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As the world population continues to increase to unsustainable levels, the importance of birth control and the development of new contraceptives are emerging. To date, male contraceptive options have been lagging behind those available to women, and those few options available are not satisfactory to everyone. To solve this problem, we have been searching for new candidate target proteins for non-hormonal contraceptives. Testis-specific proteins are appealing targets for male contraceptives because they are more likely to be involved in male reproduction and their targeting by small molecules is predicted to have no on-target harmful effects on other organs. Using in silico analysis, we identified Erich2, Glt6d1, Prss58, Slfnl1, Sppl2c, Stpg3, Tex33, and Tex36 as testis-abundant genes in both mouse and human. The genes, 4930402F06Rik and 4930568D16Rik, are testis-abundant paralogs of Glt6d1 that we also discovered in mice but not in human, and were also included in our studies to eliminate the potential compensation. We generated knockout (KO) mouse lines of all listed genes using the CRISPR/Cas9 system. Analysis of all of the individual KO mouse lines as well as Glt6d1/4930402F06Rik/4930568D16Rik TKO mouse lines revealed that they are male fertile with no observable defects in reproductive organs, suggesting that these 10 genes are not required for male fertility nor play redundant roles in the case of the 3 Glt6D1 paralogs. Further studies are needed to uncover protein function(s), but in vivo functional screening using the CRISPR/Cas9 system is a fast and accurate way to find genes essential for male fertility, which may apply to studies of genes expressed elsewhere. In this study, although we could not find any potential protein targets for non-hormonal male contraceptives, our findings help to streamline efforts to find and focus on only the essential genes., Ten testis-enriched genes are dispensable for male fertility, as determined by phenotypic analyses of knockout mice.

The Synergy Between PCI With TAXUS and Cardiac Surgery (SYNTAX) score is effective in predicting clinical outcome after percutaneous coronary intervention (PCI). However, its prediction ability is low because it reflects only the coronary characterization. We assessed the predictive value of combining the ankle-brachial index (ABI) and SYNTAX score to predict clinical outcomes after PCI. The ABI-SYNTAX score was calculated for 1,197 patients recruited from the Shinshu Prospective Multi-center Analysis for Elderly Patients with Coronary Artery Disease Undergoing Percutaneous Coronary Intervention (SHINANO) registry, a prospective, observational, multicenter cohort study in Japan. The primary end points were major adverse cardiovascular and cerebrovascular events (MACE; all-cause death, myocardial infarction, and stroke) in the first year after PCI. The ABI-SYNTAX score was calculated by categorizing and summing up the ABI and SYNTAX scores. ABI ≤ 0.49 was defined as 4, 0.5 to 0.69 as 3, 0.7 to 0.89 as 2, 0.9 to 1.09 as 1, and 1.1 to 1.5 as 0; an SYNTAX score ≤ 22 was defined as 0, 23 to 32 as 1, and ≥ 33 as 2. Patients were divided into low (0), moderate (1 to 2), and high (3 to 6) groups. The MACE rate was significantly higher in the high ABI-SYNTAX score group than in the lower 2 groups (low: 4.6% vs moderate: 7.0% vs high: 13.9%, p = 0.002). Multivariate regression analysis found that ABI-SYNTAX score independently predicted MACE (hazards ratio 1.25, 95% confidence interval 1.02 to 1.52, p = 0.029). The respective C-statistic for the ABI-SYNTAX and SYNTAX score for 1-year MACE was 0.60 and 0.55, respectively. In conclusion, combining the ABI and SYNTAX scores improved the prediction of 1-year adverse ischemic events compared with the SYNTAX score alone.

Background: CHADS2 or CHA2DS2-VASc score is used for prediction of stroke in patients with atrial fibrillation (AF). Recently, CHADS2 score is reported to have prognostic value in acute coronary syndrome without AF. However, clinical validation of CHA2DS2-VASc score for prognostic stratification in coronary heart disease (CHD) without AF remains uncertain. In this study, we evaluate whether CHA2DS2-VASc score could predict clinical outcome in CHD without known AF. Methods: SHINANO registry was a prospective, observational, multicenter cohort study, enrolling 1923 consecutive patients with CHD from August 2012 to July 2013. Two hundred nine patients were excluded because of known AF. We calculated CHA2DS2-VASc score in the remaining 1714 patients (mean age 70 ± 11 years, 23% female) without known AF. To assess the clinical validation of CHA2DS2-VASc score, we divided patients into 3 groups according to the tertiles (score 0–2, 3–4, and ≥5). The primary endpoint was MACE including death, nonfatal myocardial infarction, and ischemic stroke at 1 year. Results: One-year follow-up was completed in 1632 patients (95.2%). Cumulative incidence of MACE was 139 cases. In Kaplan–Meier analysis, incidence of MACE was significantly higher in patients with CHA2DS2-VASc score ≥5 compared to 3–4 and 0–2 (14.6% vs. 6.8% vs. 5.3%, p

Background: The clinical outcomes of elderly patients (≥80 years old) undergoing percutaneous coronary intervention (PCI) has not been well established, despite recent advances in both devices and techniques. Methods and Results: We recruited patients from the SHINANO Registry, a prospective, observational, multicenter, cohort study. From August 2012 to July 2013, a total of 1,923 consecutive patients with 2,250 elective/urgent PCIs (2,105 admissions) (mean age, 71±11 years; ≥80 years, 23%; men, 77%) were enrolled. The primary endpoint was procedural success. The secondary endpoints were in-hospital death and in-hospital major adverse cardiovascular events (MACE). The procedural success rate was significantly lower (83.7% vs. 89.1%, P=0.0001), and the rates of in-hospital mortality and MACE were significantly higher in elderly than in non-elderly patients (3.6% vs. 1.5%, P=0.005; 4.4% vs. 2.3%, P=0.016, respectively). For elective PCI, the rates of procedural success and in-hospital MACE were similar between groups (90.3% vs. 91.3%, P=0.65, 2.3% vs. 1.2%, P=0.2, respectively). On multivariate analysis, being elderly was not an independent predictor of procedural failure (OR, 1.15; CI, 0.81–1.61; P=0.43). Conclusions: In elderly patients, PCI is safe and feasible. The presence of comorbidities is a more important factor than age alone. (Circ J 2014; 78: 1097–1103)

We present a patient with Brugada syndrome and paroxysmal atrial fibrillation who underwent circumferential pulmonary vein isolation. His electrocardiogram showed normal sinus rhythm and first-degree AV block (P-R 280 ms) with coved-type ST elevation in V1–2 (+2.0 mm) before ablation. During ablation around the left pulmonary vein ostium, atrial fibrillation, progression of ST elevation (+4.5 mm), and T wave alternans occurred. After right pulmonary vein encirclement was complete, ST elevation improved to +1.0 mm. The following day, the ST segments remained lower than baseline levels.

信州大学博士（医学）・学位論文・平成24年1月30日授与（甲第923号）・嶋田健太郎, Background: Atrial fibrillation (AF) is the most common supraventricular arrhythmia, often occurring during hemodialysis (HD). Prolongation of the total filtered P-wave duration (PWD) and reduction of the root mean square voltages for the last 20 ms of the P wave (RMS20) on a P-wave signal-averaged electrocardiogram (P-SAECG) are predictors of AF. We investigated whether HD induces alterations of P-SAECG, and determined the influential factors. Methods and Results: Thirty-three end-stage kidney disease patients (66.7 +/- 12.6 years, 23 males) undergoing maintenance HD were enrolled in this study. Digital ambulatory P-SAECG monitoring and laboratory examination of serum proteins and ions were carried out before, during, and after the HD sessions. Data were analyzed by multiple regression analysis. PWD was significantly prolonged, and RMS20 significantly reduced, during HD. These values recovered after completion of HD. Multiple regression analysis showed that prolongation of PWD significantly correlated with HD duration and the rate of removal of body fluid. On the other hand, RMS20 significantly correlated with HD duration and blood urea nitrogen variation. Conclusions: HD resulted in prolongation of PWD and reduction of RMS20, indicating the vulnerability of HD patients to AF. These P-SAECG changes correlated with HD duration and the rate of removal of the body fluid. These findings underline the importance of the control of dialysis variables in the prevention of atrial arrhythmias following HD. (Circ J 2012; 76: 612-617), Article, CIRCULATION JOURNAL. 76(3):612-617 (2012)

The bone marrow derived endothelial progenitor cells (EPCs) are considered to originate from haematopoietic stem cells, which are positive for CD34.1 Human CD34 expressing cells (CD34+ cells) injected into nude mice and rats undergoing neovascularisation caused by hindlimb ischaemia are incorporated into the neovasculature and express endothelial antigens. We recently reported that transplantation of autologous bone marrow cells, including CD34+ cells, improved ischaemia in patients with critical limb ischaemia.2 Moreover, increased neovascularisation by bone marrow derived CD34+ cells was shown to improve cardiac function. Recently, a mobilisation of EPCs into circulation from bone marrow was reported in patients with acute myocardial infarction and acute coronary syndrome,3,4 but little is known about the regulation of EPC mobilisation in patients with stable coronary artery disease (CAD). In the present study, we investigated the number of circulating CD34+ cells in patients with CAD and the influence of atherosclerotic risk factors on this number. Thirty four patients (mean (SEM) age …

Ankle-Brachial Index (ABI) is used for an arteriosclerotic noninvasive index widely, and the patient with low ABI value has poor prognosis. However, little is known about relationship between ABI and coronary artery disease (CAD) complexity. The goal of the study was to evaluate the relationship