Biomedical subjects
Hans Christian Korting
Publications and source records attributed to Hans Christian Korting.
Toll-like receptors as key mediators in innate antifungal immunity.
The Toll protein of Drosophila is a transmembrane receptor involved in dorsoventral polarization during embryonic development and recognition of infection. In mammals, Toll-like receptors (TLRs) constitute a novel protein family involved in innate immunity and respond to a wide spectrum of microorganisms, including fungi, bacteria, viruses, and protozoa. Specific agonists for nine of the ten members of the human TLR family have been described to date. TLRs as well as the TLR-associated adaptor molecule MyD88 have been implicated in the recognition of the fungal pathogens Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans and Pneumocystis carinii. Moreover, several pathogen associated molecular patterns (PAMPs) located in the cell wall or cell surface of fungi have been identified as potential ligands. Yeast zymosan activates TLR2/ TLR6 heterodimers, whereas Saccharomyces cerevisiae- and C. albicans-derived mannan seems to be detected by TLR4. Phospholipomannan, present in the cell surface of C. albicans has been shown to be recognized by TLR2, while TLR4 mainly interacts with glucuronoxylomannan, the major capsular polysaccharide of C. neoformans. MyD88 has been implicated in TLR signalling of linear (1 --> 3)-beta-D-glucan, and of beta-glucan from P. carinii. These data point towards the ability of the innate immune system to utilize TLRs that are specific to different types and components of pathogenic fungi. Recent evidence further suggests that TLRs cooperate with other immune receptors involved in fungal recognition and that the selective induction of adaptor proteins finally leads to distinct signalling events upon fungal challenge.
[Grover's disease following hemodialysis in a patient with renal failure].
A 54-year-old woman with polycystic renal disease and renal failure developed Grover's disease while undergoing renal dialysis. Grover's disease or transitory acantholytic dermatosis is characterized by intensely pruritic, hyperkeratotic, succulent papules and plaques located on the trunk. The pathogenesis is unknown; genetic factors and actinic damage have been implicated. Medications, heat or immunosuppression can worsen the disease. Associations with atopic dermatitis, contact dermatitis and asteatotic dermatitis have also been described. Differential diagnostic considerations include folliculitis, scabies and dermatitis herpetiformis. Therapeutic options include moisturizing agents and phototherapy, as well as topical and systemic retinoids. There are only few case reports in the literature describing Grover's disease occurring during hemodialysis treatment. All such previous patients have been men; ours is the first woman.
Ciclopirox olamine treatment affects the expression pattern of Candida albicans genes encoding virulence factors, iron metabolism proteins, and drug resistance factors.
The hydroxypyridone ciclopirox olamine belongs to the antimycotic drugs used for the treatment of superficial mycoses. In contrast to the azoles and other antimycotic drugs, its specific mode of action is only poorly understood. To investigate the mode of action of ciclopirox olamine on fungal viability, pathogenicity, and drug resistance, we examined the expression patterns of 47 Candida albicans genes in cells grown in the presence of a subinhibitory concentration (0.6 micro g/ml) of ciclopirox olamine by reverse transcription-PCR. In addition, we used suppression-subtractive hybridization to further identify genes that are up-regulated in the presence of ciclopirox olamine. The expression of essential genes such as ACT1 was not significantly modified in cells exposed to ciclopirox olamine. Most putative and known virulence genes such as genes encoding secreted proteinases or lipases had no or only moderately reduced expression levels. In contrast, exposure of cells to ciclopirox olamine led to a distinct up- or down-regulation of genes encoding iron permeases or transporters (FTR1, FTR2, FTH1), a copper permease (CCC2), an iron reductase (CFL1), and a siderophore transporter (SIT1); these effects resembled those found under iron-limited conditions. Addition of FeCl(3) to ciclopirox olamine-treated cells reversed the effect of the drug. Addition of the iron chelator bipyridine to the growth medium induced similar patterns of expression of distinct iron-regulated genes (FTR1, FTR2). While serum-induced yeast-to-hyphal phase transition of C. albicans was not affected in ciclopirox olamine-treated cells in the presence of subinhibitory conditions, a dramatic increase in sensitivity to oxidative stress was noted, which may indicate the reduced activities of iron-containing gene products responsible for detoxification. Although the Candida drug resistance genes CDR1 and CDR2 were up-regulated, no change in resistance or increased tolerance could be observed even after an incubation period of 6 months. This was in contrast to control experiments with fluconazole, in which the MICs for cells incubated with this drug had noticeably increased after 2 months. These data support the view that the antifungal activity of ciclopirox olamine may at least be partially caused by iron limitation. Furthermore, neither the expression of certain multiple-drug resistance genes nor other resistance mechanisms caused C. albicans resistance to this drug even after long-term exposure.
Improved differentiation of benign and malignant lymphadenopathy in patients with cutaneous melanoma by contrast-enhanced color Doppler sonography.
OBJECTIVE: To evaluate whether administration of a D-galactose-based signal enhancer is useful in color Doppler sonography (CDS) for better detection of vascularity patterns, which may help to differentiate malignant from benign lymph nodes in patients with cutaneous melanomas. DESIGN: Comparison of B-mode sonography, native CDS, and signal-enhanced CDS. SETTING: Department of Dermatology and Allergology, Ludwig-Maximilians-University, Munich, Germany. PATIENTS: Twenty examinations in 19 patients (median age, 60 years; 10 men) who presented with echo-poor structures suggestive of lymphadenopathy in B-mode sonography during follow-up for cutaneous melanomas. INTERVENTIONS: Histopathologic and follow-up examinations; documentation by color prints. MAIN OUTCOME MEASURES: Frequency of detection and description of different lymph node vascularity patterns in signal-enhanced CDS. RESULTS: Signal-enhanced CDS revealed additional information about vascularization of lymph node metastases, reactive lymph nodes, hematomas, and seromas, which was helpful for the differential diagnosis in 15 of 20 examinations. For lymph node metastases, signal enhancement facilitated the detection of accessory peripheral vessels in most investigations. Concerning reactive lymph nodes, hilar vessels in part with branching to the lymph node periphery could be identified only after application of the contrast enhancer in most patients. Quantitative variables could not be measured in all cases and did not help to differentiate between malignant and reactive lymph nodes. CONCLUSIONS: Administration of a D-galactose-based signal enhancer for CDS in patients with cutaneous melanomas can help to differentiate malignant from reactive lymph nodes, hematomas, or seromas. However, these promising results require confirmation in a prospective multicenter study.
Individual acid aspartic proteinases (Saps) 1-6 of Candida albicans are not essential for invasion and colonization of the gastrointestinal tract in mice.
In order to investigate whether there is a role for individual secreted aspartic proteinases (Saps) of Candida albicans in gastrointestinal infection of mice we compared the differential expression of SAP1-6 genes and production of Sap1-6 proteins with invasion and persistence of SAP knockout strains in the gastrointestinal tract. Using an in vivo expression technology (IVET) we found a high percentage of expression of SAP4-6 genes which increased steadily in the course of infection. Expression of SAP1-3 genes was detected occasionally and in lower percentages than that of SAP4-6 genes. With reverse transcriptase-polymerase chain reaction (RT-PCR), mRNA for SAP 4 and SAP6 were detected in the stomach of all mice, whereas SAP2, SAP3 and SAP5 mRNA were detected not in all animals and SAP1 mRNA was not detectable. Also with immunoelectron microscopy we demonstrated production of Saps1-3 as well as Saps4-6 with antibodies cross-reacting with either Saps1-3 or Saps4-6. In contrast to the fact that gene expression and production of Saps were readily detectable, we were unable to demonstrate differences in the ability to invade the stomach, to disseminate to the brain as well as in the duration of faecal shedding and the number of fungi persisting in the faeces of mice infected with SAP knockout strains in comparison to control strains. We conclude that although Saps were produced, individual Saps were not indispensable factors for virulence during gastrointestinal infection of mice.
High-frequency ultrasound in the evaluation of pharmacological effects on the skin.
In 1987, the introduction of two 20-MHz B- (brightness-) scan ultrasound systems with axial and lateral resolution of 200 microm and 75-80 microm, respectively, rendered two-dimensional sonographic imaging in dermatology possible. Since then cutaneous sonography has increasingly been used to investigate drug effects on human skin. Both unwanted and wanted effects have been studied, including skin thinning due to repeated glucocorticoid application and reduction of skin thickening in hyperplastic disorders such as psoriasis vulgaris due to various treatment approaches. The resolution of 20-MHz ultrasound is sufficient for studying pathological changes and pharmacological effects in the dermis and the subcutaneous fat; for assessing the epidermis, frequencies between 50 and 100 MHz may prove to be more effective.
Different skin thinning potential of equipotent medium-strength glucocorticoids.
In this study, we investigated the effect of prednicarbate, mometasone furoate and betamethasone 17-valerate on total skin thickness over a treatment period of 6 weeks. The study was conducted as a double-blind, placebo-controlled randomized clinical trial with a confirmatory approach. The influence of these drugs on healthy human skin under non-occlusive conditions was assessed by measuring total skin thickness and epidermal thickness using 20 and 50 MHz sonography, respectively. Epidermal surface structure was evaluated using profilometry. Visual assessment addressed signs of atrophy and formation of telangiectasia. The reduction of total skin thickness induced by prednicarbate was clearly less than that caused by betamethasone 17-valerate and mometasone furoate. Prednicarbate led to a higher degree of skin thinning than vehicle. For technical reasons, epidermal thickness could not be reliably evaluated with 50 MHz sonography. Profilometry did not demonstrate any differences between treatments. Visible signs of atrophy or telangiectasia were detected in two subjects each upon betamethasone 17-valerate and mometasone furoate, but not upon prednicarbate or its vehicle. Prednicarbate is a topical glucocorticoid with an improved benefit/risk ratio, as it causes less skin atrophy than the equipotent betamethasone 17-valerate.