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The Patterns of non-Adherence to Anti-Platelet Regimen in Stented Patients (PARIS) bleeding risk score has been proposed to predict the risk of bleeding events after percutaneous coronary intervention (PCI). However, the prognostic value of the PARIS bleeding risk score for long term all-cause mortality, cardiac mortality and hospitalization due to heart failure has not yet been evaluated. Therefore, the aim of the present study was to evaluate the prognostic value of the PARIS bleeding risk score for all-cause and cardiac mortalities and hospitalization due to heart failure after PCI. Consecutive 1061 patients who had undergone PCI were divided into 3 groups based on the PARIS bleeding risk score; low (n = 112), intermediate (n = 419) and high-risk groups (n = 530). We prospectively followed up the 3 groups for all-cause and cardiac mortalities and hospitalization due to heart failure. Kaplan-Meier analysis revealed that all of the outcomes were highest in the high-risk group among the 3 groups (P0.001, P0.001 and P0.001 respectively). Multivariable Cox proportional hazard analysis, adjusted for confounding factors, revealed that all-cause mortality of the intermediate or high-risk groups was higher than those of the low-risk group (adjusted hazard ratio 6.06 and 12.50, P = 0.013 and P0.001, respectively). The PARIS bleeding risk score is a significant indicator of prognosis for all-cause mortality in patients after PCI.

Background Although the National Lung Screening Trial reported a significant reduction in lung cancer mortality when low-dose (LD) CT chest examinations are used for a diagnosis, their biologic effects from radiation exposure remain unclear. Purpose To compare LD CT and standard-dose (SD) CT for DNA double-strand breaks and chromosome aberrations (CAs) in peripheral blood lymphocytes. Materials and Methods Between March 2016 and June 2018, 209 participants who were referred to a respiratory surgery department for chest CT studies were prospectively enrolled in this study. Individuals were excluded if they had undergone radiography examinations within the last 3 days or had undergone chemotherapy or radiation therapy. Peripheral blood samples were obtained before and 15 minutes after CT. The number of γ-H2AX foci and unstable CAs in lymphocytes was quantified by immunofluorescent staining of γ-H2AX and by fluorescence in situ hybridization by using peptide nucleic acid probes for centromeres and telomeres, respectively. The Wilcoxon signed rank test was used for statistical analysis. Bonferroni correction was applied for multiple comparisons. Results Of the 209 participants (105 women, 104 men; mean age, 67.0 years ± 11.3 [standard deviation]), 107 underwent chest LD CT and 102 underwent chest SD CT. Sex distribution, age, and body size metrics were similar between the two groups. The median effective dose of LD CT and SD CT was 1.5 and 5.0 mSv, respectively. The number of double-strand breaks and CAs increased after a SD CT examination (γ-H2AX, P < .001; CAs, P = .003); the number of double-strand breaks and CAs before and after LD CT was not different (γ-H2AX, P = .45; CAs, P = .69). Conclusion No effect of low-dose CT on human DNA was detected. In the same setting, DNA double-strand breaks and chromosome aberrations increased after standard-dose CT. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Brenner in this issue.

Pulmonary hypertension (PH) caused by left-sided heart disease (LHD-PH) is classified into 2 types: isolated post-capillary PH (Ipc-PH) and combined pre- and post-capillary PH (Cpc-PH). However, the impact of pulmonary vascular resistance (PVR) or diastolic pressure gradient (DPG) on the prognosis of LHD-PH has varied among previous studies. Thus, we verified the significance of PVR or DPG on the prognosis of LHD-PH in our series.We analyzed 243 consecutive LHD-PH patients. The patients were divided into 3 groups: Group A, patients with PVR ≤ 3 Wood unit (WU) and DPG7 mmHg; Group B, patients with either PVR3 WU or DPG ≥ 7 mmHg; and Group C, patients with PVR3 WU and DPG ≥ 7 mmHg.The Kaplan-Meier curve demonstrated that Group B had lower cardiac death-free survival compared with Group A, whereas no significant differences were observed when compared with Group C. In the Cox hazard model, DPG was not associated with cardiac death in the LHD-PH patients. However, only in the ischemic heart disease group, patients with DPG ≥ 7 mmHg had worse prognosis compared with those with normal DPG.The cardiac death-free rate of patients with either increased PVR or DPG was close to that of patients with both increased PVR and DPG. It seems reasonable to define Cpc-PH only by PVR in the new criteria. However, the significance of DPG in LHD-PH might be dependent on the underlying cause of LHD-PH.

Objective This study aimed to explore whether VDR polymorphisms (Fok1, Apa1 and Taq1) are associated to the cervical cancer in Thai population. Materials and methods Subjects of 204 cervical cancer patient and 204 age-matched healthy control were enrolled in the case-control study. VDR polymorphisms were detected by using real-time PCR. Haplotype analysis of three loci was applied to the obtained genotypes. Results Significantly increased risk for cervical cancer was observed in carriers of TT genotype (p = 0.0388) and T allele (p = 0.0357) of Fok1 and TC genotype (p = 0.0001), CC genotype (p = 0.0160) and the C allele of Taq1 (p = 0.0001). Haplotype analyses revealed a significant correlation between C-T-C, T-G-C and T-T-C haplotypes and elevated risk for cervical cancer (OR = 2.06; 95%CI = 1.06-4.00; p = 0.0313, OR = 2.15; 95%CI = 1.22-3.80; p = 0.0078 and OR = 2.81; 95%CI = 1.53-5.16; p = 0.0006, respectively). Furthermore, haplotype carrying C allele of Taq1 (C-G-C + C-T-C + T-G-C + T-T-C) significantly increased cervical cancer risk with OR of 1.92 (95%CI = 1.32-2.79, p = 0.0006). Conclusion Our finding revealed an association between VDR polymorphisms and cervical cancer risk. Taq1 C allele might be a molecular marker for cervical cancer development. .

Background: Anthracycline is used to treat various types of cancer; however, cardiotoxicity negatively affects patient prognosis. Objectives: The aim of the present study was to investigate serial changes in levels of cardiac troponin I (TnI) and B-type natriuretic peptide (BNP) in patients treated with anthracycline-containing therapy. Methods: 91 consecutive cancer patients planned for anthracycline treatment were enrolled and followed up for 12 months. All patients underwent echocardiography and blood sampling at baseline, 3, 6, and 12 months. Results: The patients were divided into two groups based on their TnI level during the follow-up period: the elevated TnI group (TnI ≥0.03 ng/mL; n = 37) and the normal TnI group (n = 54). In the elevated TnI group, the TnI levels increased at 3 and 6 months, but they returned to within normal range at 12 months after anthracycline administration. Unlike TnI, the BNP levels began to increase after 6 months, and remained increased at 12 months. The occurrence of cancer therapeutics-related cardiac dysfunction was higher in the elevated TnI group than in the normal TnI group. When we set the cut-off value of TnI at 0.029 ng/mL, sensitivity and specificity to predict an elevated BNP level of more than 100 pg/mL were 90 and 63%, respectively. Multivariate logistic regression analysis revealed that elevated TnI was an independent predictor of elevated BNP levels. Conclusion: Elevated TnI was an independent predictor for the development of BNP increase. The different characteristics of TnI and BNP should be considered when managing patients treated with anthracycline-containing therapy.

Background: CYP1A1 is an enzyme in phase I of the cytochrome P450 (CYP) superfamily, and plays a key role in detoxification of carcinogens. Host genetic predisposition in the CYP1A1 may be associated with an increased susceptibility to cervical cancer.The study aimed to evaluate four common polymorphisms of the CYP1A1 and cervical cancer susceptibility among Northeast Thai women. Methods: A case-control study was conducted involving 204 patients with squamous cell cervical cancer (SCCA) and 204 age-matched healthy controls. DNA was extracted from peripheral blood leucocytes. CYP1A1 m1, m3, and m4 genotypes were detected using PCR-RFLP, whereas the CYP1A1 m2 genotype was investigated using real-time PCR. Haplotype analysis was performed using PHASE algorithm version 2.1.1. Results: CYP1A1 m3 was monomorphic. Association between the common CYP1A1 polymorphisms, m1 and m2, and cervical cancer risk was not observed (p>0.05), nor was any association found between the m1–m2–m4 haplotype and cervical cancer risk (p>0.05). Interestingly, the CA genotype of CYP1A1 m4 was observed in 30.88% of the cervical cancer patients but was absent in healthy controls. Conclusion: Our results demonstrated a possible involvement of the CYP1A1 m4 polymorphism but no other common polymorphisms (viz., m1, m2, and m3) in the risk for cervical cancer.This finding may be useful when screening for risk of cervical cancer among Northeast Thai women.

Purpose The purpose of this study was to investigate the safety and efficacy of high-power short-duration (HP-SD) ablation compared to conventional ablation in patients with atrial fibrillation (AF). Methods We enrolled consecutive 158 drug-refractory symptomatic AF patients (119 males, mean age 63 ± 10 years) who had undergone first radiofrequency pulmonary vein isolation (PVI). PVI was performed using the conventional setting (20–35 W) in 73 patients (Conventional group) and using the HP-SD setting (45–50 W) in 85 patients (HP-SD group). The rate of first pass isolation, remaining gaps after circumferential ablation, dormant conduction, and the radiofrequency application time in each pulmonary vein (PV) were compared between the groups. Results The first pass isolation ratio was significantly higher in the HP-SD group than in the Conventional group (81% vs. 65%, P = 0.027) in the right PV, but did not differ in the left PV. The remaining gaps were fewer in the right superior PV (4% vs. 21%, P = 0.001) and left inferior PV (1% vs. 8%, P = 0.032) areas, and the radiofrequency application time in each PV was shorter (right PV, 12.0 ± 8.9 min vs. 34.0 ± 31.7 min, P P Conclusion The use of the HP-SD setting might contribute to improve the first pass isolation rate and to shorten the radiofrequency application time in each PV.

Heart failure causes increased venous pressure, leading to liver dysfunction. The fibrosis-4 index is a simple index for liver fibrosis and has been reported to be useful for predicting prognosis in heart failure; however, its impact on patients with pulmonary hypertension due to left heart disease (PH-LHD) has not yet been fully elucidated.We enrolled consecutive 230 hospitalized patients who had been diagnosed as having PH-LHD. The fibrosis-4 index was calculated as follows: [aspartate transaminase (U/L) × age]/[alanine transaminase 1/2 (U/L) × platelet count (109/L) ]. We followed patients for all-cause mortality during the follow-up period (mean 1112 ± 822 days).The patients were divided into tertiles based on their fibrosis-4 index: the first tertile 0.335 to 1.381; the second tertile 1.391 to 2.311; and the third tertile 2.323 to 14.339. Compared with the first tertile, the third tertile had lower estimated glomerular filtration rates and hemoglobin levels. All-cause mortality was significantly higher in the third than in the first tertile. In a Cox proportional hazard model, the fibrosis-4 index was a predictor of all-cause mortality in PH-LHD patients (HR 1.212, 95% CI 1.099-1.337, P < 0.001).The fibrosis-4 index is associated with kidney function, anemia, and high mortality in PH-LHD patients.

Objective Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive disease that leads to right-sided heart failure with electrocardiographic abnormalities. There are only a few reports about the effects of balloon pulmonary angioplasty for CTEPH on the electrocardiographic criteria of right ventricular hypertrophy. To determine the effect of balloon angioplasty on electrocardiography in patients with CTEPH. Methods We evaluated electrocardiograms in 19 patients (mean age, 64±10 years) who underwent balloon pulmonary angioplasty. Results We compared the hemodynamic parameters after balloon pulmonary angioplasty. The mean pulmonary artery pressure was decreased (p

Objectives Semenogelin 1 and 2 (SEMG1 and SEMG2) are known as semen coagulating proteins in primates with a repetitive structure of 60-amino acids. The number of repeats varies among species and is hypothesized to be related to the level of primate sperm competition. Gibbons until recently were thought to be monogamous primates, but it is now known that gibbon social structure is flexible. Thus, hypotheses of the relationship between the SEMGs evolution and mating systems were tested. Materials and methods The sequences of the exon 2 of the SEMG1 and SEMG2 were obtained from 50 captive gibbons comprising six species belonging to three genera (Hylobates, Symphalangus, and Nomascus). Then we quantified the levels of polymorphism and estimated rates of protein evolution by calculating d N /d S ratio. Results Several mutations that create a premature stop codon in the SEMG1 and a reduction in the repeats of the SEMG2 in the genus Hylobates were observed and may alter the coding properties for these proteins. We also found different level of nucleotide diversity in each gene and between genera. Strikingly, in Nomascus leucogenys we discovered a high d N /d S ratio in the SEMG1 and SEMG2. The Nomascus SEMG2 also showed significantly lower nucleotide diversity than the other two genera. Discussion These results are consistent with the presence of a strong positive selection in the Nomascus lineage even if the exact selective forces acting on these genes are not yet conclusively known. We were not able to demonstrate, among gibbons, unambiguous relationships between the SEMGs evolution and mating systems.

The association of socio-economic-demographic (SED; e.g., income-related) factors with depression is widely confirmed in the literature. We conducted a hospital-based case–control study of 160 patients with psychiatrist-diagnosed clinical depression. The control group comprised 160 participants recruited from local communities. We used a questionnaire to collect SED data from all participants. We replaced missing values using multiple imputation analyses and further analyzed the pooled data of five imputations. We also recorded the results from the original analysis and each imputation. Univariate analyses showed income was associated with depression. Multiple logistic regression analyses revealed that, among all SED variables, high income (odds ratio = 2.088 [95% confidence interval = 1.178–3.700];p= 0.012), middle-level (completed junior or senior high school) education (1.688 [1.042–2.734];p= 0.033) and cohabitating with four or more family members (1.632 [1.025–2.597];p= 0.039) were significant predictors for the case group. We conclude that cash income is a determinant of depression in hospital outpatients in Indonesia. This study suggests health policy implications toward better hospital access and service for people with depression in middle- or low-income households, and recommends considering high income as correlated with a high risk of depression, owing to socio-cultural changes.

Gibbons (Family Hylobatidae) are a suitable model for exploring hybridization in pair-living primates as several species form hybrid zones. In Khao Yai National Park, Thailand, white-handed gibbons (Hylobates lar) and pileated gibbons (Hylobates pileatus) are distributed parapatrically and hybridize in a narrow zone. Their phenotypic characteristics suggest limited inter-species gene flow, although this has never been assessed. To uncover the history and degree of gene flow between the two species, we studied the genetic structure of gibbons in the hybrid zone by analyzing fecal DNA samples, phenotypic characteristics, vocalizations and individuals’ social status. We determined eight autosomal single nucleotide variant (SNV) loci, and mitochondrial DNA (mtDNA) and Y-chromosomal haplotypes of 72 gibbons. We compared these markers with reference types of wild pureblood white-handed gibbons (n = 12) in Kaeng Krachan National Park and pureblood pileated gibbons (n = 4) in Khao Soi Dao Wildlife Sanctuary. Autosomal genotypic analyses confirmed the various levels of mixed ancestry for several adult gibbons with or without atypical phenotypic traits in Khao Yai National Park. In some other adult gibbons, the mixed ancestry was not detected in either autosomal SNVs or their phenotypic traits but the mtDNA. Both male and female adult hybrids formed reproductive units mainly with a phenotypic pureblood partner and many of them produced offspring. Taken together, our results suggest that once hybridization occurs, white-handed-pileated-gibbon hybrids can reproduce with either parental species and that the backcrossing and thus introgression may occur in successive generations, with no drastic changes in phenotypic appearance.

In this work, individual radiosensitivity was evaluated using DNA damage response and chromosomal aberrations (CAs) in peripheral blood lymphocytes (PBLs) for the prediction of acute toxicities of chemoradiotherapy (CRT) in esophageal cancer patients. Eighteen patients with esophageal cancer were enrolled in this prospective study. Prescribed doses were 60 Gy in 11 patients and 50 Gy in seven patients. Patients received 2 Gy radiotherapy five days a week. PBLs were obtained during treatment just before and 15 min after 2 Gy radiation therapy on the days when the cumulative dose reached 2, 20, 40 Gy and 50 or 60 Gy. PBLs were also obtained four weeks and six months after radiotherapy in all and 13 patients, respectively. Dicentric and ring chromosomes in PBLs were counted to evaluate the number of CAs. Gamma-H2AX foci per cell were scored to assess DNA double-strand breaks. We analyzed the association between these factors and adverse events. The number of γ-H2AX foci before radiotherapy showed no significant increase during CRT, while their increment was significantly reduced with the accumulation of radiation dose. The mean number of CAs increased during CRT up to 1.04 per metaphase, and gradually decreased to approximately 60% six months after CRT. Five patients showed grade 3 toxicities during or after CRT (overreactors: OR), while 13 had grade 2 or less toxicities (non-overreactors: NOR). The number of CAs was significantly higher in the OR group than in the NOR group at a cumulative dose of 20 Gy (mean value: 0.63 vs. 0.34, P = 0.02), 40 Gy (mean value: 0.90 vs. 0.52, P = 0.04), and the final day of radiotherapy (mean value: 1.49 vs. 0.84, P = 0.005). These findings suggest that number of CAs could be an index for predicting acute toxicities of CRT for esophageal cancer.

Background The prognostic impact of benzodiazepines has been unclear in patients with heart failure (HF). Methods and Results This was a historical observational cohort study. A total of 826 patients who had been hospitalized for HF and were being treated for insomnia with either benzodiazepines or Z‐drugs (zolpidem, zopiclone, or eszopiclone), were enrolled and divided on the basis of their hypnotics: benzodiazepine group (n=488 [59.1%]) and Z group (n=338 [40.9%]). We compared the patient characteristics and postdischarge prognosis between the groups. The primary end points were rehospitalization for HF and cardiac death. The benzodiazepine group was older (age, 72.0 versus 69.0 years; P =0.010), had a higher prevalence of depression (17.4% versus 8.9%; P P =0.001). In the laboratory data, the benzodiazepine group demonstrated lower levels of hemoglobin (12.3 versus 13.0 g/ dL ; P =0.001), sodium (139.0 versus 140.0 mE q/L; P =0.018), and albumin (3.7 versus 3.9 g/ dL ; P =0.003). Kaplan‐Meier analysis showed that both end points were higher in the benzodiazepine group (rehospitalization for HF , log‐rank P =0.001; cardiac death, log‐rank P =0.043). Multiple Cox proportional hazard analysis revealed that the use of benzodiazepines was an independent predictor of rehospitalization for HF (hazard ratio, 1.530; 95% CI, 1.025–2.284; P =0.038). Furthermore, rehospitalization for HF was higher in the benzodiazepine group after propensity score matching (log‐rank P =0.036). Conclusions Benzodiazepine is associated with higher risk of rehospitalization for HF compared with Z‐drugs in patients with HF .

Background Cardiac amyloidosis (CA) is characterized by left ventricular hypertrophy (LVH) and autonomic nervous imbalance due to amyloid infiltration. However, autonomic dysfunction is often seen in heart failure (HF) with LVH from other etiologies. We aimed to characterize autonomic dysfunction in CA from other etiologies of LVH. Methods Fifty‐five HF patients with LVH (35 males, mean age 65 ± 16 years) were enrolled. LVH was defined as left ventricular mass index measured by echocardiography >95 g/m2 in women and 115 g/m2 in men. The etiology was as follows: amyloid light chain (AL)‐CA, n = 14; hypertrophic cardiomyopathy, n = 21; and aortic stenosis (AS), n = 20. With the patient in a clinically stable condition, heart rate variability (HRV) and heart rate turbulence (HRT), which reflect autonomic dysfunction, were measured using Holter monitoring and compared among the three groups. Results Brain natriuretic peptide levels, LVH severity, left ventricular ejection fraction, and tissue Doppler index E/e′ did not differ among the three groups. However, severe abnormalities of HRV and HRT were obtained in AL‐CA. In the ROC analysis to identify AL‐CA in HF with LVH, the best cutoff value for standard deviation of all R‐R intervals, standard deviation of the 5‐min mean R‐R intervals, turbulence onset, and turbulence slope were 68.5 ms (AUC: 0.865), 58.5 ms (AUC: 0.834), 0.25% (AUC: 0.813), and 1.00 ms/RR (AUC 0.736), respectively. Conclusion Autonomic dysfunction is a hallmark of AL‐CA, and its noninvasive assessment by Holter monitoring may be a useful tool for differential diagnosis of HF with LVH.

Pulmonary arterial hypertension is a fatal disease caused by pulmonary arterial vasoconstriction and organic stenosis due to the proliferation of pulmonary smooth muscle cells and endothelial cells. Endothelial dysfunction, including impaired nitric oxide (NO) bioavailability, plays a crucial role in the pathogenesis of pulmonary hypertension, and endothelial nitric oxide synthase (eNOS) is an important modulator of pulmonary vasodilatation. Although senescence marker protein (SMP) 30 is known as an anti-aging protein, the role of SMP30 in pulmonary vessels is still unclear. In this study, we examined the role of SMP30 in pulmonary vasculature using SMP30-deficient mice.We used female SMP30-deficient mice and wild-type littermate (WT) mice at the age of 12 to 18 weeks. The WT and SMP30-deficient mice were exposed to normoxia or hypoxia (10% oxygen for 4 weeks). In normoxia, the right ventricular systolic pressure (RVSP) was not different between the WT and SMP30-deficient mice, but in hypoxia, the RVSP was significantly higher in the SMP30-deficient mice compared to the WT mice (P < 0.05). The hypoxia-induced increases in right ventricular hypertrophy and medial smooth muscle area of the pulmonary artery were comparable between the WT and the SMP30-deficient mice. Western blotting showed that eNOS phosphorylation in lung tissue was reduced in the SMP30-deficient mice compared to the WT mice in normoxia. However, in hypoxic conditions, eNOS phosphorylation was reduced in both the WT and SMP30-deficient mice with no differences in Akt phosphorylation.Our study demonstrated that SMP30 is involved in the development of hypoxia-induced pulmonary hypertension by impairment of eNOS activity.

BACKGROUND Heart failure (HF) patients have a higher risk of recurrent HF and cardiac death, and electrical remodeling is considered to be an important factor for HF progression. The present study aimed to validate the utility of electrocardiogram and Holter monitoring for the risk stratification of HF patients. METHODS Our study comprised 215 patients (144 males, mean age 62 years) who had been hospitalized due to acute decompensated HF. Electrocardiogram (QRS duration and QTc interval) and 24-hour Holter monitoring (heart rate variability, heart rate turbulence, and T-wave alternans [TWA]) were performed in stable condition before discharge. The clinical characteristics and outcomes were then investigated. RESULTS During a median follow-up period of 2.7 years, there were 83 (38.6%) cardiac events (rehospitalization due to worsening HF [n = 51] or cardiac death [n = 32]). The patients with cardiac events had a lower turbulence slope (TS) and higher TWA compared to those without cardiac events (TS, 3.0 ± 5.5 ms/RR vs. 5.3 ± 5.6 ms/RR, P = 0.001; TWA, 66.1 ± 19.6 μV vs. 54.7 ± 15.1 μV, P

Pulmonary hypertension (PH) causes right ventricular dysfunction and central venous congestion, and may lead to congestive hepatopathy. The serum 7S domain of collagen type IV (P4NP 7S) is an established marker of liver fibrosis in chronic liver disease. We aimed to determine whether P4NP 7S is related to hemodynamic parameters, and assessed the potential values of P4NP 7S to predict mortality.Consecutive 76 pre-capillary PH patients were divided into tertiles based on their serum P4NP 7S levels. We compared right-heart catheterization, echocardiographic findings, and mortality among the tertiles, and compared P4NP 7S with other known biomarkers of mortality.Cardiac index, mean pulmonary arterial pressure, pulmonary vascular resistance, and right ventricular fractional area change did not differ among the three groups. In contrast, compared to 1st and 2nd tertiles, the 3rd tertile had higher levels of right atrial pressure, right atrial area, and right ventricular area (P0.05, respectively). In the Kaplan-Meier analysis, mortality progressively increased from the 1st to 2nd and 3rd tertiles (log-rank, P=0.002). In the Cox proportional hazard analysis, P4NP 7S was a predictor of mortality. ROC analysis demonstrated that a P4NP 7S concentration of 4.75ng/ml predicted mortality (AUC 0.85, 95% CI 0.75-0.94; P0.001), and that the prognostic value of P4NP 7S was comparable or superior to that of other biomarkers (total bilirubin, creatinine, uric acid, C-reactive protein, B-type natriuretic peptide, and troponin I).Serum P4NP 7S is associated with higher central venous pressure, right-sided volume overload, and mortality in PH patients.

Deficiency of X-ray repair cross-complementing protein 3 (XRCC3), a DNA-damage repair molecule, and the 241Met variant of XRCC3 have been reported to increase endoreduplication, which induces polyploidy. The aims of this study were to determine the impact of the XRCC3 polymorphism on the incidence of hypertension-induced left ventricular hypertrophy (LVH) and to investigate the mechanisms underlying any potential relationship. Patients undergoing chronic hemodialysis (n = 77) were genotyped to assess for the XRCC3 Thr241Met polymorphism. The XRCC3 241Thr/Met genotype was more frequent in the LVH (+) group than in the LVH (-) group (42.3 vs. 13.7%, χ2 = 7.85, p = 0.0051). To investigate possible mechanisms underlying these observations, human XRCC3 cDNA of 241Thr or that of 241Met was introduced into cultured CHO cells. The surface area of CHO cells expressing XRCC3 241Met was larger than that expressing 241Thr. Spontaneous DNA double-strand breaks accumulated to a greater degree in NIH3T3 cells expressing 241Met (3T3-241Met) than in those expressing 241Thr (3T3-241Thr). DNA damage caused by radiation induced cell senescence more frequently in 3T3-241Met. The levels of basal and TNF-α-stimulated MCP-1 mRNA and protein secretion were higher in 3T3-241Met. Finally, FACS analysis revealed that the cell percentage in G2/M phase including polyploidy was significantly higher in 3T3-241Met than in 3T3-241Thr. Furthermore, the basal level of MCP-1 mRNA positively correlated with the cell percentage in G2/M phase and polyploidy. These data suggest that the XRCC3 241Met increases the risk of LVH via accumulation of DNA damage, thereby altering cell cycle progression and inducing cell senescence and a proinflammatory phenotype.

Background Several echocardiographic parameters are currently used to evaluate left ventricular (LV) filling pressure. However, these parameters are not always consistent in the clinical setting. We aimed to determine a novel parameter by multiplying log B-type natriuretic peptide (lnBNP) and the ratio of mitral inflow early and late diastolic filling velocities (E/A) for the prediction of pulmonary capillary wedge pressure (PCWP). Methods and Results One hundred ninety-eight patients suspected of chronic heart failure were analyzed. The product of lnBNP and E/A (BNP × E/A) showed the highest correlation coefficient with mean PCWP ( R = 0.7326) compared with E/A ( R = 0.7010) and E/e′ ( R = 0.3922). Multivariate logistic regression analysis revealed that BNP × E/A was associated with elevated PCWP (odds ratio 1.640, 95% confidence interval 1.312–2.197; P .01). In the receiver operating characteristic curve analysis for detecting elevated PCWP, BNP × E/A showed the largest area under the curve (AUC) compared with E/A and E/e′ (0.880 vs 0.827 and 0.788, respectively; P .05). BNP × E/A still showed large AUC (0.842) for detection of elevated PCWP in patients with normal LV ejection fraction. Conclusion BNP × E/A is a useful parameter for detecting elevated PCWP regardless of the LV ejection fraction.

Background: Breath acetone is reported to be a noninvasive biomarker for heart failure. However, the measurement of this metabolite requires expertize and is not standardized yet. Acetone is also released from the skin; thus, measuring acetone as a skin gas may be easier than breath analysis. Methods: We analyzed skin acetone collected from 41 hospitalized patients with cardiovascular diseases. Passive samplers were used to measure skin acetone emission. Passive sampler was softly fixed on the surface of forearm skin for 10 hour at night. Results: Skin acetone emission ranged from 0.00 to 2.70 ng/cm2/h, and was significantly correlated with blood ketone bodies (r = 0.377, p = 0.017). Conclusions: This is the first study to analyze skin gas in patients with cardiovascular diseases. Skin acetone emission was found to reflect blood ketone bodies. It is feasible to measure skin acetone emission for reflecting blood ketone bodies in patients with cardiovascular diseases.

Background: Atrial septal defect is the third most common type of congenital heart disease. Surgical closure was the standard treatment for atrial septal defects before transcatheter closure was approved as minimally invasive treatment in Japan in 2006. In our hospital, this procedure has been performed since 2015. Objective: To evaluate the safety and effectiveness of transcatheter closure of atrial septal defects in our hospital. Methods: Thirty patients (mean age 57.0 ± 19.7 years, 11 males), who underwent transcatheter closure of atrial septal defect between September 2015 and February 2018 at the Fukushima Medical University Hospital, were enrolled. All procedures were performed under general anesthesia with angiographic and transesophageal echocardiographic guidance. Safety and effectiveness were evaluated by the procedural results and complications. Results: All 30 patients successfully underwent transcatheter closure of atrial septal defects and no patient developed complications. New York Heart Association functional class was improved, and the right ventricular area and right atrium area were decreased, postoperatively. Conclusion: Transcatheter closure is a safe and effective treatment for atrial septal defects, and thus could be an alternative option to open heart surgery.

The exact cause of steatosis, one of defects in Japanese beef carcasses, has not been elucidated to date, because it is very difficult to diagnose cyclopedically with certain reproducibility due to the bias in the outbreak. Therefore, the objective of this study was to assess the influence of polymorphisms in retinol dehydrogenase 16 (RDH16), myoferlin (MYOF) and vascular endothelial growth factor receptors 1 and 2 (VEGFR1, VEGFR2) on carcass-graded Musculus trapezius steatosis. For logistic regression analysis, 646 carcasses shipped from 29 farms in Miyazaki, Japan, were used. The GG genotype in RDH16 showed significant odds ratios against AA and AG. In VEGFR1, CT had a significant odds ratio against CC. After evaluating for interaction, highly significant odds ratios were observed in the combinations that included the GG risk genotype in RDH16. It is noteworthy that there was no steatosis in the combination GG (RDH16) and CC (VEGFR1). It may be concluded that there is a possibility that steatosis can be suppressed by the CC genotype in VEGFR1. The current study revealed the influence of genetic polymorphisms on M. trapezius steatosis that had not been reported until now, and may help elucidate the cause of steatosis.

Pulmonary hypertension and hereditary hemorrhagic telangiectasia (HHT) have an association mediated by activin A receptor type II-like 1 (ACVRL1) gene pathogenic variants. A 30-year-old woman was previously admitted to a hospital due to lung hemorrhage, and was diagnosed with pulmonary hypertension, but stopped follow-up visits. At 48 years of age, she was admitted to our hospital and was diagnosed with HHT. Genetic testing revealed an ACVRL1 pathogenic variant. After the initiation of pulmonary vasodilator treatment, the patient's mean pulmonary artery pressure started to decrease from 43 mmHg, declining to 37 mmHg when she was 58 years of age. This is the first report describing the 28-year follow-up of an HHT and pulmonary hypertension patient with an ACVRL1 mutation.

BACKGROUND Heart failure (HF) and cancer (CA) are becoming increasingly prevalent as the population ages. We aimed to evaluate prior history and occurrence of CA and its prognostic impact on HF.Methods and Results:Consecutive hospitalized HF patients (n=2,103) were divided into 2 groups according to prior history of CA: non-prior-CA group (n=1,828) and prior-CA group (n=275). Compared with the non-prior-CA group, the prior-CA group were older, and had higher prevalence of chronic kidney disease, anemia, and atrial fibrillation (P

Kawasaki disease (KD), first identified in 1967, is a pediatric vasculitis of unknown etiology that has an increasing incidence in Japan and many other countries. KD can cause coronary artery aneurysms. Its epidemiological characteristics, such as seasonality and clinical picture of acute systemic inflammation with prodromal intestinal/respiratory symptoms, suggest an infectious etiology for KD. Interestingly, multiple host genotypes have been identified as predisposing factors for KD. To explore experimental methodology for identifying etiological agent(s) for KD and to optimize epidemiological study design (particularly the sample size) for future studies, we conducted a pilot study. For a 1-year period, we prospectively enrolled 11 patients with KD. To each KD patient, we assigned two control individuals (one with diarrhea and the other with respiratory infections), matched for age, sex, and season of diagnosis. During the acute phase of disease, we collected peripheral blood, nasopharyngeal aspirate, and feces. We also determined genotypes, to identify those that confer susceptibility to KD. There was no statistically significant difference in the frequency of the risk genotypes between KD patients and control subjects. We also used unbiased metagenomic sequencing to analyze these samples. Metagenomic sequencing and PCR detected torque teno virus 7 (TTV7) in two patients with KD (18%), but not in control subjects (P = 0.111). Sanger sequencing revealed that the TTV7 found in the two KD patients contained almost identical variants in nucleotide and identical changes in resulting amino acid, relative to the reference sequence. Additionally, we estimated the sample size that would be required to demonstrate a statistical correlation between TTV7 and KD. Future larger scale studies with carefully optimized metagenomic sequencing experiments and adequate sample size are warranted to further examine the association between KD and potential pathogens, including TTV7.

To investigate whether physical exposure parameters such as the dose index (CTDI), dose length product (DLP), and size-specific dose estimate (SSDE) are predictive of DNA damage. In vitro, we scanned a phantom containing blood samples from five volunteers at CTDI 50, 100, and 150 mGy. One sample was not scanned. We also scanned samples in three different-size phantoms at CTDI 100 mGy. In vivo, we enrolled 45 patients and obtained blood samples before and after cardiac CT. The γ-H2AX foci were counted. In vitro, in the control and at CTDI 50, 100, and 150 mGy, the number of γ-H2AX was 0.94 ± 0.24 (standard error, SE), 1.28 ± 0.30, 1.91 ± 0.47, and 2.16 ± 0.20. At SSDE 180, 156, and 135 mGy, it was 2.41 ± 0.20, 1.91 ± 0.47, and 1.42 ± 0.20 foci/cell. The γ-H2AX foci were positively correlated with the radiation dose and negatively correlated with the body size. In vivo, the γ-H2AX foci were significantly increased after CT (from 1.21 ± 0.19 to 1.92 ± 0.22 foci/cell) and correlated with CTDI, DLP, and SSDE. DNA damage was induced by cardiac CT. There was a correlation between the physical exposure parameters and γ-H2AX. • DNA damage was induced by radiation exposure from cardiac CT. • The γ-H2AX foci number was correlated with the CT radiation dose. • Physical exposure parameters reflect the DNA damage by CT radiation exposure.

The relationship between insulin resistance and atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI) remains unclear.Drug-refractory 114 paroxysmal AF patients (89 males, 62 ± 8 years) who underwent successful PVI were enrolled. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated and a value of ≥2.5 was defined as insulin resistant. The left atrial volume index (LAVI) was measured using echocardiography before and 1 year after PVI. Tumor necrosis factor-α (TNF-α) and TGF-β1 serum levels were measured before PVI, and the left atrium (LA) conduction velocity was calculated. The patients were divided into two groups (group 1: HOMA-IR 2.5, n = 81; group 2: HOMA-IR ≥ 2.5, n = 33).The LAVI between the two groups before PVI did not significantly differ (P 0.05), nor did TNF-α (7.7 ± 2.0 vs 7.5 ± 1.0 pg/mL; P = 0.149) or TGF-β1 (28.4 ± 12.0 vs 27.6 ± 10.3 ng/mL; P = 0.757). LAVI before and 1 year after PVI in each group did not change. The conduction velocity of group 2 was slower than that of group 1 (0.7 ± 0.1 vs 1.1 ± 0.3 m/s, P 0.001). Kaplan-Meier analysis showed significantly higher AF recurrence in group 2 than that in group 1 ( P = 0.019). Cox multivariable analysis revealed that insulin resistance was an independent predictor of recurrence (hazard ratio 1.287, P = 0.004).Our results suggest that insulin resistance promotes LA electrical remodeling and might be related to AF recurrence after PVI.

Background The Get With the Guidelines–Heart Failure ( GWTG ‐ HF ) risk score was developed using American Heart Association GWTG ‐ HF program data and predicts in‐hospital mortality in patients with acute heart failure (HF). We aimed to clarify the prognostic impacts of the GWTG ‐ HF risk score in patients with HF after discharge. Methods and Results We examined the GWTG ‐ HF score in 1452 patients with HF, who were admitted to our hospital and discharged after treatment, by calculating 7 predetermined variables. We divided all subjects into 3 groups according to the GWTG ‐ HF risk score (low, moderate, and high score groups). The plasma B‐type natriuretic peptide level significantly increased with increasing GWTG ‐ HF risk score severity (median values of B‐type natriuretic peptide: 167.0 in low, 260.7 in moderate, and 418.2 pg/mL in high score groups). We followed up all subjects after discharge, and there were 347 (23.9%) all‐cause deaths and 407 (28.0%) cardiac events in follow‐up periods. A Kaplan‐Meier survival curve demonstrated that event rates of all‐cause death and cardiovascular events, including worsening HF and cardiac death, significantly increased with increasing GWTG ‐ HF risk score severity in all subjects, and also in 749 patients with HF with preserved ejection fraction (ejection fraction ≥50%) and 703 patients with HF with reduced ejection fraction (ejection fraction GWTG ‐ HF risk score was one of the significant predictors of all‐cause mortality and cardiac events (all‐cause mortality: hazard ratio, 1.537, 95% confidence interval, 1.172–2.023; cardiac events: hazard ratio, 1.584, 95% confidence interval, 1.344–1.860, per 10‐point increase of GWTG ‐ HF score). Conclusions The GWTG ‐ HF risk score is a useful multivariable score model for several years after hospitalization in patients with HF in a Japanese population.

Sarcoidosis is a systemic granulomatous disease including heart (cardiac sarcoidosis, CS). It has recently been reported that isolated CS, which presenting primarily cardiac symptoms without clinical evidence of sarcoid involvement in other organs. Diagnostic and prognostic biomarkers of CS, especially in isolated CS, have not yet been established.We studied plasma levels of angiotensin-converting enzyme (ACE), soluble interleukin-2 receptor (sIL-2R), B-type natriuretic peptide (BNP) and cardiac troponin I (cTnI) in consecutive 172 patients with diagnosed sarcoidosis. We compared these markers between non-cardiac sarcoidosis (non-CS, n = 123, 71.5%) and CS patients (n = 49, 28.5%), including non-isolated CS (n = 30, 17.4%) and isolated CS (n = 19, 11.1%). ROC analysis revealed that BNP identified CS with AUC of 0.85 (P < 0.01) in sarcoidosis patients. In addition, ACE and sIL-2R levels were significantly higher in non-isolated CS than in isolated CS (P < 0.05). Furthermore, in the Cox proportional hazard analysis, cTnI, but not ACE, IL2R or BNP, was a predictor of fatal arrhythmia in sarcoidosis patients (HR 2.418, P = 0.003).Higher ACE and sIL2-R are associated with systemic lesions, whereas BNP is a useful marker for detecting cardiac involvement in sarcoidosis patients. cTnI is a predictor of fatal arrhythmia in CS patients. A multiple biomarker approach supports comprehensive management of sarcoidosis.

The incidence of chromosomal abnormalities and cancer risk correlates well with the radiation dose after exposure to moderate- to high-dose ionizing radiation. However, the biological effects and health risks at less than 100 mGy, e.g., from computed tomography (CT) have not been ascertained. To investigate the biological effects of low-dose exposure from a CT procedure, we examined chromosomal aberrations, dicentric and ring chromosomes (dic+ring), in peripheral blood lymphocytes (PBLs), using FISH assays with telomere and centromere PNA probes. In 60 non-cancer patients exposed to CT scans, the numbers of dicentric and ring chromosomes were significantly increased with individual variation. The individual variations in the increment of dicentric and ring chromosomes after CT procedures were confirmed using PNA-FISH analysis of PBLs from 15 healthy volunteers after in vitro low-dose exposure using a 137Cs radiation device. These findings strongly suggest that appropriate medical use of low-dose radiation...

A missense variant (rs373863828:G A; p.Arg457Gln) of the CREBRF gene is strongly associated with a higher body mass index (BMI; kg/mThe aim of this study is to examine the association of rs373863828:G A with levels of serum lipids in four Pacific populations.A total of 613 adult subjects were recruited from Tonga (Polynesians) and the Solomon Islands (Melanesians and Micronesians). Multiple regression analyses adjusted for age and sex were performed to examine the association of rs373863828 with levels of serum lipids in each population.A significant association of rs373863828:G A with lower level of HDL-cholesterol was detected in the Tonga population (β = -3.32 and p-value = 0.030). The expected change in HDL-cholesterol with respect to a single copy of the rs373863828-A allele was 3.32 mg/dL. However, the association between rs373863828-A and lower levels of HDL-cholesterol was not significant after further adjustment for BMI in the Tonga population (β = -2.32 and p-value = 0.13).The rs373863828-A allele may not directly affect the level of serum HDL-cholesterol independent of BMI. To confirm the present findings, association studies with large sample sizes and functional analyses are required.

Exhaled acetone concentration is one of the expected compounds to be a breath biomarker in heart failure. However, it has not been clarified how exhaled acetone concentration changes in clinical course of heart failure.To investigate whether exhaled acetone concentration changes after treatment in acute decompensated heart failure (ADHF).This study included 19 patients with ADHF (ADHF group) and eight patients with stable heart failure (control group). Exhaled acetone was collected from these patients, and the concentration was measured with gas chromatography.The ADHF group had higher heart rates (P = 0.046), higher New York Heart Association class (P0.001), higher levels of brain natriuretic peptide (P = 0.026), blood total ketone bodies (P = 0.015), and exhaled acetone concentration (P0.001), compared with the control group. In ADHF group, exhaled acetone concentration significantly decreased after treatment (median: 2.40 versus 0.92 ppm, P0.001). However, in the control group, exhaled acetone concentration did not significantly change (median: 0.73 versus 0.49 ppm, P = 0.141).In these preliminary findings, exhaled acetone concentration in patients with ADHF drastically decreased by treatment. Serial exhaled acetone measurement might be useful to evaluate the course of ADHF.

Objective: We aimed to investigate any association between a genetic polymorphism of the detoxification GSTP1 gene and risk of cervical cancer in northeastern Thailand. Materials and Methods: Genotyping of GSTP1 was performed for 198 squamous cell cervical cancer (SCCA) patients and 198 age-matched healthy controls with the PCR-RFLP method. Results: The respective frequencies of the G allele were 0.33 and 0.26 in the controls and cases, the difference being significant (OR = 0.69 [95% CI: 0.50-0.95, p=0.0192]). Among women infected with high-risk types of HPV, being a heterozygous carrier was associated with a reduced risk of cervical cancer (adjusted OR = 0.32 [95% CI: 0.12-0.91, p=0.031]). Similarly, a decreased risk was observed in heterozygous women with a non-smoking partner (adjusted OR = 0.27 [95% CI: 0.09-0.83, p=0.023]). Conclusions: GSTP1 polymorphism could influence susceptibility to cervical cancer among northeast Thai women; either as a independent factor or in combination with high-risk HPV infection. Dual-testing of HPV and the GSTP1 might prove an effective screening tool for cervical cancer.

OBJECTIVES In group-living primates, it has been reported that the alpha male exhibits high concentrations of cortisol and testosterone in the context of mating competition. We investigated how the presence of females affected salivary cortisol and testosterone levels in males from a small captive group of chimpanzees (Pan troglodytes). Specifically, we assessed whether the presence of females resulted in a rapid increase in salivary cortisol and testosterone levels in the alpha male. MATERIALS AND METHODS We compared the social behavior and salivary hormone concentrations of four males before and after the presentation of receptive females. Three times a day, we collected saliva samples, a useful matrix for investigating short-term hormonal changes, and measured cortisol and testosterone concentration by liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS The frequency of inter-male aggression increased in the presence of females, indicating intense competition among males. Salivary cortisol levels increased in all males in the presence of females; however, the increase was significantly more pronounced in the alpha male. We found a complex three-way interaction among the presence of females, sampling timings, and male dominance rank in the analysis of salivary testosterone. Contrary to our prediction, a post hoc analysis revealed that salivary testosterone levels decreased after female introduction and that the alpha male did not show a higher level of salivary testosterone. CONCLUSIONS Our study provides experimental evidence suggesting that the presence of females plays a significant role in the rank-related variation in the cortisol levels in male chimpanzees. Furthermore, our findings demonstrate the usefulness of salivary hormones for detecting short-term physiological changes in studies of socioendocrinology.

Sex/autosome translocations are rare events. The only known example in catarrhines is in the silvered-leaf monkey. Here the Y chromosome was reciprocally translocated with chromosome 1. The rearrangement produced an X1X2Y1Y2 sex chromosome system. At least three chromosomal variants of the intact chromosome 1 are known to exist. We characterized in high resolution the translocation products (Y1 and Y2) and the polymorphic forms of the intact chromosome 1 with a panel of more than 150 human BAC clones. We showed that the translocation products were extremely rearranged, in contrast to the high level of marker order conservation of the other silvered-leaf monkey chromosomes. Surprisingly, each translocation product appeared to form independent “chromosome lineages”; each having a myriad of distinct rearrangements. We reconstructed the evolutionary history of the translocation products by comparing the homologous chromosomes of two other colobine species: the African mantled guereza and the Indian langur. The results showed a massive reuse of breakpoints: only 12, out of the 40 breaks occurred in domains never reused in other rearrangements, while, strikingly, some domains were used up to four times. Such frequent breakpoint reuse if proved to be a general phenomenon has profound implications for mechanisms of chromosome evolution.

Background Pulmonary hypertension (PH) is a common complication of chronic respiratory disease. Recent studies have reported diabetes mellitus (DM) to be a poor prognostic factor in patients with chronic respiratory disease, including chronic obstructive pulmonary disease or interstitial pneumoniae. However, the association between DM and PH in chronic respiratory disease remains unclear. In this study, we aimed to investigate whether DM is a predictor of PH in patients with chronic respiratory disease. Methods We prospectively analyzed 386 patients in our hospital with chronic respiratory disease. An echocardiographic pressure gradient between the right atrium and the right ventricle of ≥ 40 mmHg was defined as PH. We compared the clinical characteristics and impact of DM between chronic respiratory disease patients with and those without PH. Results Of the 386 patients, 42 (10.9%) were diagnosed as having PH. The PH group had higher modified medical research council (mMRC) grade and complication rate of DM, but not hypertension and hyperlipidemia, when compared to the non-PH group. Multivariable logistic regression analysis revealed that mMRC scale (odds ratio 1.702, 95% confidence interval, 1.297 to 2.232, P < 0.001) and presence of DM (odd ratio 2.935, 95% confidence interval, 1.505 to 5.725, P = 0.002) were associated with PH in chronic respiratory disease patients. Conclusion DM is potentially associated with PH and is an independent factor for prediction of PH in patients with chronic respiratory disease.

Titin is associated with myocardial stiffness and hypertrophy, and mutations in its gene have been identified in cardiac myopathies such as dilated cardiomyopathy (DC). It has recently been reported that in damaged muscle, the N-terminal fragment of titin (Titin-N) is cleaved by calpain-3, and urinary Titin-N (U-TN) could be a marker of sarcomere damage. We aimed to investigate the impact of U-TN on prognosis of DC. We measured urinary levels of Titin-N/creatinine ratio (U-TN/Cr; pmol/mg/dl) in 102 patients with DC, and followed up all the patients (mean 1,167 days). The patients were divided into 3 groups based on the U-TN/Cr: first (U-TN/Cr

Background Breath acetone is a noninvasive biomarker of heart failure; however, its significance in heart failure patients with diabetes mellitus has yet to be clarified. The objective of this study is to investigate whether exhaled acetone concentration is a noninvasive biomarker in heart failure patients with diabetes mellitus. Methods This study prospectively included 35 diabetic patients with stage C heart failure and 20 diabetic patients with or at risk of heart failure (stage A or B). Exhaled breath was collected after an overnight fast. Results The stage C group had significantly higher brain natriuretic peptide levels, larger left ventricular diameter, lower left ventricular ejection fraction, and more frequent use of β-blocker, compared with the stage A or B group. The stage C group had higher exhaled acetone concentrations than the stage A or B group (p = 0.013). Exhaled acetone concentration was correlated with total ketone bodies (r = 0.588, p

Zinc is an essential cofactor for energy transfer and physiological heart function, has antioxidant properties, and is involved in multiple signaling pathways. We aimed to investigate the associations between serum zinc levels with prognosis, as well as underlying cardiac function and exercise capacity, in patients with heart failure (HF).We measured serum zinc levels in 968 consecutive hospitalized patients with decompensated HF, who were divided into 3 groups based on serum zinc levels (µg/dL): first (zinc ≥75, n = 323), second (62≤ zinc75, n = 322), and third (zinc62, n = 323) tertiles. We examined cardiac function and exercise capacity and followed up on all patients. Although cardiac function did not differ among the 3 groups, peak oxygen consumption was significantly lower in the third tertile than in the first and second tertiles (peak oxygen consumption, 14.2 vs 15.9 and 15.2 mL/kg/min, P = .010). In the Kaplan-Meier analysis (mean duration of follow-up 1103 days), cardiac and all-cause mortality was highest in the third tertile compared with the first and second tertiles. In the Cox proportional hazard analysis, serum zinc level was a predictor of cardiac and all-cause mortality. In the subgroup analysis, there were no interactions concerning associations between serum zinc levels with prognosis and other important variables, including age, gender, comorbidities, medications, other micronutrient levels, B-type natriuretic peptide, and left ventricular ejection fraction. The associations between zinc levels with mortality were consistent in all subgroups.Decreased serum zinc levels are associated with high mortality, accompanied by impaired exercise capacity.

Aims We aimed to determine the differences of impact of cardiopulmonary exercise testing (CPX) parameters on prognosis of heart failure with reduced left ventricular ejection fraction (HFrEF), preserved ejection fraction (HFpEF) and mid-range ejection fraction (HFmrEF). Methods We compared clinical characteristics and CPX parameters among the three groups, and the value of each CPX parameter to predict adverse cardiac events (cardiac deaths and re-hospitalizations for heart failure), cardiac deaths and all-cause deaths. Results Of 1190 patients, 41.9% had HFrEF, 36.8% had HFpEF and 21.3% had HFmrEF. The patients in HFrEF group had higher rates of adverse cardiac events, cardiac death and all-cause death than those of HFpEF and HFmrEF groups. In HFrEF, the independent predictors of adverse cardiac events were peak oxygen consumption and oxygen uptake efficiency slope, predictors of cardiac death were peak oxygen consumption and oxygen uptake efficiency slope, and the predictor of all-cause death was peak oxygen consumption. In HFpEF, the predictor of adverse cardiac events was peak oxygen consumption, predictors of cardiac deaths and all-cause deaths were peak oxygen consumption and exertional oscillatory ventilation. In HFmrEF, predictors of adverse cardiac events were peak oxygen consumption and oxygen uptake efficiency slope, and the predictor of cardiac deaths and all-cause deaths was peak oxygen consumption. Conclusion Peak oxygen consumption is the strong predictor for adverse events in all groups. Oxygen uptake efficiency slope predicts adverse prognosis in HFrEF, but not in HFpEF. In contrast, exertional oscillatory ventilation is the predictor only in HFpEF. Thus, different CPX parameters may be able to differentially predict prognosis in HFrEF and HFpEF. Those for predicting prognosis in HFmrEF may be intermediate between HFrEF and HFpEF.

It is widely recognized that overt hyper- as well as hypothyroidism are potential causes of heart failure (HF). Additionally it has been recently reported that subclinical hypothyroidism (sub-hypo) is associated with atherosclerosis, development of HF, and cardiovascular death. We aimed to clarify the effect of sub-hypo on prognosis of HF, and underlying hemodynamics and exercise capacity.We measured the serum levels of thyroid stimulating hormone (TSH) and free thyroxine (FT4) in 1100 consecutive HF patients. We divided these patients into 5 groups on the basis of plasma levels of TSH and FT4, and focused on euthyroidism (0.4 ≤ TSH ≤ 4 μIU/mL and 0.7 ≤ FT4 ≤ 1.9 ng/dL; n = 911; 82.8%) and sub-hypo groups (TSH4 μIU/mL and 0.7 ≤ FT4 ≤ 1.9 ng/dL; n = 132; 12.0%). We compared parameters of echocardiography, cardiopulmonary exercise testing, and cardiac catheterization, and followed up for cardiac event rate and all-cause mortality between the 2 groups.Although left ventricular ejection fraction did not differ between the 2 groups, the sub-hypo group had lower peak breath-by-breath oxygen consumption and higher mean pulmonary arterial pressure than the euthyroidism group (peak breath-by-breath oxygen consumption, 14.0 vs 15.9 mL/min/kg; P = 0.012; mean pulmonary arterial pressure, 26.8 vs 23.5 mm Hg, P = 0.020). In Kaplan-Meier analysis (mean 1098 days), the cardiac event rate and all-cause mortality were significantly higher in the sub-hypo group than those in the euthyroidism group (log rank, P 0.01, respectively). In Cox proportional hazard analysis, sub-hypo was a predictor of cardiac event rate and all-cause mortality in HF patients (P 0.05, respectively).Sub-hypo might be associated with adverse prognosis, accompanied by impaired exercise capacity and higher pulmonary arterial pressure, in HF patients.

Modern Austronesian (AN)-speaking Melanesians are considered to be derived from the admixture of indigenous non-Austronesian (NAN)-speaking people and AN-speaking people from Southeast Asia. In this study, we analyzed mitochondrial DNA (mtDNA) variations in the D-loop region for two AN-speaking Melanesian populations (Munda and Kusaghe) and an AN-speaking Micronesian population (Rawaki) in the New Georgia Islands, the Western Province of the Solomon Islands to examine their genetic similarities to AN-speaking Polynesians in Tonga and NAN-speaking Melanesians, Gidra, in Papua New Guinea. The ‘Polynesian motif’, which is well-characterized mtDNA marker for Polynesians, was frequently observed in Munda and Kusaghe. Of particular interest, haplogroup E1a2 + 16261, which has been rarely observed in the Solomon Islands, accounted for 12.8% in Kusaghe. It has been reported that the haplogroup E1a2 arose in Island Southeast Asia (ISEA) 9400 ± 2850 years ago. Phylogenetic and principle component analyses for 24 Oceanian populations revealed that Munda and Kusaghe populations were genetically close to Tongan population, but not to Gidra. Rawaki population showed no apparent genetic similarities to populations of Tonga and Gidra. Our results suggest that considerable gene flow from AN-speaking populations originated from Southeast Asia to indigenous Melanesians occurred in the New Georgia Islands.

Macaca fascicularis aurea (Burmese long-tailed macaque) is 1 of the 10 subspecies of Macaca fascicularis. Despite having few morphological differences from other subspecies, a recent phylogeographic study showed that M. f. aurea is clearly distinct genetically from Macaca fascicularis fascicularis (common long-tailed macaque) and suggests that M. f. aurea experienced a disparate evolutionary pathway versus other subspecies. To construct a detailed evolutionary history of M. f. aurea and its relationships with other macaque species, we performed phylogenetic analyses and divergence time estimation of whole mitochondrial genomes (2 M. f. aurea, 8 M. f. fascicularis, and 16 animals of 12 macaque species) and 2871 bp of the Y chromosome (1 M. f. aurea, 2 M. f. fascicularis, and 5 animals of 5 macaque species) and haplotype network analysis of 758 bp of the Y chromosome (1 M. f. aurea, 2 M. f. fascicularis, and 21 animals of 19 macaque species). Whereas the Y chromosome of M. f. aurea clustered with those of the fascicularis species group in the phylogenetic and haplotype network analyses, its mtDNA clustered within the clade of the sinica species group. Based on this phylogenetic incongruence and the estimated divergence times, we propose that proto-M. f. aurea underwent hybridization with a population of the sinica species group between 2.5 and 0.95 MYA after divergence from the common ancestor of M. fascicularis. Hybridization and introgression might have been central in the evolution of M. f. aurea, similar to what occurred in the evolution of other macaque species and subspecies.

It has been suggested that a ‘thrifty’ genotype hypothesis can account for high prevalence of obesity in the island populations of Oceania. A recent genome-wide association study revealed that a missense variant, rs373863828-A (p.Arg457Gln), of the CREBRF gene (encoding CREB3 regulatory factor) was associated with an excessive increase in body mass index (BMI) in Samoans. In the present study, the association of rs373863828-A with an increase in BMI was examined in four Austronesian (AN)-speaking populations in Oceania. We found that rs373863828-A was frequently observed (frequency of 0.15) in Tongans (Polynesians), and was strongly associated with higher BMI (P=6.1 × 10−4). A single copy of the rs373863828-A allele increased BMI by 3.09 kg m−2 after adjustment of age and sex. No significant association was detected in the other three AN-speaking populations (Melanesians and Micronesians) living in Solomon Islands. This was probably due to the low allele frequency (0.02–0.06) of rs373863828-A as well as small sample size. The rs373863828-A allele was not found in both AN-speaking and non-AN-speaking Melanesians living in Papua New Guinea. Our results suggest that rs373863828-A of CREBRF, a promising thrifty variant, arose in recent ancestors of AN-speaking Polynesians.

OBJECTIVES It has long been recognized that in gibbons both sexes disperse from the natal group. However, the fate of dispersed individuals was rarely documented. Here we provide the first detailed information on sex differences in dispersal patterns by analyzing the spatial genetic structure of a well-known white-handed gibbon (Hylobates lar) population. MATERIALS AND METHODS Mitochondrial DNA (mtDNA) and Y-chromosomal haplotypes, and autosomal microsatellite genotypes were determined for individuals of the Mo Singto study site, Khao Yai National Park, Thailand. Mantel tests for the three genetic marker types were performed for 17 gibbon groups comprising 23 adult males and 18 adult females. RESULTS Significant positive Mantel correlations were observed for spatial distance and both autosomal microsatellite-based as well as Y-chromosomal haplotype-based genetic distance among adult males. Neighboring adult males tended to be genetically related and share Y-chromosomal haplotypes. Conversely, no significant Mantel correlations were observed either in autosomal microsatellites or mtDNA among adult females. DISCUSSION Our results confirm, at a genetic level, hypotheses from long-term demographic observations that white-handed gibbon males of the Mo Singto population primarily disperse into adjacent groups. Instead, females disperse more opportunistically either to adjacent or more distant groups. This sex-specific difference reflects an apparent greater tolerance between males than between females. The higher tolerance of adult males allows the formation of stable multimale groups and facilitates male dispersal into an adjacent group. Stable multifemale groups have never been documented for white-handed gibbons probably due to feeding competition between females.

The potential association between the GSTM1 deletion polymorphism and risk of cervical cancer was investigated in Northeastern Thailand. DNA was extracted from buffy coat specimens of 198 patients with squamous cell carcinoma of the cervix and 198 age-matched healthy controls. Genotyping of the GSTM1 was conducted by using two PCR methods, a short- and a long-PCR. Distribution of the GSTM1 genotypes in between the cases and the controls was not significantly different (p>0.5 by χ2 test). The results suggest that the GSTM1 deletion polymorphism is not a risk factor for squamous cell carcinoma of the cervix in the northeast Thai women.

Human essential hypertension is partly caused by genetic factors. Angiotensinogen (AGT), G-protein β3-subunit (GNB3) and cytochrome P450 3A5 (CYP3A5) are candidate hypertension susceptibility genes and risk alleles at these loci have been thought to arise owing to human adaptation to climatic changes following the migration out-of-Africa. This study aimed to reveal the frequencies of hypertension-susceptibility genotypes in Pacific Island populations and associations of these single-nucleotide polymorphisms (SNPs) to hypertension. Genotyping was conducted for 804 individuals from Melanesian, Micronesian and Polynesian populations at SNPs in the genes encoding AGT (rs699, rs5049 and rs5051), GNB3 (rs5443) and CYP3A5*1/*3 (rs776746). Associations between these SNPs and hypertension were tested for 383 Melanesian Solomon Islanders. We found that the A/A genotype at rs5049 was a risk factor for hypertension (P=0.025) in the Melanesian Solomon Islanders; three SNPs for AGT were in linkage disequilibrium. The ancestral alleles of rs699, rs5051 and rs776746, and the derived allele of rs5443 were as frequent in the populations surveyed here as in other equatorial populations. Although other polymorphisms associated with hypertension and additional populations remain to be studied, these findings suggest that the Pacific Islanders' susceptibility to hypertension arose because of human migration and adaptation.

OBJECTIVE:Obesity is a growing health concern in the Oceanic populations. To investigate the genetic factors associated with adult obesity in the Oceanic populations, the association of single nucleotide polymorphisms (SNPs) of the beta-2 adrenergic receptor (ADRB2) gene with obesity was examined in 694 adults living in Tonga and Solomon Islands.\nRESULTS:A screening for variation in 16 Oceanic subjects detected 17 SNPs in the entire region of ADRB2, of which nine SNPs including two non-synonymous ones, rs1042713 (Arg16Gly) and rs1042714 (Gln27Glu), were further genotyped for all subjects. The rs34623097-A allele, at a SNP located upstream of ADRB2, showed the strongest association with risk for obesity in a logistic regression analysis adjusted for age, sex, and population (P=5.6 × 10^, odds ratio [OR]=2.5, 95% confidence interval [CI]=1.5–4.2). The 27Glu was also significantly associated with obesity in the single-point association analysis (P=0.013, OR=2.0, 95%CI=1.2–3.4); however, this association was no longer significant after adjustment for rs34623097 since these SNPs were in linkage disequilibrium with each other. A copy of the obesity-risk allele, rs34623097-A, led to a 1.6 kg/m^2 increase in body mass index (BMI; defined as weight in kilograms divided by height in meters squared) (P=0.0019). A luciferase reporter assay indicated that rs34623097-A reduced the transcriptional activity of the luciferase reporter gene by approximately 10% compared with rs34623097-G. An electrophoretic mobility shift assay demonstrated that rs34623097 modulated the binding affinity with nuclear factors. An evolutionary analysis implies that a G>A mutation at rs34623097 occurred in the Neandertal genome and then the rs34623097-A allele flowed into the ancestors of present-day humans.\nCONCLUSION:The present results suggest that rs34623097-A, which would lead to lower expression of ADRB2, contributes to the onset of obesity in the Oceanic populations., 論文

Cervical cancer is a serious public health problem in Thailand. We investigated possible risk factors for cervical cancer including HPV infection, p53 polymorphism, smoking and reproductive history among women in Northeast Thailand using a case control study with 177 cases and age-matched controls. Among the HPV carriers, a significantly increased risk for cervical cancer with an OR of 36.97 (p