Ataxia Telangiectasia Mutated Signaling Delays Skin Pigmentation upon UV Exposure by Mediating MITF Function toward DNA Repair Mode.

Skin pigmentation is paused after sun exposure; however, the mechanism behind this pausing is unknown. In this study, we found that the UVB-induced DNA repair system, led by the ataxia telangiectasia mutated (ATM) protein kinase, represses MITF transcriptional activity of pigmentation genes while placing MITF in DNA repair mode, thus directly inhibiting pigment production. Phosphoproteomics analysis revealed ATM to be the most significantly enriched pathway among all UVB-induced DNA repair systems. ATM inhibition in mouse or human skin, either genetically or chemically, induces pigmentation. Upon UVB exposure, MITF transcriptional activation is blocked owing to ATM-dependent phosphorylation of MITF on S414, which modifies MITF activity and interactome toward DNA repair, including binding to TRIM28 and RBBP4. Accordingly, MITF genome occupancy is enriched in sites of high DNA damage that are likely repaired. This suggests that ATM harnesses the pigmentation key activator for the necessary rapid, efficient DNA repair, thus optimizing the chances of the cell surviving. Data are available from ProteomeXchange with the identifier PXD041121.

Food-seeking behavior is triggered by skin ultraviolet exposure in males.

Sexual dimorphisms are responsible for profound metabolic differences in health and behavior. Whether males and females react differently to environmental cues, such as solar ultraviolet (UV) exposure, is unknown. Here we show that solar exposure induces food-seeking behavior, food intake, and food-seeking behavior and food intake in men, but not in women, through epidemiological evidence of approximately 3,000 individuals throughout the year. In mice, UVB exposure leads to increased food-seeking behavior, food intake and weight gain, with a sexual dimorphism towards males. In both mice and human males, increased appetite is correlated with elevated levels of circulating ghrelin. Specifically, UVB irradiation leads to p53 transcriptional activation of ghrelin in skin adipocytes, while a conditional p53-knockout in mice abolishes UVB-induced ghrelin expression and food-seeking behavior. In females, estrogen interferes with the p53-chromatin interaction on the ghrelin promoter, thus blocking ghrelin and food-seeking behavior in response to UVB exposure. These results identify the skin as a major mediator of energy homeostasis and may lead to therapeutic opportunities for sex-based treatments of endocrine-related diseases.

Classification of node-positive melanomas into prognostic subgroups using keratin, immune, and melanogenesis expression patterns.

Cutaneous melanoma tumors are heterogeneous and show diverse responses to treatment. Identification of robust molecular biomarkers for classifying melanoma tumors into clinically distinct and homogenous subtypes is crucial for improving the diagnosis and treatment of the disease. In this study, we present a classification of melanoma tumors into four subtypes with different survival profiles based on three distinct gene expression signatures: keratin, immune, and melanogenesis. The melanogenesis expression pattern includes several genes that are characteristic of the melanosome organelle and correlates with worse survival, suggesting the involvement of melanosomes in melanoma aggression. We experimentally validated the secretion of melanosomes into surrounding tissues by melanoma tumors, which potentially affects the lethality of metastasis. We propose a simple molecular decision tree classifier for predicting a tumor's subtype based on representative genes from the three identified signatures. Key predictor genes were experimentally validated on melanoma samples taken from patients with varying survival outcomes. Our three-pattern approach for classifying melanoma tumors can contribute to advancing the understanding of melanoma variability and promote accurate diagnosis, prognostication, and treatment.

Does Abdominoplasty Intensify the Metabolic Effect of Bariatric Surgery?

BACKGROUND: The effect of weight reduction following bariatric surgery is already well known. OBJECTIVES: To investigate the effects of abdominoplasty on metabolic markers indicative of weight loss. METHODS: The authors prospectively enrolled consecutive obese patients after laparoscopic sleeve gastrectomy. They were candidates for post-bariatric surgery abdominoplasty. The authors measured metabolic markers one day prior to surgery, 24 hours after, and 3 months following surgery. They recorded medical and demographic parameters. RESULTS: Sixteen patients were recruited for participation in the study. Mean age was 47 years and 88% of the patients were female. Bariatric surgery achieved a mean decline in body mass index of 13.8 kg/m2. All patients underwent abdominoplasty. Leptin and insulin levels were slightly increased at 3 months postoperative. No significant changes were observed in glucose, hemoglobin, or triglycerides throughout the study. CONCLUSIONS: In a cohort of obese patients undergoing laparoscopic sleeve gastrectomy followed by abdominoplasty, no significant changes were noted in a patient's metabolic profiles. The results suggest that abdominoplasty has no effect on the metabolic markers tested in contrast to other reports; however, the cosmetic, behavioral, and psychological advantages of abdominoplasty are well established.

Safety of Premedication with Oral Midazolam before Rhinoplasty as Indicated by Intraoperative Levels of Blood Oxygen Saturation.

BACKGROUND: The use of oral midazolam as premedication to induce anxiolysis before surgical procedures under local anesthesia is widely accepted in plastic surgery. Rhinoplasty performed under local anesthesia is known to generate high levels of perioperative anxiety, thus the use of appropriate premedication is important. Oral midazolam has been shown to be safe in various procedures. However, the safety of oral midazolam before rhinoplasty has not been evaluated. OBJECTIVES: To evaluate the safety of premedication with oral midazolam prior to rhinoplasty by analyzing the intraoperative blood oxygen saturation levels as predictors of adverse respiratory events. METHODS: We retrospectively reviewed the anesthesia records of 62 patients who underwent rhinoplasty under local anesthesia and received premedication with oral midazolam for anxiolysis between March 2017 and December 2017. The median age of the patients was 25.4 years, and they were all classified as American Society of Anesthesiologists class 1. The patients received 10 mg midazolam hydrochloride orally 1 hour prior to the procedure. Oxygen blood saturation was monitored using a pulse oximeter and recorded every 15 minutes. RESULTS: All the patients maintained blood oxygen saturation levels above 95% (median peripheral capillary oxygen saturation 99%) on room air, and they did not require supplemental intraoperative oxygen. There were no transient hypoxemic events during and following the procedure. CONCLUSIONS: Our study confirmed the safety of oral midazolam premedication to reduce perioperative anxiety when performing rhinoplasty under local anesthesia.

Latissimus Dorsi Flap: A Winning Hand for Breast Reconstruction Salvage.

BACKGROUND: There are several methods for primary breast reconstruction following oncologic resection, including alloplastic and autologous-based reconstruction. Major complications that can lead to re-operation and reconstruction failure occur in up to 25% of the patients and necessitate salvage procedures. OBJECTIVES: To present the authors' experience using a pedicled latissimus dorsi (LD) flap for the salvage of complicated and impending failed breast reconstruction. METHODS: A retrospective cohort study was conducted of all patients who underwent breast reconstruction salvage by means of an LD flap in our institution during a 5-year period. Demographic, oncologic, surgical, and postoperative data were collected and analyzed. RESULTS: Seventeen patients underwent breast reconstruction salvage with the LD flap. Fourteen patients had alloplastic reconstruction and three patients had autologous reconstruction. Postoperative complications included wound infection in three patients, minor wound dehiscence in two, and donor site seroma in two. One case of postoperative infection required re-operation with exchange of the implant with a tissue expander. All breast reconstructions were salvaged using the LD flap. Only one patient complained of functional limitations in using the arm of the harvested LD. CONCLUSIONS: The LD flap is a valuable and reliable flap for alloplastic or autologous breast reconstruction salvage and has a high rate of salvage success despite the challenging surgical environment. This flap offers a good cosmetic reconstruction outcome with relatively low donor-site morbidity and high patient satisfaction.

UV-Protection Timer Controls Linkage between Stress and Pigmentation Skin Protection Systems.

Skin sun exposure induces two protection programs: stress responses and pigmentation, the former within minutes and the latter only hours afterward. Although serving the same physiological purpose, it is not known whether and how these programs are coordinated. Here, we report that UVB exposure every other day induces significantly more skin pigmentation than the higher frequency of daily exposure, without an associated increase in stress responses. Using mathematical modeling and empirical studies, we show that the melanocyte master regulator, MITF, serves to synchronize stress responses and pigmentation and, furthermore, functions as a UV-protection timer via damped oscillatory dynamics, thereby conferring a trade-off between the two programs. MITF oscillations are controlled by multiple negative regulatory loops, one at the transcriptional level involving HIF1α and another post-transcriptional loop involving microRNA-148a. These findings support trait linkage between the two skin protection programs, which, we speculate, arose during furless skin evolution to minimize skin damage.

Validated Assessment Scales for Décolleté Wrinkling and Pigmentation.

BACKGROUND: Décolleté aging includes skin dyspigmentation, laxity, and visible wrinkling. The development of globally accepted scales for the assessment of décolleté aging is essential for aesthetic research and patient evaluation. OBJECTIVE: To develop a set of grading scales for the objective assessment of décolleté aging criteria and establish the reliability and validity of these scales. MATERIALS AND METHODS: To describe age-related changes to the décolleté, 3 photonumeric grading scales were created and validated: décolleté wrinkles-at rest, décolleté wrinkles-dynamic, and décolleté pigmentation-at rest. Thirteen aesthetic experts rated photographs of the décolleté of 50 women at rest and at dynamic "hand-to-elbow" positions in 2 validation sessions. Responses were analyzed to assess interrater and intrarater reliability. RESULTS: Interrater and intrarater reliability were both "almost perfect" (≥0.81, intraclass correlation coefficient and weighted kappa) for décolleté wrinkles-dynamic, summary score for décolleté, and estimated age. Reliability was "substantial" (0.61-0.80) for all other décolleté assessments. There was high correlation between all décolleté scales, estimated age, and estimated aesthetic treatment effort. CONCLUSION: Consistent outcomes between raters and by individual raters at different time points confirm the reliability of the décolleté grading scales, indicating that they will be a valuable tool for use in clinical research and practice.

Ki67 as a biologic marker of basal cell carcinoma: a retrospective study.

BACKGROUND: Basal cell carcinoma (BCC) is the most common malignancy in humans. Several factors have been associated with the biological behavior of these tumors, including histopathologic type, depth of tumor invasion, perineural invasion, and the expression of several biological markers including Ki67, a proliferative marker. Previous studies assessing the relationship between the proliferative fraction, as expressed by Ki67, and the histological variants of BCC as well as its association with the tendency to recur, failed to illustrate significant statistical correlation. OBJECTIVES: To examine the proliferative index, as expressed by Ki67, in various subtypes of basal cell carcinoma, and to assess its relationship to various histological and clinical variables. METHODS: In this retrospective study 51 lesions of BCC were examined. In each case, the following data were gathered: demographic (age and gender), anatomic location, size of the lesion, and clinical follow-up. Each case was stained immunohistochemically with anti-Ki67 antigen (MIB-1), and the proliferative index was determined. Histological analysis was performed for the following data: presence of an ulcer, intensity of inflammatory infiltrate, histologic subtype, mitotic count, and the presence of perineural invasion. RESULTS: Basal cell carcinoma exhibited a wide variation of proliferative indices, ranging from 1% to 61%. A significant statistical correlation was observed between the proliferative index and the mitotic activity, tumor ulceration and brisk tumor-infiltrating lymphocytes. CONCLUSIONS: The wide variation in the degree of proliferation (from almost no activity to highly proliferative tumors) suggests that basal cell carcinoma exhibits a wide spectrum of biological characteristics. Ulcerated lesions were characterized by high proliferative index. No true correlation was demonstrated between the proliferative index and the aggressive histological subtypes, implying that other factors were more biologically significant. The degree of proliferation also showed significant statistical correlation with the degree of tumor infiltration by lymphocytes. The significance of this proliferation-associated increased immunogenicity needs to be further studied.

Clinical and genetic findings in eight Israeli patients with transthyretin-associated familial amyloid polyneuropathy.

BACKGROUND: Transthyretin (TTR)-associated familial amyloid polyneuropathy (FAP) is an autosomal dominant multisystem disease with neurological and extra-neurological manifestations. It is caused by various mutations in the TTR gene leading to the formation of insoluble amyloid. OBJECTIVES: To describe the clinical and genetic findings in patients with TTR-associated FAP in Israel. METHODS: We evaluated eight patients clinically and genetically during the years 2006 to 2011. RESULTS: At onset, all the patients exhibited sensory loss of the lower and upper limbs, five patients experienced muscle pain, and one patient had lower limb weakness. Five patients had autonomic nervous system manifestations, and four demonstrated evidence of amyloid cardiomyopathy. Nerve conduction studies showed sensorimotoraxonal neuropathy in all patients. Sural nerve biopsies were obtained in five patients; only three biopsies revealed amyloid deposit. In four patients of Yemenite descent, genetic analysis of the TTR gene demonstrated ser77tyr mutation. One patient of Tunisian descent and one Ashkenazi patient harbored the val30met mutation. One patient of Iranian descent showed val32ala mutation, and another Ashkenazi patient showed phe33leu mutation. CONCLUSIONS: TTR-associated FAP is a progressive and fatal disease that exists in the Israeli population and is unproportionally common among Yemenite Jews. This disease may be under-diagnosed and should be considered in the differential diagnosis of any patient with rapidly progressive neuropathy, especially with autonomic involvement or extra-neural features. The absence of amyloid in nerve biopsy should not rule out the diagnosis.

Clinical, electrophysiologic and pathologic findings in 10 patients with myotonic dystrophy 2.

BACKGROUND: Myotonic dystrophy type 2 (DM2) is an autosomal dominant, multisystem disorder caused by a CCTG tetranucleotide repeat expansion located in intron 1 of the zinc finger protein 9 gene (ZNF9 gene) on chromosome 3q 21.3. OBJECTIVES: To describe the clinical, electrophysiologic and pathologic findings in patients with myotonic dystrophy 2. METHODS: We evaluated 10 patients genetically, clinically and electrophysiologically during the years 2007 to 2008. RESULTS: All patients were of Jewish European ancestry. Among affected individuals, eight patients had symptoms of proximal muscle weakness, two had muscle pain, and two exhibited myotonia. On physical examination six patients had severe weakness of hip flexor muscles. Seven individuals underwent cataract surgery, and cardiac involvement was seen in one case. On the initial electromyographic (EMG) examination five patients demonstrated myotonic discharges; repeated studies showed these discharges in nine cases. Six muscle biopsies showed non-specific pathological changes. Seven patients had an affected first-degree relative with either a diagnosed or an undiagnosed muscular disorder consistent with an autosomal dominant trait. CONCLUSIONS: DM2 may often present with proximal muscle weakness without myotonia. EMG may initially fail to show myotonic discharges, but these discharges may eventually show in most cases on repeated EMG. Thus, DM2 may be underdiagnosed and should be included in the differential diagnosis of adult patients of Jewish European ancestry presenting with proximal lower limb weakness.

Acute heroin-related neuropathy.

Heroin-related peripheral nervous injury has scarcely been reported, mostly as compressive neuropathy. Rarely, other types of peripheral nervous system (PNS) injury have been recognized, such as plexopathy, polyradiculopathy, mononeuropathy, and rhabdomyolysis. These complications are usually not related to local trauma, but the nature of nerve injury remains unknown. Immunologic mechanisms have been proposed, although generally there is no laboratory evidence of inflammation and usually there is no improvement following steroid therapy. We describe six patients who developed acute PNS injury following intravenous or intranasal heroin self-administration with no evidence of compression injury or inflammation. Four patients had plexopathy (two lumbosacral and two brachial), and two had symmetric distal axonal sensorimotor neuropathy affecting the lower extremities. Of the six patients, five had concomitant rhabdomyolysis (creatine kinase, CK: 5,000-100,000 U/l) and one patient with brachial plexopathy had normal CK levels. The neurological deficit was noticed 3-36 h after heroin administration. Electromyography in five patients was consistent with sensorimotor axonal loss either confined to the affected plexus or with a diffuse distribution in the legs in the two patients with neuropathy. We propose that a toxic mechanism may be responsible for non-compression cases of acute neuropathy following heroin abuse.