The cGAS-STING pathway drives type I IFN immunopathology in COVID-19.

COVID-19, which is caused by infection with SARS-CoV-2, is characterized by lung pathology and extrapulmonary complications1,2. Type I interferons (IFNs) have an essential role in the pathogenesis of COVID-19 (refs 3-5). Although rapid induction of type I IFNs limits virus propagation, a sustained increase in the levels of type I IFNs in the late phase of the infection is associated with aberrant inflammation and poor clinical outcome5-17. Here we show that the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which controls immunity to cytosolic DNA, is a critical driver of aberrant type I IFN responses in COVID-19 (ref. 18). Profiling COVID-19 skin manifestations, we uncover a STING-dependent type I IFN signature that is primarily mediated by macrophages adjacent to areas of endothelial cell damage. Moreover, cGAS-STING activity was detected in lung samples from patients with COVID-19 with prominent tissue destruction, and was associated with type I IFN responses. A lung-on-chip model revealed that, in addition to macrophages, infection with SARS-CoV-2 activates cGAS-STING signalling in endothelial cells through mitochondrial DNA release, which leads to cell death and type I IFN production. In mice, pharmacological inhibition of STING reduces severe lung inflammation induced by SARS-CoV-2 and improves disease outcome. Collectively, our study establishes a mechanistic basis of pathological type I IFN responses in COVID-19 and reveals a principle for the development of host-directed therapeutics.

Reduced platelet activation and thrombus formation in male transgenic model mice of Alzheimer's disease suggests early sex-specific differences in platelet pathophysiology.

Alzheimer's disease (AD) is the most common form of dementia and characterized by extracellular amyloid-ß (Aß) plaques, intracellular neurofibrillary tau tangles and neurodegeneration. Over 80 % of AD patients also exhibit cerebral amyloid angiopathy (CAA). CAA is a cerebrovascular disease caused by deposition of Aß in the walls of cerebral blood vessels leading to vessel damage and impairment of normal blood flow. To date, different studies suggest that platelet function, including activation, adhesion and aggregation, is altered in AD due to vascular Aß deposition. For example, the transgenic AD model mice APP23 mice that exhibit CAA and parenchymal Aß plaques, show pre-activated platelets in the blood circulation and increased platelet integrin activation leading to a pro-thrombotic phenotype in these mice late stages of AD. However, it is still an open question whether or not platelets exhibit changes in their activation profile before they are exposed to vascular Aß deposits. Therefore, the present study examined platelets from middle-aged transgenic APP23 mice at the age of 8-10 months. At this age, APP23 mice show amyloid plaques in the brain parenchyma but not in the vasculature. Our analyses show that these APP23 mice have unaltered platelet numbers and size, and unaltered surface expression of glycoproteins. However, the number of dense granules in transgenic platelets was increased while the release was unaltered. Male, but not female APP23 mice, exhibited reduced platelet activation after stimulation of the thrombin receptor PAR4 and decreased thrombus stability on collagen under flow conditions ex vivo compared to control mice. In an arterial thrombosis model in vivo, male APP23 mice showed attenuated occlusion of the injured artery compared to controls. These findings provide clear evidence for early changes in platelet activation and thrombus formation in male mice before development of overt CAA. Furthermore, reduced platelet activation and thrombus formation suggest sex-specific differences in platelet physiology in AD that has to be considered in future studies of platelets and their role in AD.

[18F]pFBC, a Covalent CLIP-Tag Radiotracer for Detection of Viral Reporter Gene Transfer in the Murine Brain.

Preclinical models of neurological diseases and gene therapy are essential for neurobiological research. However, the evaluation of such models lacks reliable reporter systems for use with noninvasive imaging methods. Here, we report the development of a reporter system based on the CLIP-tag enzyme and [18F]pFBC, an 18F-labeled covalent CLIP-tag-ligand synthesized via a DoE-optimized and fully automated process. We demonstrated its specificity using a subcutaneous xenograft model and a model of viral vector-mediated brain gene transfer by engineering HEK293 cells and striatal neurons to express membrane-tethered CLIP-tag protein. After in vitro characterization of the reporter, mice carrying either CLIP-tag expressing or control subcutaneous xenografts underwent dynamic [18F]pFBC PET imaging. The CLIP-tag expressing xenografts showed a significantly higher uptake than control xenografts (tumor-to-muscle ratio 5.0 vs 1.7, p = 0.0379). In vivo, metabolite analysis by radio-HPLC from plasma and brain homogenates showed only one radio-metabolite in plasma and none in the brain. In addition, [18F]pFBC showed fast uptake and rapid clearance from the brain in animals injected with adeno-associated virus (AAV)-CLIP in the right striatum but no right-to-left (R-L) uptake difference in the striata in the acquired PET data. In contrast, autoradiography showed a clear accumulation of radioactivity in the AAV-CLIP-injected right striatum compared to the sham-injected left striatum control. CLIP-tag expression and brain integrity were verified by immunofluorescence and light sheet microscopy. In conclusion, we established a novel reporter gene system for PET imaging of gene expression in the brain and periphery and demonstrated its potential for a wide range of applications, particularly for neurobiological research and gene therapy with viral vectors.

Activity of amorolfine or ciclopirox in combination with terbinafine against pathogenic fungi in onychomycosis-Results of an in vitro investigation.

BACKGROUND: Onychomycoses are difficult-to-treat fungal infections with high relapse rates. Combining oral and topical antifungal drugs is associated with higher success rates. Additive or synergistic modes of action are expected to enhance treatment success rates. OBJECTIVES: Investigation of the combined effects of antifungal drugs in vitro with different modes of action and application on clinical isolates from mycotic nails. METHODS: Isolates of Trichophyton rubrum, Trichophyton interdigitale and Scopulariopsis brevicaulis were collected from infected toenail specimens of patients with onychomycosis. Susceptibility testing was performed in 96-well polystyrene plates using a standard stepwise microdilution protocol. Additive or synergistic activity at varying concentrations was investigated by the checkerboard method. RESULTS: Combining terbinafine with amorolfine tended to be more effective than terbinafine in conjunction with ciclopirox. In most combinations, additive effects were observed. Synergy was detected in combinations with involving amorolfine in S. brevicaulis. These additive and synergistic interactions indicate that combined therapy with topical amorolfine and oral terbinafine is justified. Sublimation of amorolfine (and terbinafine) may enhance the penetration in and through the nail plate, and support treatment efficacy. CONCLUSIONS: These in vitro results support the notion that combining oral terbinafine and topical amorolfine is beneficial to patients with onychomycosis, particularly if the pathogen is a non-dermatophyte fungus such as S. brevicaulis.

Clinicopathological characteristics of low-dose methotrexate-induced epidermal dysmaturation: A study of 22 patients.

BACKGROUND AND OBJECTIVE: Erosions of the skin and mucous membranes with epidermal dysmaturation are a known side effect of cytostatic chemotherapy regimens and can also be observed during low-dose methotrexate (MTX) therapy. The study aimed to delineate the clinical and histopathological alterations. PATIENTS AND METHODS: A database search of the archive for dermatopathology was conducted, identifying 22 patients who developed epidermal dysmaturation on low-dose MTX. Clinical and laboratory changes, along with an array of histologic parameters were analyzed and statistically evaluated using SPSS. RESULTS: Patients were predominantly female with a mean age of 69.1 years. The main indications were psoriasis vulgaris and rheumatoid arthritis. Clinically, patients mostly presented erosive plaques at the injection site, on mucosal surfaces, and disseminated lesions. Most patients showed normal laboratory values. Histopathologically, key findings included enlarged keratinocytes with pale cytoplasm and enlarged nuclei with prominent nucleoli, along with the degeneration of the basal layer. Consistent observations in the dermal compartment included infiltration of neutrophilic granulocytes, lymphocytes, and histiocytes. CONCLUSIONS: This study proposes clinicopathological criteria for the diagnosis of MTX-associated skin toxicity, aiming to increase awareness among clinicians and pathologists for early diagnosis. Early recognition can prevent potentially life-threatening progression.

Acidosis-mediated increase in IFN-γ-induced PD-L1 expression on cancer cells as an immune escape mechanism in solid tumors.

Immune checkpoint inhibitors have revolutionized cancer therapy, yet the efficacy of these treatments is often limited by the heterogeneous and hypoxic tumor microenvironment (TME) of solid tumors. In the TME, programmed death-ligand 1 (PD-L1) expression on cancer cells is mainly regulated by Interferon-gamma (IFN-γ), which induces T cell exhaustion and enables tumor immune evasion. In this study, we demonstrate that acidosis, a common characteristic of solid tumors, significantly increases IFN-γ-induced PD-L1 expression on aggressive cancer cells, thus promoting immune escape. Using preclinical models, we found that acidosis enhances the genomic expression and phosphorylation of signal transducer and activator of transcription 1 (STAT1), and the translation of STAT1 mRNA by eukaryotic initiation factor 4F (elF4F), resulting in an increased PD-L1 expression. We observed this effect in murine and human anti-PD-L1-responsive tumor cell lines, but not in anti-PD-L1-nonresponsive tumor cell lines. In vivo studies fully validated our in vitro findings and revealed that neutralizing the acidic extracellular tumor pH by sodium bicarbonate treatment suppresses IFN-γ-induced PD-L1 expression and promotes immune cell infiltration in responsive tumors and thus reduces tumor growth. However, this effect was not observed in anti-PD-L1-nonresponsive tumors. In vivo experiments in tumor-bearing IFN-γ-/- mice validated the dependency on immune cell-derived IFN-γ for acidosis-mediated cancer cell PD-L1 induction and tumor immune escape. Thus, acidosis and IFN-γ-induced elevation of PD-L1 expression on cancer cells represent a previously unknown immune escape mechanism that may serve as a novel biomarker for anti-PD-L1/PD-1 treatment response. These findings have important implications for the development of new strategies to enhance the efficacy of immunotherapy in cancer patients.

Cutaneous innate immune sensing of Toll-like receptor 2-6 ligands suppresses T cell immunity by inducing myeloid-derived suppressor cells.

Skin is constantly exposed to bacteria and antigens, and cutaneous innate immune sensing orchestrates adaptive immune responses. In its absence, skin pathogens can expand, entering deeper tissues and leading to life-threatening infectious diseases. To characterize skin-driven immunity better, we applied living bacteria, defined lipopeptides, and antigens cutaneously. We found suppression of immune responses due to cutaneous infection with Gram-positive S. aureus, which was based on bacterial lipopeptides. Skin exposure to Toll-like receptor (TLR)2-6-binding lipopeptides, but not TLR2-1-binding lipopeptides, potently suppressed immune responses through induction of Gr1(+)CD11b(+) myeloid-derived suppressor cells (MDSCs). Investigating human atopic dermatitis, in which Gram-positive bacteria accumulate, we detected high MDSC amounts in blood and skin. TLR2 activation in skin resident cells triggered interleukin-6 (IL-6), which induced suppressive MDSCs, which are then recruited to the skin suppressing T cell-mediated recall responses such as dermatitis. Thus, cutaneous bacteria can negatively regulate skin-driven immune responses by inducing MDSCs via TLR2-6 activation.

Treatment of aseptic facial granuloma as a manifestation of pediatric rosacea with oral macrolides.

Aseptic facial granuloma is a rare pediatric disease, presenting with asymptomatic facial nodules on the cheeks or the eyelids and may represent a form of granulomatous rosacea in children. In this retrospective case series, 12 children with aseptic facial granuloma were treated with oral macrolides (erythromycin or roxithromycin) resulting in a healing of the lesions within a mean treatment time of 5.25 months with no recurrences. The treatment was mainly well tolerated. Oral macrolides may be effective in the treatment of patients with aseptic facial granuloma.

S1 Guideline onychomycosis.

Onychomycosis is a fungal infection of the fingernails and toenails. In Europe, tinea unguium is mainly caused by dermatophytes. The diagnostic workup comprises microscopic examination, culture and/or molecular testing (nail scrapings). Local treatment with antifungal nail polish is recommended for mild or moderate nail infections. In case of moderate to severe onychomycosis, oral treatment is recommended (in the absence of contraindications). Treatment should consist of topical and systemic agents. The aim of this update of the German S1 guideline is to simplify the selection and implementation of appropriate diagnostics and treatment. The guideline was based on current international guidelines and the results of a literature review conducted by the experts of the guideline committee. This multidisciplinary committee consisted of representatives from the German Society of Dermatology (DDG), the German-Speaking Mycological Society (DMykG), the Association of German Dermatologists (BVDD), the German Society for Hygiene and Microbiology (DGHM), the German Society of Pediatric and Adolescent Medicine (DGKJ), the Working Group for Pediatric Dermatology (APD) and the German Society for Pediatric Infectious Diseases (DGPI). The Division of Evidence-based Medicine (dEBM) provided methodological assistance. The guideline was approved by the participating medical societies following a comprehensive internal and external review.

Flagellin hypervariable region determines symbiotic properties of commensal Escherichia coli strains.

Escherichia coli represents a classical intestinal gram-negative commensal. Despite this commensalism, different E. coli strains can mediate disparate immunogenic properties in a given host. Symbiotic E. coli strains such as E. coli Nissle 1917 (EcN) are attributed beneficial properties, e.g., promotion of intestinal homeostasis. Therefore, we aimed to identify molecular features derived from symbiotic bacteria that might help to develop innovative therapeutic alternatives for the treatment of intestinal immune disorders. This study was performed using the dextran sodium sulphate (DSS)-induced colitis mouse model, which is routinely used to evaluate potential therapeutics for the treatment of Inflammatory Bowel Diseases (IBDs). We focused on the analysis of flagellin structures of different E. coli strains. EcN flagellin was found to harbor a substantially longer hypervariable region (HVR) compared to other commensal E. coli strains, and this longer HVR mediated symbiotic properties through stronger activation of Toll-like receptor (TLR)5, thereby resulting in interleukin (IL)-22-mediated protection of mice against DSS-induced colitis. Furthermore, using bone-marrow-chimeric mice (BMCM), CD11c+ cells of the colonic lamina propria (LP) were identified as the main mediators of these flagellin-induced symbiotic effects. We propose flagellin from symbiotic E. coli strains as a potential therapeutic to restore intestinal immune homeostasis, e.g., for the treatment of IBD patients.

Ivermectin treatment in rosacea: How novel smartphone technology can support monitoring rosacea-associated signs and symptoms.

Rosacea lessens patients' quality of life not only by visible symptoms like erythema, papules, and pustules but also by invisible symptoms like stinging, burning, and dryness. Ivermectin 1% cream has recently been introduced as an efficient therapy for papules and pustules in rosacea patients. To investigate the potential of ivermectin 1% cream to improve rosacea-associated erythema and invisible symptoms by combining established questionnaires with the novel photography and analysis tool Scarletred®Vision. We performed an open monocentric pilot study including 25 Caucasian patients presenting with moderate to severe rosacea with erythema, less than 10 papules and/or pustules, and ≥ 15 Demodex mites/cm2 . Patients applied 1 g of ivermectin 1% cream (Soolantra®) once a day for ≥16 weeks. Skin symptoms were recorded at baseline, week 8 and ≥ week 16. Grade of erythema was determined by clinician erythema assessment (CEA) and patient self-assessment (PSA). Severity of invisible skin symptoms (stinging and/or burning, dryness, itching) were assessed by questionnaire. Erythema and skin texture were additionally quantified using Scarletred®Vision. Ivermectin 1% cream significantly reduced invisible symptoms of rosacea (stinging and/or burning, dryness: p < 0.0001; itching p < 0.001; at ≥16 weeks). Analysis with Scarletred®Vision confirmed CEA and PSA results for improvement of erythema (p < 0.0001; at ≥16 weeks) and skin roughness (p < 0.001; at ≥16 weeks). Treatment with ivermectin 1% cream is efficient in treating not only rosacea-associated papules and pustules but also erythema and invisible skin symptoms.

Prevalence of Candida species in Psoriasis.

BACKGROUND: Psoriasis patients are more frequently colonised with Candida species. The correlation between fungal colonisation and clinical severity is unclear, but may exacerbate psoriasis and the impact of antipsoriatic therapies on the prevalence of Candida is unknown. OBJECTIVES: To examine the prevalence of C species in psoriasis patients compared to an age- and sex-matched control population, we investigated the influence of Candida colonisation on disease severity, immune cell activation and the interplay on psoriatic treatments. METHODS: The prevalence of C species was examined in 265 psoriasis patients and 200 control subjects by swabs and stool samples for fungal cultures. Peripheral mononuclear blood cells (PBMCs) were collected from 20 fungal colonised and 24 uncolonised patients and stimulated. The expression of interferon (IFN)-γ, IL-17A, IL-22 and tumour necrosis factor (TNF)-α from stimulated PBMCs was measured by quantitative real-time polymerase chain reaction (qPCR). RESULTS: A significantly higher prevalence for Candida was detected in psoriatic patients (p ≤ .001) compared to the control subjects; most abundant in stool samples, showing Candida albicans. Older participants (≥51 years) were more frequent colonised, and no correlation with gender, disease severity or systemic treatments like IL-17 inhibitors was found. CONCLUSIONS: Although Candida colonisation is significantly more common in patients with psoriasis, it does not influence the psoriatic disease or cytokine response. Our study showed that Candida colonisation is particularly more frequent in patients with psoriasis ≥51 years of age. Therefore, especially this group should be screened for symptoms of candidiasis during treatment with IL-17 inhibitors.

S2k guideline: Rosacea.

This updated and upgraded S2k guideline deals with the diagnosis and treatment of rosacea, which is a common, chronic inflammatory skin disease mostly affecting the face. Initially, rosacea is characterized by recurrent erythema, telangiectasia and flushing. Later, the inflammatory component predominates, with persistent erythema with follicular papules, papulopustules and pustules. The development of phyma, which usually occurs on the acral localizations, is the most severe manifestation. For the treatment of rosacea, the interdisciplinary guideline committee, with representatives of the German Dermatological Society (DDG), the Professional Association of German Dermatologists (BVDD), the German Opthalmological Society (DOG), the Society for Dermopharmacy (GD), the Swiss Society for Dermatology and Venereology (SGDV) and the German Rosacea Aid e. V., recommends the avoidance of trigger factors and topical applications of metronidazole, azelaic acid or ivermectin. For symptomatic treatment of persistent centrofacial erythema, the topical vasoconstrictors brimonidine or oxymetazoline can also be used. Systemic therapy is recommended for therapy-resistant and severe forms of rosacea papulopustulosa. The drug of choice is low-dose doxycycline. Alternatively, low-dose isotretinoin can be recommended. Ocular rosacea should be treated with lid margin hygiene. For topical treatment, ciclosporin eye drops, azithromycin, ivermectin or metronidazole are suggested.

Proteinuric chronic kidney disease is associated with altered red blood cell lifespan, deformability and metabolism.

Anemia is a common complication of chronic kidney disease, affecting the quality of life of patients. Among various factors, such as iron and erythropoietin deficiency, reduced red blood cell (RBC) lifespan has been implicated in the pathogenesis of anemia. However, mechanistic data on in vivo RBC dysfunction in kidney disease are lacking. Herein, we describe the development of chronic kidney disease-associated anemia in mice with proteinuric kidney disease resulting from either administration of doxorubicin or an inducible podocin deficiency. In both experimental models, anemia manifested at day 10 and progressed at day 30 despite increased circulating erythropoietin levels and erythropoiesis in the bone marrow and spleen. Circulating RBCs in both mouse models displayed altered morphology and diminished osmotic-sensitive deformability together with increased phosphatidylserine externalization on the outer plasma membrane, a hallmark of RBC death. Fluorescence-labelling of RBCs at day 20 of mice with doxorubicin-induced kidney disease revealed premature clearance from the circulation. Metabolomic analyses of RBCs from both mouse models demonstrated temporal changes in redox recycling pathways and Lands' cycle, a membrane lipid remodeling process. Anemic patients with proteinuric kidney disease had an increased proportion of circulating phosphatidylserine-positive RBCs. Thus, our observations suggest that reduced RBC lifespan, mediated by altered RBC metabolism, reduced RBC deformability, and enhanced cell death contribute to the development of anemia in proteinuric kidney disease.

Extracellular vesicles released by myeloid-derived suppressor cells from pregnant women modulate adaptive immune responses.

Immunological pregnancy complications are a main challenge in reproductive medicine. Mechanisms regulating the adaptation of the maternal immune system to pregnancy are incompletely understood and therapeutic options limited. Myeloid derived suppressor cells (MDSC) are immune-modulatory cells expanding during healthy pregnancy and seem to play a crucial role for maternal-fetal tolerance. Recent studies showed that exosomes produced by MDSC have immune-modulatory effects corresponding to their parental cells under different pathological conditions. Here, we investigated immunological effects of exosomes of GR-MDSC during pregnancy. Isolated GR-MDSC exosomes from peripheral blood of pregnant women were tested for functionality in different in vitro assays. We show that GR-MDSC exosomes exhibited profound immune-modulatory effects such as suppression of T-cell proliferation, T helper 2 (Th2)-cell polarization, induction of regulatory T-cells and inhibition of lymphocyte cytotoxicity. Our results confirm that MDSC-derived exosomes functionally correspond to their parental cells and identify them as an interesting therapeutic target for immunological pregnancy complications.

Expression of DNA Methyltransferase 1 Is a Hallmark of Melanoma, Correlating with Proliferation and Response to B-Raf and Mitogen-Activated Protein Kinase Inhibition in Melanocytic Tumors.

Aberrant DNA methylation is an epigenetic hallmark of melanoma, but the expression of DNA methyltransferase (Dnmt)-1 in melanocytic tumors is unknown. Dnmt1 expression was analyzed in primary melanocytes, melanoma cell lines, and 83 melanocytic tumors, and its associations with proliferation, mutational status, and response to B-Raf and mitogen-activated protein kinase kinase (MEK) inhibition were explored. Dnmt1 expression was increased incrementally from nevi [mean fluorescence intensity (MFI), 48.1; interquartile range, 41.7 to 59.6] to primary melanomas (MFI, 68.8; interquartile range, 58.4 to 77.0) and metastatic melanomas (MFI, 87.5; interquartile range, 77.1 to 114.5) (P < 0.001). Dnmt1 expression was correlated with Ki-67 expression (Spearman correlation, 0.483; P < 0.001) and was independent of BRAF mutation status (P = 0.55). In BRAF-mutant melanoma, Dnmt1 was down-regulated during response to B-Raf and MEK inhibition and was again up-regulated on drug resistance in vitro and in vivo. Degradation of Dnmt1 by the histone deacetylase inhibitor suberoylanilide hydroxamic acid was associated with decreased cell viability in B-Raf inhibitor-sensitive and -resistant cell lines. This study demonstrates that Dnmt1 expression is correlated with proliferation in melanocytic tumors, is increased with melanoma progression, and is associated with response to B-Raf and MEK inhibition. Given its strong expression in metastatic melanoma, Dnmt1 may be a promising target for combined epigenetic and immunotherapy.

The Importance of Assessing Burning and Stinging when Managing Rosacea: A Review.

Rosacea, a chronic condition usually recognized by its visible presentation, can be accompanied by invisible symptoms, such as burning and stinging. The aim of this review is to gather the most recent evidence on burning and stinging, in order to further emphasize the need to address these symptoms. Inflammatory pathways can explain both the signs and symptoms of rosacea, but available treatments are still evaluated primarily on their ability to treat visible signs. Recent evidence also highlights the adverse impact of symptoms, particularly burning and stinging, on quality of life. Despite an increasing understanding of symptoms and their impact, the management of burning and stinging as part of rosacea treatment has not been widely investigated. Clinicians often underestimate the impact of these symptoms and do not routinely include them as part of management. Available therapies for rosacea have the potential to treat beyond signs, and improve burning and stinging symptoms in parallel. Further investigation is needed to better understand these benefits and to optimize the management of rosacea.

Guideline: Vulvovaginal candidosis (AWMF 015/072, level S2k).

Approximately 70-75% of women will have vulvovaginal candidosis (VVC) at least once in their lifetime. In premenopausal, pregnant, asymptomatic and healthy women and women with acute VVC, Candida albicans is the predominant species. The diagnosis of VVC should be based on clinical symptoms and microscopic detection of pseudohyphae. Symptoms alone do not allow reliable differentiation of the causes of vaginitis. In recurrent or complicated cases, diagnostics should involve fungal culture with species identification. Serological determination of antibody titres has no role in VVC. Before the induction of therapy, VVC should always be medically confirmed. Acute VVC can be treated with local imidazoles, polyenes or ciclopirox olamine, using vaginal tablets, ovules or creams. Triazoles can also be prescribed orally, together with antifungal creams, for the treatment of the vulva. Commonly available antimycotics are generally well tolerated, and the different regimens show similarly good results. Antiseptics are potentially effective but act against the physiological vaginal flora. Neither a woman with asymptomatic colonisation nor an asymptomatic sexual partner should be treated. Women with chronic recurrent Candida albicans vulvovaginitis should undergo dose-reducing maintenance therapy with oral triazoles. Unnecessary antimycotic therapies should always be avoided, and non-albicans vaginitis should be treated with alternative antifungal agents. In the last 6 weeks of pregnancy, women should receive antifungal treatment to reduce the risk of vertical transmission, oral thrush and diaper dermatitis of the newborn. Local treatment is preferred during pregnancy.

[Hyperplasia-associated cutaneous paraneoplasia]. / Hyperplasie-assoziierte obligate Paraneoplasien der Haut.

BACKGROUND: Hyperplasia-associated cutaneous paraneoplasia is an important differential diagnosis in everyday clinical practice. An early diagnosis of the underlying tumor disease can significantly improve the patient's prognosis. PATHOGENESIS: Hyperplasia is probably mainly cytokine-mediated. The primary tumor and/or the metastases release growth factors and transcription factors which, via epidermal growth factors, lead to hyperproliferation of keratinocytes. ACANTHOSIS NIGRICANS MALIGNA: Symmetrical mainly intertriginous hyperpigmentation with partially verrucous hyperplasia and lichenification mostly in association with gastric adenocarcinoma. Special forms are florid cutaneous papillomatosis and tripe palms. Pseudoacanthosis nigricans is to be distinguished (metabolic and hormonal disorders). LESER-TRéLAT SYNDROME: Eruptive occurrence of seborrheic keratosis associated with visceral tumors. ACROKERATOSIS BAZEX: Erythema and scaling initially at the bridge of the nose, ear helix and acra with later spread, associated with tumors of the upper aerodigestive system. It should be clinically differentiated from psoriasis. THERAPY: The treatment of the primary tumor is decisive, which also leads to a decrease of cutaneous symptoms. Reappreance suggests tumor recurrence.

The specific PKC-α inhibitor chelerythrine blunts costunolide-induced eryptosis.

Costunolide, a natural sesquiterpene lactone, has multiple pharmacological activities such as neuroprotection or induction of apoptosis and eryptosis. However, the effects of costunolide on pro-survival factors and enzymes in human erythrocytes, e.g. glutathione and glucose-6-phosphate dehydrogenase (G6PDH) respectively, have not been studied yet. Our aim was to determine the mechanisms underlying costunolide-induced eryptosis and to reverse this process. Phosphatidylserine exposure was estimated from annexin-V-binding, cell volume from forward scatter in flow cytometry, and intracellular glutathione [GSH]i from high performance liquid chromatography. The oxidized status of intracellular glutathione and enzyme activities were measured by spectrophotometry. Treatment of erythrocytes with costunolide dose-dependently enhanced the percentage of annexin-V-binding cells, decreased the cell volume, depleted [GSH]i and completely inhibited G6PDH activity. The effects of costunolide on annexin-V-binding and cell volume were significantly reversed by pre-treatment of erythrocytes with the specific PKC-α inhibitor chelerythrine. The latter, however, had no effect on costunolide-induced GSH depletion. Costunolide induces eryptosis, depletes [GSH]i and inactivates G6PDH activity. Furthermore, our study reveals an inhibitory effect of chelerythrine on costunolide-induced eryptosis, indicating a relationship between costunolide and PKC-α. In addition, chelerythrine acts independently of the GSH depletion. Understanding the mechanisms of G6PDH inhibition accompanied by GSH depletion should be useful for development of anti-malarial therapeutic strategies or for synthetic lethality-based approaches to escalate oxidative stress in cancer cells for their sensitization to chemotherapy and radiotherapy.