Maternal Undernourishment in Guinea Pigs Leads to Fetal Growth Restriction with Increased Hypoxic Cells and Oxidative Stress in the Brain.

BACKGROUND: We determined whether maternal nutrient restriction (MNR) in guinea pigs leading to fetal growth restriction (FGR) impacts markers for brain hypoxia and oxidative stress. METHODS: Guinea pigs were fed ad libitum (control) or 70% of the control diet before pregnancy, switching to 90% at mid-pregnancy (MNR). Near term, hypoxyprobe-1 (HP-1) was injected into pregnant sows. Fetuses were then necropsied and brain tissues were processed for HP-1 (hypoxia marker) and 4HNE, 8-OHdG, and 3-nitrotyrosine (oxidative stress markers) immunoreactivity (IR). RESULTS: FGR-MNR fetal and brain weights were decreased 38 and 12%, respectively, with brain/fetal weights thereby increased 45% as a measure of brain sparing, and more so in males than females. FGR-MNR HP-1 IR was increased in most of the brain regions studied, and more so in males than females, while 4HNE and 8-OHdG IR were increased in select brain regions, but with no sex differences. CONCLUSIONS: Chronic hypoxia is likely to be an important signaling mechanism in the FGR brain, but with males showing more hypoxia than females. This may involve sex differences in adaptive decreases in growth and normalizing of oxygen, with implications for sex-specific alterations in brain development and risk for later neuropsychiatric disorder

Maternal nutrient restriction in guinea pigs leads to fetal growth restriction with increased brain apoptosis

Background: We determined whether maternal nutrient restriction (MNR) in guinea pigs leading to fetal growth restriction (FGR) impacts cell death in the brain with implications for neurodevelopmental adversity. Methods: Guinea pigs were fed ad libitum (Control) or 70% of the control diet before pregnancy, switching to 90% at mid-pregnancy (MNR). Fetuses were necropsied near term and brain tissues processed for necrosis (H&E), apoptosis (TUNEL), and pro- (Bax) and anti- (Bcl-2 and Grp78) apoptotic protein immunoreactivity. Results: FGR-MNR fetal and brain weights were decreased 38% and 12%, respectively, indicating brain sparing but with brains still smaller. While necrosis remained unchanged, apoptosis was increased in the white matter and hippocampus in the FGR brains, and control and FGR-related apoptosis were increased in males for most brain areas. Bax was increased in the CA4 and Bcl-2 was decreased in the dentate gyrus in the FGR brains supporting a role in the increased apoptosis, while Grp78 was increased in the FGR females, possibly contributing to the sex-related differences. Conclusions: MNR-induced FGR results in increased brain apoptosis with regional and sex-related differences that may contribute to the reduction in brain area size reported clinically and increased risk in FGR males for later neurodevelopmental adversity

Seismic Performance of Isolated Bridges Considering Long-term Deterioration of Isolators

Mechanical properties of natural rubber seismic isolators are varied due to aging deterioration. It is needed that seismic performance of isolated bridges are maintained considering aging deterioration of isolators over their lifetime. In this study, seismic failure modes and seismic safety of isolated bridges were evaluated considering uncertainties in the material and mechanical properties and aging deterioration of isolators. It was shown that seismic safety of the isolated bridges is mainly controlled by the rupture strain of the isolator if the ultimate capacity ratio between the isolator and the column is low and that adequate capacity ratio is needed to enhance seismic safety and reparability of isolated bridges

Maternal nutrient restriction in guinea pigs as an animal model for studying growth-restricted offspring with postnatal catch-up growth

We determined the impact of moderate maternal nutrient restriction (MNR) in guinea pigs with fetal growth restriction (FGR) on offspring body and organ weights, hypothesizing that FGR-MNR animals will show catch-up growth but with organ-specific differences. Guinea pig sows were fed ad libitum (Control) or 70% of the control diet from 4 weeks preconception, switching to 90% at midpregnancy (MNR). Control newborns \u3e95 g [appropriate for gestational age (AGA); n = 37] and MNR newborns \u3c85 g (FGR; n = 37) were monitored until neonatal (~25 days) or adult (~110 days) necropsy. Birth weights and body/organ weights at necropsy were used to calculate absolute and fractional growth rates (FRs). FGR-MNR birth weights were decreased ~32% compared with the AGA-Controls. FGR-MNR neonatal whole body FRs were increased ~36% compared with Controls indicating catch-up growth, with values negatively correlated to birth weights indicating the degree of FGR leads to greater catch-up growth. However, the increase in organ FRs in the FGR-MNR neonates compared with Controls was variable, being similar for the brain and kidneys indicating comparable catch-up growth to that of the whole body and twofold increased for the liver but negligible for the heart indicating markedly increased and absent catch-up growth, respectively. While FGR-MNR body and organ weights were unchanged from the AGA-Controls by adulthood, whole body growth rates were increased. These findings confirm early catch-up growth in FGR-MNR guinea pigs but with organ-specific differences and enhanced growth rates by adulthood, which are likely to have implications for structural alterations and disease risk in later life

Maternal nutrient restriction in Guinea pigs leads to fetal growth restriction with evidence for chronic hypoxia

BackgroundWe determined whether maternal nutrient restriction (MNR) in Guinea pigs leading to fetal growth restriction (FGR) impacts markers for tissue hypoxia, implicating a mechanistic role for chronic hypoxia.MethodsGuinea pigs were fed ad libitum (Control) or 70% of the control diet before pregnancy, switching to 90% at mid-pregnancy (MNR). Near term, hypoxyprobe-1 (HP-1), a marker of tissue hypoxia, was injected into pregnant sows. Fetuses were then necropsied and liver, kidney, and placental tissues were processed for erythropoietin (EPO), EPO-receptor (EPOR), and vascular endothelial growth factor (VEGF) protein levels, and for HP-1 immunoreactivity (IR).ResultsFGR-MNR fetuses were 36% smaller with asymmetrical growth restriction compared to controls. EPO and VEGF protein levels were increased in the female FGR-MNR fetuses, providing support for hypoxic stimulus and linkage to increased erythropoiesis, but not in the male FGR-MNR fetuses, possibly reflecting a weaker link between oxygenation and erythropoiesis. HP-1 IR was increased in the liver and kidneys of both male and female FGR-MNR fetuses as an index of local tissue hypoxia, but with no changes in the placenta.ConclusionChronic hypoxia is likely to be an important signaling mechanism for the decreased fetal growth seen with maternal undernutrition and appears to be post-placental in nature

Parthenogenetic mosaicism: generation via second polar body retention and unmasking of a likely causative PER2 variant for hypersomnia

Background Parthenogenetic mosaicism is an extremely rare condition identified only in five subjects to date. The previous studies indicate that this condition is mediated by parthenogenetic activation and is free from a specific phenotype ascribed to unmaking of a maternally inherited recessive variant in the parthenogenetic cell lineage. Results We examined a 28-year-old Japanese 46,XX female with Silver-Russell syndrome and idiopathic hypersomnia. The results revealed (1) predominance of maternally derived alleles for all the differentially methylated regions examined; (2) no disease-related copy-number variant; (3) two types of regions for all chromosomes, i.e., four BAF (B-allele frequency) band regions with single major microsatellite peaks of maternal origin and single minor microsatellite peaks of non-maternal (paternal) origin, and six BAF band regions with single major microsatellite peaks of maternal origin and two minor microsatellite peaks of maternal and non-maternal (paternal) origin; (4) an unmasked extremely rare PER2 variant (c.1403G>A:p.(Arg468Gln)) with high predicted pathogenicity; (5) mildly affected local structure with altered hydrogen bonds of the p.Arg468Gln-PER2 protein; and (6) nucleus-dominant subcellular distribution of the p.Arg468Gln-PER2 protein. Conclusions The above findings imply that the second polar body retention occurred around fertilization, resulting in the generation of the parthenogenetic cell lineage by endoreplication of a female pronucleus and the normal cell lineage by fusion of male and female pronuclei, and that the homozygous PER2 variant in the parthenogenetic cells is the likely causative factor for idiopathic hypersomnia

Clinical characteristics, management strategies and outcomes of patients with recurrent venous thromboembolism in the real world

There is a paucity of data on management strategies and clinical outcomes after recurrent venous thromboembolism (VTE). In a multicenter registry enrolling 3027 patients with acute symptomatic VTE, the current study population was divided into the following 3 groups: (1) First recurrent VTE during anticoagulation therapy (N = 110); (2) First recurrent VTE after discontinuation of anticoagulation therapy (N = 116); and (3) No recurrent VTE (N = 2801). Patients with first recurrent VTE during anticoagulation therapy more often had active cancer (45, 25 and 22%, P < 0.001). Among 110 patients with first recurrent VTE during anticoagulation therapy, 84 patients (76%) received warfarin at recurrent VTE with the median prothrombin time-international normalized ratio (PT-INR) value at recurrent VTE of 1.6, although patients with active cancer had a significantly higher median PT-INR value at recurrent VTE compared with those without active cancer (2.0 versus 1.4, P < 0.001). Within 90 days after recurrent VTE, 23 patients (20.9%) during anticoagulation therapy and 24 patients (20.7%) after discontinuation of anticoagulation therapy died. Active cancer was a major cause of recurrent VTE during anticoagulation therapy as a patient-related factor, while sub-optimal intensity of anticoagulation therapy was a major cause of recurrent VTE during anticoagulation therapy as a treatment-related factor, particularly in patients without active cancer

The benefit of adenomyomectomy on fertility outcomes in women with rectovaginal endometriosis with coexisting adenomyosis

AbstractStudy ObjectiveTo evaluate the effect of removal of coexisting adenomyosis on fertility outcomes in women with rectovaginal endometriosis.DesignA retrospective cohort study.SettingA general hospital.PatientsA total of 190 women who underwent laparoscopic nodule excision surgery for rectovaginal endometriosis between April 2007 and December 2012.InterventionsSurgical excision of the rectovaginal endometriosis and coexisting uterine adenomyosis. Statistical analysis for fertility outcomes.Measurement and main resultsA total of 119 women desired postoperative pregnancy. Coexisting adenomyosis was found in 21% of the women. The overall clinical pregnancy rate was 41.2%. The only determining factor associated with a successful pregnancy was “age at surgery”. Clinical pregnancy rates with or without adenomyosis were 36.0% and 42.6%, respectively. We found no significant difference in clinical pregnancy rates between the groups.ConclusionThere is a possibility that surgical removal of coexisting adenomyosis positively effects fertility outcomes in women with rectovaginal endometriosis. However, it is also important to note that the age at surgery was a critical factor for successful pregnancy