Maternal obesity in females born small: pregnancy complications and offspring disease risk

Obesity is a major public health crisis, with 1.6 billion adults worldwide being classified as overweight or obese in 2014. Therefore, it is not surprising that the number of women who are overweight or obese at the time of conception is increasing. Obesity during pregnancy is associated with the development of gestational diabetes and preeclampsia. The developmental origins of health and disease hypothesis proposes that perturbations during critical stages of development can result in adverse fetal changes, which leads to an increased risk of developing diseases in adulthood. Of particular concern, children born to obese mothers are at a greater risk of developing cardiometabolic disease. One subset of the population who are predisposed to developing obesity are children born small for gestational age, which occurs in 10% of pregnancies worldwide. Epidemiological studies report that these growth restricted children have an increased susceptibility to type 2 diabetes, obesity and hypertension. Importantly during pregnancy, growth restricted females have a higher risk of developing cardiometabolic disease, indicating that they may have an exacerbated phenotype if they are also overweight or obese. Thus the development of early pregnancy interventions targeted to obese mothers may prevent their children from developing cardiometabolic disease in adulthood. This article is protected by copyright. All rights reserved

Self-management for osteoarthritis of the knee: Does mode of delivery influence outcome?

Background Self-management has become increasingly popular in the management of chronic diseases. There are many different self-management models. Meta analyses of arthritis self-management have concluded that it is difficult to recommend any one program in preference to another due to inconsistencies in the study designs used to evaluate different programs. The Stanford Arthritis Self-Management Program (ASMP), most commonly delivered by trained lay leaders, is a generic program widely used for people with rheumatological disorders. We have developed a more specific program expressly for people with osteoarthritis of the knee (OAKP). It includes information designed to be delivered by health professionals and results in improvements in pain, function and quality of life. Aim: To determine whether, for people with osteoarthritis (OA) of the knee, the OAKP implemented in a primary health care setting can achieve and maintain clinically meaningful improvements in more participants than ASMP delivered in the same environment. Methods/Design The effectiveness of the programs will be compared in a single-blind randomized study. Participants: 146 participants with established OA knee will be recruited. Volunteers with coexistent inflammatory joint disease or serious co-morbidities will be excluded. Interventions: Participants will be randomised into either OAKP or ASMP groups and followed for 6 months. Measurements: Assessments will be immediately before and after the intervention and at 6 months. Primary outcome measures will be WOMAC and SF-36 questionnaires and a VAS for pain. Secondary outcomes will include balance, tested using a timed single leg balance test and a timed step test and self-efficacy. Data will be analysed using repeated measures ANOVA. Discussion With an aging population the health care costs for people with arthritis are ever increasing. Although cost analysis is beyond the scope of this study, it is reasonable to expect that costs will be greater when health professionals deliver self-management programs as opposed to lay leaders. Consequently it is critical to examine the relative effectiveness of the primary care management strategies available for OA

Elevated Circulating and Placental SPINT2 Is Associated with Placental Dysfunction

From MDPI via Jisc Publications RouterHistory: accepted 2021-07-08, pub-electronic 2021-07-12Publication status: PublishedBiomarkers for placental dysfunction are currently lacking. We recently identified SPINT1 as a novel biomarker; SPINT2 is a functionally related placental protease inhibitor. This study aimed to characterise SPINT2 expression in placental insufficiency. Circulating SPINT2 was assessed in three prospective cohorts, collected at the following: (1) term delivery (n = 227), (2) 36 weeks (n = 364), and (3) 24–34 weeks’ (n = 294) gestation. SPINT2 was also measured in the plasma and placentas of women with established placental disease at preterm (34 weeks) delivery. Using first-trimester human trophoblast stem cells, SPINT2 expression was assessed in hypoxia/normoxia (1% vs. 8% O2), and following inflammatory cytokine treatment (TNFα, IL-6). Placental SPINT2 mRNA was measured in a rat model of late-gestational foetal growth restriction. At 36 weeks, circulating SPINT2 was elevated in patients who later developed preeclampsia (p = 0.028; median = 2233 pg/mL vs. controls, median = 1644 pg/mL), or delivered a small-for-gestational-age infant (p = 0.002; median = 2109 pg/mL vs. controls, median = 1614 pg/mL). SPINT2 was elevated in the placentas of patients who required delivery for preterm preeclampsia (p = 0.025). Though inflammatory cytokines had no effect, hypoxia increased SPINT2 in cytotrophoblast stem cells, and its expression was elevated in the placental labyrinth of growth-restricted rats. These findings suggest elevated SPINT2 is associated with placental insufficiency

Exercise alters cardiovascular and renal pregnancy adaptations in female rats born small on a high-fat diet

Intrauterine growth restriction programs adult cardiorenal disease, which may be exacerbated by pregnancy and obesity. Importantly, exercise has positive cardiovascular effects. This study determined if high-fat-feeding exacerbates the known adverse cardiorenal adaptations to pregnancy in rats born small and whether endurance exercise can prevent these complications. Uteroplacental insufficiency was induced by bilateral uterine vessel ligation (Restricted) or sham (Control) surgery on embryonic day 18 (E18) in Wistar-Kyoto rats. Female offspring consumed a Chow or High-fat-diet (HFD) from weaning and were randomly allocated an exercise protocol at 16 weeks; Sedentary, Exercised before and during pregnancy (Exercise), or Exercised during pregnancy only (PregEx). Systolic blood pressure was measured pre-pregnancy and rats were mated at 20 weeks. During pregnancy, systolic blood pressure (E18) and renal function (E19) were assessed. Sedentary HFD Control females had increased estimated glomerular filtration rate (eGFR) compared to Chow. Compared to Control, Sedentary Restricted females had increased eGFR, which was not influenced by HFD. Renal function was not affected by exercise and pre-pregnancy blood pressure was not altered. Restricted Chow-fed dams and dams fed a high-fat-diet had a greater reduction in systolic blood pressure during late gestation, which was only prevented by Exercise. In summary, high-fat fed females born small are at a greater risk of altered cardiorenal adaptations to pregnancy. Although cardiovascular dysfunction was prevented by Exercise, renal dysfunction was not affected by exercise interventions. This study highlights that modifiable risk factors can have beneficial effects in the mother during pregnancy, which may impact fetal growth and development. </jats:p

Maternal growth restriction and stress exposure in rats differentially alters expression of components of the placental glucocorticoid barrier and nutrient transporters

The placenta plays a major role in the development of fetal growth restriction, which affects 10% of pregnancies and contributes to chronic adult disease risk. We have reported that female rats born small develop cardiometabolic dysfunction only during pregnancy. The physiological tests performed during pregnancy induced a maternal stress response as indicated by increased maternal corticosterone concentrations. This stress effected placental growth compared to females who were unhandled during pregnancy. Maternal stress and growth restriction independently program F2 offspring metabolic dysfunction. This study investigated the effects of maternal stress and growth restriction on placental and fetal metabolic parameters that may contribute to F2 offspring metabolic disease. Maternal growth restriction reduced F2 fetal weight whilst maternal stress reduced placental weight. Stressed mothers had reduced insulin and increased glucose concentrations, changes that were reflected in the fetus. Fetal β-cell number was reduced by maternal growth restriction, but was increased by stress exposure. Maternal growth restriction reduced placental Slc2a1, Igf2, Slc38a2 and Nr3c1 gene expression. Maternal stress decreased the expression of Slc2a1, Igf2, Slc38a2, Nr3c1, Slc2a3, Slc2a4, Nr3c2, Hsd11b2, Crhr1 and Ogt. Maternal birth weight effects on fetal weight were likely due to changes in placental nutrient transporter and Igf2 expression. On the contrary, maternal stress induced a systemic effect by altering maternal metabolic parameters, placental gene expression and fetal glucose and insulin concentrations. This study highlights the importance of informing pregnant women on effective ways to cope with stress during pregnancy to prevent adverse long-term disease outcomes in their children

Uteroplacental insufficiency in rats induces renal apoptosis and delays nephrogenesis completion

Uteroplacental insufficiency in rats reduces nephron endowment, leptin concentrations and programs cardiorenal disease in offspring. Cross-fostering growth restricted (Restricted) offspring onto a mother with normal lactation restores leptin concentrations and nephron endowment. This study aimed to determine if the reduced nephron endowment in Restricted offspring is due to delayed glomerular formation and dysregulation of renal genes regulating branching morphogenesis, apoptosis or leptin signalling. Furthermore, we aimed to investigate if cross-fostering Restricted offspring onto Control mothers could improve glomerular maturation and restore renal gene abundance.Uteroplacental insufficiency was induced by bilateral uterine vessel ligation (Restricted) or sham (Control) surgery on gestation day 18 (E18). Kidneys were collected at E20, postnatal day 1 (PN1) and PN7. An additional cohort was cross-fostered onto separate mothers at birth and kidneys collected at PN7.Kidneys were lighter in the Restricted group, but weight was restored with cross-fostering. At E20, Bax, Flt1 and Vegfa abundance were increased in Restricted offspring, while Ret and Bcl2 transcripts were increased only in Restricted females. At PN7, Gdnf and Ret abundance were higher in Restricted offspring, as was Casp3. Restricted offspring had a wider nephrogenic zone with more immature glomeruli suggesting a delayed or extended nephrogenic period. Cross-fostering had subtle effects on gene abundance and glomerular maturity.Uteroplacental insufficiency induced apoptosis in the developing kidney and delayed and extended nephrogenesis. Cross-fostering Restricted offspring onto Control mothers had beneficial effects on kidney growth and renal maturity, which may contribute to the restoration of nephron endowment. This article is protected by copyright. All rights reserved

Offset of ticagrelor prior to coronary artery bypass graft surgery for acute coronary syndromes:effects on platelet function and cellular adenosine uptake

Ticagrelor is an antagonist of both platelet adenosine diphosphate (ADP) receptor P2Y12 and equilibrative nucleoside transporter-1. Optimal timing of ticagrelor cessation prior to coronary artery bypass grafting (CABG) remains unclear. We characterized the offset of ticagrelor’s effects on platelets and cellular adenosine uptake in ticagrelor-treated patients (n = 13) awaiting CABG. Blood was drawn prior to CABG at multiple timepoints 2 to 120 (h) after the last dose of ticagrelor. Platelet function (n = 13) was assessed with multiple electrode aggregometry (MEA), expressed as arbitrary units (U) derived from area-under-the-curve (AUC) in response to ADP, and inhibition of adenosine uptake by high-performance liquid chromatography (n = 7). Mean±SD AUC was 20.3 ± 8.2 U (2 h post-ticagrelor), 33.0 ± 18.3U (24 h), 56.6 ± 30.6U (48 h), 61.4 ± 20.2U (72 h), 82.8 ± 24.2U (96 h) and 96.0 ± 15.3U (120 h). There was a significant difference between 72 h and 120 h (p = .007), but not between 96 h and 120 h (p > .99). By 96 h, all patients had AUC >31U, an accepted cutoff below which surgical bleeding risk is increased. Adenosine uptake showed no significant differences between the timepoints. These data suggest it takes 4 days for platelet reactivity to recover sufficiently after cessation of ticagrelor to avoid the excess risk of CABG-related bleeding. Discontinuing ticagrelor had no measurable effect on cellular adenosine uptake

Maternal exercise and growth restriction in rats alters placental angiogenic factors and blood space area in a sex-specific manner

Fetal growth and development are dependent on adequate placental nutrient transfer. The surface area of the placental villous network is a key determinant of nutrient exchange, which is regulated by vasculogenic and angiogenic factors. These factors are altered by intrauterine growth restriction (IUGR) and maternal obesity in both the first (F1) and second (F2) generations. We investigated the impact of endurance exercise in IUGR dams fed a High-fat diet on placental vasculogenesis and angiogenesis. Uteroplacental insufficiency (Restricted) or sham (Control) surgery was induced on embryonic day (E) 18 in Wistar-Kyoto rats. F1 offspring were fed a Chow or High-fat diet from weaning, and at 16 weeks were further allocated an exercise protocol; Sedentary, Exercised prior to and during pregnancy (Exercise), or Exercised during pregnancy only (PregEx). Females were mated (20 weeks) and F2 placentae collected at E20. Maternal Restriction, High-fat feeding and Exercise had a minimal impact on placental regulators of vasculogenesis and angiogenesis. However, Restriction increased placental labyrinth tissue area in Chow-fed dams. PregEx induced overt adaptations, including increased VEGFA and decreased PLGF protein expression, and reduced blood space area. These alterations were sex-dependent and associated with alterations in miRNA27a, a known regulator of VEGF translation. These data highlight that maternal exercise initiated during pregnancy (PregEx) causes alterations in placental vasculogenesis and angiogenesis in a sex-dependent manner, with minimal Restriction and maternal diet effects. However, further investigation is required to determine if these adaptations are beneficial or harmful for maternal and fetoplacental outcomes

Treadmill Exercise before and during Pregnancy Improves Bone Deficits in Pregnant Growth Restricted Rats without the Exacerbated Effects of High Fat Diet

Growth restriction programs adult bone deficits and increases the risk of obesity, which may be exacerbated during pregnancy. We aimed to determine if high-fat feeding could exacerbate the bone deficits in pregnant growth restricted dams, and whether treadmill exercise would attenuate these deficits. Uteroplacental insufficiency was induced on embryonic day 18 (E18) in Wistar Kyoto (WKY) rats using bilateral uterine vessel ligation (restricted) or sham (control) surgery. The F1 females consumed a standard or high-fat (HFD) diet from 5 weeks, commenced treadmill exercise at 16 weeks, and they were mated at 20 weeks. Femora and plasma from the pregnant dams were collected at post-mortem (E20) for peripheral quantitative computed tomography (pQCT), mechanical testing, histomorphometry, and plasma analysis. Sedentary restricted females had bone deficits compared to the controls, irrespective of diet, where such deficits were prevented with exercise. Osteocalcin increased in the sedentary restricted females compared to the control females. In the sedentary HFD females, osteocalcin was reduced and CTX-1 was increased, with increased peak force and bending stress compared to the chow females. Exercise that was initiated before and continued during pregnancy prevented bone deficits in the dams born growth restricted, whereas a HFD consumption had minimal bone effects. These findings further highlight the beneficial effects of exercise for individuals at risk of bone deficits