Deiodinases, organic anion transporter polypeptide polymorphisms and symptoms of anxiety and depression after ischemic stroke.

BACKGROUND: Emotional disturbances, such as anxiety and depression are common after acute ischemic stroke (AIS). Individual variation in emotional outcome is strongly influenced by genetic factors. One of pituitary axis, is the hypothalamic-pituitary-thyroid axis, a critical regulator of post-stroke recovery, suggesting that allelic variants in thyroid hormone (TH) signaling regulation can influence stroke outcome. AIM: To determine associations between AIS emotional outcome and allelic variants of the TH metabolizing enzymes 1-3 type deiodinase (DIO1-3) and the membrane transporting organic anion polypeptide 1C1 (OATP1C1). METHODS: Eligible AIS patients from Lithuania (n=168) were genotyped for ten DIO1-3 and OATP1C1 single nucleotide polymorphisms (SNP): DIO1 rs12095080-A/G, rs11206244-C/T, and rs2235544-A/C; DIO2 rs225014-T/C and rs225015-G/A; DIO3 rs945006-T/G; OATP1C1 rs974453-G/A, rs10444412-T/C, rs10770704-C/T, and rs1515777-A/G. Emotional outcome was evaluated using the Hospital Anxiety and Depression Scale at discharge from the neurology department after experienced index AIS. RESULTS: After adjustment for potential confounders, the major allelic (wild-type) DIO1-rs12095080 genotype (AA) was associated with higher odds ratio of anxiety symptoms (OR = 5.16; 95% CI: 1.04-25.58; p = 0.045), conversely, DIO1-rs11206244 wild-type genotype (CC) and wild-type OATP1C1-rs1515777 allele containing the genotypes (AA + AG) were associated with lower odds ratio of symptoms of anxiety (OR = 0.37; 95% CI: 0.14-0.96; p = 0.041 and OR = 0.30; 95% CI: 0.12-0.76; p = 0.011, respectively). Wild-type OATP1C1-rs974453 genotype (GG) was associated with higher odds ratio of symptoms of depression (OR = 2.73; 95% CI: 1.04-7.12; p = 0.041). CONCLUSION: Allelic variants in thyroid axis genes may predict emotional outcomes of AIS.

Investigation of TGFßR2 SNP rs4522809, Osteopontin, TGF ß1 and their association with dilatative pathology of ascending thoracic aorta.

BACKGROUND: Dilatative pathology of the ascending thoracic aorta (DPATA) is characterized by the aortic wall expansion more than 1.5 and could be accompanied by aortic wall rupture. Mutations of TGFBR2 gene demonstrated an association with syndromic DPATA and altered pathway of transforming growth factor beta (TGF-ß). Elevated TGF-ß1 level has been found in blood samples in DPATA group. Moreover, elevated osteopontin (OPN) level was associated with mutations of TGFBR2 gene. Based on recently published findings, we aimed to evaluate genotyping results of TGFBR2 rs4522809 and the association with circulating OPN and TGF-ß1 concentrations within DPATA patients. METHODS AND FINDINGS: TGFBR2 SNP genotyping assay was performed by quantitative real-time PCR, TGF-ß1 and OPN concentrations were measured using enzyme-linked immunosorbent assay. Genotyping results showed G allele to be associated with DPATA (p = .01), the presence of G allele significantly increased the possibility of DPATA by 1.67 times (OR = 1.67, 95%, CI = 1.12-2.47). TGF-ß1 concentration was significantly higher in DPATA subjects compared with Reference group (p = 0,001). Finally, we found moderate inverse correlation (r = -0,524) between circulating TGF-ß1 and OPN levels within DPATA subjects (p = 0,002), as increasing levels of TGF-ß1 cytokine significantly decrease concentration of OPN. CONCLUSIONS: This is the first report on the association between previously defined TGFßR2 SNP rs4522809 linked with dilatation of ascending thoracic aorta. Also, for the first time we report the inversed correlation between circulating TGF-ß1 and OPN concentrations in DPATA subjects indicating the possible biomarkers for DPATA.

Association between Fibrillin1 Polymorphisms (rs2118181, rs10519177) and Transforming Growth Factor ß1 Concentration in Human Plasma.

Transforming growth factor (TGF)-ß1 is a cytokine that participates in a broad range of cellular regulatory processes and is associated with various diseases including aortic aneurysm. Increased TGF-ß1 levels are linked to Marfan syndrome (MFS) caused by fibrillin1 (FBN1) mutations and subsequent defects in signaling system. FBN1 single nucleotide polymorphisms (SNPs) rs2118181 and rs1059177 do not cause MFS but are associated with dilative pathology of aortic aneurysms (DPAAs). TGF-ß1 and FBN1 SNPs rs2118181 and rs1059177 are potential biomarkers for early diagnosis of DPAA. We investigated the relationship between TGF-ß1 levels in human blood plasma and FBN1 rs2118181 and rs1059177 in 269 individuals. The results showed a quantitative dependence of SNP genotype and TGF-ß1 concentration. Presence of a single rs2118181 minor allele (G) increased the amount of TGF-ß1 by roughly 1 ng/mL. Two copies of FBN1 rs1059177 minor allele (G) were required to have an additive effect on TGF-ß1 levels. We found higher TGF-ß1 concentrations in men compared with women (p = 0.001). A strong correlation between TGF-ß1 levels and FBN1 SNPs suggests that a single nucleotide substitution in FBN1 sequence might reduce bioavailability or binding properties of fibrillin-1 and have an effect on TGF-ß1 activation and cytokine concentration in blood plasma. By establishing the relationship between TGF-ß1 and FBN1 SNPs rs2118181 and rs1059177, we provide evidence that their combination might be used as molecular biomarkers to identify patients at risk for sporadic ascending aortic aneurysm and aortic dissection.

Genetical Signature-An Example of a Personalized Skin Aging Investigation with Possible Implementation in Clinical Practice.

We conducted a research study to create the groundwork for personalized solutions within a skin aging segment. This test utilizes genetic and general laboratory data to predict individual susceptibility to weak skin characteristics, leveraging the research on genetic polymorphisms related to skin functional properties. A cross-sectional study was conducted in a collaboration between the Private Clinic Medicina Practica Laboratory (Vilnius, Lithuania) and the Public Institution Lithuanian University of Health Sciences (Kaunas, Lithuania). A total of 370 participants agreed to participate in the project. The median age of the respondents was 40, with a range of 19 to 74 years. After the literature search, we selected 15 polymorphisms of the genes related to skin aging, which were subsequently categorized in terms of different skin functions: SOD2 (rs4880), GPX1 (rs1050450), NQO1 (rs1800566), CAT (rs1001179), TYR (rs1126809), SLC45A2 (rs26722), SLC45A2 (rs16891982), MMP1 (rs1799750), ELN (rs7787362), COL1A1 (rs1800012), AHR (rs2066853), IL6 (rs1800795), IL1Beta (rs1143634), TNF-α (rs1800629), and AQP3 (rs17553719). RT genotyping, blood count, and immunochemistry results were analyzed using statistical methods. The obtained results show significant associations between genotyping models and routine blood screens. These findings demonstrate the personalized medicine approach for the aging segment and further add to the growing literature. Further investigation is warranted to fully understand the complex interplay between genetic factors, environmental influences, and skin aging.

Circulating hsa-let-7e-5p and hsa-miR-125a-5p as Possible Biomarkers in the Diagnosis of Major Depression and Bipolar Disorders.

BACKGROUND: Evidence shows that microRNAs (miRNAs) could play a key role in the homeostasis and development of major depressive disorder and bipolar disorder. The present study is aimed at investigating the changes in circulating miRNA expression profiles in a plasma of patients suffering from major depressive disorder (MDD) and bipolar disorder (BD) to distinguish and evaluate these molecules as biomarkers for mood disorders. METHODS: A study enrolled a total of 184 subjects: 74 controls, 84 MDD patients, and 26 BD patients. Small RNA sequencing revealed 11 deregulated circulating miRNAs in MDD and BD plasma, of which expression of 5, hsa-miR-139-3p, miRNAs hsa-let-7e-5p, hsa-let-7f-5p, hsa-miR-125a-5p, and hsa-miR-483-5p, were further verified using qPCR. miRNA gene expression data was evaluated alongside the data from clinical assessment questionnaires. RESULTS: hsa-let-7e-5p and hsa-miR-125a-5p were both confirmed upregulated: 0.75-fold and 0.25-fold, respectively, in the MDD group as well as 1.36-fold and 0.68-fold in the BD group. Receiver operating curve (ROC) analysis showed mediocre diagnostic sensitivity and specificity of both hsa-let-7e-5p and hsa-miR-125a-5p with approximate area under the curve (AOC) of 0.66. ROC analysis of combined miRNA and clinical assessment data showed that hsa-let-7e-5p and hsa-miR-125a-5p testing could improve MDD and BD diagnostic accuracy by approximately 10%. CONCLUSIONS: Circulating hsa-let-7e-5 and hsa-miR-125a-5p could serve as additional peripheral biomarkers for mood disorders; however, suicidal ideation remains the major diagnostic factor for MDD and BD.

Evidence for the expression of TRPM6 and TRPM7 in cardiomyocytes from all four chamber walls of the human heart.

The expression of the channels-enzymes TRPM6 and TRPM7 in the human heart remains poorly defined, and TRPM6 is generally considered not to be expressed in cardiomyocytes. We examined their expression at protein and mRNA levels using right atrial samples resected from patients (n = 72) with or without ischemic heart disease (IHD) and samples from all chamber walls of explanted human hearts (n = 9). TRPM6 and TRPM7 proteins were detected using immunofluorescence on isolated cardiomyocytes, ELISA on tissue homogenates, and immunostaining of cardiac tissue, whereas their mRNAs were detected by RT-qPCR. Both TRPM6 and TRPM7 were present in all chamber walls, with TRPM7 being more abundant. TRPM6 was co-expressed with TRPM7. The expression levels were dependent on cell incubation conditions (presence or absence of divalent cations, pH of the extracellular milieu, presence of TRP channel inhibitors 2-aminoethoxydiphenyl-borate and carvacrol). These drugs reduced TRPM7 immunofluorescence but increased that of TRPM6. TRPM6 and TRPM7 expression was increased in tissues from IHD patients. This is the first demonstration of the presence and co-expression of TRPM6 and TRPM7 in cardiomyocytes from all chamber walls of the human heart. The increased TRPM6 and TRPM7 expression in IHD suggests that the chanzymes are involved in the pathophysiology of the disease.

Ankylosing Spondyloarthritis Resulting Severe Aortic Insufficiency and Aortitis: Exacerbation of Ankylosing Spondyloarthritis and Stenosis of the Main Left Coronary Artery after Mechanical Aortic Valve Implantation with Cardiopulmonary Bypass.

Ankylosing spondyloarthritis (AS) is a chronic inflammatory rheumatic disease, strongly related to human leukocyte antigen (HLA)-B27. Cardiac involvement in AS manifests in 2 to 10% of patients as aortic insufficiency, aortitis, mitral valve fibrosis, or disturbance in the conduction of the heart. In this article, we present a case of a 49-year-old male patient with AS, who was referred to our medical institution for elective aortic valve surgery because of severe aortic regurgitation. The histological findings revealed fibrosing endocarditis of aortic valve and nonspecific aortitis of aortic root. Late postoperatively, we observed exacerbation of AS and narrowing of the main left coronary artery (LAD). Our case highlights the importance of proper treatment of AS before and after cardiac surgery. Furthermore, in this case, we suspect association between cardiopulmonary bypass, activity of AS, and coronary artery disease.

Long Noncoding RNAs CARMN, LUCAT1, SMILR, and MALAT1 in Thoracic Aortic Aneurysm: Validation of Biomarkers in Clinical Samples.

MATERIALS AND METHODS: Relative expression of lncRNAs CARMN, LUCAT1, SMILR, and MALAT1 was tested in clinical aortic tissue and blood plasma samples from TAA and non-TAA patients using the qRT-PCR method. The Mann-Whitney U test was used to compare ΔCt values between the study groups. ROC curve analysis was performed to evaluate the diagnostic value of plasma lncRNAs. RESULTS: We found significantly reduced CARMN (p = 0.033) and LUCAT1 (p = 0.009) expression in aortic tissue samples from TAA patients. Relative expression of MALAT1 (p = 0.117) and SMILR (p = 0.610) did not differ in aortic tissue between the TAA and non-TAA groups. Expression of both LUCAT1 and SMILR was significantly decreased in TAA patients' blood plasma compared to controls (p = 0.018 and p = 0.032, respectively). However, only LUCAT1 showed the ability to discriminate aneurysmal disease in patients' blood plasma (AUC = 0.654, 95%CI = 0.534-0.775, p = 0.018). CONCLUSIONS: We have shown that the expression of lncRNAs CARMN and LUCAT1 is reduced in dilated aortic tissue and that the LUCAT1 and SMILR expression is lower in the blood plasma of TAA patients. Decreased LUCAT1 expression in TAA patients' blood plasma may have diagnostic potential in discriminating patients with TAA.

Deiodinases, organic anion transporter polypeptide polymorphisms and ischemic stroke outcomes.

BACKGROUND: Ischemic stroke is a major cause of premature death and chronic disability worldwide, and individual variation in functional outcome is strongly influenced by genetic factors. Neuroendocrine signaling by the hypothalamic-hypophyseal-thyroid axis is a critical regulator of post-stroke pathogenesis, suggesting that allelic variants in thyroid hormone (TH) signaling can influence stroke outcome. AIM: To examine associations between acute ischemic stroke (AIS) outcome and allelic variants of the TH metabolizing enzymes deiodinase type 1-3 (DIO1-3) and membrane transporting organic anion polypeptide C1 (OATP1C1). METHODS: Eligible AIS patients from Lithuania (n = 248) were genotyped for ten DIO1-3 and OATP1C1 single nucleotide polymorphisms (SNPs): DIO1 rs12095080-A/G, rs11206244-C/T, and rs2235544-A/C; DIO2 rs225014-T/C and rs225015-G/A; DIO3 rs945006-T/G; OATP1C1 rs974453-G/A, rs10444412-T/C, rs10770704-C/T, and rs1515777-A/G. Functional outcome was evaluated one year after index AIS using the modified Rankin Scale. Analyses were adjusted for important confounders, including serum free triiodothyronine. RESULTS: After adjustment for potential confounders, the major allelic (wild-type) DIO3 genotype rs945006-TT was associated with better 1-year AIS functional outcome (odds ratio [OR] = 0.25; 95% confidence interval [CI]: 0.08-0.74; p = .013), while the wild-type OATP1C1 genotype rs10770704-CC was associated with poorer outcome (OR = 2.00, 95%CI: 1.04-3.86; p = .038). CONCLUSION: Allelic variants in thyroid axis genes may prove useful for prognosis and treatment guidance.

Tissue-Specific miRNAs Regulate the Development of Thoracic Aortic Aneurysm: The Emerging Role of KLF4 Network.

MicroRNAs (miRNAs) are critical regulators of the functional pathways involved in the pathogenesis of cardiovascular diseases. Understanding of the disease-associated alterations in tissue and plasma will elucidate the roles of miRNA in modulation of gene expression throughout development of sporadic non-syndromic ascending thoracic aortic aneurysm (TAA). This will allow one to propose relevant biomarkers for diagnosis or new therapeutic targets for the treatment. The high-throughput sequencing revealed 20 and 17 TAA-specific miRNAs in tissue and plasma samples, respectively. qRT-PCR analysis in extended cohort revealed sex-related differences in miR-10a-5p, miR-126-3p, miR-155-5p and miR-148a-3p expression, which were the most significantly dysregulated in TAA tissues of male patients. Unexpectedly, the set of aneurysm-related miRNAs in TAA plasma did not resemble the tissue signature suggesting more complex organism response to the disease. Three of TAA-specific plasma miRNAs were found to be restored to normal level after aortic surgery, further signifying their relationship to the pathology. The panel of two plasma miRNAs, miR-122-3p, and miR-483-3p, could serve as a potential biomarker set (AUC = 0.84) for the ascending TAA. The miRNA-target enrichment analysis exposed TGF-ß signaling pathway as sturdily affected by abnormally expressed miRNAs in the TAA tissue. Nearly half of TAA-specific miRNAs potentially regulate a key component in TGF-ß signaling: TGF-ß receptors, SMADs and KLF4. Indeed, using immunohistochemistry analysis we detected increased KLF4 expression in 27% of TAA cells compared to 10% of non-TAA cells. In addition, qRT-PCR demonstrated a significant upregulation of ALK1 mRNA expression in TAA tissues. Overall, these observations indicate that the alterations in miRNA expression are sex-dependent and play an essential role in TAA via TGF-ß signaling.

Prevalence of O25b-ST131 clone among Escherichia coli strains producing CTX-M-15, CTX-M-14 and CTX-M-92 ß-lactamases.

BACKGROUND: Dissemination of multidrug-resistant Escherichia coli is closely associated with the worldwide spread of a single clone ST131, which is the main cause of urinary tract and bloodstream infections in patients from nursing homes and immunocompromised patients. The aim of our study was to determine the prevalence of ST131 clone and the replicons involved in the spread of blaCTX-M genes among O25b-ST131 CTX-M-producing E. coli isolates in Lithuania. METHODS: The strains included in this study were screened for CTX-M ß-lactamase-encoding genes, phylogenetic groups and ST131 clone by PCR. Bacterial conjugation was performed to identify plasmid replicon types responsible for blaCTX-M genes dissemination. RESULTS: A total of 158 E. coli clinical non-duplicate ESBL isolates were analyzed. Nearly half (n = 67, 42.4%) of the investigated E. coli isolates belonged to phylogenetic group B2. The isolates producing CTX-M-92 ß-lactamases were identified to be the ST131 clone more frequently than the non-ST131 clone (11.5% vs. 3.1%, p = .035). The CTX-M-15 isolates were identified as ST131 isolates less frequently than non-ST131 isolates (50.8% vs. 71.1%; p = .015). The ST131 clone isolates contained type L/M and A/C replicons; a fused FII/FIB replicon was found in four isolates (23.5%). Type HI1 replicon was identified in ST131 E. coli isolates producing CTX-M-15 ß-lactamases. CONCLUSIONS: This study demonstrates the predominance of the ST131 clone among CTX-M ß-lactamase-producing E. coli isolates. Dissemination of blaCTX-M genes in ST131 strains can be linked not only to highly adapted IncF plasmids such as FII/FIB and FII, but also to plasmid replicon types A/C, L/M and HI1.

Blood Plasma TGF- ß1 Concentration in Sporadic Dilatative Pathology of Ascending Aorta: More Questions than Answers.

Transforming growth factor ß1 (TGF- ß1) is a cytokine that participates in a broad range of cellular regulatory processes and is associated with various diseases including aortic aneurysm. Increased TGF- ß1 levels are associated with Marfan syndrome (MFS) caused by FBN1 mutations and subsequent defects in signaling system. We studied TGF- ß1 levels in 62 patients with sporadic, non syndromic, dilatative pathology of ascending aorta (DPAA) and in reference group subjects (n = 212). An initial screening of 212 reference individuals identified TGF- ß1 gender discrepancies and age-dependent cytokine increase in women. Patients with DPAA had increased levels of TGF- ß1 in comparison to reference group subjects (median 7.7 ng/ml, range 2.1-25.3, and median 6.2 ng/ml, range 1.0-33.1, respectively). There is a significant association between TGF-ß1 concentration and DPAA (OR 1.084, CI 1.027-1.144, p = 0.004) but the mechanisms of cause and effect have not been established yet. Slightly increased TGF-ß1 concentrations in patients with sporadic DPAA in comparison to the reference subjects show a potential use of TGF-ß1 as a biomarker for the disease. However, cytokine dependence on age, gender, and other unknown factors among individuals with no cardiovascular complains reduces its specificity for DPAA. We would also like to raise awareness regarding the choice of methods when measuring TGF-ß1 levels with an emphasis on preanalytical phase and the choice of sample.

FBN1 polymorphisms in patients with the dilatative pathology of the ascending thoracic aorta.

OBJECTIVES: To investigate polymorphisms of the fibrillin-1 (FBN1) gene (namely, rs2118181, rs1036477, rs10519177, rs755251 and rs4774517) in a case-control study for dilatative pathology of the ascending thoracic aorta (DPATA) from Lithuanians. METHODS: We studied 312 patients who had undergone aortic reconstructive surgery for DPATA. These patients were sub-divided according to the phenotypes of their DPATA into (i) ascending aortic aneurysm (n = 160), (ii) post-stenotic dilatation of the ascending aorta due to aortic valve stenosis (n = 79) and (iii) Stanford A dissection (n = 73). The reference group (n = 472) was recruited from a random sample screened within epidemiological studies of the Lithuanian population. FBN1 polymorphisms were studied by real-time polymerase-chain-reaction amplification. RESULTS: Patients within the aortic dissection sub-group had significantly higher minor allele frequencies in all five FBN1 single nucleotide polymorphism (SNPs) studied versus reference group subjects (P < 0.0001). Minor allele frequencies in SNPs rs2118181, rs1036477 were significantly higher in those with aortic aneurysm when compared with the reference group (P = 0.007). Thus, minor alleles of FBN1 SNPs studied were significantly associated with aortic dissection with odds ratios (ORs) 2.59-2.13, P < 0.001, while SNPs rs2118181 and rs1036477 with an increased risk of ascending aortic aneurysm [OR 1.67, confidence interval (CI) 95% 1.61-2.40]. The association of FBN1 genotypes with each phenotype of DPATA was assessed using logistic regression models adjusted for gender, age and hypertension. The additive model best fitted SNPs rs2118181 and rs1036477 in association with the ascending aortic aneurysm sub-group (OR 1.70, CI 95% 1.17-2.46) or the Stanford A dissection sub-group (OR 2.64, CI 95% 1.66-4.19). A recessive model fitted best the association between SNPs rs10519177, rs755251, rs4774517 and Stanford A dissection (OR 4.31, CI 95% 2.06-9.01). There were no significant associations between all studied FBN1 SNPs and post-stenotic or bicuspid aortic dilatation. CONCLUSIONS: Our study provides evidence for the following: (i) FBN1 SNPs rs2118181, rs1036477, rs10519177, rs4774517, rs755251 may increase susceptibility to aortic dissections and (ii) FBN1 SNPs rs2118181, rs1036477 to the formation of aortic aneurysms. Thus, these SNPs might be considered as biomarkers for identifying patients at risk for ascending aortic aneurysm and aortic dissection.