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Histamine is a mediator of allergic inflammation released mainly from mast cells. Although histamine strongly increases vascular permeability, its precise mechanism under in vivo situation remains unknown. We here attempted to reveal how histamine induces vascular hyperpermeability focusing on the key regulators of vascular permeability, blood flow and endothelial barrier. Degranulation of mast cells by antigen-stimulation or histamine treatment induced vascular hyperpermeability and tissue swelling in mouse ears. These were abolished by histamine H1 receptor antagonism. Intravital imaging showed that histamine dilated vasculature, increased blood flow, while it induced hyperpermeability in venula. Whole-mount staining showed that histamine disrupted endothelial barrier formation of venula indicated by changes in vascular endothelial cadherin (VE-cadherin) localization at endothelial cell junction. Inhibition of nitric oxide synthesis (NOS) by L-NAME or vasoconstriction by phenylephrine strongly inhibited the histamine-induced blood flow increase and hyperpermeability without changing the VE-cadherin localization. In vitro, measurements of trans-endothelial electrical resistance of human dermal microvascular endothelial cells (HDMECs) showed that histamine disrupted endothelial barrier. Inhibition of protein kinase C (PKC) or Rho-associated protein kinase (ROCK), NOS attenuated the histamine-induced barrier disruption. These observations suggested that histamine increases vascular permeability mainly by nitric oxide (NO)-dependent vascular dilation and subsequent blood flow increase and maybe partially by PKC/ROCK/NO-dependent endothelial barrier disruption.

Organ fibrosis often leads to end-stage organ failure, but the origin of key profibrotic cell types is still unclear. Lucie Peduto and her colleagues have used genetic lineage tracing and pharmacological ablation techniques to show that ADAM12 + perivascular cells are a key source of profibrotic cells in acute skin and muscle injury in the mouse. They also show that knockdown of ADAM12 expression is beneficial, suggesting a possible therapeutic target for the treatment of fibrosis. Profibrotic cells that develop upon injury generate permanent scar tissue and impair organ recovery, though their origin and fate are unclear. Here we show that transient expression of ADAM12 (a disintegrin and metalloprotease 12) identifies a distinct proinflammatory subset of platelet-derived growth factor receptor-α–positive stromal cells that are activated upon acute injury in the muscle and dermis. By inducible genetic fate mapping, we demonstrate in vivo that injury-induced ADAM12 + cells are specific progenitors of a major fraction of collagen-overproducing cells generated during scarring, which are progressively eliminated during healing. Genetic ablation of ADAM12 + cells, or knockdown of ADAM12, is sufficient to limit generation of profibrotic cells and interstitial collagen accumulation. ADAM12 + cells induced upon injury are developmentally distinct from muscle and skin lineage cells and are derived from fetal ADAM12 + cells programmed during vascular wall development. Thus, our data identify injury-activated profibrotic progenitors residing in the perivascular space that can be targeted through ADAM12 to limit tissue scarring.

Why mammals have poor regenerative ability has remained a long-standing question in biology. In regenerating vertebrates, injury can induce a process known as epimorphic regeneration to replace damaged structures. Using a 4-mm ear punch assay across multiple mammalian species, here we show that several Acomys spp . (spiny mice) and Oryctolagus cuniculus completely regenerate tissue, whereas other rodents including MRL/MpJ ‘healer’ mice heal similar injuries by scarring. We demonstrate ear-hole closure is independent of ear size, and closure rate can be modelled with a cubic function. Cellular and genetic analyses reveal that injury induces blastema formation in Acomys cahirinus . Despite cell cycle re-entry in Mus musculus and A. cahirinus , efficient cell cycle progression and proliferation only occurs in spiny mice. Together, our data unite blastema-mediated regeneration in spiny mice with regeneration in other vertebrates such as salamanders, newts and zebrafish, where all healthy adults regenerate in response to injury. The extent to which mammals and other vertebrates share similar mechanisms of tissue regeneration is unclear. Here, the authors use an ear punch assay in spiny mice, which regenerate fully, to show blastema formation and mesenchymal cell proliferation as cell cycle regulators p21 and p27 remain cytoplasmic.

Allergic inflammation triggered by exposure of an allergen frequently leads to the onset of chronic inflammatory diseases such as atopic dermatitis (AD) and bronchial asthma. The mechanisms underlying chronicity in allergic inflammation remain unresolved. Periostin, a recently characterized matricellular protein, interacts with several cell surface integrin molecules, providing signals for tissue development and remodeling. Here we show that periostin is a critical mediator for the amplification and persistence of allergic inflammation using a mouse model of skin inflammation. Th2 cytokines IL-4 and IL-13 stimulated fibroblasts to produce periostin, which interacted with αv integrin, a functional periostin receptor on keratinocytes, inducing production of proinflammatory cytokines, which consequently accelerated Th2-type immune responses. Accordingly, inhibition of periostin or αv integrin prevented the development or progression of allergen-induced skin inflammation. Thus, periostin sets up a vicious circle that links Th2-type immune responses to keratinocyte activation and plays a critical role in the amplification and chronicity of allergic skin inflammation.

Biofilm formation causes prolonged wound infections due to the dense biofilm structure, differential gene regulation to combat stress, and production of extracellular polymeric substances. Acinetobacter baumannii , Staphylococcus aureus , and Pseudomonas aeruginosa are three difficult-to-treat biofilm-forming bacteria frequently found in wound infections. This work describes a novel wound dressing in the form of an electrochemical scaffold (e-scaffold) that generates controlled, low concentrations of hypochlorous acid (HOCl) suitable for killing biofilm communities without substantially damaging host tissue. Production of HOCl near the e-scaffold surface was verified by measuring its concentration using needle-type microelectrodes. E-scaffolds producing 17, 10 and 7 mM HOCl completely eradicated S. aureus , A. baumannii , and P. aeruginosa biofilms after 3 hours, 2 hours, and 1 hour, respectively. Cytotoxicity and histopathological assessment showed no discernible harm to host tissues when e-scaffolds were applied to explant biofilms. The described strategy may provide a novel antibiotic-free strategy for treating persistent biofilm-associated infections, such as wound infections.

Aim The aim of this study was to construct and validate a nomogram to predict the 1-, 3- and 5-year overall survival (OS) in external ear melanoma (EEM) patients in the elderly based on the Surveillance, Epidemiology, and End Results (SEER) database. Methods The information of patients diagnosed with EEM in the elderly between 2010 and 2014 was downloaded from the SEER database. Univariable and multivariable Cox analyses were carried out to identify the independent characteristics, and the independent factors were further included to construct a nomogram. The discriminative ability and calibration of the nomogram to predict OS were tested using C-index value, and calibration plots. Based on the risk score of the nomogram, the patients were divided into high- and low-risk subgroup. Finally, the survival differences of different subgroups were explored by Kaplan–Meier curves. All statistical analyses were performed by R 4.2.0. Results A total of 710 elderly EMM patients were included and randomly divided into training cohort and validation cohort. Univariable Cox regression were used to identify age, race, sex, American Joint Committee on Cancer (AJCC), T, surgery, radiation, chemotherapy, and tumor size as independent risk factors. Then, multivariable Cox model to determine significant risk factors was used to establish the selected factors. A nomogram for predicting the 1-, 3- and 5-year OS was constructed using the independent variables including age, AJCC, T, surgery and chemotherapy. The C-index values were 0.78 (95% CI 0.75–0.81) in training set and 0.72 (95% CI 0.66–0.78) in validation set. The calibration curves were closer to ideal curves indicated the accurate predictive ability of this nomogram. The elderly patients with EEM in the low-risk group showed a longer OS than patients in the high-risk group in both training and validation cohorts. Conclusions Our study established and validated a novel model to predict 1-, 3- and 5-year OS for EEM. The individualized nomogram has a good prognostic ability and can be used as a new survival prediction tool for the elderly patients with EMM.

With over seven million infections and $25 billion treatment cost, chronic ischemic wounds are one of the most serious complications in the United States. The controlled release of bioactive factor enriched exosome from finbrin gel was a promising strategy to promote wound healing. To address this unsolved problem, we developed clinical-grade platelets exosome product (PEP), which was incorporate with injectable surgical fibrin sealant (TISSEEL), to promote chronic wound healing and complete skin regeneration. The PEP characterization stimulated cellular activities and rabbit ischemic wound healing capacity of TISSEEL-PEP were performed and analyzed. PEP, enriched with transforming growth factor beta (TGF-β), possessed exosomal characteristics including exosome size, morphology, and typical markers including CD63, CD9, and ALG-2-interacting protein X (Alix). , PEP significantly promoted cell proliferation, migration, tube formation, as well as skin organoid formation. Topical treatment of ischemic wounds with TISSEEL-PEP promoted full-thickness healing with the reacquisition of hair follicles and sebaceous glands. Superior to untreated and TISSEEL-only treated controls, TISSEEL-PEP drove cutaneous healing associated with collagen synthesis and restoration of dermal architecture. Furthermore, PEP promoted epithelial and vascular cell activity enhancing angiogenesis to restore blood flow and mature skin function. Transcriptome deconvolution of TISSEEL-PEP versus TISSEEL-only treated wounds prioritized regenerative pathways encompassing neovascularization, matrix remodeling and tissue growth. This room-temperature stable, lyophilized exosome product is thus capable of delivering a bioactive transforming growth factor beta to drive regenerative events.

Autologous techniques for the reconstruction of pediatric microtia often result in suboptimal aesthetic outcomes and morbidity at the costal cartilage donor site. We therefore sought to combine digital photogrammetry with CAD/CAM techniques to develop collagen type I hydrogel scaffolds and their respective molds that would precisely mimic the normal anatomy of the patient-specific external ear as well as recapitulate the complex biomechanical properties of native auricular elastic cartilage while avoiding the morbidity of traditional autologous reconstructions. Three-dimensional structures of normal pediatric ears were digitized and converted to virtual solids for mold design. Image-based synthetic reconstructions of these ears were fabricated from collagen type I hydrogels. Half were seeded with bovine auricular chondrocytes. Cellular and acellular constructs were implanted subcutaneously in the dorsa of nude rats and harvested after 1 and 3 months. Gross inspection revealed that acellular implants had significantly decreased in size by 1 month. Cellular constructs retained their contour/projection from the animals' dorsa, even after 3 months. Post-harvest weight of cellular constructs was significantly greater than that of acellular constructs after 1 and 3 months. Safranin O-staining revealed that cellular constructs demonstrated evidence of a self-assembled perichondrial layer and copious neocartilage deposition. Verhoeff staining of 1 month cellular constructs revealed de novo elastic cartilage deposition, which was even more extensive and robust after 3 months. The equilibrium modulus and hydraulic permeability of cellular constructs were not significantly different from native bovine auricular cartilage after 3 months. We have developed high-fidelity, biocompatible, patient-specific tissue-engineered constructs for auricular reconstruction which largely mimic the native auricle both biomechanically and histologically, even after an extended period of implantation. This strategy holds immense potential for durable patient-specific tissue-engineered anatomically proper auricular reconstructions in the future.

Background Human ear growth continues beyond puberty, resulting in ears that are typically approximately 10 millimeters (mm) larger in older individuals compared to their younger counterparts. Not only is the overall growth of the ear an indicator of age, but also the disproportionate growth of its parts. The largest part, the concha, shows the slowest growth rate, while the smallest part, the earlobe, shows the greatest growth rate. Thus, over time, the net increases in the scapha, concha, and earlobe become nearly equal. Therefore, it is appropriate to make approximately equal reductions from each unit in order to restore a youthful balance to the ear. Method Aged and large, but otherwise normal, ears were selected for use of the “rule of threes” technique. This technique involves reducing the height of each of the three units (scapha, concha, and earlobe) by approximately 3 mm. Depending on individual needs, reductions were also applied to two units or just one unit as necessary. Adjustments in reduction amounts were made for previously disproportionate ears. Patients and Results A total of 32 ears from 16 patients were included in the study. Scapha reduction was performed on six patients, scapha and concha reduction on five patients, combined (including earlobe) reduction on two patients, and isolated earlobe reduction on three patients. All patients were followed up for at least 6 months. The planned reduction target was achieved in all cases, resulting in balanced youthful ears. Two skin sloughs in the earlobe, one requiring revision, and bilateral hypertrophic scarring behind the earlobe were observed in one case. Conclusion The described ear reduction technique yields satisfactory results when performed with precision. Each ear should be assessed individually, allowing for some flexibility rather than strict adherence to the proposed amounts of reduction. Care must be taken not to disrupt the blood supply to the ear structures. Achieving harmony at junction lines requires careful planning and meticulous technique. Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266

Objective To investigate the role of MRI in the diagnosis and classification of fetal microtia. Methods Ninety-five fetuses with suspected microtia based on ultrasound and MRI performed within 1 week were enrolled in this study. The diagnosis based on MRI was compared with postnatal diagnosis. Among the microtia cases suspected on the basis of MRI, mild and severe cases were further classified. In addition, external auditory canal (EAC) atresia was evaluated by MRI in 29 fetuses with a gestational age > 28 weeks, and the accuracy of MRI in the diagnosis and classification of microtia was determined. Results Of 95 fetuses, 83 were considered to have microtia on the basis of MRI, 81 were confirmed to have microtia, and 14 were found to be normal according to postnatal diagnosis. Among 190 external ears in 95 fetuses, 40 ears were suspected to have mild microtia, and 52 ears were suspected to have severe microtia on the basis of MRI. According to the postnatal diagnosis, mild and severe microtia were confirmed in 43 and 49 ears, respectively. Among the 29 fetuses with a gestational age > 28 weeks, 23 ears were suspected to have EAC atresia according to MRI and 21 ears were ultimately confirmed to have EAC atresia. The accuracy of MRI in diagnosing microtia and EAC atresia was 93.68% and 93.10%, respectively. Conclusion MRI shows good performance in diagnosing fetal microtia and has the potential to evaluate its severity on the basis of classification and EAC status. Clinical relevance statement This study was aimed at investigating the role of MRI in the diagnosis and classification of fetal microtia. MRI shows good performance and can help evaluate microtia severity and EAC atresia, thus allowing for better clinical management. Key Points • MRI is a useful adjunct to prenatal ultrasound. • MRI has a higher accuracy rate than ultrasound in diagnosing fetal microtia. • The accurate classification of fetal microtia and the diagnosis of external auditory canal atresia through MRI may help guide clinical management.