Lipid Nanoparticles for Nucleic Acid Delivery Beyond the Liver.

Lipid nanoparticles (LNPs) are the most clinically advanced drug delivery system for nucleic acid therapeutics, exemplified by the success of the COVID-19 mRNA vaccines. However, their clinical use is currently limited to hepatic diseases and vaccines due to their tendency to accumulate in the liver upon intravenous administration. To fully leverage their potential, it is essential to understand and address their liver tropism, while also developing strategies to enhance delivery to tissues beyond the liver.

Unusual Presentation of a Gastrointestinal Stromal Tumor in a Small Intestine Diverticulum.

A 50-year-old female with no significant medical history initially presented to an urgent care center with symptoms of acute onset abdominal pain, nausea, and emesis. Chest and abdominal X-ray revealed free air under the diaphragm, prompting immediate transfer to the emergency department. Continued abdominal tenderness and pain were concerning for perforated viscus.

TV medical dramas: health sciences students' viewing habits and potential for teaching issues related to bioethics and professionalism.

Background: Medical dramas have been popular since their inception, especially among medical students. We hypothesized that the recent increase in the availability of TV medical series through online streaming platforms has probably changed health science students' viewing habits as well as the representation of bioethical conflicts and health professionals.

Methods: We invited undergraduate students of medicine, nursing, and human biology to complete a self-administered questionnaire about their viewing habits and perceptions of the depictions of bioethical issues and professionalism in TV medical series.

DNA methylation biomarkers of myocardial infarction and cardiovascular disease.

Background: The epigenetic landscape underlying cardiovascular disease (CVD) is not completely understood and the clinical value of the identified biomarkers is still limited. We aimed to identify differentially methylated loci associated with acute myocardial infarction (AMI) and assess their validity as predictive and causal biomarkers.

Results: We designed a case-control, two-stage, epigenome-wide association study on AMI (n = 391, n = 204).

Phosphorylation of mitochondrial transcription factor B2 controls mitochondrial DNA binding and transcription.

Mammalian cells contain genetic information in two compartments, the nucleus and the mitochondria. Mitochondrial gene expression must be coordinated with nuclear gene expression to respond to cellular energetic needs. To gain insight into the coordination between the nucleus and mitochondria, there is a need to understand the regulation of transcription of mitochondrial DNA (mtDNA).

Middle cerebral artery Doppler pulsatility index as a predictor of intrapartum meconium release in prolonged pregnancies.

Objectives: The aim of this study was to asses the correlation of middle cerebral artery pulsatility index (MCA-PI) and perinatal outcomes in prolonged pregnancies.

Study Design: This was a prospective study of all consecutive pregnant women beyond 41 weeks' gestation attending for obstetric surveillance during a two years period. We evaluated the predictive value of MCA-PI lower than the 5th percentile ( View Article and Find Full Text PDF

Parameters of the Mouse Embryo Assay that affect detection of peroxides in mineral oil.

Research Question: Can culture conditions influence the sensitivity of a Mouse Embryo Assay and its potential to detect peroxide-related toxicity in mineral oil samples?

Design: Protein type and concentration, embryo density and culture dish design were selected as the variables in the culture system with the potential to influence the assay's sensitivity. Fresh 1-cell mouse embryos were cultured under mineral oil samples with known peroxide concentrations. Protein type (human serum albumin [HSA] + α/β-Globulins versus HSA versus bovine serum albumin [BSA]), concentration (5 mg/ml versus 0.

DNA methylation and obesity traits: An epigenome-wide association study. The REGICOR study.

Obesity is associated with increased risk of several diseases and has become epidemic. Obesity is highly heritable but the genetic variants identified by genome-wide association studies explain only limited variability. Epigenetics could contribute to explain the missing variability.

Identification and validation of seven new loci showing differential DNA methylation related to serum lipid profile: an epigenome-wide approach. The REGICOR study.

Lipid traits (total, low-density and high-density lipoprotein cholesterol, and triglycerides) are risk factors for cardiovascular disease. DNA methylation is not only an inherited but also modifiable epigenetic mark that has been related to cardiovascular risk factors. Our aim was to identify loci showing differential DNA methylation related to serum lipid levels.

Cardiovascular Risk Factors and Ischemic Heart Disease: Is the Confluence of Risk Factors Greater Than the Parts? A Genetic Approach.

Background: Cardiovascular risk factors tend to aggregate. The biological and predictive value of this aggregation is questioned and genetics could shed light on this debate. Our aims were to reappraise the impact of risk factor confluence on ischemic heart disease (IHD) risk by testing whether genetic risk scores (GRSs) associated with these factors interact on an additive or multiplicative scale, and to determine whether these interactions provide additional value for predicting IHD risk.

Hypothesis-based analysis of gene-gene interactions and risk of myocardial infarction.

The genetic loci that have been found by genome-wide association studies to modulate risk of coronary heart disease explain only a fraction of its total variance, and gene-gene interactions have been proposed as a potential source of the remaining heritability. Given the potentially large testing burden, we sought to enrich our search space with real interactions by analyzing variants that may be more likely to interact on the basis of two distinct hypotheses: a biological hypothesis, under which MI risk is modulated by interactions between variants that are known to be relevant for its risk factors; and a statistical hypothesis, under which interacting variants individually show weak marginal association with MI. In a discovery sample of 2,967 cases of early-onset myocardial infarction (MI) and 3,075 controls from the MIGen study, we performed pair-wise SNP interaction testing using a logistic regression framework.

Assessment of the value of a genetic risk score in improving the estimation of coronary risk.

Background: The American Heart Association has established criteria for the evaluation of novel markers of cardiovascular risk. In accordance with these criteria, we assessed the association between a multi-locus genetic risk score (GRS) and incident coronary heart disease (CHD), and evaluated whether this GRS improves the predictive capacity of the Framingham risk function.

Methods And Results: Using eight genetic variants associated with CHD but not with classical cardiovascular risk factors (CVRFs), we generated a multi-locus GRS, and found it to be linearly associated with CHD in two population based cohorts: The REGICOR Study (n=2351) and The Framingham Heart Study (n=3537) (meta-analyzed HR [95%CI]: ~1.

Post-genomic update on a classical candidate gene for coronary artery disease: ESR1.

Background: After age, sex is the most important risk factor for coronary artery disease (CAD). The mechanism through which women are protected from CAD is still largely unknown, but the observed sex difference suggests the involvement of the reproductive steroid hormone signaling system. Genetic association studies of the gene-encoding Estrogen Receptor α (ESR1) have shown conflicting results, although only a limited range of variation in the gene has been investigated.

A gain-of-function SNP in TRPC4 cation channel protects against myocardial infarction.

Aims: The TRPC4 non-selective cation channel is widely expressed in the endothelium, where it generates Ca(2+) signals that participate in the endothelium-mediated vasodilatory response. This study sought to identify single-nucleotide polymorphisms (SNPs) in the TRPC4 gene that are associated with myocardial infarction (MI).

Methods And Results: Our candidate-gene association studies identified a missense SNP (TRPC4-I957V) associated with a reduced risk of MI in diabetic patients [odds ratio (OR) = 0.

Additive effect of multiple genetic variants on the risk of coronary artery disease.

Introduction And Objectives: Coronary artery disease (CAD) has a substantial genetic component and, in recent years, a number of genetic variants associated with the disease have been identified. The objective of this study was to evaluate the magnitude of the association between a genetic risk score, which is based on the accumulated number of risk alleles in all genetic variants of interest, and the presence of CAD.

Methods: The study involved in silico data from the Wellcome Trust Case-Control Consortium on 1988 patients with CAD and 5380 controls.

Qualitative assessment of previous evidence and an updated meta-analysis confirms lack of association between the ESR1 rs2234693 (PvuII) variant and coronary heart disease in men and women.

Background: Coronary heart disease (CHD) is the leading cause of mortality worldwide. CHD clusters in families but this familial aggregation remains largely unexplained. ESR1 is a candidate gene for CHD although recent meta-analyses of the rs2234693 variant reported inconsistent evidence for association with myocardial infarction (MI) in men.

Genetic variation in the KCNMA1 potassium channel alpha subunit as risk factor for severe essential hypertension and myocardial infarction.

Objective: The large conductance Ca2+ -dependent potassium channel plays a critical role in the control of vascular tone, coupling local increases in intracellular Ca2+ to membrane hyperpolarization and vascular relaxation. It also impacts blood pressure by modulating the renin-angiotensin-aldosterone system. Previous studies have shown that a polymorphism in the beta1 regulatory subunit of the Ca2+ -dependent potassium channel modulates the risk of diastolic hypertension in humans.

Association between ESR2 genetic variants and risk of myocardial infarction.

Background: Environmental and genetic factors contribute to the development of complex diseases such as myocardial infarction (MI), the leading cause of death in men and women. Women develop MI approximately 10 years later than men, a difference that could be explained by the genes coding for the estrogen receptors. Single nucleotide polymorphisms (SNPs) in the ESR2 gene may affect susceptibility for MI in a sex-dependent manner.

[Association between paraoxonase-1 and paraoxonase-2 polymorphisms and the risk of acute myocardial infarction].

Introduction And Objectives: Two particular polymorphisms, namely PON1-192 and PON2-311, in the genes encoding the antioxidant enzymes paraoxonase-1 (PON1) and paraoxonase-2 (PON2) have been associated with an increased risk of acute myocardial infarction (AMI). However, previous findings have been contradictory. The aim of this study was to investigate the association between the PON1-192 and PON2-311 polymorphisms and their interaction on AMI risk.

Relationship of classical and non-classical risk factors with genetic variants relevant to coronary heart disease.

Background: In addition to the well established cardiovascular risk factors, evidence suggests a possible role of genetic and non-classical risk factors in the development and progression of atherothrombosis. We aimed to determine the relationship of classical and non-classical cardiovascular risk factors with candidate gene polymorphisms potentially involved in cardiovascular risk in the general Mediterranean population.

Design: Cross-sectional study.

Protective effect of the KCNMB1 E65K genetic polymorphism against diastolic hypertension in aging women and its relevance to cardiovascular risk.

The E65K polymorphism in the beta1-subunit of the large-conductance, Ca2+-dependent K+ (BK) channel, a key element in the control of arterial tone, has recently been associated with low prevalence of diastolic hypertension. We now report the modulatory effect of sex and age on the association of the E65K polymorphism with low prevalence of diastolic hypertension and the protective role of E65K polymorphism against cardiovascular disease. We analyzed the genotype frequency of the E65K polymorphism in 3924 participants selected randomly in two cross-sectional studies.

[The antioxidant function of high density lipoproteins: a new paradigm in atherosclerosis].

The one disease associated with the greatest morbidity and mortality in industrialized countries is coronary heart disease (CHD). High density lipoprotein (HDL) is one of the most important independent protective factors for the arteriosclerosis which underlies CHD. Paraoxonase 1 (PON1) is an enzyme that confers antioxidant properties to HDL.

Gain-of-function mutation in the KCNMB1 potassium channel subunit is associated with low prevalence of diastolic hypertension.

Hypertension is the most prevalent risk factor for cardiovascular diseases, present in almost 30% of adults. A key element in the control of vascular tone is the large-conductance, Ca(2+)-dependent K(+) (BK) channel. The BK channel in vascular smooth muscle is formed by an ion-conducting alpha subunit and a regulatory beta(1) subunit, which couples local increases in intracellular Ca(2+) to augmented channel activity and vascular relaxation.

[Paraoxonase 1 gene 192 polymorphism, physical activity and lipoprotein in women].

Background And Objective: Regular physical activity is associated with an increase in high-density lipoprotein cholesterol (HDL-C), whose antioxidant and protective effect for coronary artery disease is well known. Paraoxonase-1 (PON1) is an enzyme related with the antioxidant activity of HDL. The PON1 gene has several genetic polymorphisms; one of them locates in codon 192, whose alleles Q and R are associated with low and high PON1-activity, respectively.