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Biomedical subjects

K Wolff

Publications and source records attributed to K Wolff.

At least 127 records · Page 7Linked to original sources
PubMed1996

Clearing of psoriasis by a novel immunosuppressive macrolide.

Accumulating evidence suggests that psoriasis may be a genetically determined immunogenic, inflammatory disorder based on an ongoing autoreactive Th-1 response. Systemic immunosuppressive therapy is highly effective but fraught with longterm side effects. Our research therefore focuses on therapeutic strategies that induce local immunosuppression in the skin by topical, transepidermal delivery of immunosuppressive drugs. SDZ 281-240 is a newly developed macrolide of the ascomycin type. It is immunosuppressive by mechanism of action similar to that of FK506 but has no antiproliferative activity against keratinocytes in vitro. To evaluate whether SDZ 281-240 exhibits antipsoriatic activity when applied topically, we tested 15 patients with severe, recalcitrant psoriasis, using a microplaque assay in randomized, double-blind, placebo-controlled study, comparing the therapeutic efficacy of the macrolide with a potent halogenated corticosteroid and vehicle. All patients showed a significant improvement of psoriatic lesions treated with two concentrations of the macrolide and, as expected, with the corticosteroid but not with placebo. Both concentrations of the macrolide led to clearing of psoriasis after 10 days of treatment and biopsies confirmed a reversal of the histopathological and immunopathological phenotype of psoriasis to that of normal skin. Thus, an immunosuppressive agent that interferes with early T cell activation can be designed to penetrate into psoriatic lesions when applied topically and to be functionally active within the skin to suppress the ongoing psoriatic process.

Administration, Topical↗
PubMed1996

Human delayed-type hypersensitivity reaction in a SCID mouse engrafted with human T cells and autologous skin.

We have developed and animal model to study human delayed-type hypersensitivity reactions occurring in a human environment within a mouse host. Human skin was grafted onto the backs and autologous human immune cells were injected into the peritoneal cavity of mice with severe combined immunodeficiency. Seven and 14 d after grafting, 2-50% of total white blood and spleen cells were of human origin. Mouse spleen-derived human T cells from tetanus toxoid-sensitized donors proliferated in response to tetanus toxoid as measured by [3H]thymidine uptake, and the strength of this proliferative response equaled that with pre-graft T cells from the same donor. Proliferation was blocked with monoclonal antibodies to human but not to mouse major histocompatibility complex antigens and with anti-human CD4 monoclonal antibodies. In vivo vaccination of mice with tetanus toxoid did not enhance proliferation of mouse spleen-derived human T cells in response to antigen. Injection of tetanus toxoid into the human skin graft caused a perivascular human CD4+/CD25+ T-cell infiltrate, which was not present when tetanus toxoid was injected into adjacent mouse skin. We conclude that human T cells grafted into mice with severe combined immunodeficiency retain their function, that human T cells specifically recognize human but not mouse skin as homing sites, and that human T-cell responses depend on the human micro-environment. This model lends itself to studies of endothelium-T-cell interactions, T-cell activation within skin, and chronic inflammatory skin diseases.

Animals↗
PubMed1996

Effects of endothelin-1 and the ETA receptor antagonist BQ-123 on resistance arteries from normal pregnant and preeclamptic women.

OBJECTIVE: To compare the effect of endothelin on isolated resistance arteries from different vascular beds in normal and preeclamptic women before and after pretreatment with the ETA receptor antagonist BQ-123. MATERIALS AND METHODS: Resistance arteries from myometrial and omental biopsies obtained at cesarean section of normal pregnant and preeclamptic women were dissected and mounted in organ baths for recording of isometric tension. The contractile response to endothelin-1 in presence and absence of BQ-123 was recorded. RESULTS: Endothelin-1 induced similar concentration-dependent contractions in all arteries investigated. In women with preeclampsia the contractile response induced by endothelin-1 was significantly higher in omental as compared to myometrial vessels. Pretreatment with BQ-123 significantly shifted the concentration-response curve to the right but only reduced the maximum contractile response in omental vessels. CONCLUSION: Endothelin-1 is a potent constrictor of resistance arteries from different vascular beds in normal pregnancy and preeclampsia. The contractile effect is at least in part mediated by ETA receptors, since it was significantly reduced after pretreatment with BQ-123. In preeclamptic but not in normal pregnant women the response to endothelin-1 was reduced in myometrial as compared to omental arteries, possibly secondary to receptor down regulation.

Adult↗
PubMed1996

Selective calmodulin antagonists fail to inhibit phorbol ester-induced superoxide anion release from human neutrophils: effects of antifungal azole derivatives.

The ability of antifungal azole derivatives to inhibit superoxide anion release from human leucocytes and the relevance of their documented calmodulin (CaM) antagonism was investigated with respect to anti-inflammatory drug activity. Econazole, miconazole and clotrimazole were found to inhibit phorbol ester-induced release of superoxide anions from human polymorphonuclear leucocytes effectively with IC50 values in the range of 36-162 mumol/l. In contrast, bifonazole and ketoconazole produced minimal or no inhibition, thus suggesting that mechanisms other than inhibition of superoxide anion release may largely account for their clinical activity in inflammatory skin disorders. The selective CaM antagonist J-8, which was used as a reference, failed to inhibit the release process, whereas W-7 as a dual CaM/protein kinase C inhibitor induced dose-dependent inhibition. When tested on protein kinase C activity in vitro, econazole, miconazole and clotrimazole were inhibitory, but bifonazole and ketoconazole were without significant effect. It is thus concluded that inhibition of superoxide anion release reflects the ability of these drugs to inhibit protein kinase C, but not their potency to antagonize CaM. Given the role of reactive oxygen species in tissue damage by neutrophils, we propose protein kinase C, rather than CaM, as another potential target of anti-inflammatory therapy.

Animals↗
PubMed1996

Non-prescribed drug use during methadone treatment by clinic- and community-based patients.

We investigated the efficacy of methadone maintenance treatment in clinic-based (n = 10) and community-based (n = 10) patients by studying the relationships between dose, plasma concentrations of methadone and non-prescribed drug-use using logistic regression. We found that clinic-based patients had significantly reduced odds of having a urine sample test positive for illicit drugs when compared to community-based patients (OR = 0.20; 95% confidence interval 0.10-0.38: p < 0.001). There was no relationship between either methadone dose or plasma methadone concentration and testing positive for non-prescribed drugs (including cocaine, cannabis, amphetamine, ecstasy, benzodiazepines). We looked specifically at the misuse of opiate drugs. Location was again important and clinic-based patients had significantly reduced odds of having a urine sample test positive for opiate drugs (OR = 0.36, 95% confidence interval 0.18-0.71: p approximately 0.004). Opiate drug use in our patients was also significantly related to plasma methadone concentration, increasing noticeably when the drug concentration < 0.48 nmol/L (p approximately 0.04). We found no relationship between methadone dose and odds of having a positive urine drug test in either clinic- or community-based patients.

Adult↗
PubMed1995

Identification and characterization of specific sequences encoding pathogenicity associated proteins in the genome of commensal Neisseria species.

The distribution of distinct sequences in pathogenic and commensal Neisseria species was investigated systematically by dot blot analysis. Probes representing the genes of Rmp, pilin and IgA1 protease were found to hybridize exclusively to the chromosomal DNA of the pathogenic species, Neisseria gonorrhoeae and/or Neisseria meningitidis. In contrast, specific sequences for the genes of the porin protein Por and the opacity protein (Opa) were also detected in a panel of commensal Neisseria species such as N. lactamica, N. subflava, N. flava, N. mucosa and N. sicca. Using opa-specific oligonucleotides as probes in chromosomal blots, the genomes of the commensal Neisseria species show a totally reduced repertoire of cross-hybridizing loci compared to the complex opa gene family of N. gonorrhoeae. DNA sequence analysis of one opa-related gene derived from N. flava and N. sicca, respectively, revealed a large degree of homology with previously described gonococcal and meningococcal genes, e.g., a typical repetitive sequence in the leader peptide and the distribution of the hypervariable and conserved regions. This observation, together with the finding, that the gene is constitutively transcribed, leads to the assumption that some of the commensal Neisseria species may have the potential for the expression of a protein harboring similar functions as the Opa proteins in pathogenic Neisseriae.

Amino Acid Sequence↗
PubMed1995

Autoantibodies to desmoplakin I and II in patients with erythema multiforme.

Erythema multiforme (EM) represents a syndrome of chronic recurrent inflammatory skin disease. Depending on the severity and extent of skin and mucosal involvement, it is defined either as EM minor or EM major. In this study we demonstrate the presence of autoantibodies (aAbs) against desmoplakin I and II, two major proteins of the desmosomal plaque, in six of six patients with the severe variant of EM, EM major. Light microscopic studies of lesional skin and mucous membranes localized in vivo bound immunoglobulin G (IgG) in a dotted desmosomal pattern along the cytoplasmic membranes of keratinocytes. By immunoelectronmicroscopy, in vivo bound IgG was confined to the desmosomal plaques. These findings were confirmed by indirect immunolocalization studies that demonstrated the presence of IgG aAbs in the serum of patients during active disease. These aAbs did not only bind to desmosomal plaques of epithelial cells where they colocalized with defined murine monoclonal antibodies directed against desmoplakin I and II, but also labeled the intercalated discs of myocardial cells. Biochemical characterization of circulating IgG aAbs revealed desmoplakin I and II as actual target autoantigens. By passive transfer of serum into newborn mice, in vivo binding of serum aAbs to keratinocytes was shown. The findings presented in this study imply a humoral immune response in certain patients with EM major and indicate a potential pathogenetic role of aAbs against desmoplakin I and II in this disease.

Animals↗
PubMed1995

Epiluminescence microscopy. A useful tool for the diagnosis of pigmented skin lesions for formally trained dermatologists.

BACKGROUND AND DESIGN: Epiluminescence microscopy (ELM) is a noninvasive technique that, by employing the optical phenomenon of oil immersion, makes subsurface structures of the skin accessible for in vivo examination and thus provides additional criteria for the clinical diagnosis of pigmented skin lesions. At present, almost all studies about the value and clinical importance of ELM are based on data derived from ELM experts (ie, dermatologists specifically trained in this technique). In the present study, we attempt to determine whether the clinical diagnosis of pigmented skin lesions is significantly improved using ELM and whether ELM-trained individuals and dermatologists not trained in this technique profit equally from this technique. Randomly selected histologically proven pigmented skin lesion specimens, photographed with (ELM) and without oil immersion (surface microscopy) were presented by slide projection to six ELM experts and 13 ELM nonexperts (ie, dermatologists not formally trained in ELM) for diagnosis. To evaluate the diagnostic performance of ELM experts and nonexperts with and without the oil immersion technique (ie, ELM vs surface microscopy), the following parameters were obtained: intraobserver and interobserver agreement by kappa statistics and sensitivity and specificity of diagnostic performance. RESULTS: Our results show that by using the ELM technique the ELM experts reach a substantially better intraobserver agreement than nonexperts (median kappa, 0.56 vs 0.36). The interobserver agreement was markedly increased in the ELM experts group (average gain, 7%) but decreased in the ELM nonexperts group (average loss, 6%). The sensitivity of diagnosis was significantly increased in the ELM experts group (average gain, 10%), but decreased in the nonexperts group (average loss, 10%). Finally, the specificity of diagnosis was excellent in the ELM experts group, both with and without oil immersion (0.91) and was somewhat improved by ELM in the nonexperts group (0.77 vs 0.85). CONCLUSIONS: We conclude that the ELM technique increases sensitivity in formally trained dermatologists, but may decrease the diagnostic ability in dermatologists not formally trained in the ELM technique. Consequently, formal broad-based training in ELM should be offered to the dermatologic community.

Clinical Competence↗
PubMed1995

Phosphorothioate oligonucleotides reduce melanoma growth in a SCID-hu mouse model by a nonantisense mechanism.

In our efforts to investigate the biologic role of Ha-ras oncogenes in human melanoma by Ha-ras phosphorothioate antisense oligonucleotides, we observed that antisense, sense, and scrambled control oligonucleotides at a concentration of 10 microM all similarly and strongly inhibited growth of our human melanoma target cell line SK-2 in vitro but without specific decrease of the target protein. Cell numbers with respect to the untreated control were reduced by 84% +/- 4.2% (ISD), 82.9% +/- 3.6%, and 84% +/- 3%, respectively. In vivo studies in a SCID-hu mouse model confirmed these findings. Both antisense and sense control oligonucleotides administered through osmotic pumps significantly (p < 0.006) reduced the mean tumor weight (1.5 g +/- 0.4 g and 1.8 g +/- 0.8 g, respectively) in comparison with saline-treated (5.7 g +/- 0.7 g) or untreated control animals (5.8 g +/- 1.0 g). The vascularity of oligonucleotide-treated tumors was greatly reduced. Clinical signs of oligonucleotide-related toxicity were not observed, and there was no evidence of histopathologic alterations in a variety of mouse tissues. We could demonstrate that the antimelanoma effects can be abrogated in vitro by adding basic fibroblast growth factor (bFGF). In the context of the importance of bFGF in melanocyte biology and angiogenesis, we argue in favor of an interaction between polyanionic phosphorothioate oligonucleotides and bFGF in our melanoma system. These findings stress the notion that phosphorothioate oligonucleotides may be promising antineoplastic lead compounds capable of employing antitumor effects by mechanisms other than specific inhibition of gene expression.

Animals↗
PubMed1995

Microdialysis in cutaneous pharmacology: kinetic analysis of transdermally delivered nicotine.

Direct measurements of cutaneous drug levels and kinetics have long been hampered by lack of appropriate methods. Recently, studies have indicated that microdialysis, a method of continuous in vivo sampling of extracellular fluid, may also be performed in human skin. The present study was designed to evaluate this technique for kinetic analyses of cutaneous drug levels. Using a transdermal nicotine delivery system with 35 mg of nicotine as a model, nicotine levels were determined in the dialysate of human skin by means of high performance liquid chromatography. In vitro studies demonstrated that nicotine levels in the dialysate strictly correlated with nicotine concentrations in the dialyzed medium. In nine healthy male volunteers receiving nicotine by transdermal delivery, nicotine was detectable within 90-180 min, and peak levels of approximately 1000 ng/ml were detected within 240-360 min of patch application. Correlation analyses of the individual data from our subjects revealed that nicotine kinetics were independent of skin barrier function, as assessed by transepidermal water loss, but indicated that the detectable maximum nicotine levels may depend on the location of the probe. In summary, the present study demonstrates that microdialysis may be a novel, powerful tool to study cutaneous pharmacology in vivo.

Administration, Cutaneous↗
PubMed1995

Varicose vein stripping--a prospective study of the thrombotic risk and the diagnostic significance of preoperative color coded duplex sonography.

Insufficiency of epifascial veins promotes venous ulceration and increases thromboembolic risk in general surgery patients. Epifascial varicose vein stripping is therefore considered the most effective prophylactic procedure. Thromboembolic risk of patients undergoing this surgical procedure has not yet been prospectively evaluated but appears to be lower than in general surgery patients. The gold standard of preoperative assessment of varicose surgery patients is ascending pressure phlebography, but this technique is invasive, time consuming and costly. We prospectively investigated 100 consecutive varicose vein surgery patients for postoperative thrombosis. Ascending pressure phlebography (APP) and colour coded duplex sonography (CCDS) were performed before and 10 to 21 days after the stripping operation in 100 and 70 patients, respectively. APP revealed no postoperative deep vein thrombosis in all 100 limbs investigated (0 percent; 95 percent confidence interval: 0 to 2.95). With regard to epifascial vein reflux there was good agreement between APP and CCDS (quadratic weighted kappa: 0.76). In 67 out of 73 superficial veins investigated excellent agreement of diagnostic accuracy was found for both diagnostic procedures (91.78 percent; 95 percent confidence interval: 82.96 to 96.92). We conclude that thrombotic risk of varicose vein surgery is low in properly selected patients. CCDS provides a high degree of accuracy in diagnosis of reflux and regular vein morphology and should therefore replace APP; however, APP does remain essential in the preoperative workup of atypical anatomical variants.

Adolescent↗
PubMed1995

[Endoparasite infection in stray and abandoned dogs in southern Switzerland].

At their entry into the animal domicile, "La Stampa", in Lugano (canton Tessin), 217 stray dogs and 154 unwanted dogs were examined for infections with intestinal parasites, filariae, Babesia and Leishmania. The following techniques were used for detection of intestinal parasites: combined sedimentation-flotation, MIFC technique and scotch tape adherence test. Prevalences of helminth egg excretion in stray dogs and in unwanted dogs, respectively, were as follows: 34% and 22% for Trichuris, 17% and 14% for Toxocara, 3% and 5% for hookworms, 4% and 0% for taeniids. Dipylidium, Toxascaris and Capillaria were diagnosed sporadically. Samples positive for taeniids were further tested for the presence of Echinococcus coproantigens in a sandwich ELISA: one of 9 dogs was strongly positive. This dog was euthanized for security reasons and upon dissection, 11 Taenia hydatigena and more than 10,000 gravid Echinococcus granulosus worms were found. Microfilariae were detected in the blood of 3 stray dogs and one unwanted dog by the Difil-test. In all 4 cases the infective species was Dirofilaria immitis as confirmed by morphology, acid phosphatase activity analysis of microfilariae and by detection of specific antigens in blood plasma by ELISA. Specific antibodies against antigen of Leishmania infantum could not be detected in any of these dogs by ELISA. However, 3 stray dogs had specific antibodies against antigen of Babesia canis as demonstrated by IFAT.

Animals↗
PubMed1994

Effects of isradipine on endothelin-induced constriction of myometrial arteries in normotensive pregnant women.

The results of our previous studies suggested that endothelin-1 (ET-1) might be contributory to the impaired uteroplacental blood flow seen in preeclampsia. The aim of this study was to investigate the in vitro influence of isradipine on ET-1-induced contraction of myometrial resistance arteries from pregnant women, as these vessels are partly responsible for the regulation of uteroplacental blood flow in preeclampsia. Small myometrial arteries were dissected from myometrium obtained from 20 normotensive term pregnant women undergoing elective cesarean section and mounted in a tissue chamber. Tension was recorded isometrically. When ET-1 (10(-8) mol/L)-contracted vessels were exposed to increasing concentrations (10(-6), 10(-5), and 10(-4) mol/L) of isradipine, the myometrial arteries demonstrated essentially no relaxation. A significant mean relaxation of 31% was seen only with the highest isradipine concentration of 10(-3) mol/L. Pretreatment with isradipine attenuated ET-1-induced contraction by 26% at 3 x 10(-4) mol/L and by up to 80% at 10(-3) mol/L. Preincubation with lower concentrations of isradipine did not significantly reduce subsequent ET-1 contraction. The present study has thus shown that isradipine at high concentrations counteracts ET-1-induced constriction of myometrial arteries in term pregnant women. Pretreatment with isradipine at high concentrations attenuates the ET-1 contraction.

Arteries↗
PubMed1994

Application of an artificial neural network in epiluminescence microscopy pattern analysis of pigmented skin lesions: a pilot study.

In vivo epiluminescence microscopy (ELM) is a non-invasive technique which improves the clinical diagnosis of naevi and malignant melanoma by providing diagnostic criteria that cannot be appreciated by the naked eye. The present study investigated whether ELM criteria pattern analysis can be employed in an objective, observer-trained, computer-aided diagnostic system, and whether artificial neural networks (ANN) can be applied to the diagnosis of pigmented skin lesions (PSL). The ELM criteria patterns of 200 PSL oil immersion images (60 common naevi, 60 dysplastic naevi, and 80 malignant melanomas) were analysed using a standardized questionnaire. One hundred randomly assigned PSL were used as a training set for an ANN, the remaining 100 PSL serving as the test set. The ANN was trained by backward propagation according to the histological diagnosis, and its performance was compared with that of human investigators. Out of the test set the human investigators correctly diagnosed 88% of PSL and the ANN 86%. In a dichotomized model comparing common, compound, and dysplastic naevi vs. malignant melanoma, i.e. benign vs. malignant PSL, the sensitivity and specificity of human diagnosis was 95 and 90%, respectively, whereas the sensitivity and specificity of the ANN diagnosis was 95 and 88%. Our data indicate that artificial neural networks can be trained to diagnose PSL at a human expert level, based on patterns provided by ELM criteria. We suggest that this technique offers a new approach to the diagnosis of PSL.

Diagnosis, Computer-Assisted↗
PubMed1994

[Therapy of cutaneous T-cell lymphomas].

Cutaneous T-cell lymphomas (CTCL) show a wide clinical spectrum of cutaneous diseases caused by a clonal proliferation of malignant T-helper cells. In the early stages of CTCL diagnosis is challenging and may require a combination of clinical, pathological, immunomorphologic and molecular findings. The identification of early disease is crucial for the rapid implementation of adequate treatment, which may even be curative as has been reported with psoralen photochemotherapy (PUVA), total skin electron beam (TSEB) irradiation and topical chemotherapy. The combination of these treatment modalities with each other and, in addition, with management by synthetic retinoids and interferons has increased the therapeutic potential. Systemic (poly)-chemotherapy has been used so far exclusively for advanced stages of CTCL and may result in partial remission. Extracorporeal photochemotherapy (photopheresis) has been shown to be the most efficient mode of treatment for the Sézary syndrome.

Combined Modality Therapy↗