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In the parent, gestational diabetes mellitus (GDM) causes both hyperglycemia and hyperlipidemia. Despite excess lipid availability, infants exposed to GDM are at risk for essential long-chain polyunsaturated fatty acid (LCPUFA) deficiency. Isotope studies have confirmed less LCPUFA transfer from the parent to the fetus, but how diabetic fuels impact placental fatty acid (FA) uptake and lipid droplet partitioning is not well-understood. We evaluated the effects of high glucose conditions, high lipid conditions, and their combination on trophoblast growth, viability, mitochondrial bioenergetics, BODIPY-labeled fatty acid (FA) uptake, and lipid droplet dynamics. The addition of four carbons or one double bond to FA acyl chains dramatically affected the uptake in both BeWo and primary isolated cytotrophoblasts (CTBs). The uptake was further impacted by media exposure. The combination-exposed trophoblasts had more mitochondrial protein (p = 0.01), but impaired maximal and spare respiratory capacities (p < 0.001 and p < 0.0001), as well as lower viability (p = 0.004), due to apoptosis. The combination-exposed trophoblasts had unimpaired uptake of BODIPY C12 but had significantly less whole-cell and lipid droplet uptake of BODIPY C16, with an altered lipid droplet count, area, and subcellular localization, whereas these differences were not seen with individual high glucose or lipid exposure. These findings bring us closer to understanding how GDM perturbs active FA transport to increase the risk of adverse outcomes from placental and neonatal lipid accumulation alongside LCPUFA deficiency.

The development of BPD in preterm neonates is increased by poor growth and nutritional deficits. The involvement of the fatty acid DHA in the development of BPD has been a focus for over a decade. However, recent clinical trials show that isolated DHA supplementation may increase BPD in subgroups of preterm neonates. One explanation for poor lung outcomes in DHA-supplemented neonates is a disruption of global fatty acid profiles and increased expression of a dominant-negative splice variant of a key driver of lung development, PPARγ. We previously developed a rat model of postnatal growth restriction (PGR) in which pups have impaired lung function and altered PPARγ activity. Here, we use our PGR rat model to assess the effects of DHA supplementation on lung outcomes. We hypothesize that the PPARγ splice variant, PPARγΔ5, will be expressed in the rat lung, and that DHA supplementation of PGR rat pups will alter circulating lipid profiles, lung mechanics, and PPARγ variant expression. Our findings demonstrate that PPARγΔ5 is expressed in the developing rat lung and that DHA supplementation of PGR rat pups alters global circulating fatty-acid profiles and does not normalize PGR-induced impaired lung mechanics or PPARγ activity.

Background: Preterm birth and respiratory support with invasive mechanical ventilation frequently leads to bronchopulmonary dysplasia (BPD). A hallmark feature of BPD is alveolar simplification. For our preterm lamb model of BPD, invasive mechanical ventilation is associated with postnatal feeding intolerance (reduced nutrition) and sedation. In contrast, preterm lambs managed by noninvasive support (NIS) have normal alveolar formation, appropriate postnatal nutrition, and require little sedation. We used the latter, positive-outcome group to discriminate the contribution of reduced nutrition vs. sedation on alveolar simplification. We hypothesized that, restricted nutrition, but not sedation with pentobarbital, contributes to impaired indices of alveolar formation in preterm lambs managed by NIS. Methods: Preterm lambs managed by NIS for 21d were randomized into three groups: NIS control, NIS plus restricted nutrition, and NIS plus excess sedation with pentobarbital. We quantified morphological and biochemical indices of alveolar formation, as well as mesenchymal cell apoptosis and proliferation. Results: Restricted nutrition impaired morphological and biochemical indices of alveolar formation, and reduced mesenchymal cell apoptosis and proliferation. Excess sedation with pentobarbital did not alter these indices, although mesenchymal cell apoptosis was less. Conclusion: Our results demonstrate that restricted nutrition, but not excess sedation, contributes to impaired alveolar formation during the evolution of BPD in chronically ventilated preterm lambs.

Intrauterine growth restriction (IUGR) programs adult disease, including obesity and insulin resistance. Our group previously demonstrated that IUGR dysregulates adipose deposition in male, but not female, weanling rats. Dysregulated adipose deposition is often accompanied by the release of proinflammatory signaling molecules, such as tumor necrosis factor alpha (TNFα). TNFα contributes to adipocyte inflammation and impaired insulin signaling. TNFα has also been implicated in the activation of the unfolded protein response (UPR), which impairs insulin signaling. We hypothesized that, in male rat pups, IUGR would increase TNFα, TNFR1, and components of the UPR (Hspa5, ATF6, p-eIF2α, and Ddit3) prior to the onset of obesity. We further hypothesized that impaired glucose tolerance would occur after the onset of adipose dysfunction in male IUGR rats. To test this hypothesis, we used a well-characterized rat model of uteroplacental insufficiency-induced IUGR. Our primary findings are that, in male rats, IUGR (1) increased circulating and adipose TNFα, (2) increased mRNA levels of UPR components as well as p-eIF2a, and (3) impaired glucose tolerance after observed TNFα increased and after UPR activation. We speculate that programmed dysregulation of TNFα and UPR contributed to the development of glucose intolerance in male IUGR rats.

Intrauterine growth restriction (IUGR) and maternal consumption of a high‐saturated‐fat diet (HFD) increase the risk of hypercholesterolemia, a leading cause of morbidity and mortality. Many pregnant women eat a HFD, thus exposing the fetus to a HFD in utero. The cumulative effect of in utero exposure to IUGR and a HFD on offspring cholesterol levels remains unknown. Furthermore, little is known about the mechanism through which IUGR and maternal HFD consumption increase cholesterol. We hypothesize that IUGR combined with a maternal HFD would increase offspring serum and hepatic cholesterol accumulation via alteration in levels of key proteins involved in cholesterol metabolism. To test our hypothesis we used a rat model of surgically induced IUGR and fed the dams a regular diet or a HFD. HFD‐fed dams consumed the same kilocalories as regular diet‐fed dams, with no difference between surgical intervention groups. In the offspring, IUGR combined with a maternal HFD increased hepatic cholesterol levels, low‐density lipoprotein (LDL) receptor protein levels, and Ldlr activity in female rat offspring at birth and both sexes at postnatal day 14 relative to non‐IUGR offspring both from regular diet‐ and HFD‐fed dams. These findings suggest that IUGR combined with a maternal HFD increases hepatic cholesterol accumulation via increased LDL cholesterol uptake into the liver with resulting persistent increases in hepatic cholesterol accumulation. Two disparate perinatal insults, intrauterine growth restriction and maternal consumption of a high‐fat diet, frequently occur together and increase the risk of developing hyperlipidemia in the offspring. Our findings show that the combination of intrauterine growth restriction and a maternal high‐fat diet in rats increases offspring hepatic cholesterol, low‐density lipoprotein receptor protein levels, and low‐density lipoprotein receptor activity at birth and at postnatal day 14.

Background: COVID-19 has placed a huge burden on healthcare systems which has led to widespread cancellation elective surgical care. Ireland is recovering from the first wave of COVID-19 and as such the expeditious return of elective surgical care is important. This is the first study to examine the attitudes of patients to undergoing total joint arthroplasty during the COVID-19 crisis. Methods: A prospective qualitative study was undertaken in our institution during the week 13/05/2020-20/05/2020. 65 patients completed a questionnaire assessing attitudes, awareness, and behavioral changes associated with COVID-19, a Charlson Comorbidity Index, modified-Harris Hip Score, and a Short Form-12 score. Results: 86% of patients felt that they were at little to no risk of COVID-19 infection. The majority of patients were happy to proceed with surgery at the current level of COVID-19 related threat (86%). Patients with higher mHHS were more likely to postpone their operation than those with lower mHHS scores. Our cohort had low patient reported outcome measures in both mHHS and SF-12, indicating the significant burden of hip osteoarthritis on both physical and mental health. Conclusion: Patients reported a significant disease-related impairment of physical function and subsequent deterioration in mental health as a result of hip osteoarthritis. Patients with worse hip function, as measured by the mHHS are more willing to proceed with surgery than those with superior hip function. This offers a potential mechanism by which to triage patients once elective surgical pathways reopen in the coming months.

Perinatal insults, including fetal undernutrition and hypoxia, are associated with an increased susceptibility to several adult-onset metabolic disorders. These include cardiovascular disease, insulin resistance, and obesity. However, the mechanisms driving the long-term phenotypic consequences have only recently begun to be elucidated. A primary mechanism accounting for perinatal adaptation is the epigenetic modification of chromatin. In this context, epigenetic modifications to chromatin are thought to arise in response to a perinatal insult in an effort to modulate gene expression and maximize fetal survival. In this symposium report, we discuss epigenetics as a mechanism by which perinatal adaptations can be made by the developing fetus. We examine the benefits of using multiple in vivo models to understand the interrelation of signals that come together and result in perinatal adaptation. Epigenetic effects on IGF-1 arising from a perinatal insult are discussed, as are the difficulties and challenges associated with this complex field. In conclusion, epigenetics provides a means of modulating gene transcription, thus allowing fetal adaptation to a broad variety of conditions.

Objective To evaluate the changes in body mass index (BMI) and waist circumference (WC) and their associations with the prevalence of hypertension and type 2 diabetes mellitus (T2DM) in Chinese adults. Design 2 consecutive population-based cross-sectional surveys. Setting A total of 12 districts and seven counties in Shanghai, China. Participants 12 329 randomly selected participants of the survey in 2002–2003, and 7423 randomly selected participants of the survey in 2009. All participants were residents of Shanghai aged 35–74 years. Outcome measures Measured BMI and WC. Previously diagnosed and newly identified hypertension and T2DM by measured blood pressure, fasting and postload glucose. Results While the participants of the two surveys were comparable in BMI in each age group, the participants of the 2009 survey had significantly larger WC than those of the 2002–2003 survey, with an annual percentage change being higher among participants aged 45–49 years in men and women. The increase in prevalence of T2DM was observed in all age groups and also appeared more evident in participants aged 45–49 years. The prevalence of hypertension was observed to increase more rapidly in elderly men and middle-aged women. Obesity, both overt and central, was associated with the risk of the two diseases, but BMI was more strongly linked to hypertension while WC appeared more evidently related with T2DM. Conclusions The prevalence of central obesity and related chronic diseases has been increasing in Shanghai, China. Our findings provide useful information for the projection of the growing burden of T2DM and hypertension in Chinese adults.