Common genetic variants associated with melanoma risk or naevus count in patients with wildtype MC1R melanoma.

BACKGROUND: Hypomorphic MC1R variants are the most prevalent genetic determinants of melanoma risk in the white population. However, the genetic background of patients with wildtype (WT) MC1R melanoma is poorly studied. OBJECTIVES: To analyse the role of candidate common genetic variants on the melanoma risk and naevus count in Spanish patients with WT MC1R melanoma. METHODS: We examined 753 individuals with WT MC1R from Spain (497 patients and 256 controls). We used OpenArray reverse-transcriptase polymerase chain reaction to genotype a panel of 221 common genetic variants involved in melanoma, naevogenesis, hormonal pathways and proinflammatory pathways. Genetic models were tested using multivariate logistic regression models. Nonparametric multifactor dimensionality reduction (MDR) was used to detect gene-gene interactions within each biological subgroup of variants. RESULTS: We found that variant rs12913832 in the HERC2 gene, which is associated with blue eye colour, increased melanoma risk in individuals with WT MC1R [odds ratio (OR) 1·97, 95% confidence interval (CI) 1·48-2·63; adjusted P < 0·001; corrected P < 0·001]. We also observed a trend between the rs3798577 variant in the oestrogen receptor alpha gene (ESR1) and a lower naevus count, which was restricted to female patients with WT MC1R (OR 0·51, 95% CI 0·33-0·79; adjusted P = 0·002; corrected P = 0·11). This sex-dependent association was statistically significant in a larger cohort of patients with melanoma regardless of their MC1R status (n = 1497; OR 0·71, 95% CI 0·57-0·88; adjusted P = 0·002), reinforcing the hypothesis of an association between hormonal pathways and susceptibility to melanocytic proliferation. Last, the MDR analysis revealed four genetic combinations associated with melanoma risk or naevus count in patients with WT MC1R. CONCLUSIONS: Our data suggest that epistatic interaction among common variants related to melanocyte biology or proinflammatory pathways might influence melanocytic proliferation in individuals with WT MC1R. What is already known about this topic? Genetic variants in the MC1R gene are the most prevalent melanoma genetic risk factor in the white population. Still, 20-40% of cases of melanoma occur in individuals with wildtype MC1R. Multiple genetic variants have a pleiotropic effect in melanoma and naevogenesis. Additional variants in unexplored pathways might also have a role in melanocytic proliferation in these patients. Epidemiological evidence suggests an association of melanocytic proliferation with hormonal pathways and proinflammatory pathways. What does this study add? Variant rs12913832 in the HERC2 gene, which is associated with blue eye colour, increases the melanoma risk in individuals with wildtype MC1R. Variant rs3798577 in the oestrogen receptor gene is associated with naevus count regardless of the MC1R status in female patients with melanoma. We report epistatic interactions among common genetic variants with a role in modulating the risk of melanoma or the number of naevi in individuals with wildtype MC1R. What is the translational message? We report a potential role of hormonal signalling pathways in melanocytic proliferation, providing a basis for better understanding of sex-based differences observed at the epidemiological level. We show that gene-gene interactions among common genetic variants might be responsible for an increased risk for melanoma development in individuals with a low-risk phenotype, such as darkly pigmented hair and skin.

Sutton Naevi as Melanoma Simulators: Can Confocal Microscopy Help in the Diagnosis?

Sutton naevi can sometimes present a challenging appearance with atypical presentation, also by dermoscopy. Reflectance confocal microscopy could help in making a diagnosis. This study prospectively collected two groups of Sutton nevi: the first one was composed by typical white halo naevi monitored for one year (13, 23%) and the second one was made up of atypical lesions excised in order to rule out melanoma, which were histologically diagnosed as Sutton naevi (21, 37%). These two groups of Sutton naevi were compared to a retrospectively collected cohort of thin melanomas with histologic regression features (23, 40%). On dermoscopy, atypical Sutton naevi and melanomas were indistinguishable. Reflectance confocal microscopy demonstrated significant differences at the dermo-epidermal junction: marked dermo-epidermal junction thickening and non-edged papilla were associated with melanoma, while the presence of nests was associated with Sutton naevi. However, reflectance confocal microscopy also detected marked intraepidermal pagetoid cells in Sutton naevi that were a combination of MelanA+ and CD1a+ cells. Sutton naevi can simulate melanoma, under both dermoscopy and reflectance confocal microscopy. Nevertheless, relevant confocal dermo-epidermal junction features and the clinical scenario can be helpful to make a final diagnosis, especially in those situations where melanoma must be ruled out.

Processing Diabetes Mellitus Composite Events in MAGPIE.

The focus of this research is in the definition of programmable expert Personal Health Systems (PHS) to monitor patients affected by chronic diseases using agent oriented programming and mobile computing to represent the interactions happening amongst the components of the system. The paper also discusses issues of knowledge representation within the medical domain when dealing with temporal patterns concerning the physiological values of the patient. In the presented agent based PHS the doctors can personalize for each patient monitoring rules that can be defined in a graphical way. Furthermore, to achieve better scalability, the computations for monitoring the patients are distributed among their devices rather than being performed in a centralized server. The system is evaluated using data of 21 diabetic patients to detect temporal patterns according to a set of monitoring rules defined. The system's scalability is evaluated by comparing it with a centralized approach. The evaluation concerning the detection of temporal patterns highlights the system's ability to monitor chronic patients affected by diabetes. Regarding the scalability, the results show the fact that an approach exploiting the use of mobile computing is more scalable than a centralized approach. Therefore, more likely to satisfy the needs of next generation PHSs. PHSs are becoming an adopted technology to deal with the surge of patients affected by chronic illnesses. This paper discusses architectural choices to make an agent based PHS more scalable by using a distributed mobile computing approach. It also discusses how to model the medical knowledge in the PHS in such a way that it is modifiable at run time. The evaluation highlights the necessity of distributing the reasoning to the mobile part of the system and that modifiable rules are able to deal with the change in lifestyle of the patients affected by chronic illnesses.

Indexing the Event Calculus: Towards practical human-readable Personal Health Systems.

Personal Health Systems (PHS) are mobile solutions tailored to monitoring patients affected by chronic non communicable diseases. In general, a patient affected by a chronic disease can generate large amounts of events: for example, in Type 1 Diabetic patients generate several glucose events per day, ranging from at least 6 events per day (under normal monitoring) to 288 per day when wearing a continuous glucose monitor (CGM) that samples the blood every 5 minutes for several days. Just by itself, without considering other physiological parameters, it would be impossible for medical doctors to individually and accurately follow every patient, highlighting the need of simple approaches towards querying physiological time series. Achieving this with current technology is not an easy task, as on one hand it cannot be expected that medical doctors have the technical knowledge to query databases and on the other hand these time series include thousands of events, which requires to re-think the way data is indexed. Anyhow, handling data streams efficiently is not enough. Domain experts' knowledge must be explicitly included into PHSs in a way that it can be easily readed and modified by medical staffs. Logic programming represents the perfect programming paradygm to accomplish this task. In this work, an Event Calculus-based reasoning framework to standardize and express domain-knowledge in the form of monitoring rules is suggested, and applied to three different use cases. However, if online monitoring has to be achieved, the reasoning performance must improve dramatically. For this reason, three promising mechanisms to index the Event Calculus Knowledge Base are proposed. All of them are based on different types of tree indexing structures: k-d trees, interval trees and red-black trees. The paper then compares and analyzes the performance of the three indexing techniques, by computing the time needed to check different type of rules (and eventually generating alerts), when the number of recorded events (e.g. values of physiological parameters) increases. The results show that customized jREC performs much better when the event average inter-arrival time is little compared to the checked rule time-window. Instead, where the events are more sparse, the use of k-d trees with standard EC is advisable. Finally, the Multi-Agent paradigm helps to wrap the various components of the system: the reasoning engines represent the agent minds, and the sensors are its body. The said agents have been developed in MAGPIE, a mobile event based Java agent platform.

Scanning Electron Microscopy and X-ray Microanalysis of Reconstructive Hair Fibers.

BACKGROUND: Reconstructive hair fibers are an innovative tool in cosmetic dermatology based on electrostatic adherent powder which bonds to the hair shaft and can disguise hair loss in men and women. AIM: This study aims to analyze and compare five different brands of organic hair fibers. MATERIALS AND METHODS: A scanning electron microscope (SEM) was used to obtain amplified images of samples to study their shape and morphological structure. X-ray microanalysis was performed to study the chemical composition of reconstructive hair fibers. The five samples were tested in patients attending a trichology unit of a tertiary hospital. RESULTS: The main component in hair fibers products 1 (Blum Secret™) and 3 (Keratin™) was cotton (cellulose of vegetal origin), while product 2 (Viviscal™) was made of a vegetal keratin. All three samples appeared as parallel-arranged fibres on the scanning electron microscope. The X-ray microanalysis showed an organic polymer mainly composed of C, O, and Si. Hair fibers 4 (Toppik™) and 5 (Nanogen™) were similar. Sample 4 derived from a keratin organic fiber and sample 5 from pure, positively charged keratin. In both cases, SEM revealed microfibers covered by a fine squamous. The X-ray microanalysis in both cases revealed a high presence of S. CONCLUSION: There was no discrepancy among the cosmetic results of the five samples, providing a successful esthetic effect in all of our patients despite the chemical differences found in the X-ray microanalysis.