The Role of Oxidative Stress in Vitiligo: An Update on Its Pathogenesis and Therapeutic Implications.

Vitiligo is an autoimmune skin disorder caused by dysfunctional pigment-producing melanocytes which are attacked by immune cells. Oxidative stress is considered to play a crucial role in activating consequent autoimmune responses related to vitiligo. Melanin synthesis by melanocytes is the main intracellular stressor, producing reactive oxygen species (ROS). Under normal physiological conditions, the antioxidative nuclear factor erythroid 2-related factor 2 (Nrf2) pathway functions as a crucial mediator for cells to resist oxidative stress. In pathological situations, such as with antioxidant defects or under inflammation, ROS accumulate and cause cell damage. Herein, we summarize events at the cellular level under excessive ROS in vitiligo and highlight exposure to melanocyte-specific antigens that trigger immune responses. Such responses lead to functional impairment and the death of melanocytes, which sequentially increase melanocyte cytotoxicity through both innate and adaptive immunity. This report provides new perspectives and advances our understanding of interrelationships between oxidative stress and autoimmunity in the pathogenesis of vitiligo. We describe progress with targeted antioxidant therapy, with the aim of providing potential therapeutic approaches.

Vitiligo: An Autoimmune Skin Disease and its Immunomodulatory Therapeutic Intervention.

Vitiligo is a chronic autoimmune depigmenting skin disorder characterized by patches of the skin losing functional melanocytes. Multiple combinatorial factors are involved in disease development, among which immune T cells play a prominent role. The immune cells implicated in melanocyte destruction through adaptive immunity include CD8+ cytotoxic T cells and regulatory T cells, and aberrantly activated skin-resident memory T cells also play a role in melanocyte destruction. Over the past several years, major progress in understanding vitiligo pathogenesis has led to the development of targeted therapies. Janus kinase (JAK) inhibitors, which share the similar mechanism that autoactivates CD8+ T cells in chronic inflammatory diseases, have been reported to have therapeutic significance in vitiligo. Recently, immunomodulatory therapeutic interventions in vitiligo have been emerging. Mesenchymal stem cells (MSCs) regulate cytokine secretion and the balance of T-cell subsets, which makes them a promising cell-based treatment option for autoimmune diseases. The induction of MSC-mediated immunomodulation is complicated and occurs by contact-dependent mechanisms and soluble extracellular vesicle (EV) mediators. EVs released from MSCs contain various growth factors and cytokines with anti-inflammatory effects in the skin immune response. Here, we summarize and discuss the progress to date in targeted therapies that immunomodulate the niche environment of vitiligo, from the clinical trial of JAK inhibitors to the potential of MSCs and MSC-EVs. The available information was collected to highlight the need for further research into the treatment of vitiligo.

Variations of Mesozoic feathers: Insights from the morphogenesis of extant feather rachises.

The rachises of extant feathers, composed of dense cortex and spongy internal medulla, are flexible and light, yet stiff enough to withstand the load required for flight, among other functions. Incomplete knowledge of early feathers prevents a full understanding of how cylindrical rachises have evolved. Bizarre feathers with unusually wide and flattened rachises, known as "rachis-dominated feathers" (RDFs), have been observed in fossil nonavian and avian theropods. Newly discovered RDFs embedded in early Late Cretaceous Burmese ambers (about 99 million year ago) suggest the unusually wide and flattened rachises mainly consist of a dorsal cortex, lacking a medulla and a ventral cortex. Coupled with findings on extant feather morphogenesis, known fossil RDFs were categorized into three morphotypes based on their rachidial configurations. For each morphotype, potential developmental scenarios were depicted by referring to the rachidial development in chickens, and relative stiffness of each morphotype was estimated through functional simulations. The results suggest rachises of RDFs are developmentally equivalent to a variety of immature stages of cylindrical rachises. Similar rachidial morphotypes documented in extant penguins suggest that the RDFs are not unique to Mesozoic theropods, although they are likely to have evolved independently in extant penguins.

The Making of a Flight Feather: Bio-architectural Principles and Adaptation.

The evolution of flight in feathered dinosaurs and early birds over millions of years required flight feathers whose architecture features hierarchical branches. While barb-based feather forms were investigated, feather shafts and vanes are understudied. Here, we take a multi-disciplinary approach to study their molecular control and bio-architectural organizations. In rachidial ridges, epidermal progenitors generate cortex and medullary keratinocytes, guided by Bmp and transforming growth factor ß (TGF-ß) signaling that convert rachides into adaptable bilayer composite beams. In barb ridges, epidermal progenitors generate cylindrical, plate-, or hooklet-shaped barbule cells that form fluffy branches or pennaceous vanes, mediated by asymmetric cell junction and keratin expression. Transcriptome analyses and functional studies show anterior-posterior Wnt2b signaling within the dermal papilla controls barbule cell fates with spatiotemporal collinearity. Quantitative bio-physical analyses of feathers from birds with different flight characteristics and feathers in Burmese amber reveal how multi-dimensional functionality can be achieved and may inspire future composite material designs. VIDEO ABSTRACT.

Comprehensive multimodal surgical treatment of end-stage lower extremity lymphedema with toe management: The combined Charles,' Homan's, and vascularized lymph node transfer (CHAHOVA) procedures.

BACKGROUND: End-stage lower extremity lymphedema (LEL) poses a particularly formidable challenge to surgeons as multiple pathological processes are at work. Because single modality treatment is often unsuccessful, we devised a comprehensive multimodal surgical treatment. The aim of this study is to share the technical considerations and examine the clinical outcomes of this combined approach. METHODS: Between 2013 and 2017, patients with International Society of Lymphology stage III, who underwent the combination treatment of Charles,' Homan's procedure with toe management and vascularized lymph node transfer (CHAHOVA), were included in this retrospective study. Outcomes evaluated were limb size, number of infectious episodes, compression garment usage, and rate of complications. RESULTS: A total of 68 patients were included. With a mean follow-up of 29 months, the overall circumference reduction rate for the upper thigh and the rest of the extremity was 67.4% (48.2-88.2%) and 98.1% (88-100%), respectively. During the follow-ups, 2 (2.9%) patients experienced episodes of cellulitis and the average number of yearly infections decreased from 4.2 to 1.2 episodes per person. All patients were able to discontinue compression therapy without recurrence of lymphedema. Nine (13.2%) patients reported minor complications. CONCLUSION: The combine CHAHOVA in a single-stage procedure is an effective and safe approach in the end-stage LEL.

Combined double vascularized lymph node transfers and modified radical reduction with preservation of perforators for advanced stages of lymphedema.

BACKGROUND: Treatment of advanced lymphedema requires not only restoration of physiological lymph drainage, but also excision of fibrotic tissue and excess skin. The aim of this study is to show how the combination of double vascularized lymph node transfers (VLNTs) and a modified radical reduction with preservation of perforators (RRPP) can accomplish both of these treatment goals. METHODS: Between 2010 and 2016, 16 patients (15 female and one male) with extremity lymphedema underwent a combined double gastroepiploic VLNTs and modified RRPP. Demographics, outcomes including circumference reduction rates, preoperative and postoperative lymphoscintigraphy, complications, and responses to the Lymphedema Quality of Life (LYMQOL) questionnaire were analyzed. RESULTS: All flaps survived. The mean follow-up period was 14.2 months (range, 12-19). The mean circumference reduction rate was 74.5% ± 6.9% for the upper limb and 68.0% ± 4.2% for the lower limb. There were no major complications. Minor complications, including numbness and hyperesthesia, were treated conservatively. LYMQOL showed a 2.7-fold quality-of-life improvement (P < 0.01). Postoperative lymphoscintigraphy showed improved lymphatic drainage in all cases. CONCLUSION: Combined double VLNTs and modified RRPP safely and effectively improves lymphatic drainage, reduces fibrotic tissue and excess skin, decreases episodes of infections, and improves patients' quality of life in the advanced stages of lymphedema.

Ileocecal vascularized lymph node transfer for the treatment of extremity lymphedema: A case report.

Vascularized lymph node (VLN) transfer has been of high interest in the past decade for the treatment of lymphedema, since it has been shown to be effective in reducing limb volumes, decreasing infectious episodes and improving quality of life. Multiple donor sites have been described in the quest for the optimal one. Herein, we describe a novel lymph node flap option based on the ileocolic artery and vein. The ileocecal vascularized lymph node (IC-VLN) flap was used in the management of a 33-year-old male patient with lower extremity lymphedema secondary to left inguinal trauma. The patient had previously underwent a pedicled omentum flap transposition with minimal improvement in limb size and persistent episodes of infection. At 15 month follow-up, the IC-VLN flap improved the lymphatic drainage in the affected limb with a mean limb circumference reduction rate of 26.3%. No donor site complications or further episodes of infection were noted. According to our findings, the IC-VLN flap may be another option for VLN transfer in very selected cases. Nevertheless, larger series with a longer follow-up are required to analyze the efficacy and long-term results of this flap.

Vascularized appendicular lymph node transfer for treatment of extremity lymphedema: A case report.

Vascularized lymph node transfer has demonstrated promising results for the treatment of extremity lymphedema. In an attempt to find the ideal donor site, several vascularized lymph nodes have been described. Each has a common goal of decreasing morbidity and avoiding iatrogenic lymphedema while obtaining good clinical results. Herein, we present the preliminary clinical outcomes of an intra-abdominal lymph node flap option based on the appendicular artery and vein used for the treatment of extremity lymphedema. A 62 year-old woman with moderate lower extremity lymphedema, on chronic antibiotics because of recurrent infections and unsatisfactory outcomes after conservative treatment underwent a vascularized appendicular lymph node (VALN) transfer. At a follow-up of 6 months, the reduction rate of the limb circumference was 17.4%, 15.1%, 12.0% and 9% above the knee, below the knee, above the ankle and foot respectively. In addition, no further episodes of infection or other complications were reported after VALN transfer. Postoperative lymphoscintigraphy demonstrated that the VALN flap was able to improve the lymphatic drainage of the affected limb. According to our findings, the use of VALN transfer minimizes donor-site morbidity, avoids iatrogenic lymphedema and may provide a strong clearance of infection because of the strong immunologic properties of the appendiceal lymphatic tissue in selected patients. Despite these promising results, further research with larger number of patients and longer follow- up is needed.

The radial forearm free flap as a "vascular bridge" for secondary microsurgical head and neck reconstruction in a vessel-depleted neck.

BACKGROUND: In a vessel-depleted neck, distant recipient sites may be the only option for secondary free flap reconstruction. While interposition vein grafts and arteriovenous loops can bridge the gap between the recipient and donor pedicle, they are not without risks. In these scenarios, we examinate the reliablity of a radial forearm free flap (RFFF) as an alternative vascular conduit. PATIENTS AND METHODS: A retrospective review of cases between March 2005 and May 2016 was performed. Demographic data, prior surgical history, intraoperative details and outcomes were recorded. A total of ten patients, eight male and two female, with a mean age of 54.2 years (range, 39-74) were identified. The RFFF was initially anastomosed to either the thoracoacromial (n = 6) or internal mammary vessels (n = 4) and subsequently served as the recipient pedicle for the second "main" flap, an anterolateral thigh (n = 4), jejunum (n = 3) or fibula flap (n = 3). RESULTS: The average RFFF dimensions were 13.8 cm by 5.8 cm. All twenty flaps, ten RFFF and ten "main' flaps survived completely with only one case of minimal epidermal loss. One patient with esophageal reconstruction with jejunum developed a fistula that required closure with a local falp. At a mean follow-up of 18.4 months (range 8-29), the reconstructive goals had been achieved in all cases. CONCLUSIONS: The RFFF serves as a reliable "vascular bridge" that extends the reach of distant recipient sites to free flaps in secondary head and neck reconstruction.

The retrograde transverse cervical artery as a recipient vessel for free tissue transfer in complex head and neck reconstruction with a vessel-depleted neck.

BACKGROUND: Reconstruction in a vessel-depleted neck is challenging. The success rates can be markedly decreased because of unavailability of suitable recipient vessels. In order to obtain a reliable flow, recipient vessels away from the zone of fibrosis, radiation, or infection need to be explored. The aim of this report is to present our experience and clinical outcomes using the retrograde flow coming from the distal transverse cervical artery (TCA) as a source for arterial inflow for complex head and neck reconstruction in patients with a vessel-depleted neck. METHODS: Between July 2010 and June 2016, nine patients with a vessel-depleted neck underwent secondary head and neck reconstruction using the retrograde TCA as recipient vessel for microanastomosis. The mean age was 49.6 years (range, 36 to 68 years). All patients had previous bilateral neck dissections and all, except one, had also received radiotherapy. Indications included neck contracture release (n = 3), oral (n = 1), mandibular (n = 3) and pharyngoesophageal (n = 2) reconstruction necessitating free anterolateral thigh (n = 3) and medial sural artery (n = 1) perforator flaps, fibula (n = 3) and ileocolon (n = 2) flaps respectively. RESULTS: There was 100% flap survival rate with no re-exploration or any partial flap loss. One case of intra-operative arterial vasospasm at the anastomotic suture line was managed intra-operatively with vein graft interposition. There were no other complications or donor site morbidity during the follow-up period. CONCLUSIONS: In a vessel-depleted neck, the reverse flow of the TCA may be a reliable option for complex secondary head and neck reconstruction in selected patients.

Comparison of long-term clinical outcomes among different vascularized lymph node transfers: 6-year experience of a single center's approach to the treatment of lymphedema.

BACKGROUND: This study evaluated the long-term clinical outcomes among different vascularized lymph node transfers (VLNT) used at our institution. METHODS: Between July 2010 and July 2016, all patients with International Society of Lymphology (ISL) stages II-III who underwent VLNT were evaluated. Demographic and clinical data (limb circumference, infectious episodes, lymphoscintigraphic studies) were recorded pre-operatively. Clinical outcomes, complications, and additional excisional procedures were analyzed post-operatively. At least 2-year follow-up was required for inclusion. RESULTS: Overall, 83 patients (Stage II:47, Stage III:36) met the inclusion criterion. Mean follow-up was 32.8 months (range, 24-49). Lymph node flaps used were groin (n = 13), supraclavicular (n = 25), gastroepiploic (n = 42), ileocecal (n = 2), and appendicular (n = 1). Total mean circumference reduction rate was 29.1% (Stage II) and 17.9% (Stage III) (P < 0.05). A paired t-test showed that VLNT significantly decreased the number of infections (P < 0.05). Three patients reported no improvement of the symptoms. Major complications included one flap loss and one donor site hematoma. After the period of follow-up, 18 patients (21.7%) underwent additional excisional procedures. CONCLUSION: VLNT is a promising technique used for the treatment of lymphedema and appears to be more effective in moderate stages (Stage II). Patients with advanced stage lymphedema (Stage III) may benefit from additional excisional procedures.

Double gastroepiploic vascularized lymph node tranfers to middle and distal limb for the treatment of lymphedema.

BACKGROUND: Vascularized lymph node (VLN) transfer for lymphedema treatment has shown promising results. Optimal donor and recipient sites remain a matter of debate. We describe the technique and outcomes of a laparoscopically harvested extended gastroepiploic VLN flap with two levels of inset. PATIENTS AND METHODS: Between 2014 and 2015, four-patients with upper limb breast cancer-related lymphedema and three-patients with lower limb pelvic cancer-related lymphedema who underwent VLN transfers were included. After harvest, the gastroepiploic VLN flap was divided into two halves that were separately inset at the level of elbow and wrist (upper limb) or knee and ankle (lower limb). The mean patient age was 53.1 years (range, 42-65 years). RESULTS: The average flap size after division was 6.3 cm in length (range, 5-7 cm) and 3.4 cm in width (range, 3-4 cm). The mean pedicle length was 3.2 cm (range, 2.5-4 cm). All flaps survived completely. No donor or recepient site complication was noted. At a mean follow-up of 9.7 months (range, 8-11 months), the mean circumference reduction rate was 43.7 ± 2.5% along the entire limb (P < 0.05). No episode of infection was noted postoperatively. CONCLUSIONS: Double gastroepiploic VLN transfers to middle and distal limb are a safe approach with very promising results. This technique may be used to improve clinical outcomes by enhancing the lymphatic drainage of the entire affected limb in a uniform fashion. In addition, the laparoscopic harvest can provide decreased donor site morbidity with a faster recovery.