Reduced Adult Hippocampal Neurogenesis and Cognitive Impairments following Prenatal Treatment of the Antiepileptic Drug Valproic Acid

SummaryPrenatal exposure to valproic acid (VPA), an established antiepileptic drug, has been reported to impair postnatal cognitive function in children born to VPA-treated epileptic mothers. However, how these defects arise and how they can be overcome remain unknown. Using mice, we found that comparable postnatal cognitive functional impairment is very likely correlated to the untimely enhancement of embryonic neurogenesis, which led to depletion of the neural precursor cell pool and consequently a decreased level of adult neurogenesis in the hippocampus. Moreover, hippocampal neurons in the offspring of VPA-treated mice showed abnormal morphology and activity. Surprisingly, these impairments could be ameliorated by voluntary running. Our study suggests that although prenatal exposure to antiepileptic drugs such as VPA may have detrimental effects that persist until adulthood, these effects may be offset by a simple physical activity such as running

The DsbA-L gene is associated with respiratory function of the elderly via its adiponectin multimeric or antioxidant properties

Oxidative stress and inflammation play a key role in the age-related decline in the respiratory function. Adipokine in relation to the metabolic and inflammatory systems is attracting growing interest in the field of respiratory dysfunction. The present clinical and experimental studies investigated the role of the disulfide bond-forming oxidoreductase A-like protein (DsbA-L) gene, which has antioxidant and adiponectin multimeric (i.e. activation) properties, on the respiratory function of the elderly. We performed a retrospective longitudinal genotype-phenotype relationship analysis of 318 Japanese relatively elderly participants (mean age ± standard deviation: 67.0 ± 5.8 years) during a health screening program and an in vitro DsbA-L knock-down evaluation using 16HBE14o-cells, a commonly evaluated human airway epithelial cell line. The DsbA-L rs1917760 polymorphism was associated with a reduction in the ratio of forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) and %FEV1 and with the elevation of the prevalence of FEV1/FVC < 70%. We also confirmed that the polymorphism was associated with a decreased respiratory function in relation to a decrease in the ratio of high-molecular-weight adiponectin/total adiponectin (as a marker of adiponectin multimerization) and an increase in the oxidized human serum albumin (as an oxidative stress marker). Furthermore, we clarified that DsbA-L knock-down induced oxidative stress and up-regulated the mucus production in human airway epithelial cells. These findings suggest that the DsbA-L gene may play a role in protecting the respiratory function of the elderly, possibly via increased systemic adiponectin functions secreted from adipocytes or through systemic and/or local pulmonary antioxidant properties

Association between preoperative toe perfusion index and maternal core temperature decrease during cesarean delivery under spinal anesthesia: a prospective cohort study

Background: The main mechanism of body temperature decrease during cesarean delivery under spinal anesthesia is core-to-peripheral redistribution of body heat, attributable to vasodilation. Perfusion index (PI) obtained with a pulse oximeter helps to assess peripheral perfusion dynamics by detecting the change in peripheral vascular tone. This study aimed to examine whether preoperative toe PI could predict the decrease in core temperature induced by spinal anesthesia during cesarean delivery.Methods: Parturients undergoing scheduled cesarean delivery under combined spinal-epidural anesthesia from September 2019 to March 2020 were enrolled in this single-center prospective cohort study. All parturients received 0.5% hyperbaric bupivacaine (10 mg) with fentanyl (15 μg) intrathecally. A pulse oximeter probe was placed on the left second toe for continuous PI measurement. The 3 M™ Bair Hugger™ Temperature Monitoring System placed over the right temporal region was used to record core temperature over time. We evaluated the association between the maximum core temperature decrease, which is the primary outcome, and the preoperative toe PI at operating room (OR) admission using a segmented regression model (SRM) and a generalized additive model (GAM). The maximum core temperature decrease was defined as the difference between core temperature at OR admission and minimum intraoperative core temperature.Results: Forty-eight patients were evaluated. In the SRM, the slope for the association between the maximum core temperature decrease and the preoperative toe PI changed from 0.031 to 0.124 after PI = 2.4%. Likewise, with the GAM, there was a small core temperature decrease when preoperative toe PI was greater than 2.0 to 3.0%.Conclusions: Low preoperative toe PI was associated with maternal core temperature decrease during cesarean delivery under spinal anesthesia. Preoperative toe PI is a simple, non-invasive, and effective tool for the early prediction of perioperative core temperature decrease during cesarean delivery.Trial registration: UMIN Clinical Trials Registry (registry number: UMIN000037965)

Effects of luseogliflozin on estimated plasma volume in patients with heart failure with preserved ejection fraction

Aims Sodium glucose co-transporter 2 inhibitors have diuretic effects in both patients with glycosuria and with natriuresis. We sought to assess the effect of luseogliflozin on estimated plasma volume (ePV) in patients with type 2 diabetes and heart failure with preserved ejection fraction (HFpEF). Methods and results This study was a post-hoc analysis of the MUSCAT-HF trial (UMIN000018395), a multicentre, prospective, open-label, randomized controlled trial that assessed the effect of 12 weeks of luseogliflozin (2.5 mg, once daily, n = 83) as compared with voglibose (0.2 mg, three times daily, n = 82) on the reduction in brain natriuretic peptide (BNP) in patients with type 2 diabetes and HFpEF. The analysis compared the change in ePV calculated by the Straus formula from baseline to Weeks 4, 12, and 24, using a mixed-effects model for repeated measures. We also estimated the association between changes in ePV and changes in other clinical parameters, including BNP levels. Luseogliflozin significantly reduced ePV as compared to voglibose at Week 4 {adjusted mean group-difference -6.43% [95% confidence interval (CI): -9.11 to -3.74]}, at Week 12 [-8.73% (95%CI: -11.40 to -6.05)], and at Week 24 [-11.02% (95%CI: -13.71 to -8.33)]. The effect of luseogliflozin on these parameters was mostly consistent across various patient clinical characteristics. The change in ePV at Week 12 was significantly associated with log-transformed BNP (r = 0.197, P = 0.015) and left atrial volume index (r = 0.283, P = 0.019). Conclusions Luseogliflozin significantly reduced ePV in patients with type 2 diabetes and HFpEF, as compared with voglibose. The reduction of intravascular volume by luseogliflozin may provide clinical benefits to patients with type 2 diabetes and HFpEF

Pattern of disease progression during third-line or later chemotherapy with nivolumab associated with poor prognosis in advanced gastric cancer: a multicenter retrospective study in Japan

[Background] Accelerated tumor growth during immunotherapy in pre-existing measurable lesions, hyperprogressive disease (HPD), has been reported. However, progression of non-measurable lesions and new lesions are frequently observed in patients with advanced gastric cancer (AGC). [Methods] This retrospective study involved AGC patients at 24 Japanese institutions who had measurable lesions and received nivolumab after ≥ 2 lines of chemotherapy. HPD was defined as a ≥ two-fold increase in the tumor growth rate of measurable lesions. The pattern of disease progression was classified according to new lesions in different organs and ascites appeared/increase of ascites. [Results] Of 245 patients, 147 (60.0%) showed progressive disease (PD) as the best response and 41 (16.7%) showed HPD during nivolumab monotherapy. There was no significant difference in overall survival (OS) between patients with HPD and those with PD other than HPD (median OS 5.0 vs 4.8 months; hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.6–1.5; p = 1.0). Fifty-three patients developed new lesions in different organs and 58 had appearance/increase of ascites; these patients showed shorter OS than those without each of these features (median OS 3.3 vs 7.1 months, HR 1.8, 95% CI 1.2–2.7, p = 0.0031 for new lesions, and 3.0 vs 7.8 months, HR 2.6, 95% CI 1.8–3.8, p < 0.0001 for ascites). Thirty-one patients who had both features showed the worst prognosis (median OS 2.6 months). [Conclusions] New lesions in different organs and appearance/increase of ascites, rather than the original definition of HPD, are the patterns of disease progression associated with poor prognosis in AGC patients receiving nivolumab whose best response was PD