Menadione Sodium Bisulfite Loaded Rhamnolipid Based Solid Lipid Nanoparticle as Skin Lightener Formulation: A Green Production Beside In Vitro/In Vivo Safety Index Evaluation.

Purpose: In the current investigation, an ultrasonic approach was performed to produce menadione sodium bisulfite-loaded solid lipid nanoparticles (MSB-SLNs) with rhamnolipid as bio-surfactant, which aimed to increase the dermal delivery and anti-pigmentation effect. Methods: To achieve optimum delivery for MSB, the impact of the ratio of two surfactants (rhamnolipid: Tween) on nanoparticle attributes and the respective functions were evaluated. In vitro diffusion process, in vitro cytotoxicity assay, determination of melanin content of melanoma cells, L-DOPA auto-oxidation inhibitory test, and skin irritation studies carried out to investigate the suitability of MSB formulation in dermal application. Results: The optimized nanoparticles showed an average particle size, zeta potential, polydispersity index (PDI), and drug entrapment efficiency of 117.26±1.12 nm, -6.28±0.33 mV, 0.262±0.002, 83.34±0.75% respectively in hydrophilic-lipophilic balance (HLB) of 12. The in vitro diffusion process demonstrated that MSB-SLN gel had a prolonged release pattern. The levels of MSB in the cutaneous layers (52.192±2.730% or 961.59±50.313 µg/cm2 ) and the receiver compartment (23.721±1.803 % or 437.049± 33.236 µg/cm2 ) for the MSB-SLN gel was higher than MSB simple and showed no cutaneous irritancy and toxicity in rats. MSB-SLN inhibited melanin formation and was remarkably higher than free MSB. MSB-SLN inhibited L-3,4- dihydroxyphenylalanine (L-DOPA) auto-oxidation to a greater extent (95.14±1.46%) than MSB solution (72.28±0.83%). Conclusion: This study's observations revealed that the produced MSB-SLN might be used as a potential nano-vehicle for MSB dermal administration, thereby opening up innovative options for the management of hyper-melanogenesis problems.

Representation of diverse skin tones in Nelson's Textbook of Pediatrics.

OBJECTIVE: Physicians are trained to visually recognize disease using images. Many pediatric dermatologic conditions are initially identified and treated by pediatricians, who need to diagnose on varied skin tones. The objective was to evaluate if figures depicting cutaneous disease in the preeminent pediatrics textbook reflect diverse skin tones. METHODS: Figures depicting dermatologic findings in Nelson's Textbook of Pediatrics were assessed using the Fitzpatrick, Massey-Martin, and Color Bar scales. The distribution was compared to the US population using American National Election Survey 2012 data. The three scales were compared for concordance. Statistical analysis included chi square with P < 0.05 significant. RESULTS: Of 515 figures, 484 were classifiable. Light skin tones were depicted in 453 (93.6%) by Fitzpatrick, 364 (75.2%) by Massey-Martin, and 406 (83.9%) by Color Bar, moderate tones in 92 (19.0%) by Massey-Martin and 53 (11.0%) by Color Bar, and dark tones in 31 (6.4%) by Fitzpatrick, 28 (5.8%) by Massey-Martin, and 25 (5.2%) by Color Bar. The textbook skin tone distribution did not reflect the US population: light 75.2% vs. 63.3%, moderate 19.0% vs. 25.8%, dark 5.8% vs. 11.0%, respectively (P < 0.00001). The three scales yielded consistent proportions for light/moderate vs. dark tones (P = 0.71). Certain conditions were mostly depicted on dark (burns, leprosy, urticaria pigmentosa) or light skin (psoriasis, acne, hemangioma, molluscum, herpes, keloid). CONCLUSION: Figures demonstrating dermatologic manifestations are predominantly depicted on light skin tones, and are not representative of the US population. Certain conditions were more commonly shown on dark or light skin tones, unrelated to epidemiology.

Deciphering the intricate relationship between macrophages, pigmentation, and prognosis in uveal melanoma.

High pigmentation and the abundance of M2 macrophages have been identified as negative predictors in uveal melanoma (UM). Risk factors associated with UM that are prevalent in high-risk white populations are still present, though less common, in relatively low-risk Asian population. Research shows that proangiogenic M2 macrophages and monosomy 3 play a significant role in UM progression. Our aim is to investigate the impact of tumor-associated macrophages in UM and examine their correlation with monosomy 3 & pigmentation. TEM was used to analyze the morphology of macrophages in UM. Forty UM samples underwent FISH for monosomy 3 identification. Immunohistochemistry was done to assess M2/M1 macrophages on 82 UM tissue samples. IL-10 and IL-12 expression was quantified in UM serum samples by ELISA. Expression of all markers was correlated with pigmentation markers (TYRP1, TYRP2, SILV & MITF). Prognostic outcomes were determined using the Cox proportional hazard model & log-rank test. Increased expression of M2/M1 macrophages was observed in 31 UM cases, which correlated with high expression of pigmentation markers. IL-10 concentration was high in UM cases. Monosomy 3 was evident in 50% of UM cases and significantly associated with increased immunoexpression of M2/M1 macrophages and pigmentation markers. Reduced MFS was observed in UM patients with high M2/M1 macrophage expression (p=0.001). High pigmentation and increased M2 macrophage density could impact the tumor microenvironment in UM. This could contribute to ineffective antitumor immune responses in UM patients. Our findings suggest avenues for developing novel therapeutic approaches to counteract these immunosuppressive effects in UM.

Impact of Skin Pigmentation on Pulse Oximetry Blood Oxygenation and Wearable Pulse Rate Accuracy: Systematic Review and Meta-Analysis.

BACKGROUND: Photoplethysmography (PPG) is a technology routinely used in clinical practice to assess blood oxygenation (SpO2) and pulse rate (PR). Skin pigmentation may influence accuracy, leading to health outcomes disparities. OBJECTIVE: This systematic review and meta-analysis primarily aimed to evaluate the accuracy of PPG-derived SpO2 and PR by skin pigmentation. Secondarily, we aimed to evaluate statistical biases and the clinical relevance of PPG-derived SpO2 and PR according to skin pigmentation. METHODS: We identified 23 pulse oximetry studies (n=59,684; 197,353 paired SpO2-arterial blood observations) and 4 wearable PR studies (n=176; 140,771 paired PPG-electrocardiography observations). We evaluated accuracy according to skin pigmentation group by comparing SpO2 accuracy root-mean-square values to the regulatory threshold of 3% and PR 95% limits of agreement values to +5 or -5 beats per minute (bpm), according to the standards of the American National Standards Institute, Association for the Advancement of Medical Instrumentation, and the International Electrotechnical Commission. We evaluated biases and clinical relevance using mean bias and 95% CI. RESULTS: For SpO2, accuracy root-mean-square values were 3.96%, 4.71%, and 4.15%, and pooled mean biases were 0.70% (95% CI 0.17%-1.22%), 0.27% (95% CI -0.64% to 1.19%), and 1.27% (95% CI 0.58%-1.95%) for light, medium, and dark pigmentation, respectively. For PR, 95% limits of agreement values were from -16.02 to 13.54, from -18.62 to 16.84, and from -33.69 to 32.54, and pooled mean biases were -1.24 (95% CI -5.31 to 2.83) bpm, -0.89 (95% CI -3.70 to 1.93) bpm, and -0.57 (95% CI -9.44 to 8.29) bpm for light, medium, and dark pigmentation, respectively. CONCLUSIONS: SpO2 and PR measurements may be inaccurate across all skin pigmentation groups, breaching U.S. Food and Drug Administration guidance and industry standard thresholds. Pulse oximeters significantly overestimate SpO2 for both light and dark skin pigmentation, but this overestimation may not be clinically relevant. PRs obtained from wearables exhibit no statistically or clinically significant bias based on skin pigmentation.

Gingival pigmentation in relation to anti-inflammatory salivary interleukin 10, a comparative study.

OBJECTIVE: To assess gingival pigmentation prevalence among students, and its relationship with anti-inflammatory salivary interleukin-10. Method: The observational, cross-sectional, comparative study was conducted at the College of Physical Education and Sport Sciences, Diyala University, Iraq, from December 2021 to March 2022, and comprised students of either gender aged 19-22 years. Students with pigmented gingiva were in group A, while those having no gingival pigmentation were in group B. The level of interleukin-10 was tested using enzyme-linked immunosorbent assay in both groups, and values were compared using the gingival pigmentation index. Data was analysed using SPSS 22. Results: Of the 1,295 students assessed, 1,044(80.62%) were males and 251(19.38%) were females. Pigmented gingiva was found in 118(9.11%), and these students represented group A, while as many subjects were enrolled in controlled group B. Pigmented gingiva was more common among males 81(68.64%) than females 37(31.36%). Salivary interleukin-10 level was significantly increased in group A compared to group B (p<0.05). However, there were no significant differences in mean value of salivary interlukin-10 with respect to severity in group A (p>0.05). CONCLUSIONS: Pigmentation was beneficial in terms of gingival protection.

Comparative study of using the Neodymium-doped yttrium Aluminium Garnet laser alone or in combination with the High Intensity Focussed Ultrasound technique for removing the professional tattoo.

Objective: To evaluate the effects of combining neodymium-doped yttrium aluminium garnet laser and highintensity focussed ultrasound techniques to remove a professionally-done tattoo. METHODS: The interventional study was conducted from November 2021 to April 2022 at the at the Postgraduate Medical Physics Laboratory of Mustansiriyah University, Baghdad, Iraq, and comprised healthy adults aged 18-60 years who wished to have their tattoo areas from their hands, arms and forearms removed. Each tattoo was divided into 3 areas. The first area was treated with multiple passes of neodymium-doped yttrium aluminium garnet laser with 450mJ. The second area was treated with multiple passes of neodymium-doped yttrium aluminium garnet laser with 450mJ and 850mJ. The third area was treated with multiple passes of neodymium-doped yttrium aluminium garnet laser with 450mJ, followed by 5-10 consecutive strokes of HIFU waves with energy 0.25-0.6mJ, 1.4mm depth, 10MHz and 7MHz frequency, and a second blow of the neodymium-doped yttrium aluminium garnet laser with 450mJ. The intervention lasted 8 sessions, and the time required between the sessions ranged 15-20 days. The percentage of pigmentation was evaluated using the image segmentation method based on fuzzy c-means. Data was analysed using SPSS 24. RESULTS: Of the 20 subjects, 12(60%) were males and 8(40%) were females. There were 10(50%) subjects aged 17-24 years, 6(30%) aged 25-35 years and 4(20%) aged 36-45 years. The tattoo pigments showed a significant reduction in all the 3 groups (p<0.05), but intergroup comparison showed that the reduction was most significant in the group treated with neodymium-doped yttrium aluminium garnet laser plus high-intensity focussed ultrasound (p<0.05). CONCLUSIONS: The combination of high-intensity focussed ultrasound and neodymium-doped yttrium aluminium garnet laser led to more positive outcome compared to the use of low- or high-intensity laser alone.

The Prognostic Significance of Tumoral Melanosis.

BACKGROUND: Tumoral melanosis (TM) is a histological term to describe a nodular aggregation of macrophages containing melanin pigment (melanophages) that is devoid of viable melanocytes. It is most often identified in skin, where it may be appreciated clinically as a pigmented lesion; however, it can also be found in other organs such as lymph nodes. The presence of TM is usually thought to signify the presence of a regressed melanoma or other pigmented tumor. Until recently, it was a relatively uncommon finding; however, with the use of effective systemic therapies against melanoma, its occurrence in histological specimens is more frequent. METHODS: We identified and reviewed all histopathological diagnoses of TM at any organ site reported at a single institution from 2006 to 2018. TM cases were paired with non-TM cases of cutaneous melanoma through propensity score matching at a 1:2 ratio, and their survival outcomes were compared. The clinical outcomes examined included recurrence-free survival (RFS), distant disease-free survival (DDFS), melanoma-specific survival (MSS), and overall survival (OS). RESULTS: TM was reported in 79 patients. Their median age was 65 years (range 22-88), with a 2:1 male predominance (51 out of 79, 65%). The most common organ involved was the skin (67%), with a third of all cases localized to a lower limb (36%). TM had a strong association with the presence of melanoma (91%) and regression at other sites of melanoma (54%), suggesting that it is part of a systemic immune response against melanoma. Most patients with TM either previously or subsequently developed histologically confirmed melanoma in the same anatomical region as the TM (89%). Thirty-five TM patients were matched with 70 non-TM cases. Patients with melanoma who developed TM without prior regional or systemic therapy showed improved MSS (p = 0.03), whereas no statistically significant differences were observed in terms of RFS, DDFS, and OS. CONCLUSIONS: TM usually occurs in the context of a previous or subsequent cutaneous melanoma and is associated with improved MSS. It is important that TM is recognized by pathologists and documented in pathology reports.

Functional redundancy of R2R3-MYB transcription factors involved in anthocyanin biosynthesis is manifested in anther pigmentation in petunia.

Accumulation of anthocyanin provides pigmentation in plant tissues. In petunia, gene expression profiles that lead to anthocyanin production have been extensively characterized in terms of pigmentation in flower petals. Anthers are also pigmented, but the transcriptional control of the genes for anthocyanin biosynthesis in anthers has not been fully characterized. Here we addressed this issue by analyzing the expression of structural genes and genes encoding transcription factors (TFs) of the pathway. Ectopic expression of the PURPLE HAZE (PHZ) gene encoding an R2R3-MYB activator induced pigmentation in anthers. The pigmentation was accompanied by an increase in mRNA levels of AN1, MYB27 and MYBx among the genes encoding TFs. Among the structural genes, mRNA levels of four late biosynthetic genes (LBGs) were higher in the transformants than in the wild type. Analyses of gene expression profile using commercial varieties indicated that mRNA levels of MYB27, MYBx and LBGs and of AN4, responsible for anther pigmentation, were higher in pigmented anthers than in nonpigmented. Differences in the gene expression profile between pigmented anthers induced by ectopic PHZ expression and their nonpigmented control and those between pigmented anthers and nonpigmented anthers of existing varieties were thus remarkably similar. These observations suggest that a high level of expression of the LBGs is characteristic of pigmented anthers and that ectopic PHZ expression in the an4 - genetic background induced changes in the transcriptional network toward the state established in pigmented anthers, which is intrinsically brought about by the function of AN4.

Efficacy of Subdermal Poly-d,l-Lactic Acid Injections for the Treatment of Melasma.

BACKGROUND: Melasma is a chronic, recurrent skin disorder with limited long-term treatment success using conventional therapies like hydroquinone and laser treatments, which primarily target epidermal components while leaving dermal aspects untreated. OBJECTIVE: To evaluate the efficacy and safety of poly-d,l lactic acid (PDLLA) subdermal injections for treating moderate melasma. METHODS: Three female patients (age range: 45-59 years) with Fitzpatrick skin types III and IV received three PDLLA injection sessions at 3-week intervals. Treatment outcomes were assessed using the Melasma Area and Severity Index (MASI) and patient satisfaction scores at 12-week follow-up. RESULTS: All patients showed significant MASI score improvements (reduction range: 3.60-6.30 points). Patient satisfaction ratings ranged from 3 to 4 out of 4. Temporary side effects included mild edema and bruising, resolving within 72 h. CONCLUSIONS: PDLLA subdermal injections showed promising results in melasma treatment, potentially due to its biostimulatory effects on collagen production and dermal remodeling. Further research, including histopathological analysis, is needed to confirm long-term efficacy and safety, and understand underlying mechanisms.

Exploring Eye, Hair, and Skin Pigmentation in a Spanish Population: Insights from Hirisplex-S Predictions.

BACKGROUND/OBJECTIVES: Understanding and predicting human pigmentation traits is crucial for individual identification. Genome-wide association studies have revealed numerous pigmentation-associated SNPs, indicating genetic overlap among pigmentation traits and offering the potential to develop predictive models without the need for analyzing large numbers of SNPs. METHODS: In this study, we assessed the performance of the HIrisPlex-S system, which predicts eye, hair, and skin color, on 412 individuals from the Spanish population. Model performance was calculated using metrics including accuracy, area under the curve, sensitivity, specificity, and positive and negative predictive value. RESULTS: Our results showed high prediction accuracies (70% to 97%) for blue and brown eyes, brown hair, and intermediate skin. However, challenges arose with the remaining categories. The model had difficulty distinguishing between intermediate eye colors and similar shades of hair and exhibited a significant percentage of individuals with incorrectly predicted dark and pale skin, emphasizing the importance of careful interpretation of final predictions. Future studies considering quantitative pigmentation may achieve more accurate predictions by not relying on categories. Furthermore, our findings suggested that not all previously established SNPs showed a significant association with pigmentation in our population. For instance, the number of markers used for eye color prediction could be reduced to four while still maintaining reasonable predictive accuracy within our population. CONCLUSIONS: Overall, our results suggest that it may be possible to reduce the number of SNPs used in some cases without compromising accuracy. However, further validation in larger and more diverse populations is essential to draw firm conclusions and make broader generalizations.

3D printing cassava starch-ovalbumin intelligent labels: Co-pigmentation effects of gallic acid on anthocyanins.

Anthocyanins are often chosen as signal converters of intelligent labels. However, they are degraded by high-temperature oxidation in the process of intelligent label preparation. The color fading seriously affects the sensitivity of color development. In this study, a green 3D printing intelligent label preparation technique was developed, in which gallic acid (GA) was added to a blueberry anthocyanin (BA) solution to enhance the color of the co-pigment to ensure the color sensitivity. The combined effect of GA-BA reduced the fade rate of the anthocyanins from 35.13 % to 26.44 % at 90 °C. The printing ink has shear-thinning viscosity characteristics and yield stresses in the range of 500-600 MPa for high-quality printing. Structural analysis revealed that GA-BA co-pigmentation enhanced the interaction between ovalbumin and cassava starch. In addition, the method of 3D printing to prepare labels was conducive to solving the problem of waste in traditional labeling process. The results of freshness testing of sea shrimp proved that labels can be applied to fresh boxes to reflect the freshness of food. We provide a method for enhancing the color of 3D-printed smart ink to prepare intelligent labels with reproducible and customizable batch shapes.

A missense mutation in the tyrosinase gene explains acromelanism in domesticated canaries.

Acromelanism is a form of albinism observed in several vertebrate species. In mammals, acromelanism is known to be caused by mutations in the tyrosinase gene (TYR) that induce a temperature-sensitive behavior of melanin synthesis, resulting in a characteristic hair color gradient. In birds, several phenotypes consistent with acromelanism have been reported, but their genetic basis remains unknown. This study aimed to identify the genetic basis of an acromelanistic phenotype in domesticated canaries known as pearl and test whether it is caused by the same molecular mechanism described for mammals. To do this, we compared the genomes of pearl and non-pearl canaries and searched for potentially causative genetic mutations. Our results suggest that the pearl phenotype is caused by a mutation in the TYR gene encoding a TYR-P45H missense substitution. Our findings further suggest that reports of acromelanism in other bird species might be explained by TYR mutations.

Modulating OCA2 Expression as a Promising Approach to Enhance Skin Brightness and Reduce Dark Spots.

The oculocutaneous albinism II (OCA2) gene encodes a melanosomal transmembrane protein involved in melanogenesis. Recent genome-wide association studies have identified several single nucleotide polymorphisms within OCA2 genes that are involved in skin pigmentation. Nevertheless, there have been no attempts to modulate this gene to improve skin discoloration. Accordingly, our aim was to identify compounds that can reduce OCA2 expression and to develop a formula that can improve skin brightness and reduce hyperpigmented spots. In this study, we investigated the effects of OCA2 expression reduction on melanin levels, melanosome pH, and autophagy induction through siRNA knockdown. Additionally, we identified several bioactives that effectively reduce OCA2 expression. Ultimately, in a clinical trial, we demonstrated that topical application of those compounds significantly improved skin tone and dark spots compared to vitamin C, a typical brightening agent. These findings demonstrate that OCA2 is a promising target for the development of efficacious cosmetics and therapeutics designed to treat hyperpigmentation.

Eumelanin and Pheomelanin Modelling in Optical Oximetry Using Pulse Oximetry (for 540 nm and 660 nm): DC Component.

Oximetry is used to quantify the presence of oxygen in soft tissues. It can be expressed as, for example, tissue oxygen saturation (StO2), arterial oxygen saturation (SaO2) and pulsatile oxygen saturation (SpO2), among others. Non-invasive medical devices are used to estimate (SaO2). Their accuracy is compromised in individuals with highly pigmented skin. The aim of this initial work is to go back few steps into the understanding of the light absorption for the DC component in pulse oximeters, by using a mixtures model for different hypothetical scenarios of normoxia and hyperoxia. Under hypoxic states, an initial and simple multi-wavelength approach could be established to identify the impact of eumelanin (EuM) and pheomelanin (PhM), which are directly related to skin pigmentation in dark skin colour individuals. We used public spectra for water (H2O), haemoglobin (HHb), oxy-haemoglobin (HbO2), eumelanin and pheomelanin, to create 1000 possible absorption combinations. These spectra simulations were used to understand the hypothetical limits, across a 450-800 nm wavelength range. These results have outlined the maximum oxy-haemoglobin concentrations that can be detected without interfering with eumelanin and pheomelanin. This initial and simple approach helped us to understand how eumelanin and pheomelanin absorption interferes and overlaps with low oxy-haemoglobin, which is a key biomarker for oxygen quantification in pulse oximeters and other non-invasive biomedical devices.

A New Index for Assessment of Severity and Extent of Gingival Pigmentation; A Diagnostic Cross-Sectional Study According to Inter and Intra-Observer Variability.

Background: Classification of gingival pigmentation (GP) is often performed using gingival pigmentation index (GPI), melanin pigmentation index (MPI), oral pigmentation index (DOPI), melanin index (MI), or physiologic/pathologic GPI. However, the internal and external reproducibility of these indexes have not been evaluated. This study aimed to introduce a new simple and applicable GPI and assess its internal and external reproducibility. Materials and Methods: This diagnostic cross-sectional study was conducted on 40 patients with maxillary and mandibular GP. Patients were in the age range of 12-60 years, and degree of GP was determined by four periodontists using DOPI, MI, MPI, GPI and the new index namely the severity and extension of gingival melanotic pigmentation index (SEMPI) under similar environmental and lighting conditions. The inclusion criteria were in the age range of 12-60 years and presence of melanin pigmentation (physiologic or pathologic) in the gingival margin, papilla, or attached gingiva. The exclusion criteria were systemic diseases, vascular lesions, hemochromatosis, amalgam tattoo, hyperbilirubinemia, or use of medications causing nonmelanotic pigmentation (hemoglobin, iron, and amalgam). Results: The Fleiss kappa between all examiners for all indexes at 0, 7, and 14 days was higher than 0.8, indicating high agreement among the examiners. The Spearman's correlation coefficient for all indexes was positive and high at 0, 7, and 14 days (P < 0.001). Conclusion: Considering the high agreement among the examiners for all indexes and at all-time points as well as the positive, strong correlations among them, it seems that the new index is useful for classification of GP.

Pigmentary Changes in Systemic Sclerosis are Associated with More Severe Cutaneous Sclerosis and Severity of Other Systems: A Cross-sectional Study from India.

Background: Pigmentary changes of the skin in systemic sclerosis in the form of diffuse hyperpigmentation and salt-and-pepper pigmentation are well documented in the literature; however, its association with disease severity and extent of underlying internal organ involvement has not been well studied. Aims: To assess the correlation between morphology and extent of pigmentary changes with the degree of cutaneous sclerosis and frequency and degree of major organ involvement. Methods: This was a cross-sectional descriptive study conducted in a tertiary care teaching hospital from December 2014 to November 2016. Consecutive patients of systemic sclerosis attending the outpatient department were screened, and patients satisfying the diagnosis as per the American Rheumatism Association criteria were recruited. Skin sclerosis was quantified using modified Rodnan skin score (MRSS), whereas pigmentary changes were calculated in terms of percentage of body surface area involved by rule-of-nine method. Investigations were carried out depending on organ involvement and as per respective specialty consultations with focus on pulmonary, cardiac, and gastrointestinal systems. Results: Of the 50 patients recruited, all had cutaneous involvement in the form of binding down of skin, followed by pigmentary changes. MRSS was significantly higher in patients with any pigmentary alteration (P = 0.03) compared to those without any pigmentary changes. There was a rising trend in between the MRSS severity and the proportion of patients with hyperpigmentation, and it was statistically significant (P = 0.04). Among systemic involvement, lung was involved in the form of interstitial lung disease in 94% patients (n = 47). However, skin pigmentation of any type was associated with lower high-resolution computed tomography scores (P = 0.02). Conclusion: This study shows that in systemic sclerosis patients presenting with pigmentary skin manifestations, cutaneous sclerosis is significantly higher.

Impact of Tumor Pigmentation in 6934 Patients with Uveal Melanoma at a Single Center.

Purpose: To evaluate clinical features and outcomes associated with degree of tumor pigmentation in patients with uveal melanoma (UM) of the choroid and ciliary body. Design: Retrospective observational study. Subjects: Six thousand nine hundred thirty-four consecutive patients with choroidal or ciliary body melanoma between 1971 and 2007 from a single ocular oncology center. Methods: Data on patient demographics, tumor characteristics, treatment approach, and clinical outcomes were collected. Comparisons between pigmented (>80% pigmentation by surface area), partially pigmented (20%-80%), and nonpigmented tumors (<20%) were performed using relevant hypothesis testing. Survival analyses for metastasis and melanoma-related death were conducted using the Kaplan-Meier method with log-rank tests for univariate comparisons. A multivariate Cox regression analysis was performed to assess the independent effects of multiple covariates on time-to-metastasis. Main Outcome Measures: Extraocular extension, ocular melanocytosis, time to tumor recurrence, tumor location, and melanoma-related metastasis and death. Results: There were 6934 eyes with UM and the degree of tumor pigmentation was classified as pigmented (n = 3762; 54%), partially pigmented (n = 2115; 31%), or nonpigmented (n = 1057; 15%). Pigmented UM was associated with extraocular extension (P < 0.001), ocular melanocytosis (P = 0.003), earlier tumor recurrence (P < 0.001), and more anterior tumor epicenter location (ciliary body, and equator to ora serrata) (P < 0.001). Pigmented UMs also exhibited the highest 10-year metastasis rate at 26%, compared with 19% for partially pigmented UMs and 16% for nonpigmented UMs (P < 0.001). Kaplan-Meier survival curves demonstrated differences among the tumor pigmentation groups for melanoma-related metastasis (P < 0.001) and melanoma-related death (P < 0.001). Multivariate Cox regression analysis for melanoma-related metastasis showed that pigmented UMs had a 29% higher relative risk of developing metastasis compared with partially pigmented UMs (P = 0.002) and a 54% higher relative risk of developing metastasis compared with nonpigmented UMs (P < 0.001). Conclusions: Pigmented choroidal and ciliary body melanoma is more often associated with ocular melanocytosis, extraocular extension, anterior tumor epicenter, and earlier tumor recurrence. We also revealed that patients with pigmented UMs demonstrate a higher 10-year rate of metastatic disease and have decreased metastatic survival relative to partially pigmented and nonpigmented UMs. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Visual input regulates melanophore differentiation.

Introduction: Developmental processes continue in organisms in which sensory systems have reached functional maturity, however, little research has focused on the influence of sensory input on cell and tissue development. Here, we explored the influence of visual system activity on the development of skin melanophores in Xenopus laevis. Methods: Melanophore number was measured in X. laevis larvae after the manipulation of visual input through eye removal (enucleation) and/or incubation on a white or black substrate at the time when the visual system becomes functional (stage 40). To determine the developmental process impacted by visual input, migration, proliferation and differentiation of melanophores was assessed. Finally, the role of melatonin in driving melanophore differentiation was explored. Results: Enucleating, or maintaining stage 40 larvae on a black background, results in a pronounced increase in melanophore number in the perioptic region within 24 h. Time lapse analysis revealed that in enucleated larvae new melanophores appear through gradual increase in pigmentation, suggesting unpigmented cells in the perioptic region differentiate into mature melanophores upon reduced visual input. In support, we observed increased expression of melanization genes tyr, tyrp1, and pmel in the perioptic region of enucleated or black background-reared larvae. Conversely, maintaining larvae in full light suppresses melanophore differentiation. Interestingly, an extra-pineal melatonin signal was found to be sufficient and necessary to promote the transition to differentiated melanophores. Discussion: In this study, we found that at the time when the visual system becomes functional, X. laevis larvae possess a population of undifferentiated melanophores that can respond rapidly to changes in the external light environment by undergoing differentiation. Thus, we propose a novel mechanism of environmental influence where external sensory signals influence cell differentiation in a manner that would favor survival.