Epidemiological Research of Microtia Combined With Congenital Heart Disease.

SUMMARY: Congenital heart disease (CHD) is one of the most common combined malformations of microtia. There is currently no specific study that investigates the relationship between microtia and CHD. METHODS: This study collected microtia inpatients admitted from May 1, 2015 to July 31, 2016. The diagnosis of CHD was based on patient's symptoms, past history, and echocardiography. Pearson χ2 test was used to analyze the correlation between CHD and microtia. RESULTS: A total of 30 cases (3.35%) were documented with CHD, including atrial septal defect (12/40.00%), ventricular septal defect (7/23.30%), patent ductus arteriosus (2/6.70%), complex congenital heart disease (3/10.00%), combined CHD (2/6.70%) and other malformations (4/13.30%). Analysis showed no statistically significant relation between CHD and the side of affected ear or gender. CONCLUSIONS: The occurrence of CHD in microtia patients was higher than that in the general population. The relationship between them was explored mainly from the etiological perspective. Microtia and CHD were often combined in syndromes such as Goldenhar syndrome, 22q11 deletion syndrome, and CHARGE syndrome. Absence of genes or abnormal embryo development associated with these syndromes leads to the occurrence of both.

Two-Dimensional Biodegradable Black Phosphorus Nanosheets Promote Large Full-Thickness Wound Healing through In Situ Regeneration Therapy.

Large full-thickness skin lesions have been one of the most challenging clinical problems in plastic surgery repair and reconstruction. To achieve in situ skin regeneration and perfect clinical outcomes, we must address two significant obstacles: angiogenesis deficiency and inflammatory dysfunction. Recently, black phosphorus has shown great promise in wound healing. However, few studies have explored the bio-effects of BP to promote in situ skin regeneration based on its nanoproperties. Here, to investigate whether black phosphorus nanosheets have positive bio-effects on in situ skin repair, we verified black phosphorus nanosheets' positive effects on angiogenic and anti-inflammatory abilities in vitro. Next, the in vivo evaluation performed on the rat large full-thickness excisional wound splinting model more comprehensively showed that the positive bio-effects of black phosphorus nanosheets are multilevel in wound healing, which can effectively enhance anti-inflammatory ability, angiogenesis, collagen deposition, and skin re-epithelialization. Then, multiomics analysis was performed to explore further the mechanism of black phosphorus nanosheets' regulation of endothelial cells in depth. Molecular mechanistically, black phosphorus nanosheets activated the JAK-STAT-OAS signaling pathway to promote cellular function and mitochondrial energy metabolism in endothelial cells. This study can provide a theoretical basis for applying two-dimensional black phosphorus nanosheets as nanomedicine to achieve in situ tissue regeneration in complex human pathological microenvironments, guiding the subsequent optimization of black phosphorus.

Repair Exposure of the Postauricular Tissue Expander Using the Modified Brent Method: A 7-Year Experience.

OBJECTIVES: Ear reconstruction is a challenging surgery for the complicated conditions in patients with microtia. The tissue expansion techniques were necessary and relatively safe for patients with insufficient soft tissue. However, complications such as necrosis of expanded flap and exposure of tissue expander limited the popularization of this method. This study described the use of modified Brent method to handle the exposure of the postauricular tissue expander. METHODS: From January 2013 to December 2019, 27 ear reconstruction patients with trauma or necrosis on an expanded skin flap and subsequent exposure of tissue expander were treated with modified Brent method, which consisted of 3 stages: removal of the expander, tension-free closure of wound, and framework fabrication; elevation of reconstructed ear; lobule rotation; and minor modification. RESULTS: Fifty-six percent of exposures occurred in the lower pole of the tissue expander. Exposure usually occurred 54.5 days after implantation. The majority of reconstructed ears had a satisfactory appearance and showed relatively stable outcomes. Only one case of cartilage exposure required revision surgery and was repaired by the temporoparietal fascia. CONCLUSION: With reasonable distribution of expanded flap, prolonged interval, and sutures under tension-free conditions, complications like the occurrence of trauma or necrosis-induced exposure of tissue expander can be repaired efficiently by a staging modified Brent method.

A modified tissue expander method for ear reconstruction in patients with excessively insufficient postauricular skin.

OBJECTIVE: For microtia patients with excessively insufficient postauricular skin, it is difficult to obtain a satisfied outcome with existing strategies. In this study, we developed a modified tissue expander method for auricular reconstruction. METHODS: The modified tissue expander method divided into 4 stages. In the first stage, a 30 ml or 50 ml kidney-shaped tissue expander was implanted in the mastoid region. A short time expansion (average 33.5 days) was conducted subsequently. In the second stage, the expander was removed and a modified cartilage framework without tragus was inserted through the same incision. A crescent-shaped cartilage pad was inserted into the incision of cartilage-harvest site at the same time. In the third stage, the reconstructed ear was elevated. Lobule rotation and remanent modification were performed in the fourth stage. The patients were followed up between half a year and 10 years. The outcomes of the reconstructed ears were scored with evaluation criteria. RESULTS: From January 2010 to December 2019, a total of 45 microtia patients with excessively insufficient postauricular skin were performed the modified tissue expander method. Fourty-two patients showed satisfied outcomes. Complications such as hyperpigmentation in the skin graft area (3, 6.7%), scar hyperplasia (3, 6.7%) and folliculitis (1, 2.2%) were found. There were no complications related to the tissue expander. CONCLUSION: The modified tissue expander method is an effective and safe technique for auricular reconstruction in patients having excessively insufficient postauricular skin, with satisfying medium-term results.

Incision and flap design during total auricular reconstruction using a 2-stage strategy.

BACKGROUND: Total auricular reconstruction is a challenge for plastic surgeons. Expanded flap method and Nagata's method with autologous costal cartilage are two leading techniques for ear reconstruction. And a two-stage strategy of expanded flap method received attention. In the present study, we report the incision and flap design of this strategy. METHODS: In the first stage, an 80 mL kidney-shaped expander was inserted in the mastoid region with the larger pole superiorly. The expander pocket was dissected subcutaneously in the scalp area and subfascially in the lower third region. In the second stage, the expander was removed from a Y-shaped lobule incision on the remanent ear. Then the remnant ear was separated into three flaps: the posterior skin flap, anterior skin flap, and lobule flap. When the framework was fabricated, the base frame and the underlying pad, which enhanced the projection, were fixed together as a whole to provide a more prominent appearance. The framework was totally wrapped into the expanded single flap without free skin grafting. Lobule transposition and tragus construction were performed simultaneously instead of a third-stage surgery. The recipient bed of rotated lobule was resected only to the epidermal layer and the subcutaneous layer was preserved to avoid central necrosis. RESULTS: A total of 21 patients received this strategy to reconstruct ear. With 3 months to 1.5 years of follow-up, 19 patients (90.5%) were satisfied with the reconstructed ears. 3 patients (14.3%) required further modification of reconstructed ear. No serious complications occurred during the procedures. CONCLUSIONS: With a Y-shaped incision, three-flap design of remanent ear and lobule rotation to an epidermal-removal area, tissue expander removal and modification of remanent ear can be performed effectively to avoid necrosis and an extra operation.

The human orthologue of murine Mpzl3 with predicted adhesive and immune functions is a potential candidate gene for immune-related hereditary hair loss.

We have recently reported a mutation within the conserved immunoglobulin V-type domain of the predicted adhesion protein Mpzl3 (MIM 611707) in rough coat (rc) mice with severe skin abnormalities and progressive cyclic hair loss. In this study, we tested the hypothesis that the human orthologue MPZL3 on chromosome 11q23.3 is a candidate for similar symptoms in humans. The predicted conserved MPZL3 protein has two transmembrane motifs flanking an extracellular Ig-like domain. The R100Q rc mutation is within the Ig-domain recognition loop that has roles in T-cell receptors and cell adhesion. Results of the rc mouse study, 3D structure predictions, homology with Myelin Protein Zero and EVA1, comprehensive database analyses of polymorphisms and mutations within the human MPZL3 gene and its cell, tissue expression and immunostaining pattern indicate that homozygous or compound heterozygous mutations of MPZL3 might be involved in immune-mediated human hereditary disorders with hair loss.

The epidermis as a bioreactor: topically regulated cutaneous delivery into the circulation.

Previous studies have documented that the skin can be used as a bioreactor to produce proteins for systemic release to treat diseases. A gene-switch system has been developed that allows regulated expression of therapeutic genes. To determine whether this system could be used in the skin, we developed a transgenic mouse model in which expression of a therapeutic gene could be topically induced in epidermal keratinocytes. After a single induction, high levels of the therapeutic protein, human growth hormone (hGH), were released from keratinocytes into the circulation. The serum levels of hGH were dependent on the amount of inducer applied, and repeated induction resulted in increased weight gain by transgenic versus control mice. Furthermore, physiological levels of hGH were detected in the serum of nude mice after topical induction of small transgenic skin grafts. These results clearly demonstrate the feasibility of using the gene-switch system to regulate the delivery of therapeutic proteins into the circulation via genetically modified keratinocytes.

Progressive hair loss and myocardial degeneration in rough coat mice: reduced lysyl oxidase-like (LOXL) in the skin and heart.

The rough coat (rc) is a spontaneous recessive mutation in mice. To identify the mutated gene, we have characterized the rc phenotype and initiated linkage mapping. The rc mice show growth retardation, cyclic and progressive hair loss, hyperplastic epidermis, abnormal hair follicles, cardiac muscle degeneration, and reduced amount of collagen and elastin in the skin and heart. The rc locus was mapped at 32.0 cM on chromosome 9, close to the loxl gene. Lysyl oxidase-like (LOXL) protein is a novel copper-containing amine oxidase that is required for the cross-linking of elastin and collagen in vitro. LOXL is expressed at high levels in the skin and heart, where the rc mice show strong phenotype. The expression pattern and the genetic proximity to rc suggested loxl as a potential candidate gene. In rc mice, the loxl mRNA was reduced in the skin and the LOXL protein in the heart, dermis, atrophic hair follicles, and sebaceous glands. No mutations, however, were identified within the coding region of loxl, and offspring from rc/rc and loxl null mice crossing were phenotypically normal. Based on these results, loxl appears non-allelic to rc. Heart- and skin-specific downregulation of LOXL in rc mice, however, may contribute to the extracellular matrix alterations and the rc phenotype.

Up-regulation and altered distribution of lysyl oxidase in the central nervous system of mutant SOD1 transgenic mouse model of amyotrophic lateral sclerosis.

Mutations of the copper-zinc superoxide dismutase (SOD1) gene can result in the development of amyotrophic lateral sclerosis (ALS). The exact cellular mechanisms causing ALS are not known, but oxidative stress is thought to play a prominent role. Lysyl oxidase (LOX) is one of the genes that are known to be up-regulated in ALS patients. In this study, we examined LOX localization in wild type rat and mouse brain sections using immunohistochemistry coupled with laser-scanning confocal microscope. The results showed that LOX, an extracellular matrix protein, was expressed in the choroid plexus, blood vessel walls, brain matrix, and neurons of normal rat and mice. In neurons, LOX was localized within the cytoplasm. LOX immunoreactivity increased in neurons of the spinal cord, brain stem and cortex, and the Purkinje cells of the cerebellum in transgenic G93A SOD1 (mSOD1) mouse model of ALS. In situ hybridization indicated that LOX gene expression was enhanced in the neurons of the spinal cord, brain stem, cortex, caudoputamen and cerebellum in mSOD1 mice compared with wild type controls. LOX enzyme activity was increased in mSOD1 mice. An increase in the amount of LOX mRNA, protein and enzyme activity was coincidental with late stage ALS, indicating that LOX may be associated with the progression of the neurodegenerative process in the mSOD1 model of ALS.

Mutation in Mpzl3, a novel [corrected] gene encoding a predicted [corrected] adhesion protein, in the rough coat (rc) mice with severe skin and hair abnormalities.

The rough coat (rc), an autosomal-recessive mutation, arose spontaneously in C57BL/6J mice. Homozygous rc mice develop severe skin and hair abnormalities, including cyclic and progressive hair loss and sebaceous gland hypertrophy. The rc locus was previously mapped to Chromosome 9. To elucidate the genetic basis underlying the rc phenotype development, we carried out positional cloning, and mapped the rc locus to a 246-kb interval. We identified a missense mutation within a novel open reading frame in the rc/rc mice, which is predicted to encode a cell adhesion molecule with the highest homology to myelin protein zero (MPZ) and myelin protein zero-like 2 (MPZL2, also called epithelial V-like antigen). We therefore named this gene Mpzl3 (myelin protein zero-like 3). The mutation in the rc/rc mice occurred at a highly conserved residue within the conserved Ig-like V-type domain, thus likely altering the MPZL3 protein function. Reverse transcriptase-PCR and Western blot analyses revealed expression of the Mpzl3 gene in various adult organs, including the skin. Using indirect immunofluorescence, we detected MPZL3 protein in the keratinocytes and sebocytes in the skin. Results from this study identified a novel gene encoding a predicted adhesion protein whose mutation in the rc/rc mice likely caused the rc phenotype.

Lysyl oxidase in development, aging and pathologies of the skin.

Lysyl oxidase (LOX) is a copper- and lysyl-tyrosyl cofactor containing amine oxidase that has been known to play a critical role in the catalysis of lysine-derived crosslinks in extracellular matrix (ECM) proteins in the dermis. Changes in the composition and crosslinked state of the ECM and alterations in LOX synthesis and activity are known to be associated with aging and a range of acquired and heritable skin disorders. It has been assumed until recently that the LOX-related changes in the skin are mediated through the catalytic activity of LOX. However, work by several laboratories over the last few years has shown that LOX is a multifunctional protein. In this review we discuss the regulation of expression, localization and activation of LOX in the normal developing and adult skin, and alterations in LOX expression and activity associated with skin aging and senescence, and in pathological conditions, including wound healing, fibrosis, hypertrophic scarring, keloids, scleroderma, and diabetic skin. We further evaluate the role of LOX in skin ECM changes associated with the normal aging process and with these pathological states. In addition to collagen and elastin cross-linkages, regulatory and activation mechanisms and cell type specific LOX interactions may contribute to a range of novel intra- and extracellular LOX functions that appear critical determinants of the cellular microenvironment in the normal skin and in these skin disorders.