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Biomedical subjects

R Kaufmann

Publications and source records attributed to R Kaufmann.

At least 55 records · Page 3Linked to original sources
PubMed2001

[Tolerability of a selective cyclooxygenase-2-inhibitor (rofecoxib) in patients with intolerance reactions to nonsteroidal anti-inflammatory agents].

BACKGROUND AND OBJECTIVE: Pseudoallergic reactions triggered by nonsteroidal anti-inflammatory drugs (NSAIDs) are common and caused by inhibition of the enzyme cyclooxygenase-1, whereas their therapeutic effects are mediated by inhibition of cyclooxygenase-2. This study analyzed the tolerability of the selective cyclooxygenase-2-inhibitor rofecoxib in patients who encountered pseudoallergic reactions to NSAIDs. PATIENTS AND METHODS: 37 patients (12 males, 25 females, mean age 35 years [15-75 years]) with a history of pseudoallergic reactions to NSAIDs underwent standardized skin prick, scratch and patch tests along with oral placebo-controlled blinded exposure to rofecoxib (maximum single dose 12.5 mg, cumulative dose 25 mg). RESULTS: 23 patients had skin reactions, 4 times respiratory symptoms were documented, and in 10 cases cutaneous as well as respiratory symptoms were reported. Salicylic acid was identified as the most common trigger for a pseudoallergic reaction (n = 28). In 9 cases several non-steroidal antiphlogistics of different chemical groups caused symptoms. All skin tests showed negative results. Oral challenge with rofecoxib was tolerated by all 37 patients without adverse effects. CONCLUSION: Given the high incidence of pseudoallergic reactions to NSAIDs the use of selective cyclooxygenase-2-inhibitors represents a therapeutic alternative as well as a means of prevention of the described reactions.

Adolescent↗
PubMed2001

Redox-modulated pathways in inflammatory skin diseases.

Inflammatory skin diseases account for a large proportion of all skin disorders and constitute a major health problem worldwide. Contact dermatitis, atopic dermatitis, and psoriasis represent the most prevalent inflammatory skin disorders and share a common efferent T-lymphocyte mediated response. Oxidative stress and inflammation have recently been linked to cutaneous damage in T-lymphocyte mediated skin diseases, particularly in contact dermatitis. Insights into the pathophysiology responsible for contact dermatitis can be used to better understand the mechanism of other T-lymphocyte mediated inflammatory skin diseases, and may help to develop novel therapeutic approaches. This review focuses on redox sensitive events in the inflammatory scenario of contact dermatitis, which comprise for example, several kinases, transcription factors, cytokines, adhesion molecules, dendritic cell surface markers, the T-lymphocyte receptor, and the cutaneous lymphocyte-associated antigen (CLA). In vitro and animal studies clearly point to a central role of several distinct but interconnected redox-sensitive pathways in the pathogenesis of contact dermatitis. However, clinical evidence that modulation of the skin's redox state can be used therapeutically to modulate the inflammatory response in contact dermatitis is presently not convincing. The rational for this discrepancy seems to be multi-faceted and complex and will be discussed.

Dermatitis, Allergic Contact↗
PubMed2001

Evidence for functionally active protease-activated receptor-4 (PAR-4) in human vascular smooth muscle cells.

1. This study investigates, whether in addition to the protease-activated receptor-1 (PAR-1), PAR-4 is present in vascular smooth muscle cells (SMC) of the human saphenous vein and whether this receptor is functionally active. PAR-1 and PAR-4 are stimulated by thrombin and by the synthetic peptides SFLLRN and GYPGQV, respectively. 2. mRNAs for both, PAR-1 and PAR-4, were detected in the SMC by using reverse transcriptase polymerase chain reaction (RT - PCR). 3. Treatment of the SMC with GYPGQV (200 microM) resulted in a transient increase in free intracellular calcium. This calcium signal was completely abolished after a preceding challenge with thrombin (10 nM), indicating homologous receptor desensitization. 4. Stimulation of the SMC with 10 nM thrombin or 200 microM SFLLRN caused a time-dependent activation of the extracellular signal-regulated kinases-1/2 (ERK-1/2) with a maximum at 5 min. In contrast, 100 nM thrombin as well as 200 microM of GYPGQV induced a prolonged phosphorylation of ERK-1/2 with a maximum at 60 min. These data suggest that PAR-1 and PAR-4 are activated by thrombin at distinct concentrations and with distinct kinetics. 5. GYPGQV stimulated [(3)H]-thymidine incorporation in SMC. At 500 microM, the peptide increased DNA synthesis 2.5 fold above controls. A comparable mitogenic effect was obtained after stimulation of the SMC by 10 nM thrombin or 100 microM SFLLRN, respectively. 6. These data indicate that a functionally active PAR-4 is present in SMC and, in addition to PAR-1, might contribute to thrombin-induced mitogenesis.

Amino Acid Sequence↗
PubMed2001

A novel keratinocyte mitogen: regulation of leptin and its functional receptor in skin repair.

Wound re-epithelialization represents a tissue movement that crucially participates in wound closure. Recently, we demonstrated that supplemented leptin improved re-epithelialization processes in leptin-deficient ob/ob mice. In this study we investigated regulation of the leptin system during normal repair in healthy animals. We found leptin to be present at the wound site during healing, although leptin levels were clearly reduced upon injury compared with uninvolved control skin. The functional leptin receptor subtype obRb was observed to be constitutively expressed in nonwounded skin. During early healing, the leptin receptor obRb was downregulated, but re-increased again from day 5 postwounding. Immunohistochemistry revealed that highly proliferative keratinocytes of the wound margin epithelia strongly expressed the functional leptin receptor subtype obRb. In vitro studies demonstrated that murine and human primary epidermal keratinocytes responded to exogenously added leptin with a proliferative response. Moreover, specificity of leptin-mediated mitogenic effects on primary keratinocytes could be shown by completely blocking leptin actions by a soluble, nonfunctional chimeric leptin receptor. Finally, we report that leptin, besides the recently described activation of the janus tyrosine kinase signal transducers, also activated extracellular signal-regulated kinase-controlled signaling pathways in primary keratinocytes.

Animals↗
PubMed2001

Activators of peroxisome proliferator-activated receptors protect human skin from ultraviolet-B-light-induced inflammation.

Peroxisome proliferator-activated receptors (PPAR) are members of a nuclear receptor superfamily, which were initially described in the context of fatty acid degradation and adipocyte differentiation. In this study we tested the hypothesis that peroxisome proliferator-activated receptor activation also controls inflammation. In an in vitro model with human keratinocytes inflammation was mimicked by irradiation with ultraviolet B light (150 mJ per cm(2)). Activators for PPAR-alpha (WY-14,643, clofibrate) were shown to reverse ultraviolet-B-light-mediated expression of inflammatory cytokines (interleukin-6, interleukin-8). An activator preferentially for PPAR-beta (bezafibrate) did not show prominent effects on interleukin-6 and interleukin-8 expression. The anti-inflammatory action of WY-14,643 on skin cells was further demonstrated by in vivo testings in which topically applied WY-14,643 markedly increased the minimal erythema dose in ultraviolet-B-irradiated skin. Additionally, it was shown that ultraviolet B irradiation led to a decrease of all three peroxisome proliferator-activated receptor subsets at the mRNA level. Also transactivation of peroxisome proliferator response element was attenuated by ultraviolet B irradiation. The downregulation of peroxisome proliferator-activated receptors by ultraviolet B irradiation provides a possible mechanism that leads to exaggerated and prolonged inflammation. This work suggests the possibility of PPAR-alpha activators as novel nonsteroidal anti-inflammatory drugs in the topical treatment of common inflammatory skin diseases such as atopic dermatitis, psoriasis, and photodermatitis.

Cell Division↗
PubMed2001

Decreased mRNA stability as a mechanism of glucocorticoid-mediated inhibition of vascular endothelial growth factor gene expression by cultured keratinocytes.

Epidermal keratinocyte-derived overexpression of vascular endothelial growth factor has been functionally linked to increased density of tortuous and hyperpermeable dermal microvessels, representing a characteristic component of cutaneous inflammation. We hypothesized that potent anti-inflammatory properties of synthetic glucocorticoids are attributed in part to their interference with the regulated vascular endothelial growth factor expression by keratinocytes. As vascular endothelial growth factor is markedly upregulated by autocrine transforming growth factor alpha and paracrine hepatocyte growth factor/scatter factor expression, the effect of glucocorticoids on growth-factor-induced vascular endothelial growth factor production by primary and immortalized keratinocytes was examined. Glucocorticoids were shown to suppress vascular endothelial growth factor protein and mRNA expression in a concentration- and time-dependent fashion. In transcriptional activation studies, however, common 5'-regulatory regions of the vascular endothelial growth factor gene failed to confer inhibitory glucocorticoid effects. Instead, glucocorticoids were shown to increase vascular endothelial growth factor mRNA turnover, indicating that post-transcriptional modes of glucocorticoid action are employed to negatively regulate induced vascular endothelial growth factor expression. Together, these studies identify vascular endothelial growth factor upregulation by epidermal keratinocytes as a putative target of glucocorticoid action in cutaneous inflammation. Our data provide strong evidence that mRNA destabilization may represent a mechanism by which glucocorticoids inhibit growth-factor-regulated vascular endothelial growth factor gene expression by keratinocytes.

Adult↗
PubMed2001

Cutaneous mucinosis of infancy: is it a real entity or the paediatric form of lichen myxoedematosus (papular mucinosis)?

We describe a girl presenting with a childhood dermal mucinosis in which we had the unique opportunity to find all the transitional histological features of lichen myxoedematosus (papular mucinosis), from its early focal mucin deposition in the reticular dermis to its late findings of interstitial mucin deposition, dermal fibrosis and fibroblast proliferation. Her father reported having had similar lesions when he was a child, which completely disappeared during adolescence. This case, and a re-evaluation of the literature, suggests that cases of cutaneous mucinosis of infancy that are not hamartomatous conditions such as mucinous naevi are in fact the infantile presentation of lichen myxoedematosus (papular mucinosis) and, in addition to other cases in the literature, suggests a genetic and familial factor in lichen myxoedematosus (papular mucinosis).

Child↗
PubMed2001

Kinetics and dose-response of photosensitivity in cream psoralen plus ultraviolet A photochemotherapy: comparative in vivo studies after topical application of three standard preparations.

BACKGROUND: Topical photochemotherapy with bath psoralen plus ultraviolet (UV) A irradiation (PUVA) has been developed to reduce possible side-effects of oral PUVA therapy. Although the efficacy of bath PUVA therapy appears to be similar to oral PUVA therapy, provision of bathing facilities has obvious economic, logistic and sanitary implications. Cream PUVA therapy has recently been developed as a variation of topical PUVA. OBJECTIVES: To understand the photobiological effects and to increase the safety and effectiveness of this novel topical PUVA therapy, we assessed the kinetics and dose-response of phototoxicity of 8-methoxypsoralen (8-MOP) cream in order to develop a treatment schedule for this treatment option. METHODS: Ninety-eight patients (63 men and 35 women) undergoing cream PUVA therapy were studied. The phototoxic properties of topically applied 8-MOP in three different water-in-oil creams as vehicles were assessed. In a dose-response study, four concentrations of 8-MOP cream (0.0006-0.005%) were used for determination of the minimal phototoxic dose (MPD). The kinetics of photosensitization were tested by determination of MPDs after different application times of 8-MOP cream (10, 20, 30 and 60 min). The persistence of phototoxicity was assessed by UVA exposure at defined time intervals after application of 8-MOP cream (0, 30, 60 and 120 min). RESULTS: The concentration required to produce sufficient but not undue photosensitization of the skin was 0.001% 8-MOP. The duration of application leading to the lowest MPD was 30 min. Greatest photosensitization was achieved when UVA irradiation was performed between 0 and 30 min after 8-MOP removal. These findings showed no significant difference between the three vehicles used. CONCLUSIONS: Based on our data we recommend application of 0.001% 8-MOP in a water-in-oil cream for 30 min. Irradiation with UVA should be performed within 30 min after removal of 8-MOP cream, as there is a rapid decrease in photosensitivity thereafter.

Administration, Cutaneous↗
PubMed2001

Cream psoralen plus ultraviolet A therapy for granuloma annulare.

BACKGROUND: Treatment modalities for granuloma annulare (GA) often remain unsatisfactory or can be accompanied by potentially hazardous side-effects. Psoralen plus ultraviolet (UV) A (PUVA) bath photochemotherapy has been reported to be highly effective in the treatment of GA. Another form of topical PUVA therapy, using 8-methoxypsoralen-containing cream or gel preparations, has been proven to be as effective as bath PUVA therapy in the treatment of palmoplantar dermatoses. OBJECTIVES: To assess the efficacy of cream PUVA photochemotherapy in patients with GA. METHODS: Five patients with GA were treated. The diagnosis was confirmed by pretreatment skin biopsies. Cream PUVA therapy was performed four times a week: the mean number of treatments was 26 (range 17-40) and mean cumulative UVA dose was 55.9 J cm-2 (range 18.2-109.2). RESULTS: Cream PUVA photochemotherapy induced significant clinical improvement (one patient) or clearance (four patients) of GA in all patients. Clearance was documented clinically and histopathologically. CONCLUSIONS: Cream PUVA phototherapy can be highly effective in patients affected by localized forms of GA.

Administration, Cutaneous↗
PubMed2001

The Western blot is a highly sensitive and efficient technique in diagnosing allergy to wasp venom.

BACKGROUND: Diagnosis of allergy to wasp venom and decision to perform immunotherapy are based on the patient's history, along with skin and in vitro tests. OBJECTIVE: Given the high prevalence of specific IgE also in non-allergic individuals, we evaluated the sensitivity and specificity of Western blots as a possible alternative to serum analyses of venom-specific IgE. METHODS: Skin prick and/or intracutaneous tests were performed in 30 patients with allergy to wasp venom (generalized reaction following sting) along with serum analysis of venom-specific IgE (AlaSTAT microplate) and Western blots. Western blots were subsequently scanned and evaluated qualitatively and semiquantitatively by means of densitometry. Bands were scored 'positive' in cases of signal intensities beyond the mean plus 3 standard deviations of control sera. Twenty newborns (age 2-7 days) and 30 adults without systemic or increased local reactions to hymenoptera stings served as controls. RESULTS: Western blot sensitivity reached 100% in the samples studied and was thus superior to the sensitivities of serum analysis of venom-specific IgE using AlaSTAT microplate assay (90%) and skin tests (87%). The sensitivity of detection of a phospholipase A1 and antigen 5-specific band was higher compared with a hyaluronidase-specific band (97%, 97% and 86%, respectively). Twenty-four out of twenty-nine (83%) patients exhibited specific IgE antibodies against at least three distinct allergens. With regard to the specificities, skin tests as well as AlaSTAT microplate assays were comparable (90% and 93%, respectively), whereas the specificity of the Western blots was 70% if the appearance of any single band was regarded as a positive result. However, when analysing the appearance of a specific band for antigen 5 or hyaluronidase the specificity and overall diagnostic value increased markedly, making it the most efficient test (specificity 97% and 100%, efficiency 96.8% and 93.2%, respectively). CONCLUSION: As allergy to wasp venom is a severe and potentially life threatening disease, false-negative test results need to be minimized. Therefore, the superiority of the Western blot with regard to sensitivity, specificity and overall efficiency makes this technique a valuable tool for its diagnosis.

Adolescent↗
PubMed2001

Role of Erbium:YAG laser in the treatment of aged skin.

Laser resurfacing procedures in actinic skin damage and the treatment of disorders associated with skin ageing are becoming more popular. For both purposes Erbium:YAG laser-technology enables us to perform a highly precise skin ablative work, which can be most helpful in the removal of circumscribed skin lesions of ageing skin as well as in larger skin resurfacing procedures. In most circumstances, superficial skin ablation is not technically demanding, is not associated with major discomfort, and can be controlled with precision. Tissue sparing ablation is of special value in the treatment of disorders in atrophic skin of elderly patients or in more delicate areas, where it can avoid prolonged healing and unwarranted side-effects.

Aluminum↗
PubMed2001

The TCR-delta repertoire in normal human skin is restricted and distinct from the TCR-delta repertoire in the peripheral blood.

The skin and the intestinal mucosa form surfaces to external environments and share similarities in anatomic structure and immunologic defense. In healthy humans, intestinal gamma/delta T cells express a highly restricted gamma/delta T cell receptor repertoire whereas gamma/delta T cells of the skin were thought to express a polyclonal repertoire. Herein we report, using complementarity-determining region 3 size spectratyping and nucleotide sequencing of T cell receptor DV1 and DV2 rearrangements, that the human skin is also composed of clonally expanded gamma/delta T cells that are widely distributed. Identical complementarity-determining region 3 profiles and T cell receptor delta rearrangements were found in two separate skin samples that were obtained as far as 2-10 cm apart. Furthermore, analysis of peripheral blood mononuclear cells of these subjects clearly demonstrated that the skin harbors a unique population of gamma/delta T cells that is distinct from that in the peripheral blood. In addition comparable data were obtained irrespective of whether DNA or RNA was analyzed, indicating that the observed oligoclonality is not secondary to the expression of large amounts of mRNA from a few activated cells. Thus, gamma/delta T cells of the skin and the intestine both express an oligoclonal repertoire that enables them to respond to a variety of deleterious antigens without the need for diverse T cell receptors, possibly by recognition of stress-induced self-antigens or of conserved foreign antigens.

Clone Cells↗
PubMed2001

Antagonistic effects of the staphylococcal enterotoxin a mutant, SEA(F47A/D227A), on psoriasis in the SCID-hu xenogeneic transplantation model.

Psoriasis is a T-cell-mediated immune dermatosis probably triggered by bacterial superantigens. This pathomechanism has been experimentally reproduced in a SCID-hu xenogeneic transplantation model. We analyzed the effects of different bacterial superantigens on the induction of psoriasis in this model. Staphylococcal enterotoxin B and exfoliative toxin triggered the onset of psoriasis when administered repetitively intracutaneously over a period of 2 wk, whereas staphylococcal enterotoxin A representing a distinct subfamily of staphylococcal enterotoxins only mimicked certain aspects of psoriasis. The biologic effects of staphylococcal enterotoxin A were more pronounced when a mutated form, SEA(H187A), of this superantigen with reduced affinity to major histocompatibility complex class II was coinjected. Another mutated variant, SEA(F47A/D227A), exhibiting no measurable major histocompatibility complex class II affinity blocked the effects triggered by wild-type staphylococcal enterotoxin A when injected in a 10-fold higher dose. Inhibition was specific as induction of psoriasiform epidermal changes by staphylococcal enterotoxin B could not be blocked. As staphylococcal enterotoxin A, in contrast to the other superantigens tested, is capable of inducing epidermal thickening but not the typical appearance of psoriasis, we conclude that bacterial superantigens may differ with regard to their effects on human nonlesional psoriatic skin. Staphylococcal-enterotoxin-A-mediated effects were blocked by a genetically engineered superantigen highlighting the potential therapeutic use of mutated superantigens.

Animals↗