split lines were observed. In the glenoid cavity, a clearly preferential orientation was found in anterior-posterior direction, usually in the middle third of the articular surface. In the femoral and humeral heads, no preferential direction of the split lines was observed in any of the specimens. We interpret the split-line patterns in the acetabulum as an expression of the tensile stress that is encountered during a "spreading open" of the socket upon bicentric (ventral-dorsal) loading in the physiologically incongruous joint. In the glenoid, the relatively weak bony support in the ventral and dorsal part of the articular surface may be responsible for bending and tensile stress, particularly in view of eccentric loading during dynamic activity, and this could explain the observed anterio-posterior split line pattern. The results support the idea that the subchondral bone of concave joint partners encounters tension, leading to a preferential direction of the collagen fibrils. This can be considered as a functional adaptation of the subchondral bone on a microstructural level.

Aged↗
PubMed1999

Derangement of Kupffer cell functioning and hepatotoxicity in hyperthyroid rats subjected to acute iron overload.

Liver oxidative stress, Kupffer cell functioning, and cell injury were studied in control rats and in animals subjected to L-3,3',5-tri-iodothyronine (T3) and/or acute iron overload. Thyroid calorigenesis with increased rates of hepatic O2 uptake was not altered by iron treatment, whereas iron enhanced serum and liver iron levels independently of T3. Liver thiobarbituric acid reactants formation increased by 5.8-, 5.7-, or 11.0-fold by T3, iron, or their combined treatment, respectively. Iron enhanced the content of protein carbonyls independently of T3 administration, whereas glutathione levels decreased in T3- and iron-treated rats (54%) and in T3Fe-treated animals (71%). Colloidal carbon infusion into perfused livers elicited a 109% and 68% increase in O2 uptake in T3 and iron-treated rats over controls. This parameter was decreased (78%) by the joint T3Fe administration and abolished by gadolinium chloride (GdCl3) pretreatment in all experimental groups. Hyperthyroidism and iron overload did not modify the sinusoidal efflux of lactate dehydrogenase, whereas T3Fe-treated rats exhibited a 35-fold increase over control values, with a 54% reduction by GdCl3 pretreatment. Histological studies showed a slight increase in the number or size of Kupffer cells in hyperthyroid rats or in iron overloaded animals, respectively. Kupffer cell hypertrophy and hyperplasia with presence of inflammatory cells and increased hepatic myeloperoxidase activity were found in T3Fe-treated rats. It is concluded that hyperthyroidism increases the susceptibility of the liver to the toxic effects of iron, which seems to be related to the development of a severe oxidative stress status in the tissue, thus contributing to the concomitant liver injury and impairment of Kupffer cell phagocytosis and particle-induced respiratory burst activity.

Animals↗
PubMed1999

Human sweat gland myoepithelial cells express a unique set of cytokeratins and reveal the potential for alternative epithelial and mesenchymal differentiation states in culture.

We have characterized precisely the cytokeratin expression pattern of sweat gland myoepithelial cells and have identified conditions for propagating this cell type and modulating its differentiation in culture. Rare, unstratified epithelioid colonies were identified in cultures initiated from several specimens of full-thickness human skin. These cells divided rapidly in medium containing serum, epidermal growth factor (EGF), and hydrocortisone, and maintained a closely packed, epithelioid morphology when co-cultured with 3T3 feeder cells. Immunocytochemical and immunoblot analysis disclosed that the cells differed from keratinocytes in that they were E-cadherin-negative, vimentin-positive, and expressed an unusual set of cytokeratins, K5, K7, K14, and K17. When subcultured without feeder cells, they converted reversibly to a spindle morphology and ceased K5 and K14 expression. Under these conditions, EGF deprivation induced flattening, growth arrest, and expression of alpha-smooth muscle actin ((&agr;)-sma). Coexpression of keratins and alpha-sma is a hallmark of myoepithelial cells, a constituent of secretory glands. Immunostaining of skin sections revealed that only sweat gland myoepithelial cells expressed the same pattern of keratins and alpha-sma and lack of E-cadherin as the cell type we had cultured. Interestingly, our immunocytochemical analysis of ndk, a skin-derived cell line of uncertain identity, suggests that this line is of myoepithelial origin. Earlier immunohistochemical studies by others had found myoepithelial cells to be K7-negative. We tested five K7-specific antibodies that can recognize this protein in western blots and in the assembled keratin filaments of mesothelial cells. Three of these antibodies did not recognize the K7 present in myoepithelial cell filaments or in HeLa cell filaments, indicating that some K7 epitopes are masked when K7 pairs with K17 instead of with its usual keratin filament partner, K19.

Biopsy↗
PubMed1997

Systemic liberation of interleukin-8 in the perioperative phase of liver transplantation.

Serum levels of interleukin-8 (IL-8) were investigated in the perioperative phase of liver transplantation (LTx) in order to help determine whether this cytokine might serve as a parameter for preservation injury. In a study of 45 patients undergoing LTx, systemic IL-8 was estimated at the end of the anhepatic phase, at 30, 60, and 120 min after reperfusion of the graft, and 24 h and 7 days after LTx. A maximum mean concentration of 665 +/- 135 pg/ml was seen 60 min after LTx. The minimum was found on the 1st postoperative day (POD 1): 328 +/- 33 pg/ml. Significant changes were found between 60 min and PODs 1 and 7, as well as between 120 min and POD 1. Differences in cold ischemia time were not found to be significant. We conclude that monitoring of systemic IL-8 levels is not useful in the development of new liver preservation concepts.

Adult↗
PubMed1997

Cultured dermal papilla cells of the rat vibrissa follicle. Proliferative activity, adhesion properties and reorganization of the extracellular matrix in vitro.

The dermal papilla of the mammalian hair follicle plays an important role in regulating and controlling the hair cycle. Distinct functional stages of dermal papilla cells (DPC) are involved in this process, thus suggesting that the dermal papilla is a highly specialized suborgan of the pilosebaceous unit. The aim of the present study was to investigate the functional properties of cultured DPC in various assays and to compare their functional properties with those of dermal fibroblasts (DFB). In monolayer cell cultures DPC showed an aggregative growth pattern, different to that of DFB, and lower proliferation rates, as compared to the controls. Adhesion assays performed using a 51[Cr]labeling method showed strong adhesion of both cell populations to collagen types I and IV, fibronectin and laminin, but DPC in vitro showed significantly higher adhesiveness to collagen type IV, a major component of the basement membrane of dermal papillae in vivo. The capacity of DPC to reorganize extracellular matrix components, as measured by gel contraction with three-dimensional collagen type I lattices, proved to be significantly lower than that of DFB and, moreover, DPC lysed the collagen lattices completely after 48 h in culture. The functional differences between DPC and DFB were paralleled by higher surface expression and synthesis levels of the beta 1, alpha 1, and alpha 5 chains of integrin adhesion receptors in DPC, as detected by fluorescence-activated cell-sorter analysis and radioimmunoprecipitation. These findings provide evidence that DPC are a highly specialized cell population, which clearly differs from another mesenchymal cell type, DFB. After their isolation and cultivation in vitro, DPC still preserve functional properties related to important steps of cell-matrix interaction involved in the hair cycle.

Animals↗