Cutaneous Nrf2-Keap1 pathway modulation by environmental factors: The Dead Sea area as a test case.

The skin is constantly exposed to exogenous environmental stressors and has to cope with excessive oxidative stress and tissue damage. However, exposure to moderate environmental stressors may be beneficial for the cutaneous tissue and assist in protecting against oxidative damage via the enhanced activation of the nuclear factor erythroid 2-related factor 2-Kelch-like ECH-associated protein 1 (Nrf2-Keap1) pathway. Such moderate stressors can be found in various locations around the globe. In this manuscript, we chose to focus on the Dead Sea (DS) area as a test case to study the effect of moderate stressors on the cutaneous tissue because of the unique combinations of moderate stressors in this area. The exceptional location of the DS at an altitude of -438 meters below sea level (the lowest place on earth) is responsible for its rare accumulation of moderate stressors such as high-water salinity, high atmospheric pressure, and unique solar radiation. In this manuscript, we hypothesized that the unique solar radiation in the DS area generates moderate oxidative stress in the skin leading to the induction of intracellular electrophiles, which in turn can activate the protecting Nrf2-Keap1 pathway. We showed that exposure of human skin organ culture from the same donor to solar radiation at the DS resulted in significant activation of the Nrf2-Keap1 pathway, induction of phase II enzymes, and lower apoptotic activity compared to a nearby location at a higher altitude (Jerusalem +700 m). This remarkable effect of activating the Nrf2 protecting pathway and the importance and characteristics of the solar irradiation at the DS is discussed.

LGR5 expressing skin fibroblasts define a major cellular hub perturbed in scleroderma.

Systemic sclerosis (scleroderma, SSc) is an incurable autoimmune disease with high morbidity and mortality rates. Here, we conducted a population-scale single-cell genomic analysis of skin and blood samples of 56 healthy controls and 97 SSc patients at different stages of the disease. We found immune compartment dysfunction only in a specific subtype of diffuse SSc patients but global dysregulation of the stromal compartment, particularly in a previously undefined subset of LGR5+-scleroderma-associated fibroblasts (ScAFs). ScAFs are perturbed morphologically and molecularly in SSc patients. Single-cell multiome profiling of stromal cells revealed ScAF-specific markers, pathways, regulatory elements, and transcription factors underlining disease development. Systematic analysis of these molecular features with clinical metadata associates specific ScAF targets with disease pathogenesis and SSc clinical traits. Our high-resolution atlas of the sclerodermatous skin spectrum will enable a paradigm shift in the understanding of SSc disease and facilitate the development of biomarkers and therapeutic strategies.

eDNA-Mediated Cutaneous Protection Against UVB Damage Conferred by Staphylococcal Epidermal Colonization.

The human skin is a lush microbial habitat which is occupied by a wide array of microorganisms. Among the most common inhabitants are Staphylococcus spp., namely Staphylococcus epidermidis and, in ≈20% of healthy individuals, Staphylococcus aureus. Both bacteria have been associated with cutaneous maladies, where they mostly arrange in a biofilm, thus achieving improved surface adhesion and stability. Moreover, our skin is constantly exposed to numerous oxidative environmental stressors, such as UV-irradiation. Thus, skin cells are equipped with an important antioxidant defense mechanism, the Nrf2-Keap1 pathway. In this work, we aimed to explore the morphology of S. aureus and S. epidermidis as they adhered to healthy human skin and characterize their matrix composition. Furthermore, we hypothesized that the localization of both types of bacteria on a healthy skin surface may provide protective effects against oxidative stressors, such as UV-irradiation. Our results indicate for the first time that S. aureus and S. epidermidis assume a biofilm-like morphology as they adhere to ex vivo healthy human skin and that the cultures' extracellular matrix (ECM) is composed of extracellular polysaccharides (EPS) and extracellular DNA (eDNA). Both bacterial cultures, as well as isolated S. aureus biofilm eDNA, conferred cutaneous protection against UVB-induced apoptosis. This work emphasized the importance of skin microbiota representatives in the maintenance of a healthy cutaneous redox balance by activating the skin's natural defense mechanism.

Fat Grafting for Improved Ileostomy Ostomy Device Fit: A Case Report.

For patients with an ostomy, a poor fitting appliance may cause leakage, peristomal dermatitis, and frequent appliance changes. PURPOSE: The purpose of this case study was to report the outcome of fat grafting to augment peristomal soft tissue and improve appliance fit. CASE STUDY: A 57-year-old woman with a history of Crohn's disease presented with soft-tissue deficiency and uneven contour around her ileostomy site. She was unable to properly fit an ostomy appliance, which resulted in leakage, chronic skin irritation, and frequent appliance changes. The patient underwent 2 rounds of fat grafting using fat harvested from her medial thighs and knees infused with dilute lidocaine with epinephrine. The patient noted immediate improvement after 34 cc of processed fat was injected in the first round. Appliance change frequency decreased from daily to every 3 to 4 days. A second graft of 32 cc provided 3 months later further improved appliance fit, reducing appliance change frequency to every 5 to 7 days and obviating the need to use adjustment rings and glue. Pre- and postoperative computed tomography showed increased thickness of abdominal wall subcutaneous tissues. CONCLUSION: Fat grafting around an ostomy site presents a viable option to improve contour and appliance fit with reduced skin irritation and leakage.

Heterogeneity in Body Contouring Outcomes Based Research: The Pittsburgh Body Contouring Complication Reporting System.

BACKGROUND: Body contouring complications after massive weight loss (MWL) vary significantly in frequency and type. Currently, no standardized recommendations exist regarding which complications are most important to report. OBJECTIVES: We aim to provide a guideline for complication reporting in the body contouring literature. The Pittsburgh Body Contouring Complication Reporting System (PBCCRS) will aid in risk stratification of body contouring procedures and will decrease under-, over-, and nonreporting of complications. METHODS: The authors reviewed the literature for the terms "body contouring," "MWL," and "complications." Elimination criteria included: non-English language, case report, meta-analysis, outpatient, non-MWL, unclear demographics, N <30 and lack of numeric results. Data were analyzed in 2 groups: truncal contouring and extremity contouring. RESULTS: Eighty-nine papers were reviewed and 21 met inclusion criteria. The weighted mean rates as percentages for complications in the extremity group were: dehiscence (29.0), seroma (18.6), scarring (14.9), infection (8.8), lymphedema (7.8), hematoma (3.5), necrosis (1.9), deep venous thrombosis (DVT) or pulmonary embolism (PE) (0), and death (0). In the truncal group, weighted mean complication rates as percentages were: dehiscence (15.4), seroma (13.1), scarring (2.9), infection (9.4), lymphedema (1.3), hematoma (6.4), necrosis (7.2), DVT/PE (1.5), and death (0.6). Lymphedema was seldom reported, and suture extrusion was not reported in any selected papers. Weighted mean rates of DVT/PE in the extremity vs truncal contouring groups were significantly different. Differences in rates of scarring, lymphedema, and hematoma rates neared significance. CONCLUSIONS: Heterogeneity amongst selected studies is explained by variability in how complications are defined. The Pittsburgh Body Contouring Complication Reporting System provides suggested recommendations on complication reporting in massive weight loss body contouring surgery.

The Challenges of Augmentation Mastopexy in the Massive Weight Loss Patient: Technical Considerations.

BACKGROUND: Augmentation mastopexy in the massive weight loss population is challenging because of poor skin elasticity and lack of inframammary support. Despite several large studies of augmentation mastopexy in the literature, few data exist regarding this unique patient population. The authors examine early postoperative ptosis, implant malposition, and strategies to optimize outcomes. METHODS: A retrospective review of massive weight loss patients who underwent augmentation mastopexy from 2003 to 2011 was performed to record age, body mass index, implant characteristics, postoperative ptosis, and implant malposition. RESULTS: Thirty patients were identified with a mean age of 44.8 ± 8.5 years, mean current body mass index of 26.1 ± 3.9 kg/m, and mean follow-up time of 283.5 days (range, 7 to 1095 days). Preoperatively, patients mostly presented with grade 3 ptosis (63.3 percent). Five patients (16.7 percent) developed postoperative ptosis within the first 3 months after surgery, with no increase after this time. Implant malposition increased significantly with time: 61.9 percent by 12 months (p = 0.006), with a median time for implant malposition of 160 days. Postoperative ptosis was significantly related to age (p = 0.039) and a larger left-side implant (p = 0.022). Implant malposition was significantly related to higher current body mass index (p = 0.047), but not to implant size. Two patients (6.6 percent) underwent revision procedures. CONCLUSION: Massive weight loss patients have an increased risk of early postoperative ptosis or implant malposition, reinforcing the need for appropriate preoperative counseling to manage patient expectations. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Periorbital reconstruction with the expanded pedicled forehead flap.

BACKGROUND: The complexity of structures within the periorbital region makes reconstruction of this area particularly a challenging endeavor. Within the literature, different techniques have been described for reconstruction of the external lamellae of the upper and lower eyelids as well as the medial and lateral canthal regions.Herein, we present the expanded pedicled forehead flap as a versatile and useful surgical option for reconstruction of various defects around the eye globe. PATIENTS AND METHODS: A tissue expander is inserted underneath the forehead skin and serially expanded. The pedicle of the expanded pedicled flap is designed either from the superior portion of the expanded skin and interpolated to reconstruct the upper and lower eyelids, and the medial or lateral canthal areas; or from the inferior portion of the expanded skin and interpolated over the eyebrow to reconstruct the area between the upper eyelid crease and eyebrow.Fifteen patients with periorbital nevi or severe scarring were treated using the expanded forehead flap between the years 2003 and 2012. Thirteen patients had complex periorbital defects involving multiple anatomic areas, and 2 patients had defects confined to the upper eyelid area only. RESULTS: Operative and postoperative course for 13 patients was uneventful. One patient had a late infection of the tissue expander but nonetheless continued with the reconstructive process. In 1 patient, the tissue expander was removed due to infection, and subsequent reconstruction was not carried out. The aesthetic and functional results of reconstruction were very good, and with excellent skin color and thickness match. In 1 patient, the flap was defattened in an ancillary procedure. No partial or complete flap loss was observed in this study. SUMMARY: We conclude that the expanded pedicled forehead flap is a safe and reliable method for reconstruction of different segments of the periorbital region, while providing good aesthetic and functional reconstructive results with minimal donor-site morbidity.

Transesophageal endoscopic myotomy for achalasia: recognizing potential pitfalls before clinical application.

BACKGROUND: Laparoscopic Heller esophagomyotomy is the standard of care for achalasia treatment. This procedure, although effective, must be performed with the patient under general anesthesia and is associated with several serious potential complications. The authors aimed to develop a method of performing transesophageal endoscopic esophagomyotomy (TEEM) that would obviate the need for both general anesthesia and external incisions while offering lower intra- and postoperative complications. METHODS: The TEEM procedure was performed on eight pigs. For six of the pigs, the procedure aimed at survival. A mid-esophageal mucosal incision was performed using an endoscope, and a submucosal plane was developed. The lower esophageal sphincter (LES) muscle fibers were clearly visualized and divided. The mucosal incision was closed using fibrin sealant. After 2 weeks of survival, a gastrografin swallow study and necropsy were performed. RESULTS: The TEEM procedure was performed successfully in all eight porcine models. The myotomy included the LES fibers and extended 4 to 6 cm proximally to the esophagus. The proximal gastric muscle was divided up to 1 to 2 cm. No injuries to the abdominal or mediastinal structures occurred. One pig died on postoperative day 1 due to an unrecognized pneumothorax. Two pigs had ischemic ulcers at the myotomy site. The last three pigs had an uneventful recovery. The mucosal incision site healed completely in all the survived pigs, and except for the pig with mediastinal sepsis, all ate heartily and gained weight as expected. CONCLUSION: The TEEM procedure is technically feasible. Due to the morbidity encountered in the first three pigs, the reported technique was modified to include a slimmer endoscope, a shorter tunnel, and a partial-thickness myotomy. These changes together with an understanding of the pitfalls involved in this procedure led to successful results for the next three pigs. Nevertheless, the authors believe that TEEM is not yet ready for prime time. Perfection of the technique and development of dedicated instruments are mandatory before safe translation of this method to human patients.

Characterization of factors that determine lentiviral vector tropism in skin tissue using an ex vivo model.

BACKGROUND: Lentiviral tropism to a solid tissue may be determined by receptor availability, the differentiation state of cells and the three-dimensional architecture of the tissue. METHODS: Using skin organ cultures, lentiviral vector tropism was compared with that of keratinocytes in cell culture. Furthermore, the tropism of lentiviral vector to mouse and human tissues was compared ex vivo, in attempt to validate the mouse skin as an experimental system for human gene therapy of skin diseases. RESULTS: The results obtained indicated that although early progenitor keratinocytes (keratin 15+ and p63+), when grown in culture are permissive to lentiviral vector, they are resistant to transduction in their native 'niche' in the skin tissue. Transiently amplifying keratinocytes (keratin 14+) on the other hand, are permissive to lentiviral vector transduction, in cell culture and in the skin, after separation of the epidermis from the dermis layer. Keratinocytes (keratin 14+) in the hair follicle of human skin are resistant to lentiviral transduction, even after partial digestion of the extracellular matrix collagen. By contrast, collagenase pretreatment of mouse tissue facilitated transduction of keratinocytes within the hair follicle. Because lentivirus pseudotyped by two envelopes (amphotropic murine leukemia virus and vesicular stomatitis virus G glycoprotein) display the same tropism, we suggest that receptor availability is not the critical factor in the pattern of skin tissue transduction. CONCLUSIONS: Taken together, the results obtained in the present study indicate that lentiviral vector tropism in the three-dimensional skin tissue is distinct from the tropism to keratinocytes in culture and is dependent on a complex interplay of extracellular restrictions.

Abdominal trauma after terrorist bombing attacks exhibits a unique pattern of injury.

BACKGROUND: The recent growth in the volume of civilian blast trauma caused by terrorist bombings warrants special attention to the specific pattern of injury associated with such attacks. OBJECTIVE: To characterize the abdominal injuries inflicted by terrorist-related explosions and to compare the pattern of injury with civilian, penetrating and blunt, abdominal trauma. METHODS: Retrospective analysis of prospectively collected data from 181 patients with abdominal trauma requiring laparotomy, who were admitted to the Hadassah Hospital, Jerusalem, Israel, from October 2000 to December 2005. Patients were divided into 3 groups according to mechanism of injury: terror-related blast injury (n = 21), gunshot wounds (GSW) (n = 73) and blunt trauma (n = 87). RESULTS: Median injury severity score in the blast group was significantly higher compared with GSW and blunt groups (34, 18, and 29, respectively, P < 0.0001). Injury to multiple body regions (> or = 3) occurred in 85.7% of blast group, 28.8% of GSW group, and 59.7% of blunt group (P < 0.001). The pattern of intra-abdominal injury was different between the groups. Bowel injury was found in 71.4% of blast victims, 64.4% of GSW, and 25.3% of blunt group (P < 0.001). Parenchymal injury was found in one third of patients in blast and GSW groups versus 60.9% of patients in blunt group (P = 0.001). Penetrating shrapnel was the cause of bowel injury in all but 1 patient in the blast group (94.4%). CONCLUSIONS: Terrorist attacks generate more severe injuries to more body regions than other types of trauma. Abdominal injury inflicted by terrorist bombings causes a unique pattern of wounds, mainly injury to hollow organs. Shrapnel is the leading cause of abdominal injury following terrorist bombings.