Analysis of Genes Involved in Oxidative Stress and Iron Metabolism in Heart Failure: A Step Forward in Risk Stratification.

INTRODUCTION: Heart failure (HF) is a clinical syndrome characterized by cardinal symptoms that may be accompanied by signs. It results from structural and/or functional abnormalities of the heart leading to elevated intracardiac pressures and/or inadequate cardiac output at rest and/or during exercise. The prevalence of iron deficiency and anemia justifies the current guidelines recommendation of screening. Genes HP, ACE, MTHFR, HFE, and CYBA are involved in oxidative mechanisms, iron metabolism, and hematologic homeostasis. This study investigates the contribution of variants Hp1/2 (HP), I/D (ACE), C677T (MTHFR), C282Y and H63D (HFE), and C242T (CYBA) to the development of HF, either independently or in epistasis. METHODS: We used a database of 389 individuals, 143 HF patients, and 246 healthy controls. Genotypes were characterized through PAGE electrophoresis, PCR, PCR-RFLP, and multiplex-ARMS. Data analysis was performed with the SPSS® 26.0 software (IBM Corp., Armonk, NY). RESULTS: We observed a significant association between the MTHFR gene and HF predisposition. The presence of allele T and genotype CT constituted risk, while genotype CC granted protection. Epistatic interactions revealed risk between genotype II of the ACE gene and genotypes CC (C282Y) or HH (H63D) of the HFE gene. Risk was also observed for interactions between genotype CC (CYBA)and genotypes 2-2 (HP), CT (MTHFR), or HH (HFE-H63D). CONCLUSION: We concluded that genes HP, ACE, MTHFR, HFE, and CYBA contribute to the susceptibility for HF, individually or in epistasis. This study contributes to the clarification of the role that genes involved in oxidative mechanisms and iron metabolism play in the physiopathology of HF. It is, therefore, a step forward in risk stratification and personalized medicine.

Effects of HCV Clearance with Direct-Acting Antivirals (DAAs) on Liver Stiffness, Liver Fibrosis Stage and Metabolic/Cellular Parameters.

INTRODUCTION: Chronic hepatitis C (CHC) is a clinical and pathological syndrome with various causes and is characterized by varying degrees of hepatocellular necrosis and inflammation. It is a significant cause of liver transplantation and liver-related death worldwide. The hepatic manifestations of CHC are typically characterized by slowly progressing liver fibrosis, which is a non-specific and often disproportionate response to tissue damage. A large majority of HCV patients have extrahepatic manifestations with varying degrees of severity. HCV infection is a risk factor for cardiovascular disease and diabetes mellitus, which increases insulin resistance, oxidative stress, and iron overload and causes chronic systemic inflammation. HCV infection is treated using direct-acting antivirals (DAAs) with cure rates of over 95 percent, minimal side effects, and shorter therapeutic courses. Despite the effective elimination of the virus, it seemed pertinent to understand to what extent HCV clearance eliminates or attenuates all the systemic alterations already induced by the virus during infection and chronicity. OBJECTIVES: Our study aimed to determine whether eliminating HCV with DAAs alters the severity of liver disease (liver stiffness and liver fibrosis stage by TE) and the metabolic/cellular profile of patients with CHC. MATERIALS AND METHODS: A group of 329 CHC patients from a Gastroenterology and Hepatology outpatient department were prospectively studied. Of these, 134 were also studied with DAAs. The liver fibrosis stage was evaluated by transient elastography (TE) using a FibroScan® device, and two groups were established for the analysis of liver stiffness (LS): mild and moderate stiffness (fibrosis F1 and F2; F1/2) and severe stiffness (fibrosis and cirrhosis F3 and F4; F3/4). Metabolic/cellular parameters were evaluated before and after antiviral treatment using standard methods: alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyl-transpeptidase (γ-GT), haptoglobin (Hp), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), free iron (Fe), transferrin saturation (TS), total iron binding capacity (TIBC), ferritin (Ft), glycemia, insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and platelets count. The results were statistically analyzed using SPSS 24.0 for Windows. RESULTS: Comparing the fibrosis stage before and after DAAs treatment, we verify a reduction in LS in 85.7% of patients and an improvement in liver fibrosis stage in 22.2% of them after DAAs treatment. Before DAAs treatment, patients showed a 2.410 risk for higher fibrosis stages (F3/4). Comparing metabolic/cellular parameters before and after DAAs treatment, patients showed lower ALP, AST, ALT, γGT, TG, Fe, TIBC, and Ft values and higher TC, LDL, and Hp values after treatment. As such, HCV elimination reduces iron overload and insulin resistance. On the other hand, it caused dyslipidemia, raising total cholesterol and LDL to levels outside the reference values. The improvement in the liver fibrosis stage by TE was mainly associated with higher baseline platelet count and HDL values and lower insulin resistance. CONCLUSIONS: With this study, we were able to contribute to the knowledge of the effects of HCV elimination with DAAs on liver disease and metabolic profile to improve the quality of treatment and follow-up of these patients after HCV elimination.

Leiomyoma and the importance of genetic variation on genes related to the vasculature system - CßS, MTHFR, NOS3, CYBA, and ACE1.

OBJECTIVE: The link between the systemic vasculature system and tumor biology is here investigated by studying the contribution of CßS (844ins68), MTHFR (677C > T), NOS3 (4a/4b), CYBA (C242T), and ACE1 (I/D) genes to leiomyoma onset, uterus and leiomyoma volumes. METHODS: DNA samples from 130 women with leiomyomas and 527 from healthy women were genotyped by PCR or PCR-RFLP. Qui-square (χ2) or Fisher's exact test were used to test associations. All the mentioned tests were performed in IBM® SPSS® Statistics Version 28. Statistical significance was defined as a p-value < 0.05. RESULTS: Results revealed that CßS (in the codominant and allelic models, p = 0.044 and, p = 0.015, OR = 1.791 [1.114-2.879], respectively), MTHFR (in the codominant, allelic and dominant models, p = 0.009, p = 0.002, OR = 0.585 [0.416-0.824] and p = 0.003, OR = 0.527 [0.346-0.802], respectively) and ACE1 (dominant model, p = 0.045, OR = 0.639 [0.411-0.992]) genes are associated with leiomyoma onset. NOS3 4a4a genotype is associated with a lower uterus volume (p = 0.004). This study also uncovers intriguing epistatic interactions among some genes that further accentuate their roles in disease modulation. Indeed, the epistatic interactions between the CC genotype (MTHFR) and (+/+) (CßS; p = 0.003), 4b4b (NOS3; p = 0.006, OR = 2.050 [1.223-3.439]) or DD (ACE1; p < 0.001, OR = 2.362 [1.438-3.880]) were shown to be associated with the disease, while 4a presence (NOS3) in epistasis with I presence (ACE1), increased the effect protection having just the I allele presence (p = 0.029, OR = 0.446 [0.214-0.930]). CONCLUSIONS: We conclude that variation in genes related to the systemic vascular system can play a role in the onset and development of leiomyoma.

Genetic Modulation of HPV Infection and Cervical Lesions: Role of Oxidative Stress-Related Genes.

Human papillomavirus (HPV) infection is a necessary but not sufficient factor for the development of invasive cervical cancer (ICC) and high-grade intraepithelial lesion (HSIL). Oxidative stress is known to play a crucial role in HPV infection and carcinogenesis. In this study, we comprehensively investigate the modulation of HPV infection, HSIL and ICC, and ICC through an exploration of oxidative stress-related genes: CßS, MTHFR, NOS3, ACE1, CYBA, HAP, ACP1, GSTT1, GSTM1, and CYP1A1. Notably, the ACE1 gene emerges as a prominent factor with the presence of the I allele offering protection against HPV infection. The association of NOS3 with HPV infection is perceived with the 4a allele showing a protective effect. The presence of the GSTT1 null mutant correlates with increased susceptibility to HPV infection, HSIL and ICC, and ICC. This study also uncovers intriguing epistatic interactions among some of the genes that further accentuate their roles in disease modulation. Indeed, the epistatic interactions between the BB genotype (ACP1) and DD genotype (ECA1) were shown to increase the risk of HPV infection, and the interaction between BB (ACP1) and 0.0 (GSTT1) was associated with HPV infection and cervical lesions. These findings underscore the pivotal role of four oxidative stress-related genes in HPV-associated cervical lesions and cancer development, enriching our clinical understanding of the genetic influences on disease manifestation. The awareness of these genetic variations holds potential clinical implications.

Genetic Modulation of the Erythrocyte Phenotype Associated with Retinopathy of Prematurity-A Multicenter Portuguese Cohort Study.

The development of retinopathy of prematurity (ROP) may be influenced by anemia or a low fetal/adult hemoglobin ratio. We aimed to analyze the association between DNA methyltransferase 3 ß (DNMT3B) (rs2424913), methylenetetrahydrofolate reductase (MTHFR) (rs1801133), and lysine-specific histone demethylase 1A (KDM1A) (rs7548692) polymorphisms, erythrocyte parameters during the first week of life, and ROP. In total, 396 infants (gestational age < 32 weeks or birth weight < 1500 g) were evaluated clinically and hematologically. Genotyping was performed using a MicroChip DNA on a platform employing iPlex MassARRAY®. Multivariate regression was performed after determining risk factors for ROP using univariate regression. In the group of infants who developed ROP red blood cell distribution width (RDW), erythroblasts, and mean corpuscular volume (MCV) were higher, while mean hemoglobin and mean corpuscular hemoglobin concentration (MCHC) were lower; higher RDW was associated with KDM1A (AA), MTHFR (CC and CC + TT), KDM1A (AA) + MTHFR (CC), and KDM1A (AA) + DNMT3B (allele C); KDM1A (AA) + MTHFR (CC) were associated with higher RDW, erythroblasts, MCV, and mean corpuscular hemoglobin (MCH); higher MCV and MCH were also associated with KDM1A (AA) + MTHFR (CC) + DNMT3B (allele C). We concluded that the polymorphisms studied may influence susceptibility to ROP by modulating erythropoiesis and gene expression of the fetal/adult hemoglobin ratio.

Influence of the TAS2R38 Gene Single Nucleotide Polymorphisms in Metabolism and Anthropometry in Thyroid Dysfunction.

The gene TAS2R38 single nucleotide polymorphisms (SNPs-P49A, A262V and V296I) can condition bitter tasting by PAV (proline-alanine-valine) and non-bitter-tasting by AVI (alanine-valine-isoleucine) homozygosity. We evaluated this polymorphisms association with thyroid function, metabolism and anthropometry parameters determined by: Endpoint analysis (SNPs); DXA (fat mass-%, total fat mass-kg, lean mass-kg); Standard methods (lipid metabolism parameters, HbA1c-%, glycemia-mg/dL, insulinemia-µIU/mL, HOMA-IR, uricemia-mg/dL, calcemia-mg/dL and BMI-kg/m2); ELISA (leptinemia-ng/mL); Spectrophotometry (Angiotensin Converting Enzyme activity-UI/L). Statistics: SPSS program; OR [IC95%]; p < 0.05. Sample: 114 hypothyroid, 49 hyperthyroid, and 179 controls. An association between A262V-valine-valine and hypothyroidism/hyperthyroidism was verified (OR = 2.841; IC95% [1.726-4.676]), p < 0.001/OR = 8.915; IC95% [4.286-18.543]), p < 0.001). Protector effect from thyroid dysfunction: A262V-alanine-valine (OR = 0.467; IC95% [0.289-0.757], p = 0.002/OR = 0.132; IC95% [0.056-0.309], p < 0.001) and PAV (OR = 0.456; IC95% [0.282-0.737], p = 0.001/OR = 0.101; IC95% [0.041-0.250], p < 0.001). Higher parameter values associated with genotypes were: fat-mass-% (V296I-valine-isoleucine), lean-mass (P49A-proline-proline; PVI), leptin (AVI), HbA1c (A262V-alanine-valine) and lower values in lean-Mass (AVI; PVV), leptin (A262V-alanine-alanine), HbA1c (PVV), uricemia (V296I-valine-isoleucine), glycemia (A262V-alanine-alanine; AAV) and plasma triglycerides (PVV). In conclusion, TAS2R38 influences thyroid function, body composition and metabolism. Bitter taste perception (PAV) and the genotype A262V-alanine-valine can protect from thyroid dysfunction. AVV, PVV and genotype A262V-valine-valine may confer higher predisposition for thyroid dysfunction, particularly PVV for hyperthyroidism.

Sleep Patterns, Eating Behavior and the Risk of Noncommunicable Diseases.

Sleep is extremely important for the homeostasis of the organism. In recent years, various studies have been carried out to address factors related to sleep patterns and their influence on food choices, as well as on the onset of chronic noncommunicable diseases. The aim of this article is to provide a scientific literature review on the possible role of sleep patterns on eating behavior and the risk of noncommunicable diseases. A search was performed on Medline (PubMed interface) using several keywords (e.g., "Factors Influencing Sleep" OR "Sleep and Chronic Diseases"). Articles published between 2000 and the present date that relate sleep to cyclic metabolic processes and changes in eating behavior were selected. Changes in sleep patterns are increasingly detected today, and these modifications are mainly caused by work and lifestyle conditions as well as a growing dependence on electronic devices. Sleep deprivation and the resultant short sleep duration lead to an increased appetite via an increase in the hunger hormone (ghrelin) and a decrease in the satiety hormone (leptin). Nowadays, sleep is undervalued, and thus often impaired, with consequences for the performance of various body systems. Sleep deprivation alters physiological homeostasis and influences eating behavior as well as the onset of chronic diseases.

The Paramount Importance of Renal Dysfunction in Heart Failure Prognosis - Results from the REFERENCE study / La importancia primordial de la disfunción renal en el pronóstico de la insuficiencia cardíaca - Resultados del estudio REFERENCE

Aims: In heart failure patients renal dysfunction represents impaired tissue perfusion. We investigated the association of customarily used renal function parameters with short-term prognosis in patients admitted with acute decompensated heart failure in class III or IV of New York Heart Association. Material and Methods: Univariate Cox proportional hazard model was used to assess the relationship between variables and outcomes. Survival curves were designed using the Kaplan-Meier method. Results: We followed 65 patients for a median of 13.7 (Q1-Q3 6.7-18.9) months. Variables associated with an increased risk for short-term rehospitalization were baseline urea (HR: 1.098, 95% CI: 1.022-1.179, P-value=0.01), admission urea (HR: 1.048, 95% CI: 1.013-1.084, P-value=0.006), baseline creatinine (HR: 1.111, 95% CI: 1.004-1.229, P-value=0.041), admission creatinine (HR: 1.047, 95% CI: 1.005-1.092, P-value=0.027) and admission glomerular filtration rate <30 mL/min (HR: 3.535, 95% CI: 1.467-8.518, P-value=0.005). Increased risk for short-term mortality was associated with baseline urea (HR: 1.145, 95% CI: 1.032-1.270, P-value=0.010), admission urea (HR: 1.076, 95% CI: 1.021-1.135, P-value=0.006), baseline creatinine (HR: 1.157, 95% CI: 1.009-1.328, P value=0.037), admission creatinine (HR: 1.127, 95% CI: 1.055-1.204, P-value<0.001) and admission glomerular filtration rate <30 mL/min (HR: 9.791, 95% CI: 2.855-33.580, P-value<0.001). Variables associated with an increased risk for end of follow-up mortality were admission urea (HR: 1.056, 95% CI: 1.019-1.094, P-value=0.003), admission creatinine (HR: 1.104, 95% CI: 1.054-1.156, P- value<0.001) and admission glomerular filtration rate <30 mL/min (HR: 3.906, 95% CI: 1.7208.871, P- value=0.001). Conclusion: Renal dysfunction was a reliable predictor of worse prognosis as several parameters correlated with short-term prognosis. (AU)

Introducción: En la insuficiencia cardíaca, la disfunción renal representa hipoperfusión tisular. Investigamos la asociación entre parámetros utilizados cotidianamente y el pronóstico precoz de enfermos ingresados por insuficiencia cardíaca descompensada en clase III o IV de la New York Heart Association. Material y métodos: Aplicamos el modelo de riesgo proporcional de Univariante Cox y curvas de supervivencia de Kaplan-Meier. Resultados: La mediana de seguimiento de los 65 enfermos fue de 13.7 (Q1-Q3 6.7-18.9) meses. Se correlacionaron con el reingreso precoz la urea basal (HR: 1.098, 95% CI: 1.022-1.179, P-value=0.01), la urea al ingreso (HR: 1.048, 95% CI: 1.013-1.084, P-value=0.006), la creatinina basal (HR: 1.111, 95% CI: 1.004-1.229, P-value=0.041), creatinina al ingreso (HR: 1.047, 95% CI: 1.005-1.092, P-value=0.027) y la tasa de filtración glomerular <30 mL/min al ingreso <30 mL/min (HR: 3.535, 95% CI: 1.467-8.518, P-value=0.005). El riesgo de mortalidad precoz se correlacionó con la urea basal (HR: 1.145, 95% CI: 1.032-1.270, P-value=0.010), la urea al ingreso (HR: 1.076, 95% CI: 1.021-1.135, P-value=0.006), la creatinina basal (HR: 1.157, 95% CI: 1.009-1.328, P value=0.037), creatinina al ingreso (HR: 1.127, 95% CI: 1.055-1.204, P-value<0.001) y la tasa de filtración glomerular <30 mL/min al ingreso <30 mL/min (HR: 9.791, 95% CI: 2.855-33.580, P-value<0.001). Se correlacionarón con la mortalidad al final del seguimiento la urea al ingreso (HR: 1.056, 95% CI: 1.019-1.094, P-value=0.003), la creatinina al ingreso (HR: 1.104, 95% CI: 1.054-1.156, P- value<0.001) y la tasa de filtración glomerular <30 mL/min al ingreso (HR: 3.906, 95% CI: 1.7208.871, P- value=0.001). Conclusiones: La disfunción renal fue un predictor de peor pronóstico precoz. (AU)

Complete blood count parameters as biomarkers of retinopathy of prematurity: a Portuguese multicenter study.

PURPOSE: To evaluate complete blood count (CBC) parameters in the first week of life as predictive biomarkers for the development of retinopathy of prematurity (ROP). METHODS: Multicenter, prospective, observational study of a cohort of preterm infants born with gestational age (GA) < 32 weeks or birth weight < 1500 g in eight Portuguese neonatal intensive care units. All demographic, clinical, and laboratory data from the first week of life were collected. Univariate logistic regression was used to assess risk factors for ROP and then multivariate regression was performed. RESULTS: A total of 455 infants were included in the study. The median GA was 29.6 weeks, and the median birth weight was 1295 g. One hundred and seventy-two infants (37.8%) developed ROP. Median values of erythrocytes (p < 0.001), hemoglobin (p < 0.001), hematocrit (p < 0.001), mean corpuscular hemoglobin concentration (p < 0.001), lymphocytes (p = 0.035), and platelets (p = 0.003) of the group of infants diagnosed with ROP any stage were lower than those without ROP. Mean corpuscular volume (MCV) (p = 0.044), red blood cell distribution width (RDW) (p < 0.001), erythroblasts (p < 0.001), neutrophils (p = 0.030), neutrophils-lymphocytes ratio (p = 0.028), and basophils (p = 0.003) were higher in the ROP group. Higher values of MCV, erythroblasts, and basophils remained significantly associated with ROP after multivariate regression. CONCLUSION: In our cohort, the increase in erythroblasts, MCV, and basophils in the first week of life was significantly and independently associated with the development of ROP. These CBC parameters may be early predictive biomarkers for ROP.

Role of Inflammatory/Immune Response and Cytokine Polymorphisms in the Severity of Chronic Hepatitis C (CHC) before and after Direct Acting Antiviral (DAAs) Treatment.

Host regulatory immune response is involved in the hepatic inflammatory process caused by the hepatitis C virus (HCV). We aimed to determine if HCV clearance with direct-acting antivirals (DAAs) changes the hepatic fibrosis stage, biochemical parameters of liver injury, and inflammatory/immune responses. Sample: 329 chronic hepatitis C (CHC) patients, 134 of them treated with DAAs. Liver fibrosis was evaluated by transient elastography (FibroScan), biochemical and cellular parameters were determined by standard methods, cytokine concentration by enzyme-linked immunoabsorbent assay (ELISA), and genetic polymorphisms by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or endpoint genotyping. Before DAA treatment, severe fibrosis or cirrhosis (F3/4) was associated with higher values of tumor necrosis factor-alpha (TNF-α) and genotypes transforming growth factor-beta-509 C/T_CC (TGF-ß-509 C/T_CC), interleukine-10-1082 T/C_CC (IL-10-1082 T/C_CC), and IL-10-592 G/T_GT. After DAA treatment, fewer F3/4 patients and lower values of TNF-α were found. Patients with TNF-α-308 G/A_GG and IL-10-592 G/T_GT were at risk for F3/4. Lack of improvement of liver fibrosis was associated with lower baseline values of platelet count for genotypes TNF-α-308 G/A_GG and haplotype TT/GG of IL-10-1082 T/C and IL-10-592 G/T. Our study showed decreased liver fibrosis/inflammation and normalization of liver injury biomarkers after DAA treatment. It also points to the importance of suppressing the pro-inflammatory response by DAAs in the resolution of hepatitis C, contributing to the improvement of liver damage evaluated by transient elastography.

Development and Implementation of a Nutritional Education Program Aimed at Improving the Integration Process of Young Orphan Refugees Newly Arrived in Portugal.

(1) Background: Refugees are a population group at imminent risk of death, being forced to migrate to countries with different cultures. Many of the refugees are at great risk of malnutrition, especially adolescent orphans. The aim of the study was to establish a nutritional and food education program to improve the integration process of young orphan refugees newly arrived in Portugal. (2) Methods: A nutrition and food education program with nine sessions of food and nutrition education over 12 weeks was carried out by a nutritionist from March to June 2016, in 15 young residents of the Reception Center for Refugee Children. The program included the application of a nutritional knowledge questionnaire, an anthropometric assessment, and the collection of data on food habits and lifestyle. The evaluation of the program was carried out by comparing the initial and final scores of the nutritional knowledge questionnaire. (3) Results: There was an improvement in nutritional knowledge among the adolescents, and a direct relationship between attendance at the sessions and improvement of this knowledge was found. Non-significant changes were observed in some anthropometric measurements between the beginning and the ending of the program. (4) Conclusions: This food education program contributed to a better understanding by young orphan refugees newly arrived in Portugal of the foods available in Portugal and of the Portuguese gastronomy.

Retinopathy of prematurity: A review of pathophysiology and signaling pathways.

Retinopathy of prematurity (ROP) is a vasoproliferative disorder of the retina and a leading cause of visual impairment and childhood blindness worldwide. The disease is characterized by an early stage of retinal microvascular degeneration, followed by neovascularization that can lead to subsequent retinal detachment and permanent visual loss. Several factors play a key role during the different pathological stages of the disease. Oxidative and nitrosative stress and inflammatory processes are important contributors to the early stage of ROP. Nitric oxide synthase and arginase play important roles in ischemia/reperfusion-induced neurovascular degeneration. Destructive neovascularization is driven by mediators of the hypoxia-inducible factor pathway, such as vascular endothelial growth factor and metabolic factors (succinate). The extracellular matrix is involved in hypoxia-induced retinal neovascularization. Vasorepulsive molecules (semaphorin 3A) intervene preventing the revascularization of the avascular zone. This review focuses on current concepts about signaling pathways and their mediators, involved in the pathogenesis of ROP, highlighting new potentially preventive and therapeutic modalities. A better understanding of the intricate molecular mechanisms underlying the pathogenesis of ROP should allow the development of more effective and targeted therapeutic agents to reduce aberrant vasoproliferation and facilitate physiological retinal vascular development.

Genetic Contribution of the Adrenergic, Cholinergic, and Serotonergic Systems to Leiomyoma Development and Treatment.

The link between the autonomic nervous system and tumor biology is being unfold. We aim to study the contribution of genes of the adrenergic (ADBR2 - rs1042713, NM_000024.6:c.46G>A, NP_000015.2:p. Gly16Arg), cholinergic (CHRNA5 - rs16969968, NM_000745.3:c.1192G>A, NP_000736.2:p.Asp398Asn), and serotonergic systems (SLC6A4 - 5-HTTVNTR-intron2, HTR2A - rs6313, NM_000621.5:c.102C>T, NP_ 001365853 .1: p. Ser 34=) to gynecological tumorigenesis and their treatment by embolization. A total of 517 DNA samples from women were analyzed. Samples were genotyped by PCR, PCR-RFLP and EndPoint genotyping. Results show a statistically significant association between the AA genotype of the ADBR2 gene and GG genotype of the CHRNA5 gene with leiomyoma (OR = 2.311; p = 0.003 and OR = 2.165; p = 0.001, respectively), and the epistatic interaction between genotypes increases the risk (OR = 2.458; p= 0.043). The GG genotype (CHRNA5) shows a lower reduction of the volume of the main leiomyoma after treatment (p=0.015). Combination of the genotypes 12/12-AA (SLC6A4 - ADBR2) increases the risk to leiomyoma (OR = 2.540, p= 0.030). TT genotype of HTR2A gene in combination with any of the two risk genotypes (of ADBR2 or CHRNA5) increases substantially the risk (OR = 5.266, p = 0.006; OR = 6.364, p=0.007, respectively). We conclude that ADBR2 and CHRNA5 genes have a relevant role that is enhanced by the epistatic relationship with the genes HTR2A and SLC6A4. CHRNA5 gene may also be a modulator of the success of embolization. We confirm the contribution of the genetics of Autonomous Nervous System to tumor biology.

The interplay between HPV, other Sexually Transmissible Infections and genital microbiome on cervical microenvironment (MicroCervixHPV study).

Background: The importance of Cervicovaginal Microbiota in protecting against infections (such as HPV) is already well established, namely through Lactobacillus spp., as well as the mechanism through which HPV leads to Cervical Neoplasia. However, it is not possible to classify HPV as a complete carcinogen. Thus, the importance of exploring Cervicovaginal dysbiosis with the intention of deciphering this interaction with HPV, takes on greater relevance. The main objectives of this study were: 1) Comparison of the MCV composition of women with or without HPV and women with ASCUS or LSIL; 2) Characterization of cytokines present in the vaginal microenvironment; 3) Evaluation of the blood count ratios as prognostic systemic inflammatory biomarkers; 4) Correlation between MCV, HPV serotypes and cytokines. Methods: This was a retrospective, observational, multicenter, cross-sectional study. CVM analysis was performed by isolation RNA and sequencing on a NGS platform. Cytokine concentrations of CVM were obtained through Multiplex platform. Statistical analysis was performed in SPSS v 26.0. An α of 0.05 was considered statistically significant. Results: Highlighting the core of the study, CVM types of CST I and CST IV were found to influence the emergence of cervical lesions. Neutrophil-to-Lymphocyte ratio was found to impact the prognosis of ASCUS. Within CVM, Lactobacillus prevent the growth of other CST IV species, while the latter express symbiotic relationships with each other and show affinity for specific HPV serotypes. At last, RANTES chemokine is significantly elevated in cervicovaginal infections. Conclusion: The importance of using vaginal cytokine profiles and CVM is highlighted in the hypothesis of prevention of Cervical Neoplasia development, as well as in its use as a prognostic biomarker. Taken together, these insights are one step closer to personalized medicine.

ABCA1 Polymorphism R1587K in Chronic Hepatitis C Is Gender-Specific and Modulates Liver Disease Severity through Its Influence on Cholesterol Metabolism and Liver Function: A Preliminary Study.

Chronic hepatitis C (CHC) progression is highly variable and can be influenced by lipid metabolism. The ATP-binding cassette transporter A1 (ABCA1) is involved in lipid metabolism and mediates cholesterol efflux from liver cells. ABCA1 gene polymorphism rs2230808 (R1587K) modulates lipid levels as it is located in an ABCA1 protein domain, which is essential for cholesterol efflux. We aimed to analyze the role of ABCA1 polymorphism R1587K (rs2230808) in modulating the biochemical parameters of lipid metabolism and liver function and its association with liver disease severity, according to gender. A total of 161 CHC patients were clinically, histologically, and biochemically evaluated. Genotyping was performed by melting-curve analysis and statistical analysis by SPSS 24.0. There were significant differences between ABCA1_rs2230808 genotypes and total cholesterol, γGT (γ-glutamyl-transpeptidase), and HCV-RNA. Gender differences: in females, ABCA1_rs2230808 (GG or GA) was associated with higher HCV-RNA serum levels; in males, ABCA1_rs2230808 (GG or GA) was associated with higher γGT, lower total cholesterol, increased risk for γGT ≥ 38 UI/L, and total cholesterol < 4.92 mmol/L. Only in the case of males were higher γGT and lower total cholesterol associated with severe fibrosis and steatosis. Total cholesterol < 4.92 mmol/L also associates with severe necroinflammation. We conclude that ABCA1_rs2230808 is gender-specific. ABCA1_rs2230808 Allele G was associated with different clinical and biochemical parameters, which are related to more severe liver disease.

Exposure to heavy metals and red blood cell parameters in children: A systematic review of observational studies.

Background: Mechanistic studies show that heavy metals interfere with the hematopoietic system by inhibiting key enzymes, which could lead to anemia. However, the link between children's exposure and red blood cell (RBC) parameters has been inconsistent. We aimed to summarize evidence on human studies exploring the association between exposure to lead, mercury, cadmium, arsenic, and chromium VI and RBC parameters in children. Methods: Following the PRISMA guidelines, we searched PubMed, Scopus, and Web of Science databases for studies published between January 2010 and April 2022. Eligible papers included human observational studies that directly assessed exposure (internal dose) to the heavy metals under study and RBC parameters in participants aged ≤ 18 years. We excluded studies using hospital-based samples. Study quality was assessed using the National Institutes of Health's Quality Assessment Tools for Cohort and Cross-Sectional Studies. We synthesized the evidence using vote counting based on the direction of the relationship. Results: Out of 6,652 retrieved papers, we included a total of 38 (33 assessing lead, four mercury, two cadmium, and two arsenic; chromium VI was not assessed in any included paper). More than half of the studies were conducted in Asia. We found evidence of a positive relationship between lead concentration and hemoglobin (proportion of studies reporting negative relationships = 0.750; 95% Confidence Interval (CI) 0.583, 0.874) and mean corpuscular hemoglobin (0.875; 95% CI 0.546, 0.986), and a positive relationship with red cell distribution width (0.000; 95%CI 0.000, 0.379). When considering only good-quality studies (24% of the Pb studies), only the relationship with hemoglobin levels remained (0.875; 95% CI: 0.546, 0.986). Conclusion: We found evidence of a negative relationship between lead concentration and hemoglobin and mean corpuscular hemoglobin and of a positive relationship with red cell distribution width in children. We also identified a need to conduct more studies in European countries. Future studies should use standardized practices and make efforts to increase study quality, namely by conducting comprehensive longitudinal studies. Our findings support the need to take further actions to limit heavy metal exposure during childhood.

Parámetros hematológicos descuidados en el pronóstico dela insuficiencia cardíaca-Evidencia del estudio REFERENCE / Neglected hematological parameters in heart failure prognosis – Disclosures from the REFERENCE study

Aims: In heart failure patients, anemia and iron deficiency are predictors of poor outcome. We studied the association of anemia, iron deficiency and relatedhematological parameters with short-term rehospitalization, short-term all-cause mortality and end of follow-up all-cause mortality in heart failure patients.Material and Methods: Anemia, iron deficiency, red cell distribution width and erythropoietin were assessed in patients hospitalized with acute decompensated heart failure.Univariate Cox proportional hazard model was used to assess the relationship between variables and outcomes.Results: 65 patients were followed for a median of 13.7 (Q1-Q3 6.7-18.9) months. Mean age was 79.2 (SD 10.8) years. The mean left ventricular ejectionfraction was 50.38 ± 19.07 %. Variables associated with an increased risk for short-term rehospitalization were red cell distribution width (HR 1.35; 95% CI 1.16-1.58), anemia (HR 3.81; 95% CI 1.29-11.28) and anemia with iron deficiency (HR 3.50; 95% CI 1.30-9.38). Increased risk for short-term mortality was associatedwith red cell distribution width (HR 1.83; 95% CI 1.29-2.59), erythropoietin (HR 1.38; 95% CI 1.04-1.82), absolute iron deficiency (HR 7.22; 95% CI 1.50-34.81)and anemia with iron deficiency (HR 4.48; 95% CI 1.26-15.88). Variables associated with increased risk for end of follow-up mortality were red cell distributionwidth (HR 1.31; 95% CI 1.12-1.54) and erythropoietin (HR 1.29; 95% CI 1.11-1.49).Conclusions: Conclusions: Anemia and red cell distribution width correlated with higher risk for short-term rehospitalization. Absolute iron deficiency, red celldistribution width and erythropoietin were associated with higher risk for short-term mortality. Red cell distribution width and erythropoietin were associatedwith higher risk for end of follow-up mortality. (AU)

Retinopathy of prematurity: contribution of inflammatory and genetic factors.

Retinopathy of prematurity (ROP) is a retinal vasoproliferative disorder that represents an important cause of childhood visual impairment and blindness. Although oxidative stress has long been implicated in ROP etiology, other prenatal and perinatal factors are also involved. This review focuses on current research involving inflammation and genetic factors in the pathogenesis of ROP. Increasing evidence suggests that perinatal inflammation or infection contributes to ROP pathogenesis. Cytokines and chemokines with a fundamental role in inflammatory responses and that significantly contributing to angiogenesis are analyzed. Microglia cells, the retinal-resident macrophages, are crucial for retinal homeostasis, however, under sustained pathological stimuli release exaggerated amounts of inflammatory mediators and can promote pathological neovascularization. Current modulation of angiogenic cytokines, such as treatment with antibodies to vascular endothelial growth factor (anti-VEGF), has shown efficacy in the treatment of ocular neovascularization; however, some patients are refractory to anti-VEGF agents, suggesting that other angiogenic or anti-angiogenic cytokines need to be identified. Much evidence suggests that genetic factors contribute to the phenotypic variability of ROP. Several studies have implicated the involvement of candidate genes from different signaling pathways in the development of ROP. However, a genetic component with a major impact on ROP has not yet been discovered. Most studies have limitations and did not replicate results. Future research involving bioinformatics, genomics, and proteomics may contribute to finding more genes associated with ROP and may allow discovering better solutions in the management and treatment of ROP.

Arginine and Arginases Modulate Metabolism, Tumor Microenvironment and Prostate Cancer Progression.

Arginine availability and activation of arginine-related pathways at cancer sites have profound effects on the tumor microenvironment, far beyond their well-known role in the hepatic urea cycle. Arginine metabolism impacts not only malignant cells but also the surrounding immune cells behavior, modulating growth, survival, and immunosurveillance mechanisms, either through an arginase-mediated effect on polyamines and proline synthesis, or by the arginine/nitric oxide pathway in tumor cells, antitumor T-cells, myeloid-derived suppressor cells, and macrophages. This review presents evidence concerning the impact of arginine metabolism and arginase activity in the prostate cancer microenvironment, highlighting the recent advances in immunotherapy, which might be relevant for prostate cancer. Even though further research is required, arginine deprivation may represent a novel antimetabolite strategy for the treatment of arginine-dependent prostate cancer.

Insuficiencia Cardíaca: una Enfermedad Maligna Conclusiones del Estudio REFERENCE / Heart Failure a Malignant Disease- Insights from the REFERENCE Study

Aims: Heart failure (HF) short-term prognosis persists poor. We studied the rate of short-term readmission due to HF, short-term all-cause mortality and end of follow-up all-cause mortality. Material and Methods: We assessed patients admitted with acuteHF in class III or IV of NYHA. Univariate Cox proportional hazard model was performed. Survival curves were plotted using the Kaplan-Meier method and compared with the log-rank test for readmission days post-discharge. Results: We followed 65 patients for a median of 13.7 (Q1-Q3 6.7-18.9) months. The 30-day post-discharge readmission rate was 13.8%, the 90-day post-discharge readmission percentage was 33.8% and year readmission rate 61.5%. The 30-day mortality rate was 10.8% and 90- day mortality was 18.5%. Year mortality rate was 36.9% and 40% of the patients were deceased by the end of the follow-up. Length of stay (LOS) correlated with short-term readmission in the general population (HR: 1.022, 95% CI: 1.009-1.036, P value<0.001) and in Heart Failure with Reduced Ejection Fraction patients (HFrEF) (HR: 1.029, 95% CI: 1.008-1.050, Pvalue=0.006). The number of hospitalizations correlated with short-term readmission in the general population (HR: 1.543, 95% CI: 1.224-1.945, P- value<0.001) and in the Heart Failure with Mid-Range Ejection Fraction subgroup (HFmrEF) (HR: 2.814, 95% CI: 1.075-7.365, P- value=0.035). In the Heart Failure with Preserved Ejection Fraction (HFpEF) subgroup both the LOS per specific admission (HR: 1.063, 95% CI: 1.006-1.123, P value=0.030) and the accumulated LOS for all admissions (HR: 1.051, 95% CI: 1.008-1.095, P value=0.019) were associated with end of followup mortality... (AU)

Introducción: La insuficiencia cardíaca (IC) tiene un mal pronóstico a corto plazo. Estudiamos las tasas de reingreso precoz por IC, mortalidad global precoz y mortalidad global al final del seguimiento. Material y métodos: Evaluamos a enfermos ingresados por IC descompensada en clase III o IV de la NYHA. Se utilizó el modelo de riesgo proporcional de Univariante Cox. Se aplicó el método de Kaplan-Meier para obtener curvas de supervivencia para dias de reingreso pós-alta e se comparó al log-rank test. Resultados: La mediana de seguimiento de los 65 enfermos fue de 13.7 (Q1-Q3 6.7-18.9) meses. La tasa de reingreso a los 30 días del alta fue del 13.8%, a los 90 días del alta fue del 33.8% y la tasa anual fue del 61.5%. La mortalidad a los 30 días del alta fue del 10.8% y del 18.5% a los 90 días. La mortalidad anual fue del 36.9% y al final del seguimiento del 40%. La duración del ingreso se correlacionó con el reingreso precoz en la población general (HR: 1.022, 95% CI: 1.009-1.036, P-value<0.001) y en el subgrupo con fracción de eyección reducida (HR: 1.029, 95% CI: 1.008-1050, P-value=0.006). El número de ingresos fue un marcador de mal pronóstico para el reingreso precoz en la población general (HR: 1.543, 95% CI: 1.224-1.945, P-value<0.001) y en el subgrupo con fracción de eyección intermedia (HR: 2.814, 95% CI: 1,075-7,365, P-value=0.035). En el subgrupo con fracción de eyección preservadala duración de ingreso por hospitalización... (AU)