Genetic study of the hepcidin gene (HAMP) promoter and functional analysis of the c.-582A > G variant

Background Hepcidin acts as the main regulator of iron homeostasis through regulation of intestinal absorption and macrophage release. Hepcidin deficiency causes iron overload whereas its overproduction is associated with anaemia of chronic diseases. The aims of the study were: to identify genetic variants in the hepcidin gene (HAMP) promoter, to asses the associations between the variants found and iron status parameters, and to functionally study the role on HAMP expression of the most frequent variant. Results The sequencing of HAMP promoter from 103 healthy individuals revealed two genetic variants: The c.-153C > T with a frequency of 0.014 for allele T, which is known to reduce hepcidin expression and the c.-582A > G with a 0.218 frequency for allele G. In an additional group of 224 individuals, the c.-582A > G variant genotype showed no association with serum iron, transferrin or ferritin levels. The c.-582G HAMP promoter variant decreased the transcriptional activity by 20% compared to c.-582A variant in cells from the human hepatoma cell line HepG2 when cotransfected with luciferase reporter constructs and plasmid expressing upstream stimulatory factor 1 (USF1) and by 12-14% when cotransfected with plasmid expressing upstream stimulatory factor 2 (USF2). Conclusions The c.-582A > G HAMP promoter variant is not associated with serum iron, transferrin or ferritin levels in the healthy population. The in vitro effect of the c.-582A > G variant resulted in a small reduction of the gene transactivation by allele G compared to allele A. Therefore the effect of the variant on the hepcidin levels in vivo would be likely negligible. Finally, the c.-153C > T variant showed a frequency high enough to be considered when a genetic analysis is done in iron overload patientsThis work was supported by a grant from the Fondo de Investigaciones Sanitarias del Instituto de Salud Carlos III (PI052249 to LL) and Xunta de Galicia (PGIDIT06PXIC9101136PN)S

Insulin resistance (HOMA-IR) cut-off values and the metabolic syndrome in a general adult population: effect of gender and age: EPIRCE cross-sectional study

Background: Insulin resistance has been associated with metabolic and hemodynamic alterations and higher cardio metabolic risk. There is great variability in the threshold homeostasis model assessment of insulin resistance (HOMA-IR) levels to define insulin resistance. The purpose of this study was to describe the influence of age and gender in the estimation of HOMA-IR optimal cut-off values to identify subjects with higher cardio metabolic risk in a general adult population. Methods: It included 2459 adults (range 20-92 years, 58.4% women) in a random Spanish population sample. As an accurate indicator of cardio metabolic risk, Metabolic Syndrome (MetS), both by International Diabetes Federation criteria and by Adult Treatment Panel III criteria, were used. The effect of age was analyzed in individuals with and without diabetes mellitus separately. ROC regression methodology was used to evaluate the effect of age on HOMA-IR performance in classifying cardio metabolic risk. Results: In Spanish population the threshold value of HOMA-IR drops from 3.46 using 90th percentile criteria to 2.05 taking into account of MetS components. In non-diabetic women, but no in men, we found a significant non-linear effect of age on the accuracy of HOMA-IR. In non-diabetic men, the cut-off values were 1.85. All values are between 70th-75th percentiles of HOMA-IR levels in adult Spanish population. Conclusions: The consideration of the cardio metabolic risk to establish the cut-off points of HOMA-IR, to define insulin resistance instead of using a percentile of the population distribution, would increase its clinical utility in identifying those patients in whom the presence of multiple metabolic risk factors imparts an increased metabolic and cardiovascular risk. The threshold levels must be modified by age in non-diabetic women

Novel synthetic routes of large-pore magnetic mesoporous nanocomposites (SBA-15/Fe3O4) as potential multifunctional theranostic nanodevices

In this paper, novel magnetic silica nanocomposites were prepared by anchoring magnetite nanoparticles onto the outer surface of mesoporous SBA-15 silica; the magnetic nanoparticles were prepared by microemulsion and solvothermal methods, varying the synthesis conditions in order to control the final physicochemical, textural and magnetic properties. The morphology and mesostructure of the materials were characterized by X-ray diffraction (XRD), Fourier-Transform Infrared Spectroscopy (FTIR), N2 adsorption–desorption, and Transmission and Scanning Electron Microscopy (TEM and SEM). Magnetic silica nanocomposites feature a two-dimensional hexagonal arrangement constituted by a homogeneous pore channel system with diameters between 13 and 18 nm and a Brunauer–Emmett–Teller (BET) surface area higher than 260 m2 g−1. The different morphologies of the samples are given by the presence of diverse magnetic nanoparticle arrangements covalently linked onto the outer surface of the mesoporous silica rods. This confers on them a superparamagnetic behaviour with a magnetic response between 50–80 emu g−1, even though the weight percent of magnetite present in the samples does not exceed 21.7%. In addition, the magnetic nanocomposites exhibit magnetic hyperthermia with moderate Specific Absorption Rate (SAR) valuesThis work was supported in part by MINECO (Spain) and FEDER Funds (projects MAT 2015-67458-P and CTQ2016-79461-R); and the European Commission (PANA project, Call H2020-NMP-2015-two-stage, Grant 686009; and the MADIA project, Call H2020-ICT-2016-1, Grant 732678)S

Glycemic Variability and Its Association With Demographics and Lifestyles in a General Adult Population

Objective: The objective was to investigate glycemic variability indices in relation to demographic factors and common environmental lifestyles in a general adult population. Methods: The A Estrada Glycation and Inflammation Study is a cross-sectional study covering 1516 participants selected by sampling of the population aged 18 years and over. A subsample of 622 individuals participated in the Glycation project, which included continuous glucose monitoring procedures. Five glycemic variability indices were analyzed, that is, SD, MAGE, MAG, CONGA1, and MODD. Results: Participants had a mean age of 48 years, 62% were females, and 12% had been previously diagnosed with diabetes. In the population without diabetes, index distributions were not normal but skewed to the right. Distributional regression models that adjusted for age, gender, BMI, alcohol intake, smoking status, and physical activity confirmed that all indices were positively and independently associated with fasting glucose levels and negatively with heavy drinking. SD, MAGE, and CONGA1 were positively associated with aging, and MAG was negatively associated with BMI. None of the GVI studied were influenced by physical activity. Age-group-specific reference values are given for the indices. Conclusions: This study yielded age-specific reference values for glucose variability indices in a general adult population. Significant increases were observed with aging. Heavy drinking of more than 140 g/week was associated with significant decreases in variability indices. No differences were found between males and females. These normative ranges provide a guide for clinical care, and may offer an alternative treatment target among persons with diabetesThe author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This research project was supported by grants from Spain’s Carlos III Institute of Health (Instituto de Salud Carlos III/ISCIII) (PI11/02219 & PI13/02594) and the European Regional Development Fund (FEDER). PDV and MAS were supported by ISCIII Preventive Activity & Health Promotion Research Network (Red de Investigación en Actividades Preventivas y de Promoción de Salud/redIAPP) grants RD06/0018/0006 & RD12/0005/0007, respectively. CCS has been partially supported by the Spanish Ministry of Science and Innovation (MTM2015-69068-REDT)S

Prevalence of Tobacco Consumption Among Working Population after the Law 42/2010, Spain

Fundamentos: El objetivo del presente trabajo consistió en analizar el impacto sobre el consumo de tabaco en población trabajadora de la Ley 42/2010 que modifica la normativa antitabaco en España. Métodos: Se obtuvieron datos de 413.473 reconocimientos médicos de Salud Laboral, realizados entre julio de 2009 y junio de 2011, en la Sociedad de Prevención de una Mutua de Accidentes de Trabajo y Enfermedades Profesionales de la Seguridad Social. Se analizó la evolución semestral del porcentaje de fumadores y la magnitud del consumo de tabaco en el total de reconocimientos, segmentando por sexo, edad, nivel ocupacional (trabajos manuales vs. no manuales) y en el subgrupo específico de camareros, bármanes y asimilados (test de chi2) Resultados: En el total de reconocimientos, el porcentaje de fumadores descendió un 5% (del 40,3% al 35,3%) a lo largo del periodo de estudio (p<0,001) y el grupo de fumadores con menor consumo diario (≤10 cigarrillos) se convirtió en el más frecuente (p<0,001). En el grupo de camareros, bármanes y asimilados las diferencias en el porcentaje semestral de fumadores no alcanzaron significación estadística (p=0,07). En este grupo, los fumadores de ≤10 cigarrillos/día también se convirtieron en el grupo de consumo más frecuente (pasando del 40,5% al 48,8%) y el porcentaje de fumadores de 21-40 cigarrillos/día disminuyó del 10,6% al 4% (p=0,008). Conclusiones: Los resultados sugieren que la nueva normativa se ha acompañado de una importante reducción del tabaquismo entre la población trabajadora española y respaldan fuertemente las medidas de lucha contra el tabaco de alcance poblacional.Background: The aim of this study was to analyze the impact on tobacco consumption among working population of the Law 42/2010, which amends smoking regulations in Spain. Methods: Data were obtained from 413,473 Occupational Health check-ups, conducted between July of 2009 and June of 2011, in the Society for Prevention of a Mutual Insurance Company. We analyzed changes in the biannual percentage of smokers and the magnitude of tobacco consumption among smokers in the overall set of medical check-ups, by gender, age, occupational level (manual vs. non-manual workers), and in the specific occupational subgroup of waiters, barmen and similar workers (chi-square test). Results: In the overall set of medical check-ups, the percentage of smokers decreased by 5% (from 40.3% to 35.3%) over the period of study (p <0.001) and the group of smokers with lower daily consumption (≤10 cigarettes) became the most frequent (p <0.001). In the group of waiters, barmen and similar workers the differences in the biannual percentage of smokers did not reach statistical significance (p =0.07). In this group, smokers of ≤10 cigarretes/ day also became the most common consumption group (increasing from 40.5% to 48.8%) and the percentage of 21-40 cigarretes/day decreased from 10.6% to 4% (p =0.008). Conclusions: These results suggest that the new regulation has been accompanied by a significant reduction in smoking among Spanish workers and strongly support population-level measures against tobacco consumption.S

Longitudinal relationship of liver injury with inflammation biomarkers in COVID-19 hospitalized patients using a joint modeling approach

The mechanisms underlying liver disease in patients with COVID-19 are not entirely known. The aim is to investigate, by means of novel statistical techniques, the changes over time in the relationship between inflammation markers and liver damage markers in relation to survival in COVID-19. The study included 221 consecutive patients admitted to the hospital during the first COVID-19 wave in Spain. Generalized additive mixed models were used to investigate the influence of time and inflammation markers on liver damage markers in relation to survival. Joint modeling regression was used to evaluate the temporal correlations between inflammation markers (serum C-reactive protein [CRP], interleukin-6, plasma D-dimer, and blood lymphocyte count) and liver damage markers, after adjusting for age, sex, and therapy. The patients who died showed a significant elevation in serum aspartate transaminase (AST) and alkaline phosphatase levels over time. Conversely, a decrease in serum AST levels was observed in the survivors, who showed a negative correlation between inflammation markers and liver damage markers (CRP with serum AST, alanine transaminase [ALT], and gamma-glutamyl transferase [GGT]; and D-dimer with AST and ALT) after a week of hospitalization. Conversely, most correlations were positive in the patients who died, except lymphocyte count, which was negatively correlated with AST, GGT, and alkaline phosphatase. These correlations were attenuated with age. The patients who died during COVID-19 infection displayed a significant elevation of liver damage markers, which is correlated with inflammation markers over time. These results are consistent with the role of systemic inflammation in liver damage during COVID-19S

Silver clusters of five atoms as highly selective antitumoral agents through irreversible oxidation of thiols

Low atomicity clusters present properties dependent on the size, due to the quantum confinement, with well-defined electronic structures and high stability. Here it is shown that Ag5 clusters catalyze the complete oxidation of sulfur to S+6. Ag5 catalytic activity increases with different oxidant species in the order O2 ≪ H2O2 < OH•. Selective oxidation of thiols on the cysteine residues of glutathione and thioredoxin is the primary mechanism human cells have to maintain redox homeostasis. Contingent upon oxidant concentration, Ag5 catalyzes the irreversible oxidation of glutathione and thioredoxin, triggering apoptosis. Modification of the intracellular environment to a more oxidized state to mimic conditions within cancer cells through the expression of an activated oncogene (HRASG12V) or through ARID1A mutation, sensitizes cells to Ag5 mediated apoptosis. While cancers evolve to evade treatments designed to target pathways or genetic mutations that drive them, they cannot evade a treatment that takes advantage of aberrant redox homeostasis, which is essential for tumor progression and metastasis. Ag5 has antitumor activity in mice with orthotopic lung tumors reducing primary tumor size, and the burden of affected lymphatic nodes. The findings suggest the unique intracellular redox chemistry of Ag5 may lead to new redox-based approaches to cancer therapyThis research was partially supported by 1) “la Caixa” Foundation, Ref. LCF/PR/PR12/11070003 to F.D. and M.A.L.Q.; 2) Ministerio de Ciencia, Innovación y Universidades (MAT2017-89678-R, AEI/FEDER, UE) to F.D. and A.V.; 3) the Consellería de Educación (Xunta de Galicia), Grants No. Grupos Ref. Comp. ED431C 2017/22, ED431C 2019/13 and AEMAT-ED431E2018/08 to M.A.L.Q.; and ED431C 2019/13 to A.V. This project has received funding from the European Union's Horizon 2020 Research and Innovation Programme (Bac-To-Fuel) under Grant Agreement No. 825999 (M.A.L.Q.). J.C.H. acknowledge financial support from European Union's Horizon 2020 research and innovation programme under grant agreement no. 823717-ESTEEM3, and the MICIIN (projects PID2019-107578GA-100 and PID-110018GA-100). J.M.D, L.J.G., and F.G.R. thank to the ANPCyT (PICT 2015-2285 and 2017-3944), UNLP (Project 11/X790) and the partial support by the Laboratório Nacional de Luz Síncrotron (LNLS, Brazil) under proposal SXS-20180280. G.B. acknowledges the CINECA Award N. IsC51, year 2017, under the ISCRA initiative, for the availability of high-performance computing resources and support. D.B. expresses gratitude for a postdoctoral grant from Xunta de Galicia, Spain (POS-A/2013/018). B.D. expresses gratitude for a predoctoral grant from MICINN, Spain (BES-2016-076765). F.D. and A.V. also acknowledged Xunta de Galicia (Centro singular de investigación de Galicia accreditation 2019-2022 ref ED431G 2019/02) and the European Union (European Regional Development Fund – ERDF). Work in M.P.M.'s lab was supported by the Medical Research Council UK (MC_U105663142). T.G.C. gratefully acknowledges the technical assistance of María José Otero-Fraga (FIDIS)S

Development and validation of a clinical score to estimate progression to severe or critical state in Covid-19 pneumonia hospitalized patients

The prognosis of a patient with Covid-19 pneumonia is uncertain. Our objective was to establish a predictive model of disease progression to facilitate early decision-making. A retrospective study was performed of patients admitted with Covid-19 pneumonia, classified as severe (admission to the intensive care unit, mechanic invasive ventilation, or death) or non-severe. A predictive model based on clinical, analytical, and radiological parameters was built. The probability of progression to severe disease was estimated by logistic regression analysis. Calibration and discrimination (receiver operating characteristics curves and AUC) were assessed to determine model performance. During the study period 1,152 patients presented with Covid-19 infection, of whom 229 (19.9%) were admitted for pneumonia. During hospitalization, 51 (22.3%) progressed to severe disease, of whom 26 required ICU care (11.4); 17 (7.4%) underwent invasive mechanical ventilation, and 32 (14%) died of any cause. Five predictors determined within 24 hours of admission were identified: Diabetes, Age, Lymphocyte count, SaO2, and pH (DALSH score). The prediction model showed a good clinical performance, including discrimination (AUC 0.87 CI 0.81, 0.92) and calibration (Brier score = 0.11). In total, 0%, 12%, and 50% of patients with severity risk scores ≤5%, 6-25%, and >25% exhibited disease progression, respectively. A simple risk score based on five factors predicts disease progression and facilitates early decision-making according to prognosis.Carlos III Health Institute, Spain, Ministry of Economy and Competitiveness (SPAIN) and the European Regional Development Fund (FEDER)Instituto de Salud Carlos II

Genome-wide association analysis of dementia and its clinical endophenotypes reveal novel loci associated with Alzheimer's disease and three causality networks : The GR@ACE project

Introduction: Large variability among Alzheimer's disease (AD) cases might impact genetic discoveries and complicate dissection of underlying biological pathways. Methods: Genome Research at Fundacio ACE (GR@ACE) is a genome-wide study of dementia and its clinical endophenotypes, defined based on AD's clinical certainty and vascular burden. We assessed the impact of known AD loci across endophenotypes to generate loci categories. We incorporated gene coexpression data and conducted pathway analysis per category. Finally, to evaluate the effect of heterogeneity in genetic studies, GR@ACE series were meta-analyzed with additional genome-wide association study data sets. Results: We classified known AD loci into three categories, which might reflect the disease clinical heterogeneity. Vascular processes were only detected as a causal mechanism in probable AD. The meta-analysis strategy revealed the ANKRD31-rs4704171 and NDUFAF6-rs10098778 and confirmed SCIMP-rs7225151 and CD33-rs3865444. Discussion: The regulation of vasculature is a prominent causal component of probable AD. GR@ACE meta-analysis revealed novel AD genetic signals, strongly driven by the presence of clinical heterogeneity in the AD series