Despite many efforts, regulation of skin and hair pigmentation is still not fully understood. This article focuses mainly on controversial aspects in pigment cell biology which have emerged over the last decade. The central role of tyrosinase as the key enzyme in initiation of melanogenesis has been closely associated with the 6BH 4 dependent phenylalanine hydroxylase (PAH) and tyrosine hydroxylase isoform I (THI) providing evidence for an old concept of the three enzyme theory in the initiation of the pigmentation process. In this context, it is noteworthy that intracellular L-phenylalanine uptake and turnover to L-tyrosine via PAH is vital for substrate supply of THI and tyrosinase. While PAH acts in the cytosol of melanocytes, THI and tyrosinase are sitting side by side in the melanosomal membrane. THI at low pH provides L-3,4-hydroxyphenylalanine L-DOPA which in turn is required for activation of met-tyrosinase. After an intramelanosomal pH change, possibly by the p-protein, has taken place, tyrosinase is subject to control by 6 ⁄ 7BH 4 and the proopiomelanocortin (POMC) peptides a-MSH melanocyte stimulating hormone and b-MSH in a receptor independent manner. cAMP is required for the activation of microphthalmia-associated transcription factor to induce expression of tyrosinase, for transcription of THI and for activation of PAH. The redundancy of the cAMP signal is discussed. Finally, we propose a novel mechanism involving H 2 O 2 in the regulation of tyrosinase via p53 through transcription of hepatocyte nuclear factor 1a which in turn can also affect the POMC response.

ObjectivesWith the objective of bringing clinical decision support systems to reality, this article reviews histopathological whole-slide imaging informatics methods, associated challenges, and future research opportunities.Target audienceThis review targets pathologists and informaticians who have a limited understanding of the key aspects of whole-slide image (WSI) analysis and/or a limited knowledge of state-of-the-art technologies and analysis methods.ScopeFirst, we discuss the importance of imaging informatics in pathology and highlight the challenges posed by histopathological WSI. Next, we provide a thorough review of current methods for: quality control of histopathological images; feature extraction that captures image properties at the pixel, object, and semantic levels; predictive modeling that utilizes image features for diagnostic or prognostic applications; and data and information visualization that explores WSI for de novo discovery. In addition, we highlight future research directions and discuss the impact of large public repositories of histopathological data, such as the Cancer Genome Atlas, on the field of pathology informatics. Following the review, we present a case study to illustrate a clinical decision support system that begins with quality control and ends with predictive modeling for several cancer endpoints. Currently, state-of-the-art software tools only provide limited image processing capabilities instead of complete data analysis for clinical decision-making. We aim to inspire researchers to conduct more research in pathology imaging informatics so that clinical decision support can become a reality.

The present study was designed to evaluate the role of fluoride in urolithiasis in humans. Two areas were selected for this purpose, a fluoride endemic area (EA) and a fluoride non-endemic area (NEA). The prevalence of uroliathiasis was 4.6 times higher in EA than in NEA. Furthermore, the prevalence was almost double in subjects with fluorosis than without fluorosis in the endemic area. No relationship was observed between urolithiasis and the duration of fluorosis. The fluoride levels in drinking water ranged from 3.5 to 4.9 ppm in EA and subjects from this area excreted more fluoride. A comparison of normal subjects (NS) from EA and NEA revealed that endemic subjects tend to have slightly higher mean serum thiobarbituric acid reactive substance (TBAR) levels and excrete more oxalate and fluoride than their non-endemic counterparts. The urinary stone formers (SF) from the two areas showed a similar tendency, though again the difference was not significant. Citrate excretion in SF was almost normal in the EA, but NEA SF had significantly lower excretion levels. Urinary stones from endemic patients had higher fluoride, oxalate and calcium levels than those from non-endemic patients. In vitro studies suggested that fluoride did not influence the heterogonous mineralization of calcium oxalate. In conclusion, the data suggest that fluoride in vivo may behave as a mild promoter of urinary stone formation by (a) excretion of insoluble calcium fluoride, (b) increasing oxalate excretion and (c) mildly increasing the oxidative burden.

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This paper presents a novel, fast and semi-automatic method for accurate cell cluster segmentation and cell counting of digital tissue image samples. In pathological conditions, complex cell clusters are a prominent feature in tissue samples. Segmentation of these clusters is a major challenge for development of an accurate cell counting methodology. We address the issue of cluster segmentation by following a three step process. The first step involves pre-processing required to obtain the appropriate nuclei cluster boundary image from the RGB tissue samples. The second step involves concavity detection at the edge of a cluster to find the points of overlap between two nuclei. The third step involves segmentation at these concavities by using an ellipse-fitting technique. Once the clusters are segmented, individual nuclei are counted to give the cell count. The method was tested on four different types of cancerous tissue samples and shows promising results with a low percentage error, high true positive rate and low false discovery rate.