Association of Glycoprotein IIIa PlA1/A2 Polymorphism with Risk of Stroke: Updated Meta-Analysis.

Cardiovascular diseases are the main cause of death in the world, with ischemic heart disease (i.e., myocardial infarction) and cerebrovascular disease (i.e., stroke) taking the highest toll. Advances in diagnosis and treatment have led to a significant alleviation of ischemic complications, specifically in the realm of pharmacotherapy and interventional devices, while pharmacogenomics has yet to be fully leveraged to improve the burden of disease. Atherothrombotic events might occur earlier or respond worse to treatment in patients with genetic variants of GP IIb/IIIa. Therefore, we aimed to quantitate the involvement of the PlA2 variant in the risk of cerebral stroke events. A systematic search and meta-analysis were performed by pooling the risks of individual studies. A total of 31 studies comprising 5985 stroke patients and 7886 controls were analyzed. A meta-analysis of four studies on hemorrhagic stroke patients showed no association with the PIA2 rs5918(C) polymorphism in both fixed-effect (OR = 0.90 95%CI [0.71; 1.14]; p = 0.398) and random-effect models (OR = 0.86 95%CI [0.62; 1.20]; p-value = 0.386). The power of this analysis was below <30%, indicating a limited ability to detect a true effect. An analysis of the 28 studies on ischemic stroke revealed a significant association with the PIA2 rs5918(C) allele in both fixed-effect (OR = 1.16 95%CI [1.06; 1.27]; p = 0.001) and random-effect models (OR = 1.20 95%CI [1.04; 1.38]; p-value = 0.012), with a power of >80%. The PIA2 allele was associated with an increased risk of ischemic stroke. No association was found with hemorrhagic stroke, most likely due to the small number of available studies, which resulted in a lack of power.

Celecoxib as a Valuable Adjuvant in Cutaneous Melanoma Treated with Trametinib.

BACKGROUND: Melanoma patients stop responding to targeted therapies mainly due to mitogen activated protein kinase (MAPK) pathway re-activation, phosphoinositide 3 kinase/the mechanistic target of rapamycin (PI3K/mTOR) pathway activation or stromal cell influence. The future of melanoma treatment lies in combinational approaches. To address this, our in vitro study evaluated if lower concentrations of Celecoxib (IC50 in nM range) could still preserve the chemopreventive effect on melanoma cells treated with trametinib. MATERIALS AND METHODS: All experiments were conducted on SK-MEL-28 human melanoma cells and BJ human fibroblasts, used as co-culture. Co-culture cells were subjected to a celecoxib and trametinib drug combination for 72 h. We focused on the evaluation of cell death mechanisms, melanogenesis, angiogenesis, inflammation and resistance pathways. RESULTS: Low-dose celecoxib significantly enhanced the melanoma response to trametinib. The therapeutic combination reduced nuclear transcription factor (NF)-kB (p < 0.0001) and caspase-8/caspase-3 activation (p < 0.0001), inhibited microphthalmia transcription factor (MITF) and tyrosinase (p < 0.05) expression and strongly down-regulated the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) signaling pathway more significantly than the control or trametinib group (p < 0.0001). CONCLUSION: Low concentrations of celecoxib (IC50 in nM range) sufficed to exert antineoplastic capabilities and enhanced the therapeutic response of metastatic melanoma treated with trametinib.

Butterfly effect and acne-The role of diet.

The authors aim to present the butterfly effect, a concept based on the theory that small changes might have a powerful effect, as an example of the important connection between diet and acne. Western diet is currently a well-known environmental factor which, mainly via the overstimulation of mTORC1 (mammalian target of rapamycin complex 1), is responsible for the development and aggravation of acne and other age-related diseases of civilization. From the authors' point of view, "the butterfly effect" extrapolated to acne and diet depicts the importance of dietary interventions in acne so as to prevent more serious mTORC1-driven diseases of civilization like obesity, diabetes, and cancer.

Tumour Microenvironment in Skin Carcinogenesis.

Tumour microenvironment is a complex system comprising cells and molecules that will provide the necessary conditions for tumour development and progression. Cells residing in the tumour microenvironment gain specific phenotypes and specific functions that are pro-tumorigenic. Tumour progression is in fact a combination between tumour cell characteristics and its interplay with tumour microenvironment. This dynamic network will allow tumour cells to grow, migrate and invade tissues. In the present chapter, we are highlighting some traits that characterise tumour microenvironment in basal cell carcinoma, squamous cell carcinoma and cutaneous melanoma. In skin cancers, there are some common tumour microenvironment characteristics such as the presence of tumour-associated macrophages and regulatory T lymphocytes that are non-tumour cells promoting tumorigenesis. There are also skin cancer type differences in terms of tumour microenvironment characteristics. Thus, markers such as macrophage migration inhibitory factor in melanoma or the extraordinary diverse genetic make-up in the cancer-associated fibroblasts associated to squamous cell carcinoma are just a few of specific traits in skin cancer types. New technological advances for evaluation of tumour environment are presented. Thus, non-invasive skin imaging techniques such as reflectance confocal microscopy can evaluate skin tumour inflammatory infiltrates for density and cellular populations. Analysing tumour micromedium in depth may offer new insights into cancer therapy and identify new therapy targets.

Influence of mitochondrial and systemic iron levels in heart failure pathology.

Iron deficiency or overload poses an increasingly complex issue in cardiovascular disease, especially heart failure. The potential benefits and side effects of iron supplementation are still a matter of concern, even though current guidelines suggest therapeutic management of iron deficiency. In this review, we sought to examine the iron metabolism and to identify the rationale behind iron supplementation and iron chelation. Cardiovascular disease is increasingly linked with iron dysmetabolism, with an increased proportion of heart failure patients being affected by decreased plasma iron levels and in turn, by the decreased quality of life. Multiple studies have concluded on a benefit of iron administration, even if just for symptomatic relief. However, new studies field evidence for negative effects of dysregulated non-bound iron and its reactive oxygen species production, with concern to heart diseases. The molecular targets of iron usage, such as the mitochondria, are prone to deleterious effects of the polyvalent metal, added by the scarcely described processes of iron elimination. Iron supplementation and iron chelation show promise of therapeutic benefit in heart failure, with the extent and mechanisms of both prospects not being entirely understood. It may be that a state of decreased systemic and increased mitochondrial iron levels proves to be a useful frame for future advancements in understanding the interconnection of heart failure and iron metabolism.

Mediators of Inflammation in Topical Therapy of Skin Cancers.

Taking into consideration that the immune system plays a very important role in the development of melanoma and non-melanoma skin cancers, which have a high prevalence in immunosuppressed patients and after prolonged ultraviolet radiation, the interest in developing novel therapies, in particular targeting the inflammation in cancer, has increased in the past years. The latest data suggest that therapies such as imiquimod (IMQ), ingenol mebutate (IM), 5-fluorouracil (5-FU), retinoids, and nonsteroidal anti-inflammatory drugs (NSAIDs) have been used with success in the topical treatment of some cancers. Herein, we review the topical treatment targeting the inflammation in skin cancer and the mechanisms involved in these processes. Currently, various associations have shown a superior success rate than monotherapy, such as systemic acitretin and topical IMQ, topical 5-FU with tretinoin cream, or IMQ with checkpoint inhibitor cytotoxic T lymphocyte antigen 4. Novel therapies targeting Toll-like receptor-7 (TLR-7) with higher selectivity than IMQ are also of great interest.

Digitally Enhanced Methods for the Diagnosis and Monitoring of Treatment Responses in Actinic Keratoses: A New Avenue in Personalized Skin Care.

Non-melanocytic skin cancers represent an important public health problem due to the increasing incidence and the important local destructive potential. Thus, the early diagnosis and treatment of precancerous lesions (actinic keratoses) is a priority for the dermatologist. In recent years, non-invasive skin imaging methods have seen an important development, moving from simple observational methods used in clinical research, to true diagnostic and treatment methods that make the dermatologist's life easier. Given the frequency of these precancerous lesions, their location on photo-exposed areas, as well as the long treatment periods, with variable, imprecise end-points, the need to use non-invasive imaging devices is increasingly evident to complete the clinical observations in the diagnosis and treatment of these lesions, with the aim of increasing accuracy and decreasing the adverse effects due to long treatment duration. This is the first review that brings together all skin imaging methods (dermoscopy, reflectance confocal microscopy, ultrasonography, dermoscopy-guided high frequency ultrasonography, and optical coherence tomography) used in the evaluation of actinic keratoses and their response to different treatment regimens.

The Importance of In Vivo Reflectance Confocal Microscopy in a Case of Desmoplastic Melanoma.

Desmoplastic melanoma accounts for 5% of all cases of melanoma, but its diagnosis can be difficult due to its frequent clinical presentation with amelanotic lesions. Histologically, spindled melanocytes surrounded by a collagenous stroma are observed. Compared with other types of melanoma, the desmoplastic types presents greater local aggression, and is more prone to local recurrence, but has a lower risk of lymph node metastasis. Early detection, accurate staging, and proper surgical management are the main factors associated with higher survival rates in melanoma patients. Reflectance confocal microscopy (RCM) has proven to be a valuable imaging tool in the diagnosis of skin neoplasms, being useful for orientating practitioners towards the diagnosis of melanoma and indicating the necessity of performing a diagnostic biopsy. We present the case of 52-year-old woman, who presented to the dermatology department with an irregular, dark-colored plaque in the right deltoid region. Dermoscopy showed asymmetry with an atypical network and some areas of regression. RCM revealed pagetoid cells in the upper epidermis, cell atypia, non-edged papillae, dermal inflammation, and nucleated cells in the dermis, which are highly suggestive of melanoma. A biopsy was also performed. A histopathology exam confirmed the diagnosis of superficially spreading melanoma with a desmoplastic component, and revealed a Breslow index of 0.9 mm, Clark level IV, an absence of mitoses, angiolymphatic invasion and regression, and complete excision. The CT and PET-CT scans were negative. A biopsy of the axillary sentinel lymph node was conducted, with a negative result obtained, establishing the IB stage of the disease. The patient will remain under follow-up to look for a recurrence or a new primary melanoma.

In Vivo Characterization of Mucin and Amyloid Deposits in Primary Basal Cell Carcinoma through Reflectance Confocal Microscopy: A Correlation with Histopathology.

Basal cell carcinoma (BCC) is the most common keratinocyte carcinoma and the most prevalent skin cancer in humans, worldwide. BCC is histologically characterized by the proliferation of basaloid cells, arranged in globular masses of varying size, often separated from the surrounding stroma by optically empty spaces. Although attributed to tumor retraction during tissue processing for the preparation of pathology slides, these spaces are also seen on cryostat sections. The aim of this study is to in vivo characterize amyloid and mucin deposits in primary BCC lesions through RCM, followed by histopathological correlation. We included twenty-two consecutive subjects totaling thirty-one primary BCCs. Each lesion underwent the same evaluation protocol which included: clinical and dermoscopic images, RCM imaging, excisional biopsy under local anesthesia, and histopathological examination (colloidal iron and cytokeratin 34betaE12 stains). Hypo-reflective peritumoral clefts and hyper-reflective globules were measured on RCM images and compared to mucin and amyloid deposits seen on histology slides. The mean differences between RCM and histology measurements in both mucin and amyloid were not statistically significant. There were medium and strong correlations between RCM and histology regarding mucin and amyloid deposits, respectively.

Nevus Sebaceous of Jadassohn in Adults-Can Reflectance Confocal Microscopy Detect Malignant Transformation?

Nevus sebaceous of Jadassohn (NSJ) is a rare congenital lesion that affects the adnexal structures of the skin. It is typically located on the scalp and face of females and presents as a well-defined, slightly elevated, yellow lesion. It is also linked to a high risk of secondary tumors, which are more frequently benign than malignant. In vivo reflectance confocal microscopy (RCM) is a non-invasive imaging technique that provides a horizontal image of the skin with a resolution similar to histology. We report a case of basal cell carcinoma (BCC) developed in an NSJ with its dermoscopic, confocal, and histopathological features. A 49-year-old female presented with a well-circumscribed, 1 cm-diameter verrucous, yellowish lesion surrounded by a poorly defined, slightly erythematous, translucent plaque, located on the scalp in the temporoparietal region, which had been present since birth, grew at puberty, and changed its appearance in the last three years. Dermoscopy of the central lesion revealed yellow globules grouped into clusters, with peripheral linear and arborescent thin vessels, surrounded by several translucent nodular lesions with fine, arborizing vessels. RCM examination showed large, monomorphic cells with a hyperreflective periphery and a hyperreflective center located on the central lesion, corresponding to sebocytes, surrounded by multiple dark silhouettes lined with hyperreflective bands of thickened collagen, corresponding to tumor islands. The histopathological findings confirmed the diagnosis of BCC developed on an NJS. RCM can be a useful technique for the non-invasive examination and monitoring of these lesions, taking into account their transformation risk and preventing unnecessary excisions that might have a detrimental aesthetic impact on patients.

Iron chelation alleviates multiple pathophysiological pathways in a rat model of cardiac pressure overload.

Iron dysmetabolism affects a great proportion of heart failure patients, while chronic hypertension is one of the most common risk factors for heart failure and death in industrialized countries. Serum data from reduced ejection fraction heart failure patients show a relative or absolute iron deficiency, whereas cellular myocardial analyses field equivocal data. An observed increase in organellar iron deposits was incriminated to cause reactive oxygen species formation, lipid peroxidation, and cell death. Therefore, we studied the effects of iron chelation on a rat model of cardiac hypertrophy. Suprarenal abdominal aortic constriction was achieved surgically, with a period of nine weeks to accommodate the development of chronic pressure overload. Next, deferiprone (100 mg/kg/day), a lipid-permeable iron chelator, was administered for two weeks. Pressure overload resulted in increased inflammation, fibrotic remodeling, lipid peroxidation, left ventricular hypertrophy and mitochondrial iron derangements. Deferiprone reduced cardiac inflammation, lipid peroxidation, mitochondrial iron levels, and hypertrophy, without affecting circulating iron levels or ejection fraction. In conclusion, metallic molecules may pose ambivalent effects within the cardiovascular system, with beneficial effects of iron redistribution, chiefly in the mitochondria.

Correlations between Histopathological and Confocal Reflectance Microscopy Aspects in a Patient with Bowenoid Papulosis.

Bowenoid papulosis is a cutaneous disease that is part of the spectrum of genital in situ carcinomas, caused primarily by infection with oncogenic strains of the HPV virus. The potential to transform into squamous cell carcinoma requires the diagnosis and treatment of the lesions. We present the case of a 34-year-old non-smoker without medical history who presented to our clinic for the appearance of multiple, asymptomatic, well-defined, flat, pigmented violaceous papules at the root of the penis in evolution for a year. Reflectance confocal microscopy (RCM) suggested the diagnosis of bowenoid papulosis, which was confirmed by histopathological examination. The treatment with Imiquimod 5% (3 times/week) and Isoprinosine (4 g/day) was initiated, followed by monitoring of the lesions by repeated RCM examination. The evolution of the patient at 6 weeks of therapy was favourable, with clinical remission of lesions and improvement in RCM aspects of the evaluated skin. In conclusion, RCM represents a useful noninvasive examination method that allows not only the diagnosis but also the follow-up of the treatment response in order to decide the appropriate length of therapy.

Subepidermal Low-Echogenic Band-Its Utility in Clinical Practice: A Systematic Review.

High-frequency ultrasonography (HF-USG) is a relatively new imaging method that allows the evaluation in a non-invasive manner of the skin layers and skin appendages. It is a diagnostic tool with increasing usefulness in numerous dermatological pathologies. High reproducibility, non-invasiveness and short diagnostic time make this method an increasingly used tool in dermatological practice. The subepidermal low-echogenic band is a relatively newly described parameter that seems to be a marker not only of intrinsic and extrinsic skin aging, but also of inflammatory processes taking place at the skin level. This systematic review aims to evaluate the role that SLEB has in the diagnosis and monitoring of the treatment of some inflammatory and non-inflammatory dermatological conditions, as well as its utility as a disease marker.

Artificial Intelligence-Based Approaches to Reflectance Confocal Microscopy Image Analysis in Dermatology.

Reflectance confocal microscopy (RCM) is a non-invasive imaging method designed to identify various skin diseases. Confocal based diagnosis may be subjective due to the learning curve of the method, the scarcity of training programs available for RCM, and the lack of clearly defined diagnostic criteria for all skin conditions. Given that in vivo RCM is becoming more widely used in dermatology, numerous deep learning technologies have been developed in recent years to provide a more objective approach to RCM image analysis. Machine learning-based algorithms are used in RCM image quality assessment to reduce the number of artifacts the operator has to view, shorten evaluation times, and decrease the number of patient visits to the clinic. However, the current visual method for identifying the dermal-epidermal junction (DEJ) in RCM images is subjective, and there is a lot of variation. The delineation of DEJ on RCM images could be automated through artificial intelligence, saving time and assisting novice RCM users in studying the key DEJ morphological structure. The purpose of this paper is to supply a current summary of machine learning and artificial intelligence's impact on the quality control of RCM images, key morphological structures identification, and detection of different skin lesion types on static RCM images.

Iron metabolism and cardiovascular disease: Basic to translational purviews and therapeutical approach.

Iron interactions with the cardiovascular system were proposed about half a century ago, yet a clear-cut understanding of this micronutrient and its intricacies with acute and chronic events is still lacking. In chronic heart failure, patients with decreased iron stores appear to benefit from intravenous administration of metallic formulations, whereas acute diseases (e.g., myocardial infarction, stroke) are barely studied in randomized controlled trials in humans. However, proof-of-concept studies have indicated that the dual redox characteristics of iron could be involved in atherosclerosis, necrosis, and ferroptosis. To this end, we sought to review the currently available body of literature pertaining to these temporal profiles of heart diseases, as well as the pathophysiologic mechanism by which iron enacts, underlining key points related to treatment options.

Feasibility of Reflectance Confocal Microscopy Monitoring in Oily, Acne-Prone Facial Skin Treated with a Topical Combination of Alpha and Beta-Hydroxy Acids, Anti-Inflammatory Molecules, and Herculane Thermal Water: A Blinded, One-Month Study.

Oily, acne-prone skin is a common skin type which may be monitored in vivo using reflectance confocal microscopy (RCM). The aim of the study was to assess the feasibility of RCM in evaluating the effectiveness of a topical combination of alpha- and beta-hydroxy acids, anti-inflammatory and antibacterial molecules, and Herculane thermal water on acne-prone skin. Thirty-five subjects with oily, acne-prone skin were prescribed topical combination products and were evaluated by clinical, Wood's lamp, and RCM imaging at baseline and after 28 days. At 28 days, the RCM-evaluated number of dilated infundibula, infundibula filled with keratotic material, and infundibula with thickened bright borders, as well as the density of the inflammatory infiltrate, were significantly decreased. Wood's light images at 28 days showed a significantly reduced number of C. acnes-colonized infundibula, and both the median area and the intensity of the red-orange fluorescence were decreased. The reduction in the clinical score was concurrent with the improvement in the RCM parameters, suggesting that this non-invasive imaging technique is appropriate for efficiency evaluations of topical acne treatments.

A Case of Multinucleate Cell Angiohistiocytoma with New Reflectance Confocal Microscopy Findings.

Multinucleate cell angiohistiocytoma (MCAH) is a rare, benign, vascular or fibrohistiocytic tumor usually presenting as single or multiple, reddish-brown papules mostly affecting the limbs and dorsum of the hands of middle-aged females. Since 1985, relatively few MCAH cases have been reported. In vivo reflectance confocal microscopy (RCM) findings of MCAH have never been described. We report a case of MCAH with new non-invasive imaging findings through RCM in correlation with dermoscopy and histopathology. A 66-year-old woman with an unremarkable family and personal history of an atypical nevus presented with a lesion on her right breast. It had appeared 12 months earlier and progressively enlarged. Physical examination revealed a 20 × 11.6 mm, non-tender, reddish-brown maculo-papular lesion with blurred margins. Dermoscopy showed diffusely arranged reddish areas, coalescing whitish patches, truncated and dotted vessels, and a peripheral brown reticulated pattern. RCM revealed a poorly outlined lesion with a normal honeycomb pattern, numerous vessels at the dermal-epidermal junction, and isolated, large, mildly reflective, bizarre structures with angulated edges. These findings correlated well with histological features, which established the diagnosis of MCAH. Even though histopathology remains the gold standard in the diagnosis of MCAH, non-invasive tools such as RCM can help rule out other entities, therefore reducing surgery-associated morbidity.

Poroid Hidradenoma: Dermoscopic and In Vivo Reflectance Confocal Microscopic Description.

Poroid hidradenoma (PH) is a rare, benign adnexal neoplasm usually presenting as a solitary, well circumscribed, asymptomatic papule or nodule that appears reddish and is occasionally tender. Since 1990, only a few cases of PH have been reported. We present a case of PH on the medial surface of the thigh and describe, for the first time, the dermoscopic and reflectance confocal microscopic (RCM) features in correlation with histology. A 67-year-old woman with unremarkable family or past medical history presented with a nodular lesion on the medial surface of the right thigh. The lesion had appeared 4 months earlier and rapidly enlarged. Physical examination revealed a 7 × 5 mm, non-tender, reddish nodule with clinically distinct margins. Dermoscopy showed central blue-grey pigmented areas, a polymorphous vascular pattern with arborizing, glomerular and hairpin vessels surrounded by white halos. RCM revealed an ovoid, well-outlined tumor, with a central area containing cells with distinctive morphologies, two types of tumor cells, tubular hypo-reflective structures, and rectilinear vessels in the stroma. These findings correlated with histological features, which established the diagnosis of PH. Even though the diagnosis of PH remains histopathological, non-invasive tools, such as RCM, can help rule out several malignancies, therefore reducing surgical-associated comorbidity.