Can ethanol affect the cell structure? A dynamic molecular and Raman spectroscopy study.

The role that tobacco consumption plays in the etiology of oral cancer carcinogenesis, and of alcohol consumption acting as a co-factor, have been well established. However, in recent years, the contribution of alcohol consumption alone to oral cancer has been proposed. In fact, a high percentage of patients who develop oral cancer have both habits (tobacco and alcohol consumption), and other small patient groups only consume alcohol or do not have any other identifiable bad habits. In the present study we demonstrate, using a combination of dynamic molecular modelling and Raman spectroscopy, that ethanol has a significant effect on oral cells in vitro, mainly interacting with the lipids of the cell membrane, changing their conformation. Thus, it is possible to conclude that ethanol can affect the cell permeability, and by consequence serve as a possible trigger in oral carcinogenesis.

In vivo Raman spectroscopic characteristics of different sites of the oral mucosa in healthy volunteers.

OBJECTIVES: Investigate the biochemistry of in vivo healthy oral tissues through Raman spectroscopy. We aimed to characterize the biochemical features of healthy condition in oral subsites (buccal mucosa, lip, tongue, and gingiva) of healthy subjects. More specifically, we investigated Raman spectral characteristics and biochemical content of in vivo healthy tissues on Brazilian population. This characterization can be used to better define normal tissue and improve the detection of oral premalignant conditions in future studies. MATERIALS AND METHODS: For spectroscopic analysis a Raman spectrometer (Kaiser Optical Systems imaging spectrograph Holospec, f / 1.8i-NIR) coupled with a laser 785 nm, 60 mW was used. Raman measurements were obtained by means of an optical fiber (EMVision fiber optic probe) coupled between the laser and the spectrometer. Three spectra per site were acquired from the lip, buccal mucosa, tongue, and gingiva of ten healthy volunteers. This resulted in 30 spectra per oral sub-site and in total 120 spectra. RESULTS: We report detailed biochemical information on these subsites and their relative composition based on deconvolution studies of their spectra. Finally, we also report classification efficiency of 61, 83, 41, and 93% for buccal, gingiva, lip, and tongue respectively after applying multivariate statistical tools. CONCLUSIONS: We quantitated the contribution of various biochemicals in terms of percentage, and this will enable comparison not only across anatomical sites but also across studies. Raman spectroscopy can rapidly probe tissue biochemistry of healthy oral regions. Moreover, the study suggests the possibility of using Raman spectroscopy combined with signal processing and multivariate analysis methods to differentiate the oral sites in healthy conditions and compare with pathological conditions in future studies. CLINICAL RELEVANCE: The spectral characterization of the healthy condition of oral tissues by a noninvasive, label-free, and real-time analytical techniques is important to create a spectral reference for future diagnosis of pathological conditions.

Position statement for the management of comorbidities in psoriasis.

BACKGROUND: The association between psoriasis and some diseases has become relevant in recent years. Providing appropriate management of psoriasis from an early stage requires prompt diagnosis and treatment of concomitant diseases and to prevent any potential comorbidity. This approach should consider the adverse events of the drugs used to treat psoriasis potentially related to the onset of comorbidities. OBJECTIVE: To provide the dermatologist with an accurate and friendly tool for systematizing the diagnosis of psoriasis-associated comorbidities, which generally escapes the scope of the dermatology setting, and to facilitate decision-making about the referral and treatment of patients with comorbidities. METHODS: These position statement recommendations were developed by a working group composed of ten experts (four dermatologists, one cardiologist, one rheumatologist, one gastroenterologist, one nephrologist, one endocrinologist and one psychiatrist) and two health services researchers. The expert group selected the psoriasis comorbidities considered according to their relevance in the dermatology setting. The recommendations on diagnostic criteria are based on the current clinical practice guidelines for each of the comorbidities. The information regarding the repercussion of psoriasis medical treatments on associated comorbid diseases was obtained from the summary of product characteristics of each drug. RESULTS: Recommendations were developed to detect and refer the following psoriasis comorbidities: psoriatic arthritis, cardiovascular risk factors (diabetes, dyslipidaemia, obesity, hypertension and metabolic syndrome), non-alcoholic fatty liver disease, inflammatory bowel disease, kidney disease and psychological disorders (anxiety and depression). In addition, alcohol consumption and tobacco consumption were included. The tables and figures are precise, easy-to-use tools to systematize the diagnosis of comorbidities in patients with psoriasis and facilitate the decision-making process regarding referral and treatment of patients with an associated disease. CONCLUSION: The application of these position statement recommendations will facilitate the dermatologist practice, and benefit psoriasis patients' health and quality of life.

Recommendations for the management of comorbidity in hidradenitis suppurativa.

BACKGROUND: The association between hidradenitis suppurativa (HS) and some diseases is becoming relevant in recent years. Providing appropriate management of HS from an early stage requires to include prompt diagnosis and treatment of concomitant diseases and to prevent any potential comorbidity. This approach should consider the adverse events of the drugs used to treat HS potentially related to the onset of a comorbidity. OBJECTIVE: To provide the dermatologist with an accurate, easily used tool that will inform the diagnosis of HS comorbidity, and to facilitate decision-making regarding the referral and treatment of patient with HS-associated comorbidity. METHODS: These recommendations have been developed by a working group composed of seven experts (three dermatologists, a cardiovascular specialist internist, a rheumatologist expert in spondyloarthritis, a gastroenterologist and a psychiatrist) and a team of three methodologist researchers. The expert group selected the HS comorbidities considered in these recommendations through a literature review. The recommendations on diagnostic criteria are based on the relevant clinical practice guidelines for each of the comorbidities and on the recommendations of the experts. The information regarding the repercussion of HS medical treatments on associated comorbid diseases was obtained from the summary of product characteristics of each drug. RESULTS: The comorbidities considered in this guide are as follows: cardiovascular risk factors (diabetes, dyslipidaemia, obesity, hypertension and metabolic syndrome), inflammatory bowel disease, inflammatory joint disorders and psychological disorders (anxiety and depression). In addition, the association between HS and the consumption of alcohol and tobacco is included. The tables and figures are a precise, easy-to-use tool to systematize the diagnosis of comorbidity in patients with HS and facilitate the decision-making process regarding referral and treatment of patients with an associated disease. CONCLUSION: The application of these recommendations will facilitate the dermatologist practice and benefit HS patients' health and quality of life.

Raman spectral post-processing for oral tissue discrimination - a step for an automatized diagnostic system.

Most oral injuries are diagnosed by histopathological analysis of a biopsy, which is an invasive procedure and does not give immediate results. On the other hand, Raman spectroscopy is a real time and minimally invasive analytical tool with potential for the diagnosis of diseases. The potential for diagnostics can be improved by data post-processing. Hence, this study aims to evaluate the performance of preprocessing steps and multivariate analysis methods for the classification of normal tissues and pathological oral lesion spectra. A total of 80 spectra acquired from normal and abnormal tissues using optical fiber Raman-based spectroscopy (OFRS) were subjected to PCA preprocessing in the z-scored data set, and the KNN (K-nearest neighbors), J48 (unpruned C4.5 decision tree), RBF (radial basis function), RF (random forest), and MLP (multilayer perceptron) classifiers at WEKA software (Waikato environment for knowledge analysis), after area normalization or maximum intensity normalization. Our results suggest the best classification was achieved by using maximum intensity normalization followed by MLP. Based on these results, software for automated analysis can be generated and validated using larger data sets. This would aid quick comprehension of spectroscopic data and easy diagnosis by medical practitioners in clinical settings.

Phenotypic and histologic characteristics of cutaneous melanoma in patients with melanocortin-1 receptor polymorphisms.

BACKGROUND: The melanocortin-1 receptor (MC1R) is an important risk factor for melanoma due to its role in the production of melanin in response to sun exposure. OBJECTIVES: To analyze the phenotypic and histologic characteristics of cutaneous melanoma in patients carrying mutations in MC1R and assess the influence of sun exposure on the occurrence of melanoma. MATERIAL AND METHODS: A total of 224 patients with a diagnosis of melanoma seen in the Department of Dermatology at Hospital General Universitario Gregorio Marañón in Madrid, Spain between September 2004 and December 2009 were included in the study. The genomic sequence of MC1R was analyzed by polymerase chain reaction. RESULTS: At least one of the following MC1R variants was present in 58% of the patients: V60L, V92M, I155T, R160W, D294H, and R163Q. Carriers of those variants had a history of sunburn (P=.018) and melanomas located on areas with intermittent sun exposure (P=.019), and the majority had a diagnosis of superficial spreading melanoma. These associations were especially significant in patients with the R160W and D294H variants. Carriers of R160W also had melanomas associated with melanocytic nevi (P=.028). CONCLUSIONS: The results of our study suggest that there may be a relationship between the expression of certain MC1R variants and sun exposure, history of sunburn, and skin type. They also indicate a higher frequency of superficial spreading melanomas and melanomas associated with melanocytic nevi in patients carrying certain mutations in MC1R.

Role of glutathione S-transferases in melanoma susceptibility: association with GSTP1 rs1695 polymorphism.

BACKGROUND: Glutathione S-transferases (GSTs) GSTM1, GSTT1 and GSTP1 are multifunctional enzymes involved in the detoxification of a wide range of reactive oxygen species produced during melanin synthesis and oxidative stress processes. OBJECTIVES: Single nucleotide polymorphisms (SNPs) in GSTP1 and copy number variants in GSTM1 and GSTT1 may be candidate low-penetrance variants with a role in susceptibility to malignant melanoma (MM). METHODS: In this case-control study, 562 Spanish patients with sporadic MM and 338 cancer-free control subjects were included, and the role of polymorphisms in these GST genes was investigated. Genotypes were established by quantitative real-time polymerase chain reaction for GSTM1 and GSTT1 while TaqMan probes were used to genotype GSTP1 SNPs. RESULTS: The GSTP1 polymorphism rs1695, which encodes the amino acid change p.Ile105Val, was individually associated with MM [odds ratio (OR): 1·32, 95% confidence interval (CI): 1·06-1·63]. Furthermore, individuals carrying one or two MC1R nonsynonymous changes and GSTP1 rs1695 rare allele had an increased risk of developing MM (OR: 3·34, 95% CI: 1·42-8·09 and OR: 20·42, 95% CI: 2·80-417·42, respectively). CONCLUSIONS: This is the first time that the GSTP1 rs1695 polymorphism is reported to be associated with MM. In addition, this study is one of the largest GST polymorphism studies undertaken in the Spanish population and the first time that copy number variants have been scrutinized in relation to MM.

Cost-efficacy of adalimumab, etanercept, infliximab and ustekinumab for moderate-to-severe plaque psoriasis.

BACKGROUND: Different biological agents are used for the treatment of psoriasis. Previous data have shown adalimumab to be the most efficient drug in terms of cost-efficacy. However, newer data are required to include recent drugs. OBJECTIVE: To estimate the cost-efficacy ratios of biological agents licensed in Spain (adalimumab, etanercept, infliximab and ustekinumab) for the treatment of patients with moderate-to-severe psoriasis. METHODS: An economic evaluation model was developed by building a decision tree for each drug regimen for which scientific evidence was available. The payer perspective (Spanish National Health System) was considered, taking into account only the drug costs. Data on efficacy [proportion of patients with a 75% reduction in the Psoriasis Area and Severity Index score (PASI 75)] reported in the randomized controlled trials were used. When more than one trial for each treatment had been published, a meta-analysis was performed. In case of weight-dependent doses (infliximab), weight of the study subjects was standardized by age and gender of the Spanish population, corrected for the increase in weight in subjects with psoriasis. Uncertainty was assessed by sensitivity analysis. RESULTS: Incremental efficacy ranged from 31.19% (etanercept at a dosage of 25 mg twice a week for 12 weeks) to 78.35% (infliximab at 5 mg/kg for 24 weeks). Efficiency, in terms of incremental cost-efficacy, ranged from 8013€ (adalimumab) to 17 981€ (ustekinumab at a dose of 90 mg) per PASI 75 responder gained. CONCLUSION: In terms of cost-efficacy, the most efficient biological drug was adalimumab. The robustness of this finding was confirmed by sensitivity analysis.

[Phenotypic and histologic characteristics of cutaneous melanoma in patients with melanocortin-1 receptor polymorphisms]. / Características fenotípicas e histológicas de los pacientes con melanoma cutáneo en función de los polimorfismos del MC1R.

BACKGROUND: The melanocortin-1 receptor (MC1R) is an important risk factor for melanoma due to its role in the production of melanin in response to sun exposure. OBJECTIVES: To analyze the phenotypic and histologic characteristics of cutaneous melanoma in patients carrying mutations in MC1R and assess the influence of sun exposure on the occurrence of melanoma. MATERIAL AND METHODS: A total of 224 patients with a diagnosis of melanoma seen in the Department of Dermatology at Hospital General Universitario Gregorio Marañón in Madrid, Spain between September 2004 and December 2009 were included in the study. The genomic sequence of MC1R was analyzed by polymerase chain reaction. RESULTS: At least one of the following MC1R variants was present in 58% of the patients: V60L, V92M, I155T, R160W, D294H, and R163Q. Carriers of those variants had a history of sunburn (P=.018) and melanomas located on areas with intermittent sun exposure (P=.019), and the majority had a diagnosis of superficial spreading melanoma. These associations were especially significant in patients with the R160W and D294H variants. Carriers of R160W also had melanomas associated with melanocytic nevi (P=.028). CONCLUSIONS: The results of our study suggest that there may be a relationship between the expression of certain MC1R variants and sun exposure, history of sunburn, and skin type. They also indicate a higher frequency of superficial spreading melanomas and melanomas associated with melanocytic nevi in patients carrying certain mutations in MC1R.

[Diagnostic utility of dermoscopy in pigmented actinic keratosis]. / Utilidad de la dermatoscopia en el diagnóstico de las queratosis actínicas pigmentadas.

The diagnosis of pigmented actinic keratosis can be complicated in clinical practice. The differential diagnosis with lentigo maligna melanoma can be difficult due to common clinical and dermoscopic characteristics. We present 5 cases of pigmented actinic keratosis in 4 patients. The most common dermoscopic finding was a grayish-brown granulation with a perifollicular distribution, present in all lesions, followed by rhomboidal structures in 4 cases, and an annular-granular pattern in 3. In no case were asymmetrical pigmented follicular openings observed. We draw attention to key findings that aid preoperative diagnosis of pigmented actinic keratosis.

Paediatric psoriasis--narrowband UVB treatment.

UNLABELLED: Narrowband UV-B is a safe and efficacious option for the treatment of adult psoriasis. However, the use of this therapy has been limited in children due to its long-term carcinogenic potential. It has proven to be an adequate alternative in patients whose condition is refractory to topical treatment. AIMS: To evaluate the efficacy and short-term safety of narrowband UV-B in the treatment of paediatric psoriasis, and to compare our results with those obtained in other studies on paediatric psoriasis. MATERIALS AND METHODS: Over a period of 2 years and 4 months, we administered narrowband UV-B to 20 children diagnosed with psoriasis that was refractory to topical therapy. The therapeutic response was measured using the Psoriasis Area and Severity Index (PASI). RESULTS: Between August 2005 and December 2007, 20 children received narrowband UV-B. Their median age was 13 years (range, 5-17 years), and the median initial PASI score was 8.25 (2.7-22.2). A median of 28 (10-59) sessions was required to achieve clearance, reaching almost complete or total remission (median final PASI) in all but two patients. Six patients required a new therapeutic course because of relapse, and the mean duration of remission was 8 months (4-18). No patients experienced severe adverse events during therapy, and only one discontinued treatment, for unrelated reasons. DISCUSSION AND CONCLUSION: Narrowband UV-B for the treatment of paediatric psoriasis has received little attention in the literature. This treatment has been limited in children because of its potential long-term carcinogenic effects, and most information has been extrapolated from adults. Nevertheless, narrowband UV-B phototherapy is an effective and well-tolerated therapeutic alternative in paediatric patients with severe psoriasis.

[Efficiency of biologic agents in the treatment of moderate to severe psoriasis]. / Eficiencia de los agentes biológicos en el tratamiento de la psoriasis moderada-grave.

BACKGROUND: In the treatment of psoriasis, biologic agents are more expensive than conventional therapy while showing similar or superior efficacy. However, their efficiency in terms of cost/efficacy (cost per responder in clinical trial conditions) is unknown. OBJECTIVE. To estimate the cost/efficacy ratios of adalimumab, etanercept, infliximab, and efalizumab in the management of moderate to severe psoriasis. MATERIAL AND METHODS: A model for the costs analysis was elaborated by building a decision tree for each of the treatments for which scientific evidence was available. The payer perspective (Spanish national health system) was used, only considering drug costs.The efficacy (proportion of patients who respond according to Psoriasis Area Severity Index [PASI] 75 criterion) was assigned according to the results of the clinical trials. When more than 1 trial was available per treatment, a meta-analysis was undertaken. In the case of weight-dependent dosing, the weight of the study participants was adjusted by age and sex to the standard Spanish population with correction for increased weight in individuals with psoriasis. Uncertainty was investigated with a sensitivity analysis. RESULTS AND CONCLUSIONS: Assigning the efficacy reported in the 15 published clinical trials, the most efficient biologic agent in terms of the cost/efficacy ratio was adalimumab, with one PASI 75 response at a cost of 8,013 Euro. For the remaining biologic agents and with different regimens, the cost per responder ranged from 9,370 Euro to 17,112 Euro. The sensitivity analysis confirmed the robustness of these figures.

SLC45A2: a novel malignant melanoma-associated gene.

Human pigmentation appears to be one of the strongest risk factors for malignant melanoma (MM). In humans, there is a long list of genes known to be involved in rare pigmentary disorders such as albinism. These genes explain most of the variation in pigmentation phenotypes seen in human populations, and they do this by regulating the level of synthesis, chemical composition, packaging, and distribution of melanin. This Spanish case-control study included 131 consecutive melanoma patients and 245 control subjects frequency-matched for sex and age. A total of 23 SNPs in six candidate genes (ASP, OCA2, TYR, TYRP1, SILV, and SLC45A) belonging to the pigmentation pathway were genotyped. We found that the variant allele of c.1122C>G, p.Phe374Leu (NCBI dbSNP rs16891982) in SLC45A2 (membrane associated transporter previously known as MATP) was associated with protection from MM (OR, 0.41; 95% CI, 0.24-0.70; P=0.008 after adjustment for multiple testing). This association was validated by the consistent link observed with dark hair, dark skin, dark eye color, and the presence of solar lentigins and childhood sunburns. This is the first time SLC45A2 has been described as a melanoma susceptibility gene in a light-skinned population.

MC1R: three novel variants identified in a malignant melanoma association study in the Spanish population.

The human melanocortin-1 receptor (MC1R) gene, which plays a crucial role in pigmentation, also appears to be important in malignant melanoma (MM). This case-control study in the Spanish population included 116 consecutive MM patients and 188 controls frequency matched for sex and age. Sequence analysis of the entire coding region of MC1R was performed, identifying 21 variants, all of them previously reported except for three novel non-synonymous changes: Ser41Phe, Met128Thr and Asn281Ser. Simulated structural analyses suggested disruption of the local structure around Phenylalanine 41, possible destabilization of the hydrophobic interior of the molecule in Threonine 128 and that Asparagine 281 could be in a region of functional importance. The fact that these three novel variants were not present in 1,000 healthy individuals tested adds further weight to them having putative adverse effects on the functional protein. Six variants, all non-synonymous changes, were individually associated with MM risk (Arg160Trp, Asp294His, Val60Leu, Val92Met, Ile155Thr and Arg163Gln). Carrying two non-synonymous variants was associated with much higher risk of MM (odds ratio: 10.44, 95% confidence interval = 4.48-24.33, P = 5 x 10(-8)) and haplotype analysis, verified by cloning, confirmed that this is predominantly due to carrying each on a different chromosome. Our results suggest that both red hair colour (RHC) and non-red hair colour variants, and possibly other rare non-synonymous variants, in MC1R are implicated in the development of MM. In addition to carrying MC1R variant alleles, having blond/red hair and childhood sunburns were independent risk factors for MM.

[Erythrodermic lichen planus pemphigoides]. / Liquen plano penfigoide eritrodérmico.

Lichen planus pemphigoides is a clinico-histological subtype of lichen planus in which there are bullous lesions similar to those of bullous pemphigoid. Lichen planus is included among the rare causes of erythroderma. We present a case of erythrodermic lichen planus pemphigoides in a 49-year-old female patient who satisfactorily responded to treatment with cyclosporine. A detailed physical examination and immunofluorescence study are key to the diagnosis of lichen planus pemphigoides.

Burow's grafts in the facial region.

BACKGROUND: Full-thickness skin grafts are an important tissue source for reconstructive surgery. Burow's grafts are full-thickness skin grafts that use adjacent lax skin as the donor site. This technique has also been referred to as island grafts, dog-ear grafts or adjacent-tissue skin grafts. OBJECTIVE: The objective was to describe the technique of Burow's grafts for reconstruction of facial defects taking account of its benefits and limitations. METHODS: The operative technique is simple: after a circular excision of the cutaneous lesion, we enlarged the excision line (towards one or both sides of the defect) following the relaxed tension lines. We created a secondary triangular defect by excising skin that is then used for the graft (as donor site). After adequate undermining, we proceeded to direct linear closure of this secondary defect. Finally, the graft was placed and sutured in the remaining defect. RESULTS: The proximity of the donor site provides an excellent tissue match because colour, hair density, texture, sebaceous features and thickness are similar to the recipient site. A good cosmetic result is therefore ensured. CONCLUSION: Burow's grafts can be a good choice for reconstruction of extensive facial surgical defects because of aesthetic results. In addition, it is a simple technique that can be performed in one sole surgical act, with local anaesthesia and without changing the operative site.

[Epidemiology and survival of cutaneous melanoma in Spain: a report of 552 cases (1994-2003)]. / Epidemiología y supervivencia del melanoma cutáneo en España: estudio de 552 casos (1994-2003).

Studies on epidemiology and survival of patients diagnosed of cutaneous melanoma in our country are few. We described epidemiological, clinical, histopathologic and survival characteristics of patients diagnosed of cutaneous melanoma at Hospital Gregorio Marañón of Madrid during ten years (1994-2003). The incidence of melanoma has doubled in the last decade. An important proportion of melanomas continues to be diagnosed in advanced stages (III-IV; 14.5%). The following factors were associated with a poor global survival: Tumor thickness, ulceration, nodular type, masculine gender and age older than 65.

[Tetracaine-induced systemic contact-type dermatitis]. / Dermatitis sistémica de contacto por tetracaínas.

We report the case of a 71-year-old-man with dermatitis in the groin area. Forty-eight hours previously, he had undergone transurethral resection for benign prostatic hyperplasia. During the prostatectomy, the probe was lubricated with a urological ointment containing the topical anesthetic, tetracaine. The patient had previously experienced severe pruritus and fissures in the perianal area after using antihemorrhoidal ointments. Biopsy and patch testing with the standard series and lubricant ointment showed positive reactions to this lubricant, called "urological lubricant" (UL) (+ + +) with caine mix (+ + +). The patient was diagnosed with systemic contact-type dermatitis due to caine mix. The dermatitis improved with topical steroids and oral antihistamine agents.