Nlrp6- and ASC-Dependent Inflammasomes Do Not Shape the Commensal Gut Microbiota Composition.

The gut microbiota regulate susceptibility to multiple human diseases. The Nlrp6-ASC inflammasome is widely regarded as a hallmark host innate immune axis that shapes the gut microbiota composition. This notion stems from studies reporting dysbiosis in mice lacking these inflammasome components when compared with non-littermate wild-type animals. Here, we describe microbial analyses in inflammasome-deficient mice while minimizing non-genetic confounders using littermate-controlled Nlrp6-deficient mice and ex-germ-free littermate-controlled ASC-deficient mice that were all allowed to shape their gut microbiota naturally after birth. Careful microbial phylogenetic analyses of these cohorts failed to reveal regulation of the gut microbiota composition by the Nlrp6- and ASC-dependent inflammasomes. Our results obtained in two geographically separated animal facilities dismiss a generalizable impact of Nlrp6- and ASC-dependent inflammasomes on the composition of the commensal gut microbiota and highlight the necessity for littermate-controlled experimental design in assessing the influence of host immunity on gut microbial ecology.

Histopathologic regression in patients with primary cutaneous melanoma undergoing sentinel lymph node biopsy is associated with favorable survival and, after metastasis, with improved progression-free survival on immune checkpoint inhibitor therapy: A single-institutional cohort study.

BACKGROUND: Histopathologic regression of cutaneous melanoma is considered a favorable prognostic factor, but its significance in clinical practice remains controversial. OBJECTIVE: To investigate the prognostic importance of regression in patients with primary cutaneous melanoma undergoing sentinel lymph node (SLN) biopsy and to assess its significance in patients progressing to an unresectable stage requiring systemic therapy. METHODS: We retrospectively reviewed patients with newly diagnosed melanoma undergoing SLN biopsy between 2010 and 2015 and available information on histopathologic regression (n = 1179). Survival data and associations of clinical variables with SLN status were assessed. RESULTS: Patients with regressive melanoma showed favorable relapse-free (hazard ratio [HR], 0.52; P = .00013), distant metastasis-free (HR, 0.56; P = .0020), and melanoma-specific survival (HR, 0.35; P = .00053). Regression was associated with negative SLN (odds ratio, 0.48; P = .0077). In patients who progressed to an unresectable stage, regression was associated with favorable progression-free survival under immune checkpoint inhibition (HR, 0.43; P = .031) but not under targeted therapy (HR, 1.14; P = .73) or chemotherapy (HR, 3.65; P = .0095). LIMITATIONS: Retrospective, single-institutional design. CONCLUSIONS: Regression of cutaneous melanoma is associated with improved prognosis in patients eligible for SLN biopsy as well as in patients with unresectable disease receiving systemic therapy with immune checkpoint inhibitors.

Human sleep consolidates allergic responses conditioned to the environmental context of an allergen exposure.

Allergies are highly prevalent, and allergic responses can be triggered even in the absence of allergens due to Pavlovian conditioning to a specific cue. Here we show in humans suffering from allergic rhinitis that merely reencountering the environmental context in which an allergen was administered a week earlier is sufficient to trigger an allergic response-but only if participants had slept after allergen exposure. This context-conditioning effect was entirely absent when participants stayed awake the night after allergen exposure or were tested in a different context. Unlike in context conditioning, cue conditioning (to an odor stimulus) occurred independently of sleep, a differential pattern that is likewise observed for conditioning in the behavioral domain. Our findings provide evidence that allergic responses can be conditioned to contextual information alone, even after only a single-trial conditioning procedure, and that sleep is necessary to consolidate this rapidly acquired maladaptive response. The results unravel a mechanism that could explain part of the strong psychological impact on allergic responses.

Non invasive in vivo monitoring of dimethyl fumarate treatment in EAE by assessing the glucose metabolism in secondary lymphoid organs.

[18 F]FDG-PET/CT is a high sensitive functional diagnostic imaging modality to monitor tumor but also immune cell activation by determination of the glucose metabolism. Our results show that the anti-inflammatory effects of immunotherapeutics like DMF can be assessed non invasively in vivo during Th1/Th17 cell-mediated encephalomyelitis (EAE) by [18 F]FDG-PET/CT imaging of the draining lymph nodes.

Improving the thermal stability of natural bioactive ingredients via encapsulation technology.

Bioactive compounds (bioactives) such as phenolic acids, coumarins, flavonoids, lignans and carotenoids have a marked improvement effect on human health by acting on body tissues or cells. Nowadays, with increasing levels of knowledge, consumers prefer foods that can provide bioactives beside the necessary nutrients (e.g., vitamins, essential fatty acids and minerals). However, an important barrier for incorporating bioactives into foods is their low thermal stability. Nevertheless, thermal processing is widely used by the food industries to achieve food safety and desired texture. The aim of this work is to give an overview of encapsulation technology to improve thermal stability of bioactives incorporated into different food products. Almost all thermal analysis and non-thermal methods in the literature suggest that incorporation of bioactives into different walls can effectively improve the thermal stability of bioactives. The level of such thermal enhancement depends on the strength of the bioactive interaction and wall molecules. Furthermore, contradictory results have been reported in relation to the effect of encapsulation technique using the same wall on thermal stability of bioactives. To date, the potential to increase the thermal resistance of various bioactives by gums, carbohydrates, and proteins have been extensively studied. However, further studies on the comparison of walls and encapsulation methods to form thermally stable carriers seem to be needed. In this regard, the same nature of bioactives and the specific protocol in the report of study results should be considered to compare the data and select the optimum conditions of encapsulation to achieve maximum thermal stability.

Immunophenotyping in pemphigus reveals a TH17/TFH17 cell-dominated immune response promoting desmoglein1/3-specific autoantibody production.

BACKGROUND: TH2 cells were thought to be a pivotal factor for initiation of the autoimmune blistering disease pemphigus. However, the role of other T-cell subsets in pemphigus pathogenesis remained unclear. OBJECTIVE: We aimed to characterize the exact phenotype of T cells responsible for the development of pemphigus. METHODS: Whole transcriptome shotgun sequencing was performed to determine differential gene expression in pemphigus lesions and skin of healthy individuals. The cutaneous cytokine signature was further evaluated by real-time quantitative PCR. In peripheral blood, the distribution of TH cell and folliclular helper (TFH) cell subsets was analyzed by flow cytometry. Finally, the capacity of TH and TFH cell subsets to induce desmoglein (Dsg)-specific autoantibodies by memory B cells was evaluated in coculture experiments. RESULTS: Transcriptome analysis of skin samples identified an IL-17A-dominated immune signature in patients with pemphigus, and Kyoto Encyclopedia of Genes and Genomes pathway analysis confirmed the dominance of the IL-17A signaling pathway. Increased expression of IL17A and associated cytokines was also detected by real-time quantitative PCR comparing lesional with perilesional or healthy skin. Interestingly, utilization of flow cytometry showed that patients with active pemphigus had elevated levels of circulating IL-17+, TH17, TFH17, and TFH17.1 cells. Notably, levels of TH17 and TFH17 cells correlated with levels of Dsg-specific CD19+CD27+ memory B cells, and patients with acute pemphigus showed higher levels of Dsg3-autoreactive TFH17 cells. Coculture experiments revealed TFH17 cells as primarily responsible for inducing Dsg-specific autoantibody production by B cells. CONCLUSION: Our findings show that TFH17 cells are critically involved in the pathogenesis of pemphigus and offer novel targets for therapeutic intervention.

Infections with Herpes simplex and Varicella zoster virus.

Human herpes viruses belong to the DNA viruses and are among the most common viral pathogens. Currently, eight human herpes viruses have been characterized. Primary infection is typically followed by virus latency. Viral reactivations are more often symptomatic than primary infections and lead more often to medical consultation. In daily practice, infections with herpes simplex virus (HSV) and varicella zoster virus (VZV) are the most common. If HSV primary infections become clinically manifest, they are often accompanied by systemic symptoms whereas manifest HSV reactivations are usually harmless, self-limiting and present as grouped vesicles on an erythematous base (herpetiform). Primary VZV infection leads to the clinical picture of varicella (chickenpox). VZV reactivation manifests clinically as shingles and can be accompanied by severe acute neuralgiform pain. In immunosuppression, complicated (necrotizing, ulcerative, hemorrhagic, generalized) manifestations may occur. The diagnosis is usually made clinically. Therapeutic options include topical agents and systemic antivirals. Adequate therapeutic management includes the recognition and treatment of complications such as the possible involvement of other organ systems and pain. Infection during pregnancy may result in transmission to the unborn child.

Infektionen mit Herpes-simplex- und Varizella-zoster-Virus.

Humane Herpesviren gehören zu den DNA-Viren und zählen zu den häufigsten Erregern viraler Infektionen beim Menschen. Nach der Primärinfektion mit einem dieser Viren kommt es typischerweise zur Latenz mit dem Potenzial späterer Reaktivierungen, die häufiger symptomatisch sind und zum Arztbesuch führen als die Primärinfektion. In der täglichen Praxis sind Infektionen mit dem Herpes-simplex-Virus (HSV) und dem Varizella-zoster-Virus (VZV) am häufigsten vertreten. Sofern HSV-Primärinfektionen klinisch manifest werden, gehen sie häufig mit Allgemeinsymptomen einher. HSV-Reaktivierungen verlaufen meist harmlos und selbstlimitierend und präsentieren sich als gruppierte Bläschen auf erythematösen Grund (herpetiform). Die VZV-Primärinfektion führt zum klinischen Bild der Varizellen (Windpocken). Bei Immunsuppression kann es zu komplizierten (nekrotisierenden, ulzerierenden, hämorrhagischen, generalisierten) Verläufen kommen. Die VZV-Reaktivierung manifestiert sich klinisch als Herpes zoster (Gürtelrose) und kann mit starken akuten Schmerzen einhergehen. Die Diagnosestellung erfolgt meist klinisch. Therapeutisch stehen Topika und systemische Virostatika zur Verfügung. Das adäquate therapeutische Management umfasst das Erkennen und Behandeln von Komplikationen wie der möglichen Beteiligung weiterer Organsysteme und Schmerzen. Eine Infektion in der Schwangerschaft kann zur Übertragung auf das ungeborene Kind führen.

Using the Structure of Evaluative Components as a basis for comparing the oral narratives of schizophrenics and healthy individuals.

In this study, evaluative language in narratives of 15 healthy and 15 schizophrenic females was compared using the Structure of Evaluative Components. The two groups were matched for chronological age and socioeconomic status. A movie named "The Pear Film" ( http://chafe.faculty.linguistics.ucsb.edu/pearfilm.htm ) was used to elicit the narratives. The Goal evaluative component in the schizophrenic population and the Ownership in healthy individuals were used more than other components within the narratives of each respective group. Significant differences (Mann-Whitney and t-test) between the two groups in using evaluative components were determined using statistical analysis. In general, patients used less evaluative components in their narratives compared to healthy participants and as per specific components, healthy subjects utilized five evaluative components more than patients, which was found to be a significant difference; Goal, Assumption, Ownership, Metaphor, and Causality were those five components. These findings confirm that the ability to use evaluative language in schizophrenia is reduced.

Inflammasome activators induce interleukin-1α secretion via distinct pathways with differential requirement for the protease function of caspase-1.

Through their capacity to sense danger signals and to generate active interleukin-1ß (IL-1ß), inflammasomes occupy a central role in the inflammatory response. In contrast to IL-1ß, little is known about how IL-1α is regulated. We found that all inflammasome activators also induced the secretion of IL-1α, leading to the cosecretion of both IL-1 cytokines. Depending on the type of inflammasome activator, release of IL-1α was inflammasome dependent or independent. Calcium influx induced by the opening of cation channels was sufficient for the inflammasome-independent IL-1α secretion. In both cases, IL-1α was released primarily in a processed form, resulting from intracellular cleavage by calpain-like proteases. Inflammasome-caspase-1-dependent release of IL-1α and IL-1ß was independent of caspase-1 catalytic activity, defining a mode of action for caspase-1. Because inflammasomes contribute to the pathology of numerous chronic inflammatory diseases such as gout and diabetes, IL-1α antagonists may be beneficial in the treatment of these disorders.

Stevens-Johnson syndrome and toxic epidermal necrolysis: a 10-year experience in a burns unit.

OBJECTIVE: Stevens-Johnson syndrome (SJS) and its more severe counterpart, toxic epidermal necrolysis (TEN), are skin hypersensitivity reactions defined by epidermal blistering and necrosis. The exact pathophysiology of SJS/TEN is yet to be deciphered, but a number of risk factors have been identified including adverse drug reactions. The diagnosis of SJS/TEN is made on a clinical basis, and treatment consists of supportive care and occasionally immunosuppressants, such as cyclosporin, high-dose intravenous immunoglobulins and/or corticosteroids. Mortality rates can reach 20-25% in adults but are reduced with early intervention. To identify optimal treatment regimens, to better understand the patient cohort affected, and to help identify key risk factors for mortality, we report our experience with the treatment and management of SJS/TEN patients. METHODS: A retrospective review of consecutive patients with SJS and/or TEN admitted to a single burns centre in Germany, between 2008 and 2018, was conducted. The primary outcomes of demographics, clinical course, treatment and patient-reported outcomes were recorded and compared with a control group of patients with burns without a diagnosis of SJS/TEN. RESULTS: A total of 23 patients with SJS/TEN met the inclusion criteria: 17 (74%) with TEN; four (17%) with SJS/TEN overlap; and two (9%) with SJS. Of the patients, 14 (61%) were female and nine (39%) were male. Patient age ranged from 32-78 years (mean: 52 years). A matched cohort of 23 patients with burns served as the control group. All patients received standard of care with a multidisciplinary team. Compared with the control group, SJS/TEN patients had higher mortality rates (n=6, 26% versus n=8, 35%, respectively). The average age of death was 69 years in SJS/TEN patients versus 63 years in control group patients. Age and SCORTEN scores were significant predictors of mortality. CONCLUSIONS: SJS and TEN are rare but extreme reactions of the skin and mucosa, associated with high disease mortality rates. This 10-year single-centre retrospective review contributes to the bank of information for reviews evaluating the management of SJS/TEN patients.

Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis.

OBJECTIVE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and severe skin and mucosal reactions that are associated with high mortality. Despite the severity, an evidence-based treatment protocol for SJS/TEN is still lacking. METHOD: In this systematic review and meta-analysis, the PubMed database was searched using the following terms: [Stevens-Johnson syndrome] OR [toxic epidermal necrolysis] AND [therapy] OR [treatment] over a 20-year period (1999-2019) in the German and English language. All clinical studies reporting on the treatment of SJS/TEN were included, and epidemiological and diagnostic aspects of treatment were analysed. A meta-analysis was conducted on all comparative clinical studies that met the inclusion criteria. RESULTS: A total of 88 studies met the inclusion criteria, reporting outcomes in 2647 patients. Treatment was either supportive or used systemic corticosteroid, intravenous immunoglobulin, plasmapheresis, cyclosporine, thalidomide or cyclophosphamide therapy. The meta-analysis included 16 (18%) studies, reporting outcomes in 976 (37%) patients. Systemic glucocorticoids showed a survival benefit for SJS/TEN patients in all analyses compared with other forms of treatment. Cyclosporine treatment also showed promising results, despite being used in a small cohort of patients. No beneficial effects on mortality could be demonstrated for intravenous immunoglobulins. CONCLUSION: Glucocorticoids and cyclosporine may be tentatively recommended as the most promising immunomodulatory therapies for SJS/TEN, but these results should be investigated in future prospective controlled trials.

RIPK1 and TRADD Regulate TNF-Induced Signaling and Ripoptosome Formation.

TNF is a proinflammatory cytokine that is critical for the coordination of tissue homeostasis. RIPK1 and TRADD are the main participants in the transduction of TNF signaling. However, data on the cell fate-controlling functions of both molecules are quite controversial. Here, we address the functions of RIPK1 and TRADD in TNF signaling by generating RIPK1- or TRADD-deficient human cell lines. We demonstrate that RIPK1 is relevant for TNF-induced apoptosis and necroptosis in conditions with depleted IAPs. In addition, TRADD is dispensable for necroptosis but required for apoptosis. We reveal a new possible function of TRADD as a negative regulator of NIK stabilization and subsequent ripoptosome formation. Furthermore, we show that RIPK1 and TRADD do not appear to be essential for the activation of MAPK signaling. Moreover, partially repressing NF-κB activation in both RIPK1 and TRADD KO cells does not result in sensitization to TNF alone due to the absence of NIK stabilization. Importantly, we demonstrate that RIPK1 is essential for preventing TRADD from undergoing TNF-induced ubiquitination and degradation. Taken together, our findings provide further insights into the specific functions of RIPK1 and TRADD in the regulation of TNF-dependent signaling, which controls the balance between cell death and survival.

Importance of diagnostics and risk of secondary malignancies in primary cutaneous lymphomas.

BACKGROUND AND OBJECTIVES: Primary cutaneous lymphomas (PCL) often strongly differ in clinical behavior and prognosis from systemic lymphomas of the same histopathologic type. The aim of the study was to investigate the distribution of PCL subtypes, the average time from disease manifestation to diagnosis, the importance of diagnostic procedures, the occurrence of secondary malignancies and the different treatment modalities. PATIENTS AND METHODS: Retrospective analysis of 152 patients with PCL examined at the Department of Dermatology of the University Hospital Tübingen from 2010-2012. RESULTS: 105 patients with CTCL (69.1 %) and 47 patients with CBCL (30.9 %) were included. The average time from disease manifestation to diagnosis was four years. The most common diagnosed lymphoma was mycosis fungoides (MF) (47.4 %). First-line therapies here include phototherapy only (psoralen-UV-A [PUVA], n = 48; UVB 311 nm, n = 7) or combination therapies primarily phototherapy with systemic retinoids (n = 18). Most frequent second-line therapy was interferon (INF)-α plus PUVA (n = 15). The outcome was favorable (45.2 % remission, 28.6 % stable disease, 22.6 % progressive disease). Malignant comorbidities were observed more frequently compared to a healthy control group. CONCLUSIONS: The diagnosis of lymphoma often takes several years. The value of staging procedures is still low and the treatment modalities for MF in earlier stages are mainly based on phototherapy.

Stellenwert diagnostischer Verfahren und Risiko von Zweittumoren bei primär kutanen Lymphomen.

HINTERGRUND: Primär kutane Lymphome (PCL) unterscheiden sich oft stark im klinischen Verhalten und in der Prognose von systemischen Lymphomen des gleichen histopathologischen Typs. Ziel der Studie war es, die Verteilung der PCL-Subtypen, die Zeitspanne von der Krankheitsmanifestation bis zur Diagnosestellung, den Stellenwert diagnostischer Verfahren, das Auftreten von Zweittumoren und die verschiedenen Behandlungsmodalitäten im Rahmen des Krankheitsverlaufs zu untersuchen. PATIENTEN UND METHODIK: Retrospektive Analyse von 152 Patienten mit PCL, die von 2010-2012 an der Universitäts-Hautklinik Tübingen behandelt wurden. ERGEBNISSE: 105 Patienten mit primär kutanem T-Zell-Lymphom (CTCL) (69,1 %) und 47 Patienten mit primär kutanem B-Zell-Lymphom (CBCL) (30,9 %) wurden eingeschlossen. Die Zeitspanne von der Krankheitsmanifestation bis zur Diagnose betrug durchschnittlich vier Jahre. Mycosis fungoides (MF) (47,4 %) wurde am häufigsten diagnostiziert. Die First-Line-Therapien umfassten hier entweder eine alleinige Phototherapie (PUVA, n = 48; UVB 311 nm, n = 7) oder Kombinationstherapien (PUVA mit systemischen Retinoiden, n = 18). Häufigste Second-Line-Therapie war Interferon (INF)-α plus PUVA (n = 15). Der Behandlungsverlauf war insgesamt günstig (45,2 % Remission, 28,6 % stabile Erkrankung, 22,6 % Progress). Maligne Komorbiditäten wurden im Vergleich zu einer gesunden Vergleichsgruppe häufiger beobachtet. SCHLUSSFOLGERUNGEN: Bis zur Diagnosestellung der PCL dauert es oft mehrere Jahre. Der Wert der Staging-Verfahren ist gering. Die Behandlungsmodalitäten in früheren MF-Stadien basieren hauptsächlich auf der Phototherapie.

Prevalence and Impact of Type I Sensitization to Alpha-Gal in Patients Consulting an Allergy Unit.

BACKGROUND: Alpha-gal syndrome is a complex allergy with high clinical relevance regarding mammalian-derived food and drugs and is characterized by the presence of IgE antibodies directed at the carbohydrate galactose-α-1,3-galactose. As not all alpha-gal sIgE-positive individuals pre-sent clinical symptoms upon consumption of mammalian meat, the diagnostic value of alpha-gal sIgE has yet to be clarified. OBJECTIVE: To investigate the prevalence of alpha-gal-sIgE positivity among allergy patients, examine the impact of tick bites as associated risk factors and determine the diagnostic value of alpha-gal-sIgE positivity. METHODS: A retrospective cross-sectional study evaluating patients in the Allergy Unit was performed. Alpha-gal-sIgE levels were assessed by ImmunoCAP assay. Exposure to tick bites was assessed by a questionnaire. A receiver operating characteristics (ROC) curve analysis was performed to determine the diagnostic value of alpha-gal sIgE for the diagnosis of alpha-gal syndrome. RESULTS: In the study population (n = 1369), the overall prevalence of alpha-gal-sIgE-positive (≥0.10 kUA/L) individuals was 19.9%, and the highest prevalence (30.2%) was found in patients with insect venom allergies. A reported tick bite within the 12 months prior to blood sampling significantly increased the risk of alpha-gal-sIgE positivity (OR 2.084). The ROC curve analysis indicated alpha-gal sIgE ≥0.54 kUA/L as the optimal cutoff point for assessing the diagnostic value of alpha-gal syndrome in allergy patients. CONCLUSIONS: In allergy care settings, alpha-gal-sIgE positivity is a common finding. Alpha-gal sIgE is a sensitive marker in the diagnosis of alpha-gal syndrome but has limited predictive value for the characteristics or severity of this allergy.

Molecular Mechanisms of Hair Growth and Regeneration: Current Understanding and Novel Paradigms.

Hair is a defining feature of mammals and has critical functions, including protection, production of sebum, apocrine sweat and pheromones, social and sexual interactions, thermoregulation, and provision of stem cells for skin homeostasis, regeneration, and repair. The hair follicle (HF) is considered a "mini-organ," consisting of intricate and well-organized structures which originate from HF stem and progenitor cells. Dermal papilla cells are the main components of the mesenchymal compartments in the hair bulb and are instrumental in generating signals to regulate the behavior of neighboring epithelial cells during the hair cycle. Mesenchymal-epithelial interactions within the dermal papilla niche drive HF embryonic development as well as the postnatal hair growth and regeneration cycle. This review summarizes the current understanding of HF development, repair, and regeneration, with special focus on cell signaling pathways governing these processes. In particular, we discuss emerging paradigms of molecular signaling governing the dermal papilla-epithelial cellular interactions during hair growth and maintenance and the recent progress made towards tissue engineering of human hair follicles.

Comparison of functional outcomes of cartilage tympanoplasty with silastic sheet versus Gelfoam packing in middle ear.

BACKGROUND AND AIM: Tympanoplasty is a common surgery in otorhinolaryngology field. In majority of procedures, in addition to the graft used for closure of tympanic membrane, a packing material is essential to be placed in the middle ear cavity. The main goals of packing can be summarized as providing support to the tympanic membrane and ossicular grafts, aeration of middle ear cavity and hemostasis. Several packing materials are currently available for using in middle ear surgeries. Each agent is associated with particular advantages and disadvantages, so choosing the proper packing agent is essential in tympanoplasty surgeries. In this study we aimed to compare two common packing materials (Gelfoam and silastic sheets) in cartilage tympanoplasty surgeries. METHODS AND MATERIALS: In this block-randomized clinical trial, 78 patients undergoing tympanoplasty in Vali-e-asr hospital in 2017 and 2018 were enrolled. They were randomly assigned to silastic sheet or gelfoam groups. The functional outcomes were compared between the groups. Statistical analysis was performed by SPSS. RESULTS: Success was achieved in 32 (82.1%) patients and 34 (87.2%) patients in gelfoam and silastic sheets' groups, respectively (p = 0.530). The perforation area percentage was significantly lower (P = 0.007) in Gelfoam group. The other parameters were statistically the same in both groups (P > 0.05). CONCLUSION: Overall, Gelfoam and silastic sheet methods had similar efficacy in cartilage tympanoplasty. Using each method depends on the preferrence of surgeon and patients' characteristics. Multi-center studies with larger sample sizes are needed for more conclusive results.

TNF Is Partially Required for Cell-Death-Triggered Skin Inflammation upon Acute Loss of cFLIP.

cFLIP is required for epidermal integrity and skin inflammation silencing via protection from TNF-induced keratinocyte apoptosis. Here, we generated and analyzed cFLIP epidermal KO mice with additional TNF deficiency. Intriguingly, the ablation of TNF rescued the pathological phenotype of epidermal cFLIP KO from characteristic weight loss and increased mortality. Moreover, the lack of TNF in these animals strongly reduced and delayed the epidermal hyperkeratosis and the increased apoptosis in keratinocytes. Our data demonstrate that TNF signaling in cFLIP-deficient keratinocytes is the critical factor for the regulation of skin inflammation via modulated cytokine and chemokine expression and, thus, the attraction of immune cells. Our data suggest that autocrine TNF loop activation upon cFLIP deletion is dispensable for T cells, but is critical for neutrophil attraction. Our findings provide evidence for a negative regulatory role of cFLIP for TNF-dependent apoptosis and partially for epidermal inflammation. However, alternative signaling pathways may contribute to the development of the dramatic skin disease upon cFLIP deletion. Our data warrant future studies of the regulatory mechanism controlling the development of skin disease upon cFLIP deficiency and the role of cFLIP/TNF in a number of inflammatory skin diseases, including toxic epidermal necrolysis (TEN).

Postoperative complications in dermatological patients undergoing microscopically controlled surgery in inpatient setting (next-day surgery): A single-center epidemiological study.

BACKGROUND: Surgical site infections (SSI), bleeding, and necrosis are possible complications of dermatological surgery, and their rates are well described for Mohs surgery (same-day surgery). However, there are only limited data on their occurrence in microscopically controlled surgery of the form in which it is practiced in German hospitals (next-day surgery). MATERIALS AND METHODS: We performed a retrospective analysis of patient records of patients hospitalized for microscopically controlled surgery during the year 2017 (12 months) in the Department of Dermatology and Allergology at the University Hospital of the RWTH Aachen (Aachen, Germany). The investigation addressed postoperative outcomes. RESULTS: 319 patients underwent 528 dermatosurgical procedures in the defined period. Bleeding and necrosis occurred in 3.8 % (20/528) and 1.7 % (9/528) of the procedures, respectively. SSI occurred in 5.1 % (27/528) of the cases. The occurrence of bleeding was a statistically significant risk factor for SSI (p  =  0.01). Furthermore, bleeding, SSI, and wound closure with a full-thickness graft were statistically significant risk factors for the development of necrosis (p < 0.05). Diabetes or immunosuppression were not found to be statistically significant risk factors for the development of SSI or necrosis after dermatologic surgery (p > 0.05). CONCLUSIONS: Complication rates in microscopically controlled surgery (next-day surgery) are generally low and similar to those reported for Mohs surgery (same-day surgery). Therefore, it appears that some evidence-based perioperative recommendations that have been developed for Mohs surgery could be applied to German inpatient dermatosurgery. However, prospective studies with larger patient numbers are required to offer concrete recommendations specifically for microscopically controlled surgery (next-day surgery).