The role of reflectance confocal microscopy in the diagnosis of eccrine poroma: A retrospective case-control study.

Eccrine poroma (EP) is a rare benign adnexal tumor that may mimic benign or malignant tumors and differential diagnosis may be difficult under clinical and dermoscopic examination. Reflectance confocal microscopy (RCM) examination may add important information to diagnosis and subsequent management of solitary lesions for which dermoscopy can be challenging. The aim of the present study was to investigate features of EP at RCM in order to detect the characteristics that might aid in the differential diagnosis of EP versus other solitary lesions (benign or malignant). Secondary objective was to correlate the resulting features with histopathological findings. This monocentric retrospective observational case-control study included all EPs registered with RCM between January 2007 and May 2018. Control cases were benign or malignant lesions similar in clinical appearance, morphology, and dermoscopic features to EPs. RCM evaluators were blinded to clinical-dermoscopic images and to final histopathological diagnoses. Finally, RCM-histopathological correlation was performed. A total of 11 EPs and 33 controls were included in the present study. Among RCM parameters, "cords without palisading," "dark holes," "prominent vascularization" and "abundant stroma" resulted positively associated with EP in univariate analysis. RCM features correspond to the histopathological diagnosis of EP in 97% of cases, as illustrated by the cluster analysis. An excellent correlation between diagnostic features of conventional histopathology and RCM was observed. RCM assists in the differential diagnosis of solitary lesions, allowing to reach a correct diagnosis of EP through the identification of its four characteristics.

Aging, sex and NLRP3 inflammasome in cardiac ischaemic disease.

Experimentally, many strong cardioprotective treatments have been identified in different animal models of acute ischaemia/reperfusion injury (IRI) and coronary artery disease (CAD). However, the translation of these cardioprotective therapies for the benefit of the patients into the clinical scenario has been very disappointing. The reasons for this lack are certainly multiple. Indeed, many confounding factors we must deal in clinical reality, such as aging, sex and inflammatory processes are neglected in many experiments. Due to the pivotal role of aging, sex and inflammation in determining cardiac ischaemic disease, in this review, we take into account age as a modifier of tolerance to IRI in the two sexes, dissecting aging and myocardial reperfusion injury mechanisms and the sex differences in tolerance to IRI. Then we focus on the role of the gut microbiota and the NLRP3 inflammasome in myocardial IRI and on the possibility to consider NLRP3 inflammasome as a potential target in the treatment of CAD in relationship with age and sex. Finally, we consider the cardioprotective mechanisms and cardioprotective treatments during aging in the two sexes.

Challenges facing the clinical translation of cardioprotection: 35 years after the discovery of ischemic preconditioning.

Since coronary reperfusion was introduced into clinical practice in the late 1970s, the further translation of several successful animal experiments on cardioprotection into clinical practice has been disappointing to date. Animal experiments are often performed on young, healthy animals lacking the risk factors, co-morbidities and co-medications characteristic of acute myocardial infarction patients. Many hopes were kindled in 1986 when ischemic preconditioning was discovered. However, it is not yet known how long ischemia can last and what is the best modality for additional cardioprotection through conditioning to obtain benefits. There is a lack of experimental studies on the long-term effects of additional cardioprotection, in addition to the reduction in infarct size; in particular, there is a lack of studies on vessel protection, repair, inflammation, remodeling, and mortality. The reproducibility and robustness of experimental studies are often limited by species differences, the role of co-morbidities, vascular damage, inflammatory processes, and co-medications, which are not adequately considered. In particular, inflammatory processes, including NLRP3 inflammasome, play an important role in the long-term effects. Future studies should focus on interventions/agents with robust preclinical data and should recruit patients who truly have the potential to benefit from further cardioprotection. Here we focus on the main mechanisms and targets of cardioprotection during remote conditioning and their alteration by one of the most common co-morbidities, namely diabetes, in which microvascular lesions and inflammatory processes play extremely important roles.

A TRICk to Improve the Effectiveness of RIC: Role of Limb Temperature in Enhancing the Effectiveness of Remote Ischemic Conditioning.

BACKGROUND: Treatment of myocardial ischemia/reperfusion (IR) injury is still an unmet clinical need. A large variability of remote ischemic conditioning (RIC) protection has been reported; however, no studies have considered the temperature of the ischemic limb. We analyzed the effects of temperature on RIC protection. METHODS: Left hind-limbs of anesthetized male mice were immersed in warm (40 °C, warm-RIC) or cold (20 °C, cold-RIC) water and subjected to a RIC protocol (4 × 5 min limb ischemia/reperfusion). In the control groups (warm-CTR or cold-CTR), the limbs underwent thermic conditions only. Isolated hearts underwent 30 min ischemia and 60 min reperfusion. A PI3K-inhibitor, LY294002 (5 µM), was infused in warm-RIC hearts before the IR protocol (warm-RIC LY). Infarct size was evaluated by nitro blue tetrazolium staining and expressed as the percent of risk area. RESULTS: While cold-RIC did not reduce the infarct size compared to cold-CTR (51 ± 1.62% vs. 54 ± 1.07% of risk area, p =NS), warm-RIC (44 ± 1.13%) significantly reduced the infarct size with respect to either cold-RIC (p <0.001) or warm-CTR (58 ± 1.41%, p <0.0001). LY294002 infusion revealed the PI3K/Akt involvement in the warm-RIC protection. Infarct size reduction was abrogated by LY294002 pretreatment (warm-RIC: 44 ± 1.13% vs. warm-CTR 58 ± 1.41% p <0.0001; vs. warm-RIC LY 54 ± 1.69% p =0.0002). CONCLUSION: our study shows a remarkable difference between warm-RIC and cold-RIC in terms of infarct size reduction, supporting a pivotal role for limb temperature in RIC-induced cardioprotection.

HIV and syphilis: incidence rate of coinfection and syphilis reinfection in a cohort of newly diagnosed HIV patients.

BACKGROUND: Syphilis represents a major public health concern disproportionately affecting HIV positive patients and, in many cases, both infections are newly diagnosed at the same time. To date, limited studies are available on syphilis incidence in patients with a new HIV diagnosis. METHODS: Patients newly diagnosed with HIV in 2010-2018 were included in the study and screening tests for syphilis were performed at baseline and at least once a year. Primary aims were to analyze the incidence rate of HIV-syphilis coinfection and syphilis reinfection. Secondary objective was to identify characteristics independently associated with coinfection and reinfection. RESULTS: Of 500 newly diagnosed HIV patients, 20% presented a concomitant positive syphilis serology. Among them, 54 patients had a serology indicative for an active syphilis requiring therapy, while 46 had a history of prior treatments. The independent factors for syphilis acquisition were: MSM contact (OR=2.64; 95% CI: 1.48-4.72; P<0.001), male gender (OR=2.43; 95% CI: 1.08-5.48; P=0.032), and age (OR=1.03; 95% CI: 1.01-1.05; P=0.005 per year increasing). Presence of syphilis at the time of HIV diagnosis remained fairly stable during the study period (P for trend, P=0.689). We observed 52 syphilis reinfections related to 37 people. Patients with at least one reinfection were all males and 86.5% MSM. CONCLUSIONS: Males and MSM with HIV presented high rates of syphilis coinfection and reinfection suggesting persistent high-risk sexual behaviors and the need for appropriate intervention strategies in order to early detect and treat syphilis avoiding life-threatening complications and the spread of the infection in the community.

Ischemic heart disease and cardioprotection: Focus on estrogenic hormonal setting and microvascular health.

Ischemic Heart Disease (IHD) is a clinical condition characterized by insufficient blood flow to the cardiac tissue, and the consequent inappropriate oxygen and nutrients supply and metabolic waste removal in the heart. In the last decade a broad scientific literature has underlined the distinct mechanism of onset and the peculiar progress of IHD between female and male patients, highlighting the estrogenic hormonal setting as a key factor of these sex-dependent divergences. In particular, estrogen-activated cardioprotective pathways exert a pivotal role for the microvascular health, and their impairment, both physiologically and pathologically driven, predispose to vascular dysfunctions. Aim of this review is to summarize the current knowledge on the estrogen receptors localization and function in the cardiovascular system, particularly focusing on sex-dependent differences in microvascular vs macrovascular dysfunction and on the experimental models that allowed the researchers to reach the current findings and sketching the leading estrogen-mediated cardioprotective mechanisms.

Folliculotropism in head and neck lentigo maligna and lentigo maligna melanoma.

BACKGROUND: Lentigo maligna (LM) and lentigo maligna-melanoma (LMM) are histotypes of melanoma arising in skin with cumulative solar radiation damage. The extension of atypical melanocytes to the hair follicle (folliculotropism) is a histopathological feature of LM/LMM. Its role has not been totally clarified, but it may be correlated to treatment response in LM or to progression in LMM. OBJECTIVE: This retrospective, multicentric study aims to identify dermatoscopic features associated with folliculotropism in LMs/LMMs. PATIENTS AND METHODS: We analyzed cases of head and neck LMs/LMMs diagnosed between 2005-2014 at Melanoma Units, University of Bologna/Modena/Florence/Siena (Italy), Nice (France): 25 LMs and 73 LMMs were included. RESULTS: Grey circles (44 %) indicated an isthmic/bulb level of involvement, which were completely absent in the infundibular LM lesions (P = 0.041). In the group of LMMs, light/dark brown pseudonetwork and light brown structureless areas were an indicator of diffuse distribution of malignant melanocytes in the follicular units (P < 0.001 and P = 0.001, respectively), while grey circles indicated focal or diffuse distribution (P < 0.001). CONCLUSIONS: A better understanding of the extension of malignant melanocytes is helpful, aiding clinicians in their decision to perform a radical excision or obtaining a biopsy in the most invasive area of the lesion, which includes potential folliculotropism.

Epidemiology of skin diseases in the Tigray region of Ethiopia.

BACKGROUND: Skin diseases are very common among people living in poor countries. Although many of these pathologies might not be fatal, some can have a great impact on the patient, impairing their ability to work or worsening his/her relationship with the community. Understanding the epidemiology of skin diseases in these areas, determining the prevalence of different disorders, is fundamental to develop better educational and preventative programs. METHODS: We collected data from 467 consecutive patients referring to the Dermatology Center of the Axum Referral Hospital (Tigray region, Ethiopia). We investigated health status and environmental data. Diagnoses were classified into 6 groups (i.e. infectious, inflammatory, etc.). A statistical analysis was performed using IBM SPSS™ software version 25.0.1 (IBM SPSS Inc. Chicago, Illinois) and Stata™ software release 14.2 (Stata Corporation, College Station, Texas). Normality of the distributions was assessed using the Kolmogorov-Smirnov test. Categorical variables are compared with the use of the Chi Square test or the Fisher's exact test, as appropriate. RESULTS: Inflammatory and infectious diseases were the most frequently observed. No significant differences in inferential tests between access to water, housing, education level, and any diagnoses group were found. Curiously, a statistically significant difference between inflammatory diseases and unemployment was found. CONCLUSIONS: Easier access to medical care, medications, and clean water, together with a cleaner work and home environment, are the first goals to be achieved in order to decrease morbidity in these areas.

Combination treatment with secukinumab and dimethyl fumarate in a patient with psoriasis and recent diagnosis of multiple sclerosis.

The therapeutic approach to patients with psoriasis and concomitant multiple sclerosis is challenging. We report the clinical case of a 44-year-old man affected by psoriasis and psoriatic arthritis treated with secukinumab for 2 years, who received also dimethyl fumarate because of a recent diagnosis of relapsing remitting multiple sclerosis. Moreover, a mini-review of the available literature regarding the use of secukinumab in patients with psoriasis or ankylosing spondylitis and coexisting central nervous system demyelinating diseases was performed. To the best of our knowledge, this is the first case of successfully combining secukinumab and dimethyl fumarate for the treatment of two different immune mediated inflammatory diseases with good response and safety outcomes. Our case emphasizes the potential efficacy of this combination therapy, which may represent an effective synergistic strategy to manage such challenging patients.

Cutaneous myiasis in a traveler returning from Argentina.

Myiasis is a common travel-associated dermatosis. We describe a 52-year-old Italian man who acquired Dermatobia hominis when bitten by a mosquito during a visit to Argentina. He had a painful nodular lesion on the left cheek that had been present for about 3 weeks. The complete removal of the larva is the goal of medical treatment. Prescription of antibiotics to avoid secondary infections is not recommended. For psychological reasons and due to the failure of previous therapies, the lesion was excised. Travelers to endemic areas should be informed of preventive measures to reduce mosquito bites and transmission of the infestation.

Lesions Mimicking Melanoma at Dermoscopy Confirmed Basal Cell Carcinoma: Evaluation with Reflectance Confocal Microscopy.

BACKGROUND: Atypical basal cell carcinoma (BCC), characterized by equivocal dermoscopic features typical of malignant melanoma (MM), can be difficult to diagnose. Reflectance confocal microscopy (RCM) enables in vivo imaging at nearly histological resolution. OBJECTIVES: To evaluate with RCM atypical melanocytic lesions identified in dermoscopy, according to common RCM criteria for the differential diagnosis of BCC, and to identify representative RCM parameters for superficial (sBCCs) and nonsuperficial (nsBCCs) basal cell carcinomas (BCCs). METHODS: A retrospective analysis of consecutive patients evaluated with RCM, selecting excised lesions classified at dermoscopy with ≥1 score from the re visited 7-point checklist, mimicking melanoma, registered between 2010 and 2016. Cluster analysis identified BCC subclassifications. RESULTS: Of 178 atypical lesions, 34 lesions were diagnosed as BCCs with RCM. Lesions were confirmed BCCs with histopathology. Dermoscopic features included atypical network (55.9%) and regression structures (35.5%) associated with sBCCs, and an atypical vascular pattern (58.8%) and irregular blotches (58.8%) with nsBCCs. Hierarchical cluster analysis identified 2 clusters: cluster 1 (100% sBCCs) was characterized by the presence of cords connected to the epidermis (90%, p < 0.001), tumor islands located in the epidermis (100%, p < 0.001), smaller vascular diameter (100%, p < 0.001) and solar elastosis (90%, p = 0.017), and cluster 2 (nsBCCs 85%) was defined by the dermic location of tumor islands (87.5%, p < 0.001) with branch-like structures (70.8%, p = 0.007) and surrounding collagen (83.3%, p = 0.012), peripheral palisading (83.3%, p = 0.012) and coiled vascular morphology (79.2%, p < 0.001) with a larger vascular diameter (50%, p < 0.001). CONCLUSIONS: RCM is able to diagnose BCCs mimicking melanoma at dermoscopy and seems able to identify sBCCs and nsBCCs.

Cardioprotective Properties of Human Platelets Are Lost in Uncontrolled Diabetes Mellitus: A Study in Isolated Rat Hearts.

Platelets affect myocardial damage from ischemia/reperfusion. Redox-dependent sphingosine-1-phosphate production and release are altered in diabetic platelets. Sphingosine-1-phosphate is a double-edged sword for ischemia/reperfusion injury. Therefore, we aimed to verify whether: (1) human healthy- or diabetic-platelets are cardioprotective, (2) sphingosine-1-phosphate receptors and downstream kinases play a role in platelet-induced cardioprotection, and (3) a correlation between platelet redox status and myocardial ischemia/reperfusion injury exists. Isolated rat hearts were subjected to 30-min ischemia and 1-h reperfusion. Infarct size was studied in hearts pretreated with healthy- or diabetic-platelets. Healthy-platelets were co-infused with sphingosine-1-phosphate receptor blocker, ERK-1/2 inhibitor, PI3K antagonist or PKC inhibitor to ascertain the cardioprotective mechanisms. In platelets we assessed (i) aggregation response to ADP, collagen, and arachidonic-acid, (ii) cyclooxygenase-1 levels, and (iii) AKT and ERK-phosphorylation. Platelet sphingosine-1-phosphate production and platelet levels of reactive oxygen species (ROS) were quantified and correlated to infarct size. Infarct size was reduced by about 22% in healthy-platelets pretreated hearts only. This cardioprotective effect was abrogated by either sphingosine-1-phosphate receptors or ERK/PI3K/PKC pathway blockade. Cyclooxygenase-1 levels and aggregation indices were higher in diabetic-platelets than healthy-platelets. Diabetic-platelets released less sphingosine-1-phosphate than healthy-platelets when mechanical or chemically stimulated in vitro. Yet, ROS levels were higher in diabetic-platelets and correlated with infarct size. Cardioprotective effects of healthy-platelet depend on the platelet's capacity to activate cardiac sphingosine-1-phosphate receptors and ERK/PI3K/PKC pathways. However, diabetic-platelets release less S1P and lose cardioprotective effects. Platelet ROS levels correlate with infarct size. Whether these redox alterations are responsible for sphingosine-1-phosphate dysfunction in diabetic-platelets remains to be ascertained.

Imatinib-induced diffuse hyperpigmentation of the oral mucosa, the skin, and the nails in a patient affected by chronic myeloid leukemia: report of a case and review of the literature.

BACKGROUND: Imatinib mesylate is a tyrosine-kinase inhibitor used as the first-line treatment in chronic myeloid leukemia patients, but it is also indicated for other hematological diseases and solid tumors. Imatinib treatment is often associated with hypopigmentation, but only a few cases of hyperpigmentation are described in literature. METHODS: We are reporting the first case of imatinib-related hyperpigmentation involving the oral mucosa, skin, and nails in a patient affected by chronic myeloid leukemia and treated with imatinib since 2002. A review of all the available literature regarding the imatinib-related hyperpigmentation was performed, and one additional case was analyzed. Due to the possibility of a post-inflammatory hyperpigmentation, all cases of pigmentary changes previously characterized by a rash and/or pruritus in the same body areas were excluded. RESULTS: Thirty cases of well-documented imatinib-related hyperpigmentation were described in literature. In our case, imatinib therapy was well tolerated for several years, and it led to an excellent hematological and cytogenetic response. However, the patient gradually developed a blue-gray pigmentation that involved the nose, fingernails, toenails, pretibial regions, posterior axillary folds, and hard palate. Other causes of pigmentary changes were excluded, and histopathological examination confirmed the clinical suspicion of imatinib-related hyperpigmentation. CONCLUSIONS: Hyperpigmentation induced by imatinib is an adverse reaction rarely described in literature. The underlying pathogenetic mechanisms are not yet completely clear, and further studies are necessary to elucidate them. Currently, no treatment is required for this condition, and there is no indication to discontinue imatinib treatment.

Obestatin regulates cardiovascular function and promotes cardioprotection through the nitric oxide pathway.

Patients with ischaemic heart disease or chronic heart failure show altered levels of obestatin, suggesting a role for this peptide in human heart function. We have previously demonstrated that GH secretagogues and the ghrelin gene-derived peptides, including obestatin, exert cardiovascular effects by modulating cardiac inotropism and vascular tone, and reducing cell death and contractile dysfunction in hearts subjected to ischaemia/reperfusion (I/R), through the Akt/nitric oxide (NO) pathway. However, the mechanisms underlying the cardiac actions of obestatin remain largely unknown. Thus, we suggested that obestatin-induced activation of PI3K/Akt/NO and PKG signalling is implicated in protection of the myocardium when challenged by adrenergic, endothelinergic or I/R stress. We show that obestatin exerts an inhibitory tone on the performance of rat papillary muscle in both basal conditions and under ß-adrenergic overstimulation, through endothelial-dependent NO/cGMP/PKG signalling. This pathway was also involved in the vasodilator effect of the peptide, used both alone and under stress induced by endothelin-1. Moreover, when infused during early reperfusion, obestatin reduced infarct size in isolated I/R rat hearts, through an NO/PKG pathway, comprising ROS/PKC signalling, and converging on mitochondrial ATP-sensitive potassium [mitoK(ATP)] channels. Overall, our results suggest that obestatin regulates cardiovascular function in stress conditions and induces cardioprotection by mechanisms dependent on activation of an NO/soluble guanylate cyclase (sGC)/PKG pathway. In fact, obestatin counteracts exaggerated ß-adrenergic and endothelin-1 activity, relevant factors in heart failure, suggesting multiple positive effects of the peptide, including the lowering of cardiac afterload, thus representing a potential candidate in pharmacological post-conditioning.

Cardioprotective effects of calcitonin gene-related peptide in isolated rat heart and in H9c2 cells via redox signaling.

The calcitonin-gene-related-peptide (CGRP) release is coupled to the signaling of Angeli's salt in determining vasodilator effects. However, it is unknown whether CGRP is involved in Angeli's salt cardioprotective effects and which are the mechanisms of protection. We aimed to determine whether CGRP is involved in myocardial protection induced by Angeli's salt. We also analyzed the intracellular signaling pathway activated by CGRP. Isolated rat hearts were pre-treated with Angeli's salt or Angeli's salt plus CGRP8-37, a specific CGRP-receptor antagonist, and subjected to ischemia (30-min) and reperfusion (120-min). Moreover, we studied CGRP-induced protection during oxidative stress (H2O2) and hypoxia/reoxygenation protocols in H9c2 cardiomyocytes. Cell vitality and mitochondrial membrane potential (ΔYm, MMP) were measured using MTT and JC-1 dyes. Angeli's salt reduced infarct size and ameliorated post-ischemic cardiac function via a CGRP-receptor-dependent mechanism. Pre-treatment with CGRP increased H9c2 survival upon challenging with either H2O2 (redox stress) or hypoxia/reoxygenation (H/R stress). Under these stress conditions, reduction in MMP and cell death were partly prevented by CGRP. These CGRP beneficial effects were blocked by CGRP8-37. During H/R stress, pre-treatment with either CGRP-receptor, protein kinase C (PKC) or mitochondrial KATP channel antagonists, and pre-treatment with an antioxidant (2-mercaptopropionylglycine) blocked the protection mediated by CGRP. In conclusion, CGRP is involved in the cardioprotective effects of Angeli's salt. In H9c2 cardiomyocytes, CGRP elicits PKC-dependent and mitochondrial-KATP-redox-dependent mechanisms. Hence, CGRP is an important factor in the redox-sensible cardioprotective effects of Angeli's salt.

Myocardial ischemia/reperfusion upregulates the transcription of the Neuregulin1 receptor ErbB3, but only postconditioning preserves protein translation: Role in oxidative stress.

BACKGROUND: Neuregulin1 (Nrg1) and its receptors ErbB are crucial for heart development and for adult heart structural maintenance and function and Nrg1 has been proposed for heart failure treatment. Infarct size is the major determinant of heart failure and the mechanism of action and the role of each ErbB receptor remain obscure, especially in the post-ischemic myocardium. We hypothesized that Nrg1 and ErbB are affected at transcriptional level early after ischemia/reperfusion (I/R) injury, and that the protective postconditioning procedure (PostC, brief cycles of ischemia/reperfusion carried out after a sustained ischemia) can influence this pathway. METHODS AND RESULTS: The Langendorff's heart was used as an ex-vivo model to mimic an I/R injury in the whole rat heart; after 30min of ischemia and 2h of reperfusion, with or without PostC, Nrg1 and ErbB expression were analysed by quantitative real-time PCR and Western blot. While no changes occur for ErbB2, ErbB4 and Nrg1, an increase of ErbB3 expression occurs after I/R injury, with and without PostC. However, I/R reduces ErbB3 protein, whereas PostC preserves it. An in vitro analysis with H9c2 cells exposed to redox-stress indicated that the transient over-expression of ErbB3 alone is able to increase cell survival (MTT assay), limiting mitochondrial dysfunction (JC-1 probe) and apoptotic signals (Bax/Bcl-2 ratio). CONCLUSIONS: This study suggests ErbB3 as a protective factor against death pathways activated by redox stress and supports an involvement of this receptor in the pro-survival responses.

Maladaptive Modulations of NLRP3 Inflammasome and Cardioprotective Pathways Are Involved in Diet-Induced Exacerbation of Myocardial Ischemia/Reperfusion Injury in Mice.

Excessive fatty acids and sugars intake is known to affect the development of cardiovascular diseases, including myocardial infarction. However, the underlying mechanisms are ill defined. Here we investigated the balance between prosurvival and detrimental pathways within the heart of C57Bl/6 male mice fed a standard diet (SD) or a high-fat high-fructose diet (HFHF) for 12 weeks and exposed to cardiac ex vivo ischemia/reperfusion (IR) injury. Dietary manipulation evokes a maladaptive response in heart mice, as demonstrated by the shift of myosin heavy chain isoform content from α to ß, the increased expression of the Nlrp3 inflammasome and markers of oxidative metabolism, and the downregulation of the hypoxia inducible factor- (HIF-)2α and members of the Reperfusion Injury Salvage Kinases (RISK) pathway. When exposed to IR, HFHF mice hearts showed greater infarct size and lactic dehydrogenase release in comparison with SD mice. These effects were associated with an exacerbated overexpression of Nlrp3 inflammasome, resulting in marked caspase-1 activation and a compromised activation of the cardioprotective RISK/HIF-2α pathways. The common mechanisms of damage here reported lead to a better understanding of the cross-talk among prosurvival and detrimental pathways leading to the development of cardiovascular disorders associated with metabolic diseases.