Lethality among individuals infected with visceral leishmaniasis in Brazil: a retrospective study (2007-2018).

Visceral leishmaniasis (VL) is a public health problem with a high prevalence and lethality in Brazil. This study aims to estimate the lethality and associated factors in individuals with VL and assess survival time, emphasizing VL/HIV coinfection. This retrospective study has 37,583 individuals notified and confirmed with VL in the Sistema de Informação de Agravos de Notificação (SINAN) between 2007 and 2018 (Brazil). Lethality was evaluated considering VL deaths, deaths from other causes (OC), and non-deaths. We performed a multinomial logistic regression, with non-death as the benchmark category. We conducted a survival analysis (Kaplan-Meier method), emphasizing VL/HIV coinfection. Most individuals were young, male, mixed race, low schooling level, and urban dwellers. The lethality rate was 10.2% (VL and OC deaths) and 7.8% (VL deaths). The prevalence of HIV infection was 8.81%. A higher likelihood of VL and OC deaths was observed in older age groups, females, and with a higher number of symptoms. A higher likelihood of OC deaths was identified in individuals with HIV. A lower likelihood of VL and OC deaths was observed for individuals on VL therapy. The mean survival time was longer for VL/HIV individuals, who had a lower survival rate than those with VL. The data point to the need for attention to the timely diagnosis of VL and HIV and adequate pharmacological treatment in this population.

Flow Cytometry Characterization of Pluripotent Transmembrane Glycoproteins on Resident Cervix Uteri Cells in Patients Screened for Cervical Cancer.

The aim of this study was to characterize both by flow cytometry analysis and immunohistochemistry cervix uteri cells of nulliparous women screened for cervical intraepithelial neoplasia (CIN) in comparison to a group without CIN by using mesenchymal stem cell-like and hematopoietic lineage markers. A significant expression for CD29, CD38, HLA-I, and HLA-II was correlated positively to the CIN degree and it was more relevant in patients positive for human papilloma virus (HPV). Thus, identification and detailed characterization of pluripotent resident in uteri cells could be a promising therapeutic target.

Genetic background, epigenetic factors and dietary interventions which influence human longevity.

Longevity is mainly conditioned by genetic, epigenetic and environmental factors. Different genetic modifications seem to be positively associated to longevity, including SNPs in SIRT1, APOE, FOXO3A, ACE, ATM, NOS1 and NOS2 gene. Epigenetic changes as DNA hyper- and hypo-methylation influence significantly human longevity by activating/deactivating different genes involved in physiological mechanisms. Several studies have confirmed that centenarians have a lower DNA methylation content compared to young subjects, which showed more homogeneously methylated DNA region. Also the up-regulation of miR-21 seems to be more associated with longevity in different populations of long-lived subjects, suggesting its role as potential epigenetic biomarkers. A non-pharmacological treatment that seems to contrast age-related diseases and promote longevity is represented by dietary intervention. It has been evaluated the effects of dietary restriction of both single nutrients or total calories to extend lifespan. However, in daily practice it is very difficult to guarantee adherence/compliance of the subjects to dietary restriction and at the same time avoid dangerous nutritional deficiencies. As consequence, the attention has focused on a variety of substances both drugs and natural compounds able to mime the beneficial effects of caloric restriction, including resveratrol, quercetin, rapamycin, metformin and 2-deoxy-D-glucose.

Built and Social Environment by Systematic Social Observation and Leisure-Time Physical Activity Report among Brazilian Adults: a Population-Based Study.

The aim of this study was to investigate the relationship between built and social environment and leisure-time physical activity (LTPA) among adults living in an urban center. The individual data was from the household survey and the environmental data was assessed through systematic social observation by trained observers on street segments of respondents' residences. The relationship between environmental factors and LTPA was examined using multilevel logistic regression. The prevalence of LTPA was 30.2% (95% CI 27.4-32.9%). Individuals living in census tracts with higher walking environment indicators (OR = 1.20; 95% CI 1.02 to 1.40) and safety (OR = 1.18; 95% CI 1.01 to 1.38) were more likely to be active during leisure time, even after adjusting for individual variables. Improving the built and social environment is an important step for achieving higher levels of LTPA in the population in a middle-income country.

The dating of thrombus organization in cases of pulmonary embolism: an autopsy study.

BACKGROUND: Pulmonary embolism (PE) is associated to high mortality rate worldwide. However, the diagnosis of PE often results inaccurate. Many cases of PE are incorrectly diagnosed or missed and they are often associated to sudden unexpected death (SUD). In forensic practice, it is important to establish the time of thrombus formation in order to determine the precise moment of death. The autopsy remains the gold standard method for the identification of death cause allowing the determination of discrepancies between clinical and autopsy diagnoses. The aim of our study was to verify the morphological and histological criteria of fatal cases of PE and evaluate the dating of thrombus formation considering 5 ranges of time. METHODS: Pulmonary vessels sections were collected from January 2010 to December 2017. Sections of thrombus sampling were stained with hematoxylin and eosin. The content of infiltrated cells, fibroblasts and collagen fibers were scored using a semi-quantitative three-point scale of range values. RESULTS: The 30 autopsies included 19 males (63.3%) and 11 females (36.7%) with an average age of 64.5 ± 12.3 years. The time intervals were as follows: early (≤1 h), recent (> 1 h to 24 h), recent-medium (> 24 h to 48 h), medium (> 48 h to 72 h) and old (> 72 h). In the first hour, we histologically observed the presence of platelet aggregation by immunofluorescence method for factor VIII and fibrinogen. The presence of lymphocytes has been identified from recent thrombus (> 1 h to 24 h) and the fibroblast cells were peripherally located in vascular tissue between 48 and 72 h, whereas they resulted central and copious after 72 h. CONCLUSIONS: After a macroscopic observation and a good sampling traditional histology, it is important to identify the time of thrombus formation. We identified histologically a range of time in the physiopathology of the thrombus (early, recent, recent-medium, medium, old), allowing to determine the dating of thrombus formation and the exact time of death. CLINICAL TRIAL NUMBER: NCT03887819. TRIAL REGISTRATION: The trial registry is Cliniclatrials.gov, with the unique identifying number NCT03887819. The date of registration was 03/23/2019 and it was "Retrospectively registered".

Effect of nitric oxide reduction on arterial thrombosis.

OBJECTIVES: Nitric oxide (NO) represents the most powerful endogenous molecule with vasodilator action mainly produced by endothelial nitric oxide synthase (eNOS) enzyme. Polymorphisms and epigenetic-sensitive mechanisms can modulate the expression of eNOS gene, leading to the endothelial dysfunction. This review updates on the mechanistic role of NO in the regulation of platelet activation, as well as the impact of eNOS genetic and epigenetic modifications on arterial thrombosis onset. DESIGN: A systematic search was addressed to examination of PubMed databases with the following terms: nitric oxide; arterial thrombosis; endothelial dysfunction; DNA variations; epigenetic modifications; personalized therapy; network medicine. RESULTS: G894T, -786T/C, and 4b/4a variable number tandem repeat (VNTR), are the main classes of polymorphisms harbored in eNOS gene associated to increased arterial thrombosis risk. DNA methylation, histone/non-histone modifications, and microRNA (miRNAs) can modulate eNOS gene expression. Investigators largely focused on the role of miRNAs in modulating NO production in arterial thrombosis development. In detail, miR-195, and miR-582 are inversely correlated both to eNOS and NO levels, thus suggesting novel biomarkers. CONCLUSION: We are far from incorporating omics pathogenic data from bench to arterial thrombosis bedside. Network medicine is an emerging paradigm that ideally overcomes the current shortcomings of the reductionist approach. Despite several clinical limitations, the network-based analysis of the interactome might reveal the key nodes underlying the perturbations of the arterial thrombosis, thus advancing personalized therapy.

Impact of epigenetic mechanisms on therapeutic approaches of hemoglobinopathies.

Hemoglobinopathies are inherited disorders characterized by anomalies of structure, function or production of globin chains. From conception to adulthood, the different expressions over time of the various globin chains depend on the activation/deactivation of different globin genes through methylation and chromatin remodeling processes. The most significant clinical disorders are ß-thalassemia and sickle cell disease. The clinical management of these disorders engages regular blood transfusions. Another therapy is represented by allogeneic hematopoietic cells transplantation. There are several studies based on the innovative therapeutic strategies that involve some epigenetic mechanisms focused on the reactivation of γ-globin gene expression. The induction of fetal hemoglobin expression in adulthood is an effective therapy for these disorders. Particularly interesting are the recent data on miRNAs showing the interaction of these molecules with different transcription factors such as MYB, KLF, BCL11A and SOX6. The aim of this review was to report an update on the dynamic epigenetic modifications as targets for therapy in hemoglobinopathies.

Erythrocyte genotyping for transfusion-dependent patients at the Azienda Universitaria Policlinico of Naples.

BACKGROUND AND OBJECTIVES: Although minor erythrocyte antigens are not considered clinically significant in sporadic transfusions, they may be relevant for multi-transfusion patients. When serological assay is not conceivable, molecular genotyping allows predicting the red blood cell phenotype, extending the typing until minor blood groups. The aim of this study was to evaluate the utility of blood group genotyping and compare the molecular typing of erythrocyte antigens with the established serological methods. MATERIALS AND METHODS: We selected 225 blood donors and 50 transfusion-dependent patients at the Division of Immunohematology of the Second University of Naples. Blood samples were analyzed with NEO Immucor automated system and genotyped for 38 red blood cell antigens and phenotypic variants with the kit HEA BeadChip™. The comparative study was conducted for RhCE and Kell antigens whose typing is available with both methods. RESULTS: We observed a good correlation between serological and molecular methods for donors that were concordant for 99.5% (224/225) and discordant for 0.5% (1/225). Patients resulted concordant only for 46.0% (23/50) and discordant for 54.0% (27/50); discrepancies were 46.0% (23/50) and 8.0% (4/50) for RhCE and Kell systems respectively. Through molecular genotyping we also identified polymorphisms in RhCE, Kell, Duffy, Colton, Lutheran and Scianna loci in donors and patients. CONCLUSIONS: Blood group genotyping is particularly useful for poly-transfused patients. Molecular analysis confirms and extends serological test data and then allows us to obtain a better match. This molecular assay can be used in the future to prevent alloimmunization in transfusion-dependent patients.

Lung transplantation: Current insights and outcomes.

Until now, the ability to predict or retard immune-mediated rejection events after lung transplantation is still limited due to the lack of specific biomarkers. The pressing need remains to early diagnose or predict the onset of chronic lung allograft dysfunction (CLAD) and its differential phenotypes that is the leading cause of death. Omics technologies (mainly genomics, epigenomics, and transcriptomics) combined with advanced bioinformatic platforms are clarifying the key immune-related molecular routes that trigger early and late events of lung allograft rejection supporting the biomarker discovery. The most promising biomarkers came from genomics. Both unregistered and NIH-registered clinical trials demonstrated that the increased percentage of donor-derived cell-free DNA in both plasma and bronchoalveolar lavage fluid showed a good diagnostic performance for clinically silent acute rejection events and CLAD differential phenotypes. A further success arose from transcriptomics that led to development of Molecular Microscope® Diagnostic System (MMDx) to interpret the relationship between molecular signatures of lung biopsies and rejection events. Other immune-related biomarkers of rejection events may be exosomes, telomer length, DNA methylation, and histone-mediated neutrophil extracellular traps (NETs) but none of them entered in registered clinical trials. Here, we discuss novel and existing technologies for revealing new immune-mediated mechanisms underlying acute and chronic rejection events, with a particular focus on emerging biomarkers for improving precision medicine of lung transplantation field.

Role of HLA matching and donor specific antibody development in long-term survival, acute rejection and cardiac allograft vasculopathy.

Although there are different data supporting benefits of HLA matching in kidney transplantation, its role in heart transplantation is still unclear. HLA mismatch (MM) between donor and recipient can lead to the development of donor-specific antibodies (DSA) which produces negative events on the outcome of heart transplantation. Moreover, DSAs are involved in the development of antibody-mediated rejection (AMR) and are associated with an increase in cardiac allograft vasculopathy (CAV). In this study it is analyzed retrospectively the influence of HLA matching and anti-HLA antibodies on overall survival, AMR and CAV in heart transplantation. For this retrospective study are recruited heart transplanted patients at the Cardiac Transplantation Centre of Naples between 2000 and 2019. Among the 155 heart transplant patients, the mean number of HLA-A, B, -DR MM (0 to 6) between donor and recipient was 4.5 ± 1.1. The results show a negative association between MM HLA-DR and survival (p = 0.01). Comparison of patients with 0-1 MM at each locus to all others with 2 MM, for both HLA class I and class II, has not showed significant differences in the development of CAV. Our analysis detected DSA in 38.1% of patients. The production of de novo DSA reveals that there is not an influence on survival (p = 0.72) and/or AMR (p = 0.39). Instead, there is an association between the production of DSA class II and the probability of CAV development (p = 0.03). Mean fluorescence intensity (MFI) values were significantly higher in CAV-positive patients that CAV-negative patients (p = 0.02). Prospective studies are needed to evaluate HLA class II matching as an additional parameter for heart allocation, especially considering the increment of waiting list time.

Which physical and social characteristics of Brazilian cities contribute to physical activity of adolescents?

This study aimed to analyze the association between adolescents' physical activity and the Brazilian capitals' built and social environment. The units of analysis of this ecological study were the 26 capitals and the Federal District, with data from the National Adolescent Health Survey (2012). The outcome variable was the reported regular physical activity (PA) of ninth graders in Brazilian schools. Exposure variables included characteristics of the natural environment, socioeconomic and educational indicators, urban infrastructure, urban violence, and sociocultural factors retrieved from several secondary sources of Brazilian databases. We adopted multiple linear regression to verify the association between PA and exposure variables. The percentage of active adolescents was 33.0% (95%CI: 32.1; 33.9). In the final model, higher PA was associated with lower temperature, higher Primary Education Development Index, the higher percentage of ramps for wheelchair users, and a higher percentage of leisure-time active adults. The data show that climatic and educational factors, the infrastructure, and the social environment of the capitals can contribute to Brazilian adolescents complying with the recommended weekly PA levels.

Novel Insights Regarding Nitric Oxide and Cardiovascular Diseases.

Nitric oxide (NO) is a powerful mediator with biological activities such as vasodilation and prevention of vascular smooth muscle cell proliferation as well as functional regulation of cardiac cells. Thus, impaired production or reduced bioavailability of NO predisposes to the onset of different cardiovascular (CV) diseases. Alterations in the redox balance associated with excitation-contraction coupling have been identified in heart failure (HF), thus contributing to contractile abnormalities and arrhythmias. For its ability to influence cell proliferation and angiogenesis, NO may be considered a therapeutic option for the management of several CV diseases. Several clinical studies and trials investigated therapeutic NO strategies for systemic hypertension, atherosclerosis, and/or prevention of in stent restenosis, coronary heart disease (CHD), pulmonary arterial hypertension (PAH), and HF, although with mixed results in long-term treatment and effective dose administered in selected groups of patients. Tadalafil, sildenafil, and cinaguat were evaluated for the treatment of PAH, whereas vericiguat was investigated in the treatment of HF patients with reduced ejection fraction. Furthermore, supplementation with hydrogen sulfide, tetrahydrobiopterin, and nitrite/nitrate has shown beneficial effects at the vascular level.

Soft drinks and sweeteners intake: Possible contribution to the development of metabolic syndrome and cardiovascular diseases. Beneficial or detrimental action of alternative sweeteners?

The rapid increase in obesity, metabolic syndrome, and cardiovascular diseases (CVDs) has been related to the rise in sugar-added foods and sweetened beverages consumption. An interesting approach has been to replace sugar with alternative sweeteners (AS), due to their impact on public health. Preclinical and clinical studies, which analyze the safety of AS intake, are still limited. Major pathogenic mechanisms of these substances include ROS and AGEs formation. Indeed, endothelial dysfunction involving in the pathogenesis of micro- and macro-vascular diseases is mitochondrial dysfunction dependent. Hyperglycemia and endoplasmic reticulum stress together produce ROS, contributing to the development and progression of cardiovascular complications during type 2 diabetes (T2D), thus causing oxidative changes and direct damage of lipids, proteins, and DNA. Epidemiological studies in healthy subjects have suggested that the consumption of artificial AS can promote CV complications, such as glucose intolerance and predisposition to the onset of T2D, whereas natural AS could reduce hyperglycemia, improve lipid metabolism and have antioxidant effects. Long-term prospective clinical randomized studies are needed to evaluate precisely whether exposure to alternative sugars can have clinical implications on natural history and clinical outcomes, especially in children or during the gestational period through breast milk.

Network Medicine Approach in Prevention and Personalized Treatment of Dyslipidemias.

Dyslipidemias can affect molecular networks underlying the metabolic homeostasis and vascular function leading to atherogenesis at early stages of development. Since disease-related proteins often interact with each other in functional modules, many advanced network-oriented algorithms were applied to patient-derived big data to identify the complex gene-environment interactions underlying the early pathophysiology of dyslipidemias and atherosclerosis. Both the proprotein convertase subtilisin/kexin type 7 (PCSK7) and collagen type 1 alpha 1 chain (COL1A1) genes arose from the application of TFfit and WGCNA algorithms, respectively, as potential useful therapeutic targets in prevention of dyslipidemias. Moreover, the Seed Connector algorithm (SCA) algorithm suggested a putative role of the neuropilin-1 (NRP1) protein as drug target, whereas a regression network analysis reported that niacin may provide benefits in mixed dyslipidemias. Dyslipidemias are highly heterogeneous at the clinical level; thus, it would be helpful to overcome traditional evidence-based paradigm toward a personalized risk assessment and therapy. Network Medicine uses omics data, artificial intelligence (AI), imaging tools, and clinical information to design personalized therapy of dyslipidemias and atherosclerosis. Recently, a novel non-invasive AI-derived biomarker, named Fat Attenuation Index (FAI™) has been established to early detect clinical signs of atherosclerosis. Moreover, an integrated AI-radiomics approach can detect fibrosis and microvascular remodeling improving the customized risk assessment. Here, we offer a network-based roadmap ranging from novel molecular pathways to digital therapeutics which can improve personalized therapy of dyslipidemias.

[Cooccurrence of obesogenic risk factors in Brazilian adolescents: the role of sociodemographic characteristics and parental presence]. / Coocorrência de fatores de risco obesogênicos em adolescentes brasileiros: o papel das características sociodemográficas e da presença parental.

The study aimed to estimate the prevalence of cooccurrence of obesogenic risk factors in Brazilian adolescents and associated sociodemographic and family characteristics. This is a cross-sectional study of data from the Brazilian National School Health Survey, 2009 (n = 53,274). The outcome variable (cooccurrence of obesogenic risk factors) varied from zero to five and was obtained as the sum of the risk behaviors: daily consumption of soft drinks; daily consumption of candy; insufficient consumption of fruits; insufficient consumption of vegetables; and insufficient physical activity. The explanatory variables were sex, age, skin color, region of Brazil, household goods and services score, maternal schooling, type of school, family composition, parental monitoring, and main meals shared with parents or guardians. A Venn diagram was used for exploratory analysis, plus ordinal logistic regression with partial proportional odds model for multivariate analysis. The results showed higher odds of simultaneous occurrence of the factors in adolescent girls, in teens with less parental supervision, and teens who shared fewer meals with their parents or guardians. Meanwhile, adolescents living in more developed regions of the country and those whose mothers had more schooling showed lower odds of cooccurrence of obesogenic risk factors. Actions that encourage greater family involvement and supervision in dietary behavior can have a positive impact on the prevention of obesity in Brazilian adolescents, especially in less developed regions and in homes where the mothers have less schooling.

O objetivo do estudo foi estimar a prevalência da coocorrência de fatores de risco obesogênicos em adolescentes brasileiros e características sociodemográficas e familiares associadas. É um estudo transversal, com dados da Pesquisa Nacional de Saúde do Escolar, 2009 (n = 53.274). A variável resposta (coocorrência de fatores de risco obesogênicos) variou de zero a cinco e foi obtida com base no somatório dos comportamentos de risco: consumo diário de refrigerantes; consumo diário de guloseimas; consumo insuficiente de frutas; consumo insuficiente de hortaliças e atividade física insuficiente. As variáveis explicativas foram sexo, idade, cor da pele, região brasileira, escore de bens e serviços do domicílio, escolaridade materna, tipo de escola, composição familiar, monitoramento parental e realização de refeições principais com os responsáveis. Utilizou-se o diagrama de Venn para a análise exploratória e a regressão logística ordinal com modelo de odds proporcionais parciais para análise multivariada. Verificou-se maior chance de ocorrência simultânea dos fatores nos adolescentes do sexo feminino, naqueles que tinham menor monitoramento parental e que realizavam menor número de refeições com os responsáveis. Em contraste, adolescentes que residiam em regiões mais desenvolvidas do país e aqueles cujas mães possuíam maior escolaridade apresentaram menor chance de coocorrência de fatores de risco obesogênicos. Ações que estimulem mais envolvimento e supervisão familiar no comportamento alimentar podem promover impacto positivo na prevenção da obesidade em adolescentes brasileiros, principalmente em regiões menos desenvolvidas e em lares com mães de menor escolaridade.

El objetivo del estudio fue estimar la prevalencia de la coocurrencia de factores de riesgo obesogénicos en adolescentes brasileños, así como las características sociodemográficas y familiares asociadas. Se trata de un estudio transversal, con datos de la Encuesta Nacional de Salud del Escolar, 2009 (n = 53.274). La variable respuesta (coocurrencia de factores de riesgo obesogénicos) varió de cero a cinco, y se obtuvo a partir del sumatorio de los comportamientos de riesgo: consumo diario de refrescos; consumo diario de golosinas; consumo insuficiente de frutas; consumo insuficiente de hortalizas y actividad física insuficiente. Las variables explicativas fueron: sexo, edad, color de piel, región brasileña, marcador de bienes y servicios del domicilio, escolaridad materna, tipo de escuela, composición familiar, monitoreo parental y realización de comidas principales con los responsables. Se utilizó el diagrama de Venn para un análisis exploratorio y regresión logística ordinal con un modelo de odds proporcionales parciales para el análisis multivariado. Se verificó una mayor oportunidad de ocurrencia simultánea de los factores en adolescentes del sexo femenino, en aquellos que tenían un menor monitoreo parental y que realizaban un menor número de comidas con los responsables. En contraste, adolescentes que residían en regiones más desarrolladas del país, y aquellos cuyas madres poseían una mayor escolaridad, presentaron una menor oportunidad de coocurrencia de factores de riesgo obesogénicos. Acciones que estimulen más implicación y supervisión familiar en el comportamiento alimentario pueden promover un impacto positivo en la prevención de la obesidad en adolescentes brasileños, principalmente en regiones menos desarrolladas y en hogares con madres de menor escolaridad.

Noise annoyance, sociodemographic and health patterns, and neighborhood perceptions in a Brazilian metropolis: BH Health Study.

OBJECTIVE: The present study aims to analyze the association of noise annoyance with individual and sociodemographic factors and self-perception of the neighborhood in an urban center. METHODS: Data were collected through a population-based cross-sectional study held in two of the nine health districts in the city of Belo Horizonte, Minas Gerais, Brazil, from 2008 to 2009. The study included 3,934 individuals of both genders, aged 18 years and older. The response variable was the self-perception of noise, investigated by the question: "In your neighborhood, does the noise bother you?" The explanatory variables were grouped into the following domains: sociodemographic, social determinants, self-rated health, and self-reported diseases. RESULTS: The prevalence of noise annoyance was 47% for women and 39.8% for men. For both genders, noise annoyance was independently associated with bad traffic and the presence of loud music, discussions, and late-night parties. CONCLUSION: Gender differences were identified in the association of noise annoyance with sociodemographic characteristics and self-reported morbidity. Traffic and social customs were the main sources of noise in the regions under study.

Current Drugs and Nutraceuticals for the Treatment of Patients with Dyslipidemias.

Coronary heart disease (CHD) remains the leading cause of disability and death in industrialized Countries. Among many conditions, which contribute to the etiology and progression of CHD, the presence of high low density lipoprotein-cholesterol (LDL-C) levels represents the major risk factor. Therefore, the reduction of LDL-C levels plays a key role in the management of patients with high or very high cardiovascular risk. Although statins represent the gold standard therapy for the reduction of cholesterol levels, these drugs do not allow to achieve target levels of LDL-C in all patients. Indeed, a significant number of patients resulted intolerants, especially when the dosage increased. The availability of new lipid-lowering drugs, such as ezetimibe and PCSK9 inhibitors, may represent an important alternative or complement to the conventional lipid-lowering therapies. However, long-term studies are still needed to define both efficacy and safety of use of these latter new drugs. Some nutraceuticals may become an adequate and effective support in the management of some patients. To date, several nutraceuticals with different mechanism of actions that provide a good tolerability are available as lipidlowering agents. In particular, the most investigated are red yeast rice, phytosterols, berberine, beta-glucans and soy. The aim of this review was to report recent data on the efficacy and safety of principle hypocholesterolemic drugs available and to evaluate the possible role of some nutraceuticals as support therapy in the management of patients with dyslipidemias.

Clinical Role of Epigenetics and Network Analysis in Eye Diseases: A Translational Science Review.

Network medicine is a molecular-bioinformatic approach analyzing gene-gene interactions that can perturb the human interactome. This review focuses on epigenetic changes involved in several ocular diseases, such as DNA methylation, histone and nonhistone post-translational modifications, and noncoding RNA regulators. Although changes in aberrant DNA methylation play a major role in the pathogenesis of most ocular diseases, histone modifications are seldom investigated. Hypermethylation in TGM-2 and hypomethylation in MMP-2/CD24 promoter genes may play a crucial role in pterygium development; hypermethylation in regulatory regions of GSTP1 and OGG1 genes appear to be diagnostic biomarkers of cataract; hypomethylation of TGF-ß1 promoter may trigger glaucoma onset; hypermethylation of the LOXL1 gene might be associated with pseudoexfoliation syndrome. A large panel of upregulated micro-RNAs (miRNAs), including hsa-hsa-miR-494, hsa-let-7e, hsa-miR-513-1, hsa-miR-513-2, hsa-miR-518c, hsa-miR-129-1, hsa-miR-129-2, hsa-miR-198, hsa-miR-492, hsa-miR-498, hsa-miR-320, hsa-miR-503, and hsa-miR-373, ∗ may have a putative role in the development of retinoblastoma. Hypermethylation of H3K4 and hypomethylation of H3K27 at the TGFBIp locus are putative pathogenic mechanisms involved in corneal dystrophies. Determining how, where, and when specific epigenetic changes trigger ocular diseases may provide useful clinical biomarkers for their prevention, diagnosis, and management, as well as innovative drug targets. PF-04523655, a 19-nucleotide methylated double-stranded siRNA targeting the RTP80 gene, showed a dose-related improvement in best-corrected visual acuity (BCVA) in patients affected by diabetic macular edema. The observed results support a clinical network-based research program aimed to clarify the role of epigenetic regulators in the development of ocular diseases and personalized therapy.

Interplay between genetics and epigenetics in modulating the risk of venous thromboembolism: A new challenge for personalized therapy.

Although venous thromboembolism (VTE) shows a polygenic nature, the crossroad between genome and environment is not fully understood. Genetics explains only a part of VTE hereditability and not defined molecular causes are found in approximately 50% of thrombotic patients. Thus, a major understanding of molecular mechanisms may clarify the missing hereditability. Concerning epigenetics, a particular histone modification (citrullination) plays a key role in increasing the rate of venous occlusive events by inducing neutrophil apoptosis and expulsion of neutrophil extra-cellular traps (NETs), which may be useful biomarkers of active disease. Moreover, an over-expression of miR-320a/b, miR-582, miR-195, miR-424-5p, and miR-532, or a down-regulation of miR495, miR-136-5p and miR-26a may improve the accuracy of VTE diagnosis. No clinical studies have focused on DNA methylation in VTE. Nowadays, no validated epigenetics biomarkers are routinely used for diagnosis and prevention of VTE. In the era of personalized therapy, several clinical trials are investigating the putative role of statins, a class of lipid-lowering epigenetic-based drugs, as additional therapeutic agents in VTE. Furthermore, single nucleotide polymorphisms (SNPs) in CYP2C9, VKORC1, and MIR133 genes can help physicians to predict individual warfarin dose requirement. Consequently, a comprehensive understanding of the mechanisms involved in the control of blood clot development is crucial to design novel therapeutic strategies. This review summarizes the current clinical concepts both in genetic and epigenetic VTE framework. Furthermore, we discuss the contribution of the innovative network medicine paradigm into advancing our knowledge about molecular underpinnings needed to support novel VTE diagnostic and therapeutic options.