Thesis (M.Sc. (Clinical Tropical Medicine))--Mahidol University, 1984.

No / The skin pigment melanin is produced in melanocytes in highly specialized organelles known as melanosomes. Melanosomes are related to the organelles of the endosomal/lysosomal pathway and can have a low internal pH. In the present study we have shown that melanin synthesis in human pigment cell lysates is maximal at pH 6.8. We therefore investigated the role of intramelanosomal pH as a possible control mechanism for melanogenesis. To do this we examined the effect of neutralizing melanosomal pH on tyrosinase activity and melanogenesis in 11 human melanocyte cultures and in 3 melanoma lines. All melanocyte cultures (9 of 9) from Caucasian skin as well as two melanomacell lines with comparable melanogenic activity showed rapid (within 24 h) increases in melanogenesis in response to neutralization of melanosomal pH. Chemical analysis of total melanin indicated a preferential increase in eumelanin production. Electron microscopy revealed an accumulation of melanin and increased maturation of melanosomes in response to pH neutralization. In summary, our findings show that: (i) near neutral melanosomal pH is optimal for human tyrosinase activity and melanogenesis; (ii) melanin production in Caucasian melanocytes is suppressed by low melanosomal pH; (iii) the ratio of eumelanin/phaeomelanin production and maturation rate of melanosomes can be regulated by melanosomal pH. We conclude that melanosomal pH is an essential factor which regulates multiple stages of melanin production. Furthermore, since we have recently identified that pink locus product (P protein) mediates neutralization of melanosomal pH, we propose that P protein is a key control point for skin pigmentation. We would further propose that the wide variations in both constitutive and facultative skin pigmentation seen in the human population could be associated with the high degree of P-locus polymorphism.

Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2008. / Härtill 4 uppsatser.

No description available.

No / The present invention relates to compositions and methods useful in studying or modulating melanin pigmentation in the skin. Particularly, the invention relates to compositions comprising a substance capable of modulating the activity or expression of ALK6 (SEQ ID 2) or Cdc42 which in turn are capable of modulation of the transfer of melanin from melanocytes to keratinocytes and potentially from keratinocytes to keratinocytes. The invention also relates to assays for identifying such compositions, and methods of modulating skin pigmentation.

Yes / The Arp2/3 complex is essential for the assembly of branched filamentous actin but its role in physiology and development is surprisingly little understood. Melanoblasts deriving from the neural crest migrate along the developing embryo and traverse the dermis to reach the epidermis colonising the skin and eventually homing within the hair follicles. We have previously established that Rac1 and Cdc42 direct melanoblast migration in vivo We hypothesised that the Arp2/3 complex might be the main downstream effector of these small GTPases. Arp3 depletion in the melanocyte lineage results in severe pigmentation defects in dorsal and ventral regions of the mouse skin. Arp3 null melanoblasts demonstrate proliferation and migration defects and fail to elongate as their wild-type counterparts. Conditional deletion of Arp3 in primary melanocytes causes improper proliferation, spreading, migration and adhesion to extracellular matrix. Collectively, our results suggest that the Arp2/3 complex is absolutely indispensable in the melanocyte lineage in mouse development, and indicate a significant role in developmental processes that require tight regulation of actin-mediated motility. / Cancer Research UK, (A180076), Medical Research Council (MR/R017255/1), Engineering and Physical Sciences Research Council (EP/P001114/1), Helmholtz-Gemeinschaft

Adverse effects of amiodarone are rarely seen in pediatric patients, but may occur if amiodarone is applied for long-term treatment. Two rather rare phenomena are blue-gray skin pigmentation and pulmonary mass. They represent important differential diagnoses from more common clinical complications like pneumonia and drug-induced toxic skin lesions.

O melanoma é uma doença complexa, associada com diversos fatores de risco genéticos e ambientais. Este o tipo mais agressivo de câncer de pele e origina-se nos melanócitos, as células da pele produtoras de pigmento nos mamíferos. Polimorfismos de base única (Single Nucleotide Polymorphisms - SNPs) presentes em genes envolvidos na pigmentação têm sido descritos envolvidos na modulação de risco para o melanoma, porém o conhecimento neste campo ainda é bastante limitado. Neste estudo, foi avaliado o efeito de quatro SNPs em quatro genes de pigmentação: TYR (rs1126809), HERC2 (rs1129038), SLC24A5 (rs1426654) e SLC45A2 (rs16891982) no aumento de risco para melanoma, usando análises de regressão logística multivariada e redução de dimensão multifatorial (MDR), em uma abordagem caso-controle. Em 255 indivíduos (120 pacientes com melanoma e 135 controles sem melanoma) provenientes do Rio Grande do Sul, Brasil, identificamos associação com o risco para melanoma em três dos quatro SNPs investigados (HERC2 rs1129038, P=0.017; SLC24A5 rs1426654, P<0.001; e SLC45A2 rs16891982, P=0.002). Além disso, a interação entre rs1426654 e rs16891982 (genótipos AA e GG, respectivamente), aumentou significamente o risco para melanoma nas análises de regressão logística multivariada e análises de MDR [OR = 6.936 (CI 95%: 1.607 – 50.294), P= 0.022]. Estes resultados contribuem para o conhecimento atual, indicando que esses SNPs contribuem para o aumento de risco de desenvolvimento de melanoma. / The melanoma is a complex disease, associated with several environmental and genetic risk factors. This is the most aggressive type of skin cancer and originates in melanocytes, the pigment producing skin cells in mammals. Single nucleotide polymorphisms (SNPs) in pigmentation genes have been describe in melanoma risk modulation but our knowledge in the field is still limited. Here, we assessed the effect of SNPs in four pigmentation genes – TYR (rs1126809), HERC2 (rs1129038), SLC24A5 (rs1426654), and SLC45A2 (rs16891982) on increase of melanoma risk using multivariate logistic regression and a multifactorial dimension reduction (MDR) analysis, in a case-control approach. In 255 individuals (120 melanoma patients and 135 controls free melanoma) from Rio Grande do Sul, Brazil, we identified an association of melanoma risk with three of the four SNPs studied (HERC2 rs1129038, P=0.017; SLC24A5 rs1426654, P<0.001; and SLC45A2 rs16891982, P=0.002). In addition, the interaction between rs1426654 and rs16891982 (AA and GG genotypes, respectively) significantly increased the risk of melanoma [OR = 6.936 (CI 95%: 1.607 – 50.294), P= 0.022] in both MRD and multivariate logistic regression analyses. Our results contribute to the current knowledge, indicating that SNPs contribute to the increase risk of melanoma.

Vitamin D plays a critical role in bone metabolism and many cellular and immunological processes, and low vitamin D levels have been associated with several chronic and infectious diseases. Previous studies have reported that many otherwise healthy adults of European ancestry living in Canada have low vitamin D concentrations during the wintertime. However, individuals of non-European ancestry are at a higher risk of having low vitamin D levels. This thesis examined vitamin D status in a sample of young adults of diverse ancestry living in the Greater Toronto Area. In my research I found that: 1) vitamin D levels (measured as 25(OH)D concentrations) are low in Canadian young adults, particularly in those of non-European ancestry; 2) vitamin D intakes, which were estimated to be on average higher than current Health Canada recommendations of 200 International Units (IU) per day, were inadequate to maintain optimal vitamin D levels year-round; 3) vitamin D levels undergo large seasonal changes. Winter 25(OH)D concentrations are substantially lower than those observed during the fall; 4) vitamin D intake is an important year-round predictor of 25(OH)D concentrations, but skin pigmentation and sun exposure are also important predictors during the times when UVB is adequate for cutaneous synthesis; and 5) vitamin D binding protein (VDBP) polymorphisms are significant predictors of 25(OH)D concentrations, but their effects vary by ancestry and season, indicating gene-environment interaction effects. My research shows that higher vitamin D intakes are needed to offset the seasonal drop in vitamin D levels and to ensure adequate vitamin D levels year-round for those at higher risk of insufficiency.

Vitamin D plays a critical role in bone metabolism and many cellular and immunological processes, and low vitamin D levels have been associated with several chronic and infectious diseases. Previous studies have reported that many otherwise healthy adults of European ancestry living in Canada have low vitamin D concentrations during the wintertime. However, individuals of non-European ancestry are at a higher risk of having low vitamin D levels. This thesis examined vitamin D status in a sample of young adults of diverse ancestry living in the Greater Toronto Area. In my research I found that: 1) vitamin D levels (measured as 25(OH)D concentrations) are low in Canadian young adults, particularly in those of non-European ancestry; 2) vitamin D intakes, which were estimated to be on average higher than current Health Canada recommendations of 200 International Units (IU) per day, were inadequate to maintain optimal vitamin D levels year-round; 3) vitamin D levels undergo large seasonal changes. Winter 25(OH)D concentrations are substantially lower than those observed during the fall; 4) vitamin D intake is an important year-round predictor of 25(OH)D concentrations, but skin pigmentation and sun exposure are also important predictors during the times when UVB is adequate for cutaneous synthesis; and 5) vitamin D binding protein (VDBP) polymorphisms are significant predictors of 25(OH)D concentrations, but their effects vary by ancestry and season, indicating gene-environment interaction effects. My research shows that higher vitamin D intakes are needed to offset the seasonal drop in vitamin D levels and to ensure adequate vitamin D levels year-round for those at higher risk of insufficiency.