Correction: Palmeira et al. Preliminary Virtual Screening Studies to Identify GRP78 Inhibitors Which May Interfere with SARS-CoV-2 Infection. Pharmaceuticals 2020, 13, 132.

There was an error in the original publication [...].

The methylome of buccal epithelial cells is influenced by age, sex, and physiological properties.

Epigenetic modifications, particularly DNA methylation, have emerged as regulators of gene expression and are implicated in various biological processes and disease states. Understanding the factors influencing the epigenome is essential for unraveling its complexity. In this study, we aimed to identify how the methylome of buccal epithelial cells, a noninvasive and easily accessible tissue, is associated with demographic and health-related variables commonly used in clinical settings, such as age, sex, blood immune composition, hemoglobin levels, and others. We developed a model to assess the association of multiple factors with the human methylome and identify the genomic loci significantly impacted by each trait. We demonstrated that DNA methylation variation is accurately modeled by several factors. We confirmed the well-known impact of age and sex and unveiled novel clinical factors associated with DNA methylation, such as blood neutrophils, hemoglobin, red blood cell distribution width, high-density lipoprotein cholesterol, and urea. Genomic regions significantly associated with these traits were enriched in relevant transcription factors, drugs, and diseases. Among our findings, we showed that neutrophil-impacted loci were involved in neutrophil functionality and maturation. Similarly, hemoglobin-influenced sites were associated with several diseases, including aplastic anemia, and the genomic loci affected by urea were related to congenital anomalies of the kidney and urinary tract. Our findings contribute to a better understanding of the human methylome plasticity and provide insights into novel factors shaping DNA methylation patterns, highlighting their potential clinical implications as biomarkers and the importance of considering these physiological traits in future medical epigenomic investigations.NEW & NOTEWORTHY We have developed a quantitative model to assess how the human methylome is associated with several factors and to identify the genomic loci significantly impacted by each trait. We reported novel health-related factors driving DNA methylation patterns and new site-specific regulations that further elucidate methylome dynamics. Our study contributes to a better understanding of the plasticity of the human methylome and unveils novel physiological traits with a potential role in future medical epigenomic investigations.

Diltiazem efficacy and CYP2D6 gene polymorphism in patients with atrial fibrillation with rapid ventricular response.

BACKGROUND: Diltiazem stands out as one of the front-line drugs administered in the emergency department to achieve acute rate control in patients suffering from atrial fibrillation with rapid Ventricular Response. One of the cytochrome enzymes involved in the metabolism of diltiazem is cytochrome P450 2D6 (CYP2D6). Interindividual differences can act on drug metabolism and thus drug efficacy due to the genetic polymorphism induced by the CYP2D6 enzyme. This study explores the association between the efficacy of diltiazem and the genetic polymorphism of CYP2D6 in patients with atrial fibrillation with rapid ventricular response. RESULTS: 87 out of 93 individuals with ventricular rate > 120 beats/min constituted the patient cohort. The patients were administered 0.25 mg/kg diltiazem intravenously. As a second dose, 0.35 mg/kg diltiazem was administered to patients who reportedly did not receive adequate drug efficacy. Heart rate control was considered to be achieved in patients whose heart rate fell below 110 beats/min and did not rise above 110 beats/min for 2 h. CYP2D6 *2, *3, *4 and *10 represent allele variants and *1 represents wild type (wt) allele. Achieving rate control after one or two doses of diltiazem in normal allele (wt/wt) carriers proved significantly higher than wt/*2, wt/*4 and wt/*10 heterozygous variant carriers. No significant difference was noted in wt/*3 heterozygous variant carriers. CONCLUSION: The presence of *2, *4 and *10 alleles was observed to significantly compromise the drug efficacy. *3 allele was found to bear no relation to the effect of diltiazem on achieving rate control.

Investigation of Serum Angiotensin-Converting Enzyme (ACE) Concentration and ACE Gene Polymorphism in Patients With SARS-CoV-2 Pneumonia Admitted to the Emergency Department.

Background This study seeks to investigate the distribution of the angiotensin-converting enzyme (ACE) gene polymorphism and serum levels in patients with viral pneumonia and predict which polymorphism will lead to severe progression of the disease. Methodology The serum ACE levels and ACE gene polymorphisms were successfully evaluated with respect to subsequent viral pneumonia using records of 100 patients with viral pneumonia and 100 healthy controls. Results ACE serum concentration was statistically significantly elevated. ACE serum concentration with a cut-off value of ≥5,256.05 pg/mL had 85.3% sensitivity and 83.2% selectivity. In addition, patients with ACE genotype D/D were 0.08 times more likely to manifest severe lung involvement than those with I/I, and patients with the I/D genotype were 0.02 times more likely than their counterparts with I/I. The computed tomography findings of the patients revealed that ACE serum concentration was significantly effective in discriminating between mild and moderate-to-severe lung involvement. No significant difference was observed between the blood parameters and ACE genotype distributions. Conclusions I/D polymorphism likely affects the expression of the ACE gene and/or the function of the angiotensin I converting enzyme. The D/D genotype is associated with vessel wall thickness and higher blood pressure. Strong evidence was found between D/D and I/D genotypes in the patient cohort concerning genotypes and ACE serum concentration. Further analysis showed that ACE serum levels were more elevated in the D/D genotype compared to the I/D genotype in the patient cohort.

A Hypertrophic Spinal Pachymeningitis Patient With Factor V Leiden (G1691A), MTHFR C677T, MTHFR A1298C, PAI-1 4G-5G, Glycoprotein IIIa L33P Gene Mutations.

Hypertrophic pachymeningitis (HP) is a rare clinical entity of diverse etiology, characterized by a chronic inflammation that causes dura thickening. Reports of Idiopathic hypertrophic cranial pachymeningitis (IHCP) were related to infections, trauma, tumors, and rheumatologic conditions. It was first described by Charcot and Joffroy regarding spinal meninges in 1869. HP has three stages; progressive radicular symptoms begin first, then muscle weakness and atrophy start. Findings such as paraplegia, loss of bladder and bowel control, and respiratory distress caused by intercostal and diaphragmatic denervation are considered the third stage of the disease. Especially in the cranial form of the disease, nerve ischemia and various cranial neuropathic findings may occur. Factor V Leiden (G1691A), MTHFR C677T, MTHFR A1298C, and PAI-1 4G-5G gene mutation analysis were measured with an ABI Prism. In this case report, the authors present a case of hypertrophic mutations pachymeningitis with Factor V Leiden (G1691A), MTHFR C677T, MTHFR A1298C, PAI-1 4G-5G, Glycoprotein IIIa L33P gene. In conclusion, we report a case of HP with Factor V Leiden (G1691A), MTHFR C677T, MTHFR A1298C, PAI-1 4G-5G, and Glycoprotein IIIa L33P gene mutations. We emphasize that the identification of pachymeningitis can be easily bypassed with the application of limited laboratory techniques. As in this case report, we think that these mutations should be analyzed in patients diagnosed with pachymeningitis.

Galectin-3 as a Potential Prognostic Biomarker for COVID-19 Disease: A Case-Control Study.

Background Recent studies have investigated the importance of Galetin-3 in inflammation, fibrosis, cell proliferation, cardiac disease, diabetes, and tumor formation. Aims This study aims to investigate the role of the Galectin-3 level in the diagnosis of COVID-19 pneumonia and the value of the Galectin-3 level in predicting the clinical course of the patient. Methods This study employed a prospective, case-control study design and was conducted at Bakircay University Cigli Training and Research Hospital. A total of 100 patients (40 had moderate and 60 had severe/critical COVID-19 disease according to World Health Organisation guidelines) and 50 non-symptomatic healthy volunteers participated in the study. Blood samples were taken from patients at the time of hospital admission, after which serum was isolated. Following the isolation of serum, Galectin-3 levels were evaluated using the enzyme-linked immunosorbent assay (ELISA) method.  Results The serum Galectin-3 level was measured as 13.57 (10.9-16.4) ng/mL in the control group, 13.52 (10.69-16.6) ng/mL in the moderate disease group, and 11.65 (6.09-14.33) ng/mL in the severe/critical disease group. Serum Galectin-3 levels were significantly lower in the severe/critical disease group compared to the control and moderate disease groups (p=0.001 and p=0.019, respectively). Using ROC analysis, a larger area under the curve (AUC) for the serum Galectin-3 levels of the control group (AUC=0.622, 95% CI =0.529-0.714; p=0.015) was calculated compared to the COVID-19 patient group for the diagnosis of COVID-19 disease. The Galectin-3 level was found to be 75% sensitive and 50% specific at a cut-off level of 11.3 ng/mL in predicting the need for ICU treatment. Conclusion Galectin-3 levels may be a beneficial biomarker in predicting the clinical severity of COVID-19 disease when used in conjunction with other known biomarkers, at the time of admission to the emergency department (ED).

Evaluation of Serum Ischemia Modified Albumin in Patients With COVID-19 Pneumonia: A Case-Control Study.

INTRODUCTION: Various biomarkers are used when evaluating the hospitalization needs of patients diagnosed with Coronavirus disease (COVID-19). Ischemia-modified albumin (IMA) is a biomarker that causes blood levels to increase as a result of hypoxia and acidosis. We think that an increase in IMA in the blood may be caused by hypoxia stemming from lung damage. This study aimed to compare the mean/median of the blood IMA value in patients with pneumonia due to COVID-19 infection with a control group. METHODS: The case group included patients with COVID-19 pneumonia detected by lung imaging and a positive COVID test. Demographic information of the case group, the severity of pneumonia, and their PCR test results were recorded in the data set. FINDINGS: A total of 150 people, 90 of whom were in the case group and 60 of whom were in the control group, participated in the study. No statistically significant differences were found between the blood IMA levels of the case group and the control group. When the blood IMA levels of the case group were compared according to pneumonia severity, no statistically significant differences were found between the mild-moderate and severe pneumonia groups. CONCLUSION: Blood IMA levels are not a diagnostic biomarker for patients with COVID-19 pneumonia and are not helpful in predicting the severity of pneumonia.

The Correlation Between Peroxisome Proliferator-Activated Receptor Alpha and Gamma Polymorphisms and Acute Coronary Syndrome.

OBJECTIVE: This study aims to evaluate the relationship between peroxisome proliferator-activated receptor (PPAR) alpha and gamma gene polymorphisms and acute coronary syndrome (ACS) clinically. SUBJECT AND METHODS: Peripheral blood samples were collected from a total of 200 people, including 100 acute coronary syndrome patients and 100 controls aged 19 to 93 years, admitted to the Pamukkale University Emergency Medicine Department. The healthy volunteers had no known chronic or acute diseases, no history of drug use, and no recent history of coronary artery disease (CAD). PPAR alpha L162V and PPAR gamma C161T gene polymorphic regions were detected using DNA sequencing analyses. In addition, data collected from the hemogram and biochemical parameters and comorbidities of the patients were statistically analyzed. RESULTS: PPAR gamma C161T polymorphisms were compared between groups. The CT heterozygous rate in the patient group (74%) was higher than in the control group (7%). The T allele was more common in the patient group (0.37) compared to the control group (0.03). When PPAR alpha L162V polymorphism was compared, VV homozygous individuals were %19 in the patient group and none in the control group. The V allele was found to be statistically higher in patients with ACS (p<0.01). CONCLUSION: The findings revealed that elevated PPAR alpha L162V and PPAR gamma C161T gene polymorphisms were associated with a progressive risk of ACS.

DNA methylation profiles in pneumonia patients reflect changes in cell types and pneumonia severity.

Immune cell-type composition changes with age, potentially weakening the response to infectious diseases. Profiling epigenetics marks of immune cells can help us understand the relationship with disease severity. We therefore leveraged a targeted DNA methylation method to study the differences in a cohort of pneumonia patients (both COVID-19 positive and negative) and unaffected individuals from peripheral blood.This approach allowed us to predict the pneumonia diagnosis with high accuracy (AUC = 0.92), and the PCR positivity to the SARS-CoV-2 viral genome with moderate, albeit lower, accuracy (AUC = 0.77). We were also able to predict the severity of pneumonia (PORT score) with an R2 = 0.69. By estimating immune cellular frequency from DNA methylation data, patients under the age of 65 positive to the SARS-CoV-2 genome (as revealed by PCR) showed an increase in T cells, and specifically in CD8+ cells, compared to the negative control group. Conversely, we observed a decreased frequency of neutrophils in the positive compared to the negative group. No significant difference was found in patients over the age of 65. The results suggest that this DNA methylation-based approach can be used as a cost-effective and clinically useful biomarker platform for predicting pneumonias and their severity.

Association Between S100b Levels and COVID-19 Pneumonia: A Case Control Study.

BACKGROUND/AIM: Extracellular S100b effects are mediated by the receptor for advanced glycation end products (RAGE), which is the S100b membrane receptor. RAGE belongs to the immunoglobulin superfamily of cell surface molecules and serves as a multiligand receptor and is expressed in high abundance by alveolar type I (AT-I) cells in adult pulmonary tissue. This study aimed to provide an insight into the association between the severity of COVID-19 disease and serum S100b levels during admission to the emergency department (ED). PATIENTS AND METHODS: A total of 64 patients (34 mild cases; 30 severe cases) were diagnosed with COVID-19 pneumonia and 30 healthy volunteers were admitted to study. Serum S100b levels were measured by using enzymle linked immunoassay method from blood serum samples. RESULTS: Serum S100b levels showed a significantly higher mean value in mild and severe disease cohorts than in healthy controls (p=0.036 and p=0.028 respectively). Receiver operating characteristic (ROC) analysis indicated greater area under the curve (AUC) for serum S100b levels of the COVID-19 patients (AUC=0.663, 95% CI=0.541-0.785; p=0.014). In addition, serum S100b concentration was measured as 151.7 ng/ml at 79.3% sensitivity and 51.7% specificity (p=0.014). Serum S100b protein levels can serve as a valuable clinical marker in establishing diagnosis of patients. Though not useful in identifying different stages of COVID-19 infection, serum S100b concentration along with other known markers can be utilized to reliably predict clinical severity along with other clinical parameters.

Associations between serum lipids and mannose levels in coronary artery disease among nondiabetic patients.

Aim: Nondiabetic patients have been studied to determine whether modest elevations in plasma mannose levels may be associated with a greater incidence of coronary artery disease (CAD). Materials & methods: The plasma mannose, lipids (triglyceride, low-density lipoprotein, high-density lipoprotein, very low-density lipoprotein) and lactate dehydrogenase levels were successfully evaluated with respect to subsequent CAD using records of 120 nondiabetic patients and 120 healthy volunteers. CAD was identified from myocardial infarction and new diagnoses of angina. Results: Of 120 patients studied, the plasma mannose, triglyceride, lactate dehydrogenase and very low-density lipoprotein levels of patients were significantly higher than control groups. Conclusion: Our findings showed that elevated baseline mannose in plasma was associated with a progressive risk of CAD with time.

Annexin A1 as a potential prognostic biomarker for COVID-19 disease: Case-control study.

BACKGROUND: Annexin A1 (AnxA1) is an important endogenous glucocoticoid protein that contributes to the suppression of inflammation by limiting the production of neutrophil and pro-inflammatory cytokines. This study aims to determine the clinical predictivity value of blood AnxA1 levels in patients with mild and severe-critical pneumonia induced by COVID-19. METHODS: This study employed a prospective, case-control study design and was conducted at Ankara Training and Research hospital between 10 February 2021 and 15 March 2021. A total of 74 patients (42 of whom had moderate and 32 of whom had severe/critical cases of COVID-19 disease according to World Health Organization guidelines) and 50 nonsymptomatic healthy volunteers participated in the study. Blood samples were taken from patients at the time of hospital admission, after which serum was isolated. Following the isolation of serum, AnxA1 levels were evaluated using the enzyme-linked immunosorbent assay method. RESULTS: The serum AnxA1 levels were measured as 25.5 (18.6-38.6) ng/ml in the control group, 21.2 (14.7-32) ng/ml in the moderate disease group, and 14.8 (9.7-26.8) ng/ml in the severe/critical disease group. Serum AnxA1 levels were significantly lower in the severe/critical disease group compared with the control and moderate disease groups (P = .01 and P = .0001, respectively). Using receiver operating characteristic analysis, a larger area under the curve (AUC) for the serum AnxA1 levels of the control group (AUC = 0.715, 95% CI = 0.626-0.803; P = .0001) was calculated compared with the COVID-19 patient group for the diagnosis of COVID-19 disease. The AnxA1 level was found to be 80% sensitive and 54.1% specific at a cut-off level of 18.5 ng/ml for the diagnosis of COVID-19 disease. Moreover, the AnxA1 level was found to be 69.8% sensitive and 58.1% specific at a cut-off level of 17.2 ng/ml in predicting the need for intensive care unit (ICU) treatment. CONCLUSION: AnxA1 levels may be a beneficial biomarker in the diagnosis of COVID-19 pneumonia and in predicting the need for ICU treatment in patients with COVID-19 pneumonia at the time of admission to the emergency department.

Soluble P-selectin as a potential diagnostic and prognostic biomarker for COVID-19 disease: A case-control study.

INTRODUCTION: To our knowledge, the diagnostic value of the sP-Selectin level in the diagnosis of COVID-19 disease has not yet been investigated. In this study, we aimed to assess this by evaluating the relationship between sP-Selectin level and the clinical severity of COVID-19 infections. METHODS: A total of 80 patients (50 with mild to moderate and 30 with severe COVID-19 pneumonia), and 60 non-symptomatic healthy volunteers participated in the study. Following serum isolation, sP-Selectin levels were assessed by Enzyme-Linked Immunosorbent Assay (ELISA) method. RESULTS: The serum sP-Selectin level was 1.7 ng/ml in the control group (1-3.78); 6.24 ng/ml (5.14-7.23) in mild-to-moderate pneumonia group; and 6.72 ng/ml (5.36-8.03) in the severe pneumonia group. Serum sP-Selectin levels in both mild-to-moderate pneumonia and severe pneumonia groups were found to be higher than the control group, with statistical significance (p = 0.0001 and p = 0.0001, respectively). Receiver operating characteristic analysis (ROC) showed greater area under the curve (AUC) for the serum sP-Selectin levels of the COVID-19 patients (AUC = 0.913, 95% CI = 0.857-0.969; p = 0.0001). The serum sP-Selectin level was found to be 97.5% sensitive and 80% specific at 4.125 ng/ml level for diagnosis (p = 0.0001). The serum sP-Selectin level was found to be 76.9% sensitive and 51.9% specific at the level of 6.12 ng/ml (p = 0.005) to predict the need for intensive care treatment. CONCLUSION: This study showed that sP-Selectin can be used as a valuable biomarker in both diagnosing and predicting the need for intensive care treatment of COVID-19 infection.

High GRP78 levels in Covid-19 infection: A case-control study.

INTRODUCTION: Covid-19 infection was declared a global pandemic by WHO on March 11, 2020. GRP78 protein is known to be involved in the intrusion of numerous viruses. Our current study tries to provide some insight into the variation of GRP78 protein levels in patients with Covid-19 (-) pneumonia, Covid-19 (+) pneumonia, and CT negative Covid-19 infection in comparison to the normal population through a larger number of cases. MATERIALS AND METHODS: 42 patients who have Covid-19 (-) pneumonia; 72 patients who have Covid-19 infection (30 pneumonia,42 CT negative patients) and 30 patient who have no known diseases (control group) have included in the study after the clinical and radiological evaluation. Serum GRP78 levels of the subjects were measured through a commercially available enzyme-linked immunosorbent assay (ELISA) kit. RESULTS: The GRP78 level was found to be significantly higher in the Covid-19 infection group than both Covid-19 (-) pneumonia and control group (p = 0.031 and p = 0.0001, respectively).No significant difference was evident between Covid-19 (-) pneumonia, Covid-19 (+) pneumonia and CT negative Covid 19 infection groups with respect to GRP78 levels (p = 0.09). In addition, the GRP78 levels were significantly higher in the Covid-19 (-) pneumonia group than the control group (p = 0.0001). CONCLUSION: This prospective case-control study reveals that the serum GRP78 levels significantly increased during Covid-19 infection in comparison to both the Covid-19 (-) pneumonia and the control group. As the association between SARS-CoV-2 virus and GRP78 protein is revealed more clearly, this association may come to the fore as a therapeutic target.

Molecular and Biochemical Parameters Related to Plasma Mannose Levels in Coronary Artery Disease Among Nondiabetic Patients.

Aims: Nondiabetic patients were studied to determine whether modest elevations in plasma mannose may be associated with a greater incidence of coronary artery disease (CAD). Materials and Methods: Plasma insulin, mannose, glucose, hexokinase 1-2, GLUT1-GLUT4 levels, and serum mannose phosphate isomerase enzyme levels were evaluated with respect to subsequent CAD using records from 120 nondiabetic CAD patients and 120 healthy volunteers. CAD was identified from myocardial infarction and new diagnoses of angina. Results: Of 120 nondiabetic CAD patients studied, their plasma GLUT4 and HK1 levels were significantly lower than those of the control group. In addition, a significant increase in plasma mannose levels was found in the patient group compared to the control group. Conclusion: Our findings showed that elevated baseline mannose levels in plasma are associated with an increased risk of CAD over time.

Preliminary Virtual Screening Studies to Identify GRP78 Inhibitors Which May Interfere with SARS-CoV-2 Infection.

SARS-CoV-2 Spike protein was predicted by molecular docking to bind the host cell surface GRP78, which was suggested as a putative good molecular target to inhibit Covid-19. We aimed to confirm that GRP78 gene expression was increased in blood of SARS-CoV-2 (+) versus SARS-CoV-2 (-) pneumonia patients. In addition, we aimed to identify drugs that could be repurposed to inhibit GRP78, thus with potential anti-SARS-CoV-2 activity. Gene expression studies were performed in 10 SARS-CoV-2 (-) and 24 SARS-CoV-2 (+) pneumonia patients. A structure-based virtual screen was performed with 10,761 small molecules retrieved from DrugBank, using the GRP78 nucleotide binding domain and substrate binding domain as molecular targets. Results indicated that GRP78 mRNA levels were approximately four times higher in the blood of SARS-CoV-2 (+) versus SARS-CoV-2 (-) pneumonia patients, further suggesting that GRP78 might be a good molecular target to treat Covid-19. In addition, a total of 409 compounds were identified with potential as GRP78 inhibitors. In conclusion, we found preliminary evidence that further proposes GRP78 as a possible molecular target to treat Covid-19 and that many clinically approved drugs bind GRP78 as an off-target effect. We suggest that further work should be urgently carried out to confirm if GRP78 is indeed a good molecular target and if some of those drugs have potential to be repurposed for SARS-CoV-2 antiviral activity.

Endoplasmic Reticulum Stress Markers in SARS-COV-2 Infection and Pneumonia: Case-Control Study.

BACKGROUND/AIM: A novel human coronavirus, named SARS-COV-2, has recently caused thousands of deaths all around the world. Endoplasmic reticulum (ER) stress plays an important role in the development of diseases. PATIENTS AND METHODS: We aimed to to investigate the relationship between ER stress markers in patients infected with SARS-COV-2 and patients with pneumonia. A total of 9 patients (4 patients diagnosed with pneumonia and 5 patients diagnosed with SARS-COV-2 infection) who admitted to the emergency Department with symptoms of pneumonia and SARS-COV-2 were included in the study. A total of 18 healthy individuals without any known chronic or acute disease and drug use were included as the healthy control group. Serum human glucose regulated protein 78 (GRP78), serum human C/EBP homologous protein (CHOP) and serum human phospho extracellular signal regulated kinase (PERK) levels were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: GRP78 levels were found to be significantly higher in SARS-COV-2 positive cases compared to individuals in other groups. Serum GRP-78 level median value was statistically significantly higher in SARS-COV-2-positive group compared to the other groups (p=0.0003). Serum PERK level was statistically significantly higher in SARS-COV-2-positive pneumonia cases (p=0.046). CONCLUSION: An association was shown between GRP78 and SARS-COV-2 infection. Although a small number of patients was investigated, these results will be important and guide future treatments of SARS-COV-2.

Genome-wide DNA Methylation Profiling of Blood from Monozygotic Twins Discordant for Myocardial Infarction.

BACKGROUND/AIM: This study aimed to measure the DNA methylation state of thousands of CpG islands in the blood of two monozygotic twins that were discordant for cardiovascular disease (CVD). Twin 1 had suffered myocardial infarction, while the other was healthy. PATIENTS AND METHODS: Since the aim of this study was to identify differentially methylated regions which might act as potential markers, reduced-representation bisulfite libraries were used for whole-genome methylation analysis. RESULTS: According to the analysis, 11 genes lipid droplet associated hydrolase (LDAH), apolipoprotein B (APOB), acyl-CoA synthetase medium chain family member 2A (ACSM2A), acyl-CoA synthetase medium chain family member 5(ACSM5), acyl-CoA synthetase family member 3 (ACSF3), carboxylesterase 1 (CES1), carboxylesterase 1 pseudogene 1 (CES1P1), AFG3 like matrix AAA peptidase subunit 2 (AFG3L2), iron-sulfur cluster assembly enzyme (ISCU), SEC14 like lipid binding 2 (SEC14L2) and microsomal triglyceride transfer protein (MTTP) were all hypomethylated in DNA from twin 2, the unaffected twin. Methylation changes were observed at different multiple loci between the twins, suggesting loci that are affected by disease status in identical genetic backgrounds. CONCLUSION: This twin study may contribute significantly to the understanding of the genetic basis of CVD and resulting myocardial infarction. This approach may allow identification of possible target loci associated with aberrant epigenetic regulation in CVD.

Predictive Value of Endoplasmic Reticulum Stress Markers in Low Ejection Fractional Heart Failure.

BACKGROUND/AIM: Endoplasmic reticulum (ER) stress plays a critical role in the development of cardiac hypertrophy and heart failure. Heart failure is a crucial health problem that affects 23 million people worldwide, causes approximately 2.4 million people to be hospitalized every year in the USA, and leads to the death of more than 300,000 people. In this study, we aimed to investigate the clinical significance of ER stress markers and the predictive value of acute decompensated heart failure in patients with low ejection fraction heart failure (ADHF). PATIENTS AND METHODS: This is a prospective case control study. The data included laboratory parameters pertaining to patients with ADHF in the emergency service and lipid parameters obtained during their admission to the hospital. In addition, the same parameters obtained from the control group patients with chronic heart failure (CHF) during their routine polyclinic control were recorded in the data set. Admission time to the hospital and length of hospital stay were included in the data. The levels of glucose regulated protein (GRP78), protein kinase RNA-like endoplasmic reticulum kinase (PERK), and C/EBP homologous protein (CHOP) in peripheral blood serum obtained from the patients and the control group were measured using the ELISA method. RESULTS: Serum GRP78 concentration was lower in the HF group (p=0.003) compared to the control. The median value of serum PERK concentration in the HF group was higher than that of the control group (573 pg/ml, IQR=477.5-650 vs. 495.5 pg/ml, IQR=294-648, respectively) (p=0.001). However, there were no statistically significant differences in GRP78 and PERK serum concentrations between ADHF and CHF subgroups. Receiver operating characteristic (ROC) curve analysis showed greater area under the curve (AUC) for the serum GRP78 levels of the healthy individuals (AUC=0.748, 95% CI=0.681-0.814, p=0.0003). The serum GRP78 level was found to be 80% sensitive and 70% specific at 147.5 pg/ml (p=0.0003) for distinguishing healthy individuals from HF patients. In the ADHF subgroup, there was a moderate correlation between hospitalization time and serum CHOP concentrations (Spearman rho=0.586 and p=0.001). CONCLUSION: High GRP78 serum concentration may protect the patient from ER stress. In addition, the serum PERK level is high in patients with HF, whereas it is insufficient in predicting acute decompensation. CHOP may be useful in predicting the length of hospital stay in patients with ADHF.

The role of UGT1A1 promoter polymorphism and exon-1 mutations in neonatal jaundice.

OBJECTIVE: In the present study, we investigated the effects of promoter polymorphism and an exon-1 mutation (G71R) in the UGT1A1 gene in neonates with unexplained hyperbilirubinemia and direct Coombs-negative [DC(-)] ABO incompatibility. METHODS: Two-hundred term neonates in their first week of life and without additional icterogenic factors were included in the study. Neonates with a serum total bilirubin (STB) level ≥17 mg/dL constituted the hyperbilirubinemia group (n = 100), while the control group comprised healthy neonates with a STB level <12.9 mg/dL (n = 100). The cases were further subdivided into unexplained hyperbilirubinemia (n = 50), ABO(+) hyperbilirubinemia (n = 50), ABO(-) control (n = 50), and ABO(+) control (n = 50) groups on the basis of the presence or absence of DC(-) ABO incompatibility. DNA was isolated from peripheral blood and amplified by PCR, and UGT1A1 gene promoter and exon-1 were sequenced to verify sequence alterations. RESULTS: The frequency of TA6/6, TA6/7, TA7/7, and GGA/GGA, GGA/AGA, AGA/AGA genotypes was found to be 63.5%, 21%, 15.5%, and 91.5%, 8%, 0.5%, respectively. While both heterozygous and homozygous TA7 polymorphism increased risk of hyperbilirubinemia in the ABO(+) hyperbilirubinemia group (heterozygous OR 16.76, 95% CI:3.52-79.70, p < 0.0001; homozygous OR 6.81, 95% CI:1.98-23:42, p = 0.002), only heterozygous TA7 polymorphism increased jaundice risk (OR 5.08 95% CI:76-14.65, p = 0.003) in unexplained hyperbilirubinemia. But, the coexistence of G71R mutation and promoter polymorphism or G71R mutation and DC(-) ABO incompatibility did not increase the severity of hyperbilirubinemia (p > 0.05). CONCLUSIONS: UGT1A1 gene promoter polymorphism and G71R mutation are possible risk factors for Turkish neonates with DC(-) ABO incompatibility and unexplained hyperbilirubinemia.