Female Reproductive Events and Subclinical Atherosclerosis of the Brain and Carotid Arteriopathy: the Ohasama Study

Aims: Few studies have investigated the subclinical atherosclerotic changes in the brain and carotid artery, and in East Asian populations. We sought to investigate whether gravidity, delivery, the age at menarche and menopause and estrogen exposure period are associated with subclinical atherosclerosis of the brain and carotid arteriopathy.Methods: This cross-sectional study formed part of a cohort study of Ohasama residents initiated in 1986. Brain atherosclerosis and carotid arteriopathy were diagnosed as white matter hyperintensity (WMH) and lacunae evident on brain magnetic resonance imaging (MRI) and carotid intimal media thickness (IMT) or plaque revealed by ultrasound, respectively. The effect of the reproductive events on brain atherosclerosis and carotid arteriopathy was investigated using logistic regression and general linear regression models after adjusting for covariates.Results: Among 966 women aged ≥ 55 years in 1998, we identified 622 and 711 women (mean age: 69.2 and 69.7 years, respectively) who underwent either MRI or carotid ultrasound between 1992–2008 or 1993–2018, respectively. The highest quartile of gravidity (≥ 5 vs. 3) and delivery (≥ 4 vs. 2), and the highest and second highest (3 vs. 2) quartiles of delivery were associated with an increased risk of WMH and carotid artery plaque, respectively. Neither of age at menarche, menopause, and estrogen exposure period estimated by subtracting age at menarche from age at menopause was associated with atherosclerotic changes of brain and carotid arteries.Conclusions: Higher gravidity and delivery are associated with subclinical atherosclerosis of the brain and carotid plaque

Aldo-keto reductase inhibitors increase the anticancer effects of tyrosine kinase inhibitors in chronic myelogenous leukemia

Tyrosine kinase inhibitors (TKIs) are widely utilized in clinical practice to treat carcinomas, but secondary tumor resistance during chronic treatment can be problematic. AKR1B1 and AKR1B10 of the aldo-keto reductase (AKR) superfamily are highly expressed in cancer cells and are believed to be involved in drug resistance. The aim of this study was to understand how TKI treatment of chronic myelogenous leukemia (CML) cells changes their glucose metabolism and if inhibition of AKRs can sensitize CML cells to TKIs. K562 cells were treated with the TKIs imatinib, nilotinib, or bosutinib, and the effects on glucose metabolism, cell death, glutathione levels, and AKR levels were assessed. To assess glucose dependence, cells were cultured in normal and low-glucose media. Pretreatment with AKR inhibitors, including epalrestat, were used to determine AKR-dependence. Treatment with TKIs increased intracellular glucose, AKR1B1/10 levels, glutathione oxidation, and nuclear translocation of nuclear factor erythroid 2-related factor 2, but with minimal cell death. These effects were dependent on intracellular glucose accumulation. Pretreatment with epalrestat, or a selective inhibitor of AKR1B10, exacerbated TKI-induced cell death, suggesting that especially AKR1B10 was involved in protection against TKIs. Thus, by disrupting cell protective mechanisms, AKR inhibitors may render CML more susceptible to TKI treatments

The long-term reproducibility of the white-coat effect on blood pressure as a continuous variable from the Ohasama Study

Abstract There is little information about the reproducibility of the white coat effect, which was treated as a continuous variable. To investigate a long-term interval reproducibility of the white-coat effect as a continuous variable. We selected 153 participants without antihypertensive treatment (men, 22.9%; age, 64.4 years) from the general population of Ohasama, Japan, to assess the repeatedly measured white-coat effect (the difference between blood pressures at the office and home) in a 4-year interval. The reproducibility was assessed by testing the intraclass correlation coefficient (two-way random effect model-single measures). The white-coat effect for systolic/diastolic blood pressure slightly decreased by 0.17/1.56 mmHg at the 4-year visit on average. The Bland–Altman plots showed no significant systemic error for the white-coat effects (P ≥ 0.24). The intraclass correlation coefficient (95% confidence interval) of the white-coat effect for systolic blood pressure, office systolic blood pressure, and home systolic blood pressure were 0.41 (0.27–0.53), 0.64 (0.52–0.74), and 0.74 (0.47–0.86), respectively. Change in the white-coat effect was mainly affected by a change in office blood pressure. Long-term reproducibility of the white-coat effect is limited in the general population without antihypertensive treatment. The change in the white-coat effect is mainly caused by office blood pressure variation

Nocturnal blood pressure decline based on different time intervals and long-term cardiovascular risk: the Ohasama Study

<p>A diminished nocturnal decline in blood pressure (BP) represents a risk factor for cardiovascular disease. To define daytime and nighttime ambulatory BP, clock time-dependent methods are used when information on diary-based sleeping time is unavailable. We aimed to compare fixed-clock intervals with diary records to identify nocturnal BP declines as a predictor of long-term cardiovascular risk among the general population. Data were obtained from 1714 participants with no history of cardiovascular disease in Ohasama, Japan (mean age, 60.6 years; 64.9% women). We defined extreme dippers, dippers, non-dippers, and risers as nocturnal systolic BP decline ≥20%, 10–19%. 0–9%, and <0%, respectively. Over a mean follow-up period of 17.0 years, 206 cardiovascular deaths occurred. Based on diary records, multivariable-adjusted hazard ratios (HRs) for cardiovascular death compared with dippers were 1.24 (95% confidence interval [CI], 0.82–1.87) in extreme dippers, 1.21 (0.87–1.69) in non-dippers, and the highest HR of 2.31 (1.47–3.62) was observed in risers. Using a standard fixed-clock interval (daytime 09:00–21:00; nighttime 01:00–06:00), a nighttime 2 h-early shifted fixed-clock (daytime 09:00–21:00; nighttime 23:00–04:00), or a nighttime 2 h-late shifted fixed-clock (daytime 09:00–21:00; nighttime 03:00–08:00), the HR (95%CI) in risers compared with dippers was 1.57 (1.08–2.27), 2.02 (1.33–3.05), or 1.29 (0.86–1.92), respectively. Although use of diary records remains preferable, the standard and nighttime 2 h-early shifted fixed-clock intervals appear feasible for population-based studies.</p