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Zu den schweren, blasenbildenden Arzneimittelreaktionen an der Haut gehören das Stevens-Johnson-Syndrom (SJS) und die toxisch epidermale Nekrolyse (TEN). Allopurinol, Antikonvulsiva, Sulfonamidantibiotika und nichtsteroidale Antirheumatika vom Oxicam-Typ sind wiederholt als Auslöser beschrieben. Zunehmend rücken auch Immuntherapien als Auslöser schwerer Hautreaktionen in den Fokus. Vorgestellt werden 2 Patienten mit bullösen Hauterscheinungen nach Gabe des Checkpointinhibitors Pembrolizumab. Da das klinische Bild nicht immer eine zweifelsfreie Einordnung zulässt, ist eine histologische Mitbeurteilung vielfach unverzichtbar.

Eine Metallallergie kann zu Unverträglichkeit von Metallimplantaten führen. Vor Implantation sollte eine Epikutantestung aber nicht prophetisch-prophylaktisch, sondern nur bei anamnestischen Hinweisen auf eine potentielle Metallallergie erfolgen. Sofern nach Einsetzen von Metallimplantaten – speziell Endoprothesen – Komplikationen wie Schmerzen, Ergüsse, Hauterscheinungen, Bewegungseinschränkung oder Lockerung auftreten, empfiehlt sich nach orthopädisch-chirurgischer Differentialdiagnostik bei Verdacht auf das Vorliegen einer Metallimplantatallergie ein Epikutantest mit der Nickel-, Kobalt-, Chrom-Präparationen enthaltenden DKG-Standardreihe. Studien zum Einsatz von Metalllegierungsplättchen haben gezeigt, dass damit kein verlässlicher Nachweis einer Metallallergie möglich ist, und bei einer allergischen Epikutantestreaktion auf ein Metallplättchen diese auch keinem konkreten Legierungs-Metall der Plättchen zugeordnet werden kann. Zudem besteht die Gefahr der unkritischen, breiten Testanwendung der leicht zugänglichen Metalllegierungsplättchen. Aufgrund fehlenden Zusatznutzens gegenüber der Epikutantestung mit standardisierten Metallsalzpräparationen empfehlen wir die Testung mit Legierungsplättchen nicht. Intolerance reactions to metal implants may be caused by metal allergy. However, prior to implantation, patch testing should not be done in a prophylactic-prophetic approach. Pre-implant patch testing should only be performed to verify or exclude metal allergy in patients with a reported respective history. In the case of implant—in particular arthroplasty—related complications like, for example, pain, effusion, skin changes, reduced range of motion, or loosening, orthopedic-surgical differential diagnostics should be performed first. Allergological workup of suspected metal implant allergy should be done with the DKG baseline series which contains nickel-, cobalt- and chromium-preparations. Various studies assessing the usefulness of metal alloy discs for patch testing proved that this approach does not give reliable information about metal allergy. Positive patch test reactions to the discs cannot be assigned to a specific metal within the disc alloy components. Furthermore, availability of such metal discs might be an invitation to uncritical testing. Accordingly, due to lack of benefit in comparison to patch testing with standardized metal salt preparations, we do not recommend patch testing with metal alloy discs.

Introduction:Transdermal patch systems are an effective method of administering active ingredients through the skin, with considerable advantages over other drug delivery routes, for example, maintenance of constant plasma drug levels and avoidance of first-pass metabolism. However, repeated epicutaneous application may be associated with local skin reactions.Areas covered:This review addresses current issues regarding the effective/safe use of transdermal patch systems, and provides a critical analysis of the addition of ‘‘skin-caring’’ ingredients to patch systems. Effective use of transdermal systems includes choosing an appropriate body area for application, maintaining regular skin care regimens before application and not replacing a patch in the same area (rotation) within 7 days. Another strategy, developed in an attempt to improve the tolerability of transdermal systems, is the addition of assumed ‘‘skin-caring’’ ingredients (e.g., Aloe Vera) to patch systems. However, at present there is neither proof nor clinical evidence of any benefit. On the contrary, plant-derived ingredients might be associated with allergenic potential.Expert opinion:Transdermal systems are generally well tolerated; physicians must adequately inform patients of the most effective ways to use these formulations for maximum therapeutic benefit, while minimising local adverse events. Skin-caring agents, including Aloe Vera, cannot be recommended until well-controlled clinical trials with standardised extracts are available.

ABSTRACTIn renal bacterial infections granulocytes are of major importance in the primary immune defense against invading pathogens. However, the mechanisms of granulocytic activation in renal interstitial invasion have not been clarified. Renal tubular epithelial cell mechanisms inducing granulocytic activation and bacterial killing may include tubular cell expression of Tamm-Horsfall protein (THP), a urinary protein that is known to enhance cytokine expression in monocytes. We studied the role of THP in granulocytic activation. A strong binding of THP to human granulocytes was demonstrated by fluorescence-activated cell sorter analysis. Urinary THP and supernatants of THP-expressing cultured tubular epithelial cells (MDCK) enhanced interleukin-8 (IL-8) expression by human granulocytes. Renal tubular cells growing polarized on polycarbonate membranes were used to study apical versus basal THP expression. By electron microscopy THP immunoreactivity was exclusively found on the apical surfaces of tubular cells and was absent on the basolateral cell membrane. In the apical cell culture compartment we found significantly more stimulatory activity for granulocytic IL-8 expression. CD62L, a selectin less expressed in activated granulocytes, was decreased in granulocytes incubated with urinary THP and in supernatants of THP-producing renal tubular cells but not in supernatants from THP-negative cells. Again, the effect on CD62L expression was found only in apical culture media and was absent in the basal compartment. In summary our data give evidence that renal tubular cell THP expression may be relevant in kidney diseases since THP is a potent activator of human granulocytes. The regulation of apical versus basal THP expression and release in vivo may be crucial in the induction of the inflammatory response, e.g., in bacterial renal diseases.

In renal bacterial infections granulocytes are of major importance in the primary immune defense against invading pathogens. However, the mechanisms of granulocytic activation in renal interstitial invasion have not been clarified. Renal tubular epithelial cell mechanisms inducing granulocytic activation and bacterial killing may include tubular cell expression of Tamm-Horsfall protein (THP), a urinary protein that is known to enhance cytokine expression in monocytes. We studied the role of THP in granulocytic activation. A strong binding of THP to human granulocytes was demonstrated by fluorescence-activated cell sorter analysis. Urinary THP and supernatants of THP-expressing cultured tubular epithelial cells (MDCK) enhanced interleukin-8 (IL-8) expression by human granulocytes. Renal tubular cells growing polarized on polycarbonate membranes were used to study apical versus basal THP expression. By electron microscopy THP immunoreactivity was exclusively found on the apical surfaces of tubular cells and was absent on the basolateral cell membrane. In the apical cell culture compartment we found significantly more stimulatory activity for granulocytic IL-8 expression. CD62L, a selectin less expressed in activated granulocytes, was decreased in granulocytes incubated with urinary THP and in supernatants of THP-producing renal tubular cells but not in supernatants from THP-negative cells. Again, the effect on CD62L expression was found only in apical culture media and was absent in the basal compartment. In summary our data give evidence that renal tubular cell THP expression may be relevant in kidney diseases since THP is a potent activator of human granulocytes. The regulation of apical versus basal THP expression and release in vivo may be crucial in the induction of the inflammatory response, e.g., in bacterial renal diseases.

Background: The frequency and importance of pruritus vulvae and vulvodynia are frequently underestimated. We conducted a survey to examine the prevalence and characteristics of these complaints. Methods: Using a questionnaire which we developed, patients hospitalized at the University Dermatology Clinic Halle were questioned about any vulvar complaints and their characteristics. Results: 108 questionnaires were evaluated. Of the respondents, 27 (25.2%) had current or past genital problems. Vulvodynia was present in 3, pruritus vulvae in 16, and both symptoms (pain and itching) in 8 patients of this group. Pain was described as burning or stabbing. Dyspareunia was, however, only reported by 7 patients. While the symptoms disappeared within a week in 10 patients, the duration of complaints in 10 other cases was 1–6 months, and even longer than 6 months in another 3 cases. The patients showed a surprising willingness to talk about their problems. Only 4 patients did not talk about their complaints. Conclusion: Current and chronic vulvar complaints are apparently frequent in hospitalized patients in a dermatological clinic. The assumption that such complaints are taboo does not appear to be confirmed. However, in taking a patient’s history, specific questions about genital problems should be asked.

In upper urinary tract infections, tubular epithelial cells (TEC) may play a pivotal role in the initiation of the renal inflammatory response. They exert crucial immunological functions such as processing and presentation of foreign antigen, secretion of proinflammatory cytokines (interleukin-6 [IL-6] and tumor necrosis factor alpha) and chemokines (IL-8, MCP-1, ENA-78, and RANTES). Since monolayer cultures are a limited model for polarized tubular epithelial cells, we studied the side-dependent IL-8 secretion of TEC by using cell culture inserts as a basement membrane imitation. Primary cultures of proximal TEC were stimulated with differently fimbriated mutants of Escherichia coli, E. coli LPS, S-fimbria isolates, and IL-1alpha. IL-8 protein was measured by enzyme-linked immunosorbent assay, and IL-8-like biological activity was tested by measuring elastase release from polymorphonuclear cells in supernatants of the upper and lower compartments. IL-8 mRNA was compared by competitive PCR. IL-8 secretion by TEC into the basolateral environment was significantly higher than secretion into the apical compartment, representing the tubular lumen. However, stimulation of IL-8 secretion by TEC was restricted to IL-1alpha and was not inducible by E. coli mutants, S fimbriae, or lipopolysaccharide. With this in vitro model of polarized TEC, we show that luminal contact of TEC with uropathogenic E. coli does not result in enhanced IL-8 secretion. The basolaterally directed production of the neutrophil chemotactic factor IL-8 by TEC after stimulation with IL-1alpha might play an important role in the initiation of inflammatory cell influx into the renal parenchyma.

Background.Peritoneal catheter exit-site infections cause a relevant morbidity in peritoneal dialysis patients and are frequently caused by Staphylococcus aureus. We tested the hypothesis that adherence of exit-site-derived S.aureus to epithelial cells and peritoneal catheter silicone tubes discriminates virulent and less virulent strains.
Methods.The binding of isolated S. aureus to an epithelial cell line (HEp-2) and to silicone tubes was analyzed using light-microscopy or radioactive labeling of bacteria.
Results.Of 378 exit-site swabs, 99% (26%) were positive for microbial growth. S. aureus was cultured in 25 of 99 positive swabs; three of 13 swabs taken in exit-site infections grade 3 and 4 that had tested positive for S. aureus. Adherence of S. aureus from exit-site infections grade 2, 3 and 4 to Hep-2 cells did not differ from adherence of bacteria isolated from asymptomatic or moderately inflamed catheter exit sites (grade 0-2). However, binding of S. aureus to silicone tubes was enhanced in grade 0/1 compared with grade 2-4 exit-site isolates.
Conclusions.Staphylococcus aureus is an important pathogen in CAPD-related exit-site infection being isolated in about 6.6% of all exit-site swabs (and in 25% of all positive swabs). Silicone-adhesive strains may be of more clinical significance in peritoneal dialysis patients since adhesion to silicone was increased in S. aureus strains isolated in more severe exit-site infections.
Keywords:adherence; catheter exit-site; HEp-2 cells; peritoneal dialysis; Staphylococcus aureus; silicone

Peritoneal catheter exit-site infections cause a relevant morbidity in peritoneal dialysis patients and are frequently caused by Staphylococcus aureus. We tested the hypothesis that adherence of exit-site-derived S. aureus to epithelial cells and peritoneal catheter silicone tubes discriminates virulent and less virulent strains.

A prospective, controlled and standardized animal experiment was performed to study the influence of various anticancer drugs. The Novikoff hepatoma transplanted into male Spraque-Dawley rats was treated with fluorouracil (FUra), mitomycin C, methotrexate, cisplatin and fluorodeoxyuridine (FdUrd) at equi-effective dosage, in terms of side effects (weight loss), in comparison to a control group (0.9% saline solution) by locoregional application via the hepatic artery. The tumor multiplication factor (TMF = tumor volume day 12/tumor volume day 5) served as the parameter to compare the tumor growth of the various groups. All drugs showed a significant (P<0.05) effect on the tumor growth. In comparison to the control group (mean TMF 9.66), FdUrd (3.78) and FUra (3.03) only limited the tumor growth, mitomycin C (0.96) produced stable tumor, cisplatin (0.64) and methotrexate (0.15) significantly reduced (P<0.01) the tumor size. We suggest that, in addition to the established (FUra, FdUrd, mitomycin C) drugs, methotrexate and cisplatin should be considered in further studies of the treatment of primary and secondary liver malignancies.

To determine whether turbo spin echo (TSE) sequences can replace conventional T2-weighted spin echo (SE) sequences in MRI of the liver, 40 patients with focal liver lesions were imaged at 0.5 T. A T2-weighted SE sequences (TR/TE 1800/90 ms, number of signals averaged [NEX]=2, scan time=7:16 min), a TSE sequence (TR/TE 1800/90 ms, NEX=4, number of echos per excitation=13, echo spacing=12.9 ms, scan time=4:16 min) and a T1-weighted SE sequence (TR/TE 350/15 ms, NEX=2, scan time=4:21 min) were obtained and image quality, lesion detectability and lesion differentiation were evaluated qualitatively by subjective assessment using scores and quantitatively by lesion-liver contrast-to-noise (CNR) and tumour/liver signal intensity (SI) ratios. The image quality of the TSE sequence was substantially better compared with the T2-weighted SE sequence due to a reduction in motion artefacts and better delineation of anatomical details. Of a total of 158 visible lesions the T1-weighted SE, TSE, and T2-weighted SE sequences showed 91%, 81% and 65% of the lesions, respectively. Thus the TSE sequence depicted 24% (P< 0.001) more lesions than the T2-weighted SE sequence. In all types of pathology the lesion-liver CNR of the TSE sequence was significantly (P< 0.001) higher compared to the CNR of the T2-weighted SE sequence (+ 55–65%), indicating superior lesion conspicuity. Lesion characterization was equally good on the two T2-weighted sequences with no difference in the tumour/liver SI ratio. Using a criterion of tumour/liver SI ratio equal to or higher than 2, haemangiomas larger than 1 cm in diameter could be differentiated from other lesions with a sensitivity and specificity of 95% and 96%, respectively. Our results indicate that the TSE sequence is suitable for replacing the conventional T2-weighted SE sequence in MRI of focal liver lesions.

Abstract.: The aim of this work was to compare MR imaging and CT in the detection of renal masses and in the differential diagnosis between benign and malignant lesions. In 33 patients with 54 renal lesions CT and MR images were evaluated by four readers with regard to tumor detection and characterization using a receiver-operating-characteristics (ROC) analysis. The MRI protocol consisted of a T1-weighted spin-echo (SE) sequence (TR/TE: 300/10 ms) before and after contrast administration and a heavily T2-weighted turbo-SE (TSE) sequence (TR/TE: 5500/150 ms). Az values for the area under the ROC curves for lesion detection were 0.92 ± 0.04 for CT and 0.91 ± 0.05 for MRI, respectively, which was not statistically different. The MRI technique was slightly, but not significantly, better than CT in the overall characterization (accuracy in differentiation between benign and malignant) of renal lesions with an Az value of 0.90 ± 0.05 compared with 0.88 ± 0.06 for CT. The MRI technique proved to be statistically superior to CT (p < 0.01) in the correct characterization of benign renal lesions. MRI equals CT in the overall detection and differential diagnosis of renal masses. MRI is very helpful for further differential diagnosis of lesions which are equivocal on CT especially in the differentiation between complicated cysts and cystic or hypovascular renal cell carcinoma.

We have recently reported an increase of expression of the intercellular adhesion molecule 1 by renal carcinoma cells in response to S fimbriae of Escherichia coli. Now we demonstrate that E. coli expressing S and P fimbriae strongly binds to human proximal tubular epithelial cells. However, in primary and simian virus 40-transfected renal tubular epithelial cells S fimbriae do not enhance the expression of intercellular adhesion molecule 1.

The production of interleukin-6, intracellular adhesion molecule 1, and major histocompatibility complex class II molecules by a renal carcinoma cell line (ACHN) in response to S fimbriae of uropathogenic Escherichia coli was studied. S fimbriae adhered to ACHN cells and stimulated the production of interleukin-6 and intercellular adhesion molecule 1 but did not affect major histocompatibility complex class II expression by renal carcinoma cells. Our data demonstrate that S fimbriae of E. coli display immunomodulating properties on kidney-derived epithelial cells.

A 95-kDa protein was isolated from Staphylococcus saprophyticus 7108 grown on dialysis membranes placed on the surface of brain heart infusion agar. Strain CCM883 did not produce this protein. Ultrathin sections revealed the presence of very thin, tuftlike, 50- to 75-nm-long structures on the surface of strain 7108, whereas strain CCM883 was comparably smooth. The surface material could be removed by digestion with proteinase K, suggesting that the surface structures contain protein. High-resolution scanning electron microscopy showed a thick layer of surface material on strain 7108, whereas strain CCM883 appeared smooth. The 95-kDa protein was purified by Sephacryl S-300 chromatography, and an antiserum was raised in rabbits. This antiserum was used in immunogold labeling experiments, which showed that the protein is associated with the surface structures. Our experiments thus demonstrate the presence of a fibrillar protein on the surface of S. saprophyticus (Ssp for S. saprophyticus surface-associated protein).

The sex pheromone system of Enterococcus faecalis is a unique, highly efficient plasmid collection mechanism for this species. A crucial role in this system is played by an adhesin called aggregation substance which enables the cell-cell contact between donor and recipient strains. The existence of the amino acid motif Arg-Gly-Asp-Ser in the adhesin prompted us to look for a possible binding of E. faecalis cells expressing aggregation substance to eucaryotic cells. We were able to show that the adhesin mediated binding to cultured renal tubular cells (porcine cell line LLC-PK1) via light microscopic, electron microscopic, and enzyme-linked immunosorbent assay-based studies. Synthesis of the adhesin was induced by some component(s) of serum. These data are interpreted to mean that aggregation substance is an adhesin mediating not only cell-cell contact between different E. faecalis strains but also binding of E. faecalis to eucaryotic cells, and therefore it might contribute to virulence.

Escherichia coli K-12 strains producing S-fimbrial adhesins, F1C fimbriae, and mutagenized fimbriae were tested in a binding assay with a renal tubular cell line. S-fimbrial adhesins and F1C fimbriae mediated binding to tubular cells. The SfaA, SfaG, and SfaS subunits of S fimbriae contributed to attachment. Site-specific mutations in the sfaS gene reduced binding. The inhibition profile of F1C fimbriae resembled that of S fimbriae.

The uropathogenic Escherichia coli strain 536 (O6:K15:H31) possesses pathogenicity islands which are incorporated into two tRNA genes, the selC and the leuX gene. The leuX gene influences the expression of different putative virulence factors. We demonstrate an effect of the leuX-specific tRNA on adherence and uropathogenicity.

Beside its role in calcium and phosphorus metabolism, 1,25-dihydroxycholecalciferol (1,25-D3) exerts multiple effects on cytokine and major histocompatibility complex (MHC) class II expression in monocytes and lymphocytes. In different renal diseases tubular epithelial cells express MHC class II molecules and cell adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1). Therefore, modulation of MHC class II and ICAM-1 expression in renal tubular epithelial cells by 1,25-D3 may be relevant to lymphocyte adhesion to tubular epithelial cells and immune mediated renal injury. However, the expression of MHC class II antigens and cellular adhesion molecules by renal tubular epithelial cells in response to 1,25-D3 has not been investigated.

The uropathogenic Escherichia coli strain 536 (O6:K15:H31) possesses pathogenicity islands which are incorporated into two tRNA genes, the selC and the leuX gene. The leuX gene influences the expression of different putative virulence factors. We demonstrate an effect of the leuX-specific tRNA on adherence and uropathogenicity.

We have recently reported an increase of expression of the intercellular adhesion molecule 1 by renal carcinoma cells in response to S fimbriae of Escherichia coli. Now we demonstrate that E. coli expressing S and P fimbriae strongly binds to human proximal tubular epithelial cells. However, in primary and simian virus 40-transfected renal tubular epithelial cells S fimbriae do not enhance the expression of intercellular adhesion molecule 1.

Fosfomycin and mesna were investigated in rats and mice concerning their detoxifying effects on cisplatin toxicity in comparison to sodium thiosulfate, a known protector against cisplatin nephrotoxicity. After separate i.p. injection of cisplatin and fosfomycin (500 mg/kg) or mesna (800 mg/kg) a slight increase in the 50% lethal dose of cisplatin was found in all animals. In mice sodium thiosulfate proved to be far more effective in preventing lethal toxicity and nephrotoxicity as measured by blood urea nitrogen increase. Fosfomycin and mesna were almost without influence on cisplatin treatment of L-1210 leukemia whereas their inhibition of the antitumor effect against S-180 ascites sarcoma (increase of in cisplatin dose to cure 50% of animals from 2.0 mg/kg to 3.5/4.7 mg/kg cisplatin) was similar to thiosulfate, which showed a strong inhibiting effect in the treatment of both tumors. In rats fosfomycin distinctively reduced the antitumor efficacy of cisplatin against Yoshida ascites sarcoma. Thus the concurrent injection of fosfomycin and mesna reduced both the toxicity and the antitumor activity of cisplatin. Therefore their simultaneous administration in addition to cisplatin via the same injection route should be avoided. Due to the weak detoxifying efficacy of fosfomycin and mesna they cannot be used instead of sodium thiosulfate for renal protection against cisplatin toxicity in local i.p. treatment modalities.

We report on a 29-year-old patient with a unilateral nevoid telangiectasia syndrome (UNTS). Based on microcirculation examinations, both functional impairments at the blood vessel level (laser-Doppler flowmetry) and morphologically altered capillaries (capillary microscopy) could be observed. We could demonstrate that microcirculatory examinations are suitable to demonstrate pathophysiological defects at the vascular level, especially since subclinical functional defects can also be recorded. To our knowledge, no such observations have yet been published with regards to UNTS.

AbstractWe report on a 29-year-old patient with a unilateral nevoid telangiectasia syndrome (UNTS). Based on microcirculation examinations, both functional impairments at the blood vessel level (laser-Doppler flowmetry) and morphologically altered capillaries (capillary microscopy) could be observed. We could demonstrate that microcirculatory examinations are suitable to demonstrate pathophysiological defects at the vascular level, especially since subclinical functional defects can also be recorded. To our knowledge, no such observations have yet been published with regards to UNTS.Copyright © 2004 S. Karger AG, Basel

Abstract: The case of a 9-month-old girl with glutaric aciduria type 1 (GA 1) is reported. On initial presentation at 6 months of age, the patient demonstrated bilateral subdural hemorrhages and widening of the basal cisterns. After neurosurgical intervention the subdural effusions regressed; their etiology remained unclear. At the age of 9 months the patient presented again because of progressive loss of psychomotor abilities and a dystonic movement disorder. Cerebral MRI revealed regressive subdural hematoma, but marked frontotemporal atrophy as well. Because of a suspected metabolic disorder, urinary analysis of organic acids was performed. This repeatedly showed marked excretion of glutaric acid, 3-hydroxyglutaric acid and glutaconic acid, indicating a diagnosis of GA 1. Considering our patient's history, we recommend the inclusion of GA 1 in the differential diagnosis of patients with unexplained subdural hematoma and neurological deficits.

Summary The nephroprotective effect of fosfomycin against tubulotoxicity induced bycis-diaminedichloroplatin (DDP) and cyclosporin A (Cs) was studied in the rat. The parameter of nephrotoxicity was urinary tubular cell excretion. The experiments revealed that fosfomycin, given either concomitantly or in advance was able to reduce the nephrotoxic effect of DDP and Cs significantly. We conclude from these studies that fosfomycin is a broad-spectrum nephroprotective agent.