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Preterm birth (PTB) is a leading cause of neonatal morbidity and mortality. Although PTB is known to recur, interpregnancy preventive strategies for PTB have not been established to date. Annual BMI change can serve as a specific target value for preventing obstetric complications during interpregnancy care/counseling. This value can also account for age-related weight gain (0.2 kg/m2/year). In a multicenter retrospective study, we investigated the optimal annual BMI change for preventing PTB recurrence using the data of individuals who had two singleton births from 2009 to 2019. The association between annual BMI change and spontaneous PTB (sPTB) was analyzed by separating cases of medically indicated PTB (mPTB) from those of sPTB. Previous history of sPTB was strongly associated with sPTB in the subsequent pregnancy (adjusted odds ratio [aOR], 12.7; 95% confidence interval [CI], 6.5–24.8). Increase in annual BMI was negatively associated with sPTB (aOR, 0.6; 95% CI 0.5–0.9). The sPTB recurrence rate was significantly lower in patients with an annual BMI change of ≥ 0.25 kg/m2/year than in those with an annual BMI change of < 0.25 kg/m2/year (7.7% vs. 35.0%, p = 0.011). Our findings suggest that age-related annual BMI gain between pregnancies may help prevent sPTB recurrence. [ABSTRACT FROM AUTHOR]

Weight gain during interpregnancy period is related to hypertensive disorders of pregnancy (HDP). However, in interpregnancy care/counseling, the unpredictability of the timing of the next conception and the difficulties in preventing age-related body weight gain must be considered while setting weight management goals. Therefore, we suggest considering the annual change in the body mass index (BMI). This study aimed to clarify the association between annual BMI changes during the interpregnancy period and HDP risk in subsequent pregnancies. A multicenter retrospective study of data from 2009 to 2019 examined the adjusted odds ratio (aOR) of HDP in subsequent pregnancies. The aORs in several annual BMI change categories were also calculated in the subgroups classified by HDP occurrence in the index pregnancy. This study included 1,746 pregnant women. A history of HDP (aOR, 16.76; 95% confidence interval [CI], 9.62 − 29.22), and annual BMI gain (aOR, 2.30; 95% CI, 1.76 − 3.01) were independent risk factors for HDP in subsequent pregnancies. An annual BMI increase of ≥ 1.0 kg/m2/year was related to HDP development in subsequent pregnancies for women without a history of HDP. This study provides data as a basis for interpregnancy care/counseling, but further research is necessary to validate our findings and confirm this relationship. [ABSTRACT FROM AUTHOR]

The vesicular nucleotide transporter (VNUT) is responsible for the vesicular storage and release of ATP from various ATP-secreting cells, and it plays an essential role in purinergic signaling. Although extracellular ATP and its degradation products are known to mediate various inflammatory responses via purinoceptors, whether vesicular ATP release affects steatohepatitis and acute liver injury is far less understood. In the present study, we investigated the effects of clodronate, a potent and selective VNUT inhibitor, on acute and chronic liver inflammation in mice. In a model of methionine/choline-deficient diet-induced non-alcoholic steatohepatitis (NASH), the administration of clodronate reduced hepatic inflammation, fibrosis, and triglyceride accumulation. Clodronate also protected mice against high-fat/high-cholesterol diet-induced steatohepatitis. Moreover, prophylactic administration of clodronate prevented d-galactosamine and lipopolysaccharide-induced acute liver injury by reducing inflammatory cytokines and hepatocellular apoptosis. In vitro, clodronate inhibited glucose-induced vesicular ATP release mediated by VNUT and reduced the intracellular level and secretion of triglycerides in isolated hepatocytes. These results suggest that VNUT-dependent vesicular ATP release plays a crucial role in the recruitment of immune cells, cytokine production, and the aggravation of steatosis in the liver. Pharmacological inhibition of VNUT may provide therapeutic benefits in liver inflammatory disorders, including NASH and acute toxin-induced injury. [ABSTRACT FROM AUTHOR]

To evaluate the impact of maternal hypertensive disorders of pregnancy (HDP) on mortality and neurological outcomes in extremely and very preterm infants using a nationwide neonatal database in Japan. This population-based retrospective study was based on an analysis of data collected by the Neonatal Research Network of Japan from 2003 to 2015 of neonates weighing 1,500 g or less at birth, between 22 and 31 weeks' gestation. A total of 21,659 infants were randomly divided into two groups, HDP (n = 4,584) and non-HDP (n = 4,584), at a ratio of 1:1 after stratification by four factors including maternal age, parity, weeks of gestation, and year of delivery. Short-term (neonatal period) and medium-term (3 years of age) mortality and neurological outcomes were compared between the two groups by logistic regression analyses. In univariate analysis, HDP was associated with an increased risk for in-hospital death (crude odds ratio [OR], 1.31; 95% confidence interval, 1.04–1.63) and a decreased risk for severe intraventricular haemorrhage (0.68; 0.53–0.87) and periventricular leukomalacia (0.60; 0.48–0.77). In multivariate analysis, HDP was significantly associated with a lower risk for in-hospital death (adjusted OR, 0.61; 0.47–0.80), severe intraventricular haemorrhage (0.47; 0.35–0.63), periventricular leukomalacia (0.59; 0.45–0.78), neonatal seizures (0.40; 0.28–0.57) and cerebral palsy (0.70; 0.52–0.95) at 3 years after adjustment for covariates including birth weight. These results were consistent with those of additional analyses, which excluded cases with histological chorioamnionitis and which divided the infants into two subgroups (22–27 gestational weeks and 28–31 gestational weeks). Maternal HDP was associated with an increased risk for in-hospital death without adjusting for covariates, but it was also associated with a lower risk for mortality and adverse neurological outcomes in extremely and very preterm infants if all covariates except HDP were identical. [ABSTRACT FROM AUTHOR]

To estimate whether antenatal corticosteroids (ACS) improve short- and long-term preterm offspring outcomes in singleton pregnancies complicated by hypertensive disorders of pregnancy (HDP) similar to pregnancies without HDP. This population-based retrospective study was conducted based on an analysis of data collected by the Neonatal Research Network of Japan on 21,014 singleton neonates weighing ≤1,500 g between 24 and 31 weeks' gestation during 2003–2016. Logistic regression analyses were performed to compare short- and long-term offspring outcomes between mothers receiving ACS treatment and those who did not among pregnancies with HDP and without HDP. Of 21,014 neonates, 4,806 (22.9%) were born to mothers with HDP. ACS treatment was associated with significant decreases in short-term adverse outcomes in the both HDP and non-HDP groups, with similar reduced odds of neonatal death, respiratory distress syndrome, and intraventricular haemorrhage (IVH). However, ACS treatment did not significantly decrease severe IVH (aOR 0.76; 95% CI 0.51–1.13) and periventricular leukomalacia (1.14; 0.78–1.66) in the HDP group. In addition, ACS treatment in mothers without HDP significantly decreased cerebral palsy (aOR 0.70; 95% CI 0.58–084), developmental quotient scores <85 (0.79; 0.69–0.90), and composite adverse outcomes (0.85; 0.75–0.96) at 3 years of age, whereas ACS treatment in mothers with HDP did not significantly improve these outcomes (1.04; 0.69–1.57, 1.11; 0.88–1.39, 0.96; 0.75–1.22, respectively). ACS treatment was associated with significantly decreased major short-term morbidities and mortality among extremely and very preterm neonates of mothers with HDP, with ACS treatment having a decreased effect compared to that observed in neonates of mothers without HDP. Although ACS treatment has no additional effects on offspring outcomes at 3 years of age, our results did not suggest that ACS treatment should be withheld from mothers with HDP. [ABSTRACT FROM AUTHOR]

Microglia are highly sensitive to even small changes in the brain environment, such as invasion of non-hazardous toxicants or the presymptomatic state of diseases. However, the physiological or pathophysiological consequences of their responses remain unknown. Here, we report that cultured microglia sense low concentrations of the neurotoxicant methylmercury (MeHglow) and provide neuroprotection against MeHg, for which astrocytes are also required. When exposed to MeHglow, microglia exocytosed ATP via p38 MAPK- and vesicular nucleotide transporter (VNUT)-dependent mechanisms. Astrocytes responded to the microglia-derived ATP via P2Y1 receptors and released interleukin-6 (IL-6), thereby protecting neurons against MeHglow. These neuroprotective actions were also observed in organotypic hippocampal slices from wild-type mice, but not in slices prepared from VNUT knockout or P2Y1 receptor knockout mice. These findings suggest that microglia sense and respond to even non-hazardous toxicants such as MeHglow and change their phenotype into a neuroprotective one, for which astrocytic support is required. [ABSTRACT FROM AUTHOR]

Neuroendocrine cells store ATP in secretory granules and release it along with hormones that may trigger a variety of cellular responses in a process called purinergic chemical transmission. Although the vesicular nucleotide transporter (VNUT) has been shown to be involved in vesicular storage and release of ATP, its physiological relevance in vivo is far less well understood. In Vnut knockout (Vnut-1-) mice, we found that the loss of functional VNUT in adrenal chromaffin granules and insulin granules in the islets of Langerhans led to several significant effects. Vesicular ATP accumulation and depolarization-dependent ATP release were absent in the chromaffin granules of Vnut-1- mice. Glucose-responsive ATP release was also absent in pancreatic β-cells in Vnut-1- mice, while glucose-responsive insulin secretion was enhanced to a greater extent than that in wild-type tissue. Vnut-1- mice exhibited improved glucose tolerance and low blood glucose upon fasting due to increased insulin sensitivity. These results demonstrated an essential role of VNUTin vesicular storage and release of ATP in neuroendocrine cells in vivo and suggest that vesicular ATP and/or its degradation products act as feedback regulators in catecholamine and insulin secretion, thereby regulating blood glucose homeostasis. [ABSTRACT FROM AUTHOR]