bluuebunny/crossref_metadata_2025_split huggingface dataset:
Epigenetic regulation of oxidative and inflammatory phenotypes in women with gestational diabetes and offspring
Authors: Di Pietrantonio N , Shumliakivska M , Suades R , Di Tomo P , Bonfini T , Pandolfi A , Cosentino F 
Published: October 2021

Abstract

Background
Hyperglycemia-induced oxidative stress and inflammation are potent drivers of atherosclerotic cardiovascular disease (ASCVD). Gestational diabetes (GDM) is characterized by chronic hyperglycemia during pregnancy and may represent a clinical model to study the mechanisms of oxidative stress and inflammation induced by hyperglycemia. GDM is associated with a range of adverse perinatal and long-term outcomes for both mother and offspring. In this perspective, it is emerging a putative association between maternal GDM and offspring's epigenetic trait.

Purpose
To investigate the link between histone modifications, oxidative stress and inflammatory phenotype as well as the transmission of epigenetic signatures to the offspring.

Methods
We analyzed peripheral blood mononuclear cells (PBMC) from GDM and control mothers as well as human umbilical vein endothelial cells (HUVEC) and cord blood mononuclear cells (CBMC) isolated from newborn umbilical cords obtained at delivery from both groups. Histone methyltransferase MLL1-dependent trimethylation of histone 3 at lysine 4 amino residue (H3K4me3) on NF-kB p65 subunit promoter region was assessed by chromatin immunoprecipitation (ChIP) and real-time qPCR in HUVEC, PBMC and CBMC, respectively. MLL1 and downstream inflammatory and redox genes were determined by real-time qPCR and immunocytochemistry in the presence and in the absence of MLL1 inhibitor MM-102. Measurement of reactive oxygen species (ROS) was performed by electron spin resonance spectroscopy.

Results
For the first time, we demonstrated a significant increase of MLL1 expression with subsequent MLL1-induced upregulation of NF-kB p65 gene via H3K4me3 in GDM as compared to control cells. MLL1-driven epigenetic remodeling of NF-kB p65 promoter is upstream to the activation of inflammatory pathway. Indeed, treatment with MM-102 decreased H3K4me3 and blunted expression of NF-kB p65 as well as VCAM-1, MCP-1 and IL-6 genes. We also found that expression of ROS scavenger aldehyde dehydrogenase 2 is reduced, whereas pro-oxidant nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit NOX4 is upregulated. Interestingly, the increased ROS generation observed in GDM is involved in the upregulation of MLL1 as shown by the restoring effect of antioxidant vitamin C on MLL1 expression levels.

Conclusions
Our results suggest that a complex interplay between oxidative stress and histone modifications are responsible for the GDM maternal inflammatory and oxidative phenotypes and its transmission to the offspring. The deciphering of epigenetic-induced chromatin remodelling opens the perspective for pharmacological reprogramming of adverse chromatin changes to reduce the burden of early development of metabolic phenotypes and ASCVD.

Funding Acknowledgement
Type of funding sources: Public Institution(s). Main funding source(s): University G. d'Annunzio MIUR fundings Schematic figure
Proatherogenic gut-microbiome metabolite trimethylamine elicits a gut-liver circuit to regulate TMAO metabolism and atherosclerosis via mediation of CREBH
Authors: Su Q , Kaluzny S 
Published: October 2021

Abstract

Introduction
In humans, circulating metabolite Trimethylamine N-oxide (TMAO) is closely associated with higher risk of cardiovascular disease. Trimethylamine (TMA), a precursor of TMAO, is produced by gut microbiome using dietary components, i.e., choline and carnitine, as substrates. The gut-derived TMA is then transferred to the liver where it is further oxidized to TMAO by the flavin-containing monooxygenases (FMOs). The ER-resident transcription factor c-AMP responsive element binding protein H (CREBH/CREB3L3) is exclusively expressed in the liver and intestine. Perturbation of CREBH activity contributes to the development of hyperlipidemia and cardiovascular disease. Therefore, the Purpose of this study is to investigate the regulatory effect of a gut bacterium, Akkermansia muciniphila (A. muciniphila), on TMA and TMAO metabolism and the role of CREBH in this process.

Methods
Two groups of wild type (WT) and CREBH knockout (CREBH-KO) mice were inoculated with 200 μL of A. muciniphila (2×108 cfu/0.2 mL) in PBS or the vehicle (PBS) alone as control every other day through oral gavage for 2 weeks. Plasmas, liver and intestinal tissues were collected for metabolomics analysis, immunoblotting analysis and q-RT-PCR.

Results
Metabolomics analysis of the plasmas from the experimental mice revealed that increased colonization of A. muciniphila in the gut significantly reduced circulating TMA in the WT mice but not in CREBH-KO mice (P&lt;0.05), suggesting that depletion of CREBH altered the microenvironment of gut microbiome which affected the metabolism of TMA by gut bacteria. In the livers, A. muciniphila treatment markedly reduced mRNA expression of FMO1 and FMO3 (P&lt;0.05), which subsequently inhibited the enzymatic conversion of TMA to TMAO in hepatocytes. Immunoblotting analysis further revealed that LDL receptor was upregulated whereas ER stress markers, GRP94 and JNK1/2, were downregulated in the A. muciniphila treated KO mice, indicating an acceleration in lipoprotein (VLDL remnant) clearance from the circulation and the improvement of metabolic inflammation. In vitro, incubation of mouse hepatocytes AML12 with TMA (600 mM) for 12 hours stimulated expression of FMOs to facilitate the conversion of TMA to TMAO and induced lipotoxicity.

Conclusion
CREBH mediates the crosstalk between gut microbiome and liver metabolic system that regulates TMA and TMAO metabolism, which contributes to the induction of metabolic inflammation and atherogenesis. This novel finding may lend support to the therapeutic strategy of atherosclerosis.

Funding Acknowledgement
Type of funding sources: Foundation. Main funding source(s): British Heart Foundation
Eicosapentaenoic acid inhibits lipopolysaccharide (LPS)-induced nitrite production and cytokine release from J774 macrophages
Authors: Sherratt S C R , Libby P , Dawoud H , Bhatt D L , Malinski T , Mason R P 
Published: October 2021

Abstract

Background
Eicosapentaenoic acid (EPA), an omega-3 (ω-3) fatty acid, reduced cardiovascular (CV) events in high-risk patients (REDUCE-IT) but the mechanism is not fully understood. Activated macrophages, characterized by cytokine release and increased inducible nitric oxide synthase (iNOS) activity, contribute to atherosclerosis. As both a substrate for and potential inhibitor of cyclooxygenase (COX), EPA may reduce iNOS activity.

Purpose
The purpose of this study was to evaluate the dose-dependent effects of EPA on nitrite and cytokine release from lipopolysaccharide (LPS)-activated macrophages.

Methods
Murine J774 macrophages were pretreated with vehicle or EPA at 10, 20 and 40 μM for 2 h, then challenged with LPS at 1.0 μg/ml. After 24 hr, iNOS activity was measured by nitrite production using the Griess assay. EPA was compared to the COX inhibitor diclofenac at 1.0 μg/ml. Levels of interleukin-1β (IL-1β) and tumor necrosis factor alpha (TNF-α) in cell supernatant were measured by immunochemistry using colchicine as a positive control.

Results
Activated macrophages caused a &gt;4-fold increase in nitrite production (p&lt;0.001) that was reduced by EPA in a dose-dependent manner. EPA decreased nitrite levels by 40, 62 and 77% at 10, 20 and 40 μM, respectively (p&lt;0.01). Diclofenac separately reduced nitrite levels by 40% (p&lt;0.01). EPA also reduced expression of IL-1β and TNF-α by 40% and 31%, respectively (p&lt;0.01), in a manner similar to equimolar colchicine (10 μM). The reductions in IL-1β and TNF-α with EPA were dose-dependent.

Conclusions
EPA reduced macrophage activation as evidenced by decreased nitrite production and cytokine release similar to other anti-inflammatory agents. These findings indicate a novel effect of EPA on mechanisms of inflammation associated with vascular disease.

Funding Acknowledgement
Type of funding sources: Private company. Main funding source(s): Amarin Pharma Inc., Elucida Research
Tubulin-folding cofactor E deficiency is associated with vascular dysfunction and endoplasmatic reticulum stress of vascular smooth muscle cells
Authors: Efentakis P , Molitor M , Kossmann S , Bochenek M , Wild J , Lagrange J , Finger S , Jung R , Karbach S , Schaefer K , Schulz A , Wild P , Muenzel T , Wenzel P 
Published: October 2021

Abstract

Introduction
Endothelial function assessed via flow mediated dilatation (FMD) has shown to predict risk in individuals with established cardiovascular diseases, whereas its predictive value is uncertain in the setting primary prevention.

Purpose
The aim of the current work was to discover and evaluate novel mediators of vascular dysfunction in the general population and in conditional knock-out transgenic animal models.

Methods
In order to identify novel targets that were negatively correlated with FMD and investigate their contribution in vascular function, a Genome Wide Association Study (GWAS) of 5,000 participants was performed and subsequently immune cell-, endothelial- and vascular smooth muscle cell (VSMCs)-targeted conditional knockout mouse models were generated and characterized.

Results
GWAS analysis revealed that single nucleotide polymorphisms (SNPs) in the tubulin folding cofactor E (TBCE) gene were negatively correlated with FMD and TBCE expression in the peripheral blood mononuclear cells (PBMCs). Myelomonocytic cell-targeted TBCE deficiency did not lead to any vascular dysfunction in vivo in the LysM+Cre+/−TBCEfl/fl mice. Endothelial-targeted TBCE deficiency led to an NLR family pyrin domain containing 3 (NLRP3)-dependent activation of the inflammasome in the endothelial cells of Tie2-ERT2Cre+/−TBCEfl/fl mice. Importantly, VSMC-targeted TBCE deficiency was associated with endothelial dysfunction, increased aortic wall thickness and endoplasmatic reticulum (ER) stress-mediated VSMC hyperproliferation in vivo (SMMHC-ERT2Cre+/−TBCEfl/fl), paralleled by calnexin upregulation. Administration of the blood pressure hormone angiotensin II exacerbated the vascular dysfunction and phenotype. Administration of the ER stress modulator tauroursodeoxycholic acid to the SMMHC-ERT2Cre+/−TBCEfl/fl mice reversed vascular dysfunction, paralleled by induction of Raptor/Beclin-1-dependent autophagy both in vitro and in vivo.

Conclusion
TBCE and tubulin homeostasis in the vascular musculature seem to be novel markers of vascular function and represent a new druggable target for the treatment of ER-stress-mediated vascular dysfunction.

Funding Acknowledgement
Type of funding sources: Foundation. Main funding source(s): This work was supported by grants of the German Federal Ministry for Education and Research (BMBF01EO1003 and BMBF01EO1503), the DFG Major Research Instrumentation Programme (DFG INST 371/47-1 FUGG) as well as the Boehringer Ingelheim Foundation. PW received funds from the German Research Foundation in support of his work (DFG WE4361-4-1 and WE 4361/7-1). KS, TM and PW are PIs of the DZHK.
Assessment of heart rate variability and tone of the autonomic nervous system in puberty-aged children with undifferentiated connective tissue dysplasia
Authors: Sidorovich O V , Elizarova S Y U , Khizhnyak A V , Kuznetsova N A , Prosova E E 
Published: October 2021

Abstract

Within the framework of the research into pathological conditions and syndromes associated with undifferentiated connective tissue dysplasia (UCTD), an emphasis needs to be placed on the changes in heart rhythm. In puberty, the severity of neurovegetative disorders caused by the presence of UCTD might increase manifold. The features of heart rate variability (HRV) in pubertal children against the background of UCTD have been studied insufficiently and require more detailed analysis.
This study aims to assess heart rate variability and tone of the autonomic nervous system (ANS) in puberty-aged children with UCTD.
Two groups of children were examined, with methods including electrocardiography and cardiointervalography. The main group consisted of 36 puberty-aged children with UCTD, the control group consisted of 30 healthy children.
ANS tone was assessed based on the HRV. In the control group of children aged 11, the value of variation range (VR) was 0.18±0.4, mode amplitude (MA) 35.2±2.4, stress index (IN) 72.8±4.3, which corresponds to the state of vegetative balance. As the puberty progresses, the state of eutonia is replaced by the activation of the sympathetic division of the ANS, which becomes most pronounced at the age of 13 years. In the control group of children aged 13, the value of VR was 0.08±0.02, MA 61.7±2.1, SI 210.6±8.6, which corresponds to moderate sympathicotonia. By the end of puberty, in healthy children, the severity of sympathetic activation begins to decrease, and at the age of 15 years, vegetative balance is again observed. However, this pattern is violated in children with UCTD. Upon entering puberty, moderate activation of the sympathetic division of the ANS is already observed in children with UCTD. At the age of 11 years in this group, the value of VR is 0.06±0.02, MA 72.4±3.1, SI 211.2±8.6. At the age of 13, pronounced sympathicotonia is observed, which is confirmed by the values of VR - 0.04±0.01, MA 80.2±4.3 and SI 34.3±14.7. By the end of puberty in children with UCTD, in contrast to the control group, the analyzed parameters indicate not an equilibrium of the ANS, but the predominance of parasympathetic activation.
The research provides an insight into heart rate variability in puberty-aged children with UCTD. It was established that healthy children enter puberty in a state of equilibrium of the autonomic nervous system, which in the middle of puberty is replaced by moderate sympathicotonia, and then returns to its original values. Children with the presence of UCTD enter puberty with moderately pronounced sympathicotonia, which gradually increases to pronounced values and is replaced by moderate vagotonia.

Funding Acknowledgement
Type of funding sources: None.
A resilient type of familial hypercholesterolaemia: case–control follow-up of genetically characterized older patients in the SAFEHEART cohort
Authors: Pérez de Isla Leopoldo , Watts Gerald F , Muñiz-Grijalvo Ovidio , Díaz-Díaz Jose Luis , Alonso Rodrigo , Zambón Daniel , Fuentes-Jimenez Francisco , Mauri Marta , Padró Teresa , Vidal-Pardo José I , Barba Miguel A , Ruiz-Pérez Enrique , Michán Alfredo , Mediavilla Juan D , Hernandez Antonio M , Romero-Jimenez Manuel J , Badimon Lina , Mata Pedro ,   SAFEHEART Investigators
Published: October 2021

Abstract

Aims
Knowledge of the features of patients with familial hypercholesterolaemia (FH) who are protected from atherosclerotic cardiovascular disease (ASCVD) is important for the clinical and prognostic care of this apparently high-risk condition. Our aim was to investigate the determinant and characteristics of patients with FH who are protected from ASCVD and have normal life expectancy, so-called ‘resilient’ FH (R-FH).

Methods and results
Spanish Familial Hypercholesterolaemia cohort study (SAFEHEART) is an open, multicentre, nation-wide, long-term prospective cohort study in genetically defined patients with heterozygous FH in Spain. Patients in the registry who at the time of analysis were at least 65 years or those who would have reached that age had they not died from an ASCVD event were analysed as a case–control study. Resilient FH was defined as the presence of a pathogenic mutation causative of FH in a patient aged ≥65 years without clinical ASCVD. Nine hundred and thirty registrants with FH met the study criteria. A defective low-density lipoprotein (LDL)-receptor mutation, higher plasma level of high-density lipoprotein cholesterol (HDL-C), younger age, female gender, absence of hypertension, and lower plasma lipoprotein (a) [Lp(a)] concentration were independently predictive of R-FH. In a second model, higher levels of HDL-C and lower 10-year score in SAFEHEART-RE were also independently predictive of R-FH.

Conclusion
Resilient FH may be typified as being female and having a defective LDL-receptor mutation, higher levels of plasma HDL-C, lower levels of Lp(a), and an absence of hypertension. The implications of this type of FH for clinical practice guidelines and the value for service design and optional care of FH remains to be established.

Trial registration
ClinicalTrials.gov number NCT02693548.
COVID vaccination efficiency in nursing homes: from nursing home-centred to resident-centred
Authors: Delespierre T , Pierre A 
Published: October 2021

Abstract

Background
Korian® group is specialized in care and support for fragile people. Its data warehouse manages 304 French nursing homes (NH). The transmissions' table (TT), daily-fed by caregivers, contains key data about residents' care and health. Following GDPR rules, we could still build residents' life trajectories and detail all the residents' health events using indexes. In the past, we designed syndromes such as falls, flu, and last year, COVID with the standard query language. Now we want to combine ‘hard' data such as sociodemographic profiles and COVID vaccines with ‘soft' textual data such as COVID and emergency calls syndromes to get a better residents vaccine monitoring.

Methods
First, we selected all residents with at least one transmission, from December 21, to January 11, just before the COVID vaccination start, from 34 NH chosen for their variety of size and geographic location. We followed them for eleven weeks starting January 4, 2021. We selected the residents' age, sex, autonomy level, comorbidities and risks and then, vaccinations (0, 1 or 2), syndromes, hospitalizations and deaths date events. We searched for sample data inconsistencies by filtering COVID textual information in the TT and comparing it with the vaccination table. We described the sample according to the NH size, and then according to the number of vaccinations. Finally, we assessed COVID syndromes, falls, hospitalizations, emergency calls and deaths according to vaccinations followed by Poisson and logistic regressions.

Results
We built a 2,051 residents cohort with 1,401 vaccinated at least once and 650 not yet vaccinated. Data corrections then added 60 vaccinations. Residents in big structures were more masculine (72,9% vs 75,1%), more vaccinated (77,2% vs 67,2%), younger (86,7 vs 87,5), more autonomous (2,6, vs 2,4). Vaccination rates were also greater among those with comorbidities and risks.

Conclusions
By focusing on the TT resident's health events, we improved health modelization

Key messages
By using all the COVID information available in the database, we were able to show both, the beneficial effect of vaccination and the nefarious effect of COVID in a same model with machine learning. Aggregating hard categorical and numerical data with soft textual information about the resident’s health events, dates included, gives a precise and complete resident’s profile and health trajectory.
Cold spell effect on daily mortality in districts in Madrid considering sociodemographic variables
Authors: López-Bueno JA , Díaz J , Sánchez-Guevara C , Sánchez-Martínez G , Franco M , Gullón P , Núñez-Peiró M , Linares C 
Published: October 2021

Abstract

Background
While there is much research that focuses on the association between cold spell and their impacts on daily mortality at the city level, we analyze the impact related to social context and demographic variables at levels lower than the municipal.

Methods
The objective of this study was to determine the role of the percentage of people over age 65, income level and percentage of homes without heating in the analysis of the impact of cold waves on daily mortality between January 1, 2010 and December 31, 2013 in different districts of the municipality of Madrid. We calculated Relative Risks (RR) and Attributable Risks (RA) for each of 17 districts to determine correlations between the effect of cold waves and daily mortality due to natural causes (CIEX: A00-R99) using Generalized Linear Models (GLM) of the Poisson family (link log). The pattern of risks obtained by district was analyzed using binomial family models (link logit), considering socioeconomic and demographic variables.

Results
In terms of results, an impact of cold on mortality was detected in 9 of the 17 districts analyzed. The analysis of risk patterns revealed that the probability of detecting an impact in a district increases in a statistically significant way (p-value &lt;0.05) with a higher percentage of homes without heating systems and a higher percentage of population over age 65.

Conclusions
The results obtained identify the factors that should be considered in public health policies that target the district level to reduce the impact of cold waves.

Key messages
Ageing and the absence of heating systems are key variables which explain vulnerability to cold spell. Cold spell related mortality risks can be reduced by applying prevention health public plans.
Web-based planning tool for obesity prevention in childhood and youth – first trial period
Authors: Schröder M , Berner R , Schmidt L , Babitsch B , Hassel H 
Published: October 2021

Abstract

Background
The systematic and theory-based development of interventions is complex and requires time and personnel resources. WEPI is a web-based planning tool for municipalities and schools, that follows the evidence-based intervention mapping approach (IMA) but also supports the planning process of obesity prevention user oriented. The project is supported by the Federal Ministry of Health, Germany.

Methods
Data of a systematic literature review (SLR), expert interviews and focus group discussions served as the foundation for the first version of WEPI. Two further SLR were conducted in the databases Pubmed, LIVIVO and Cochrane on evidence-based determinants of obesity development and on proven obesity intervention methods, to meet the requirements of the IMA. In October 2020 the second version of WEPI was tested with selected municipalities and schools. The prototype as a third version was tested by three municipalities and two schools in February 2021. Feedback was collected through questionnaires and interviews.

Results
In a total of 806 hits of the first SLR, determinants for the development of obesity were identified in 8 guidelines and 37 reviews. They were adopted in form of 15 problem areas which support the WEPI user to conduct an evidence-based problem analysis. Result of the second SLR are 25 obesity prevention interventions which were developed using the IMA. Based on this, 192 evaluated methods were identified and integrated as good practice examples into WEPI. In the first trial the expert feedback revealed aspects of content and user-friendliness as well as technical aspects that should be optimized. The feedback of the municipalities and schools underlines, that scientific findings need to be translated into practical logic.

Conclusions
WEPI provides a comprehensive roadmap to the planning process, guiding the user step by step. Acceptance and usability of the planning tool will be evaluated with municipalities and schools from April to November 2021.

Key messages
WEPI enables user oriented, structured and evidence-based planning of prevention interventions. Requirements resulting from practice were considered in the development of the planning tool.