High maternal adiposity during pregnancy programs an imbalance in the lipidome and predisposes to diet-induced hepatosteatosis in the offspring.

BACKGROUND: Exposure to high maternal adiposity in utero is a significant risk factor for the later-life development of metabolic syndrome (MetS), including non-alcoholic fatty liver disease (NAFLD). We have previously shown that high pre-pregnancy adiposity programs adipose tissue dysfunction in the offspring, leading to spillover of fatty acids into the circulation, a key pathogenic event in obesity-associated MetS. Herein, we hypothesized that programming of adipose tissue dysfunction in offspring born to overweight dams increases the risk for developing NAFLD. RESULTS: Females heterozygous for leptin receptor deficiency (Hetdb) were used as a model of high pre-pregnancy adiposity. Female wild-type (Wt) offspring born to Hetdb pregnancies gained significantly more body fat following high-fat/fructose diet (HFFD) compared with Wt offspring born to Wt dams. HFFD increased circulating free fatty acids (FFA) in male offspring of control dams, while FFA levels were similar in HFFD-fed offspring from Wt dams and CD or HFFD-fed Wt offspring from Hetdb dams. Despite female-specific protection from diet-induced FFA spillover, both male and female offspring from Hetdb dams were more susceptible to diet-induced hepatosteatosis. Lipidomic analysis revealed that CD-offspring of overweight dams had decreased hepatic polyunsaturated FA (PUFA) levels compared with control offspring. Changes to saturated FA (SFA) and the de novo lipogenic (DNL) index were diet driven; however, there was a significant effect of the intrauterine environment on FA elongation and Δ9 desaturase activity. CONCLUSION: High maternal adiposity during pregnancy programs a susceptibility to diet-induced hepatosteatosis.

Exploring oxidative stress and endothelial dysfunction as a mechanism linking bisphenol S exposure to vascular disease in human umbilical vein endothelial cells and a mouse model of postnatal exposure.

BACKGROUND: Structural analogues used to replace bisphenol A (BPA) since the introduction of new regulatory restrictions are considered emerging environmental toxicants and remain understudied with respect to their biological actions and health effects. Studies reveal a link between BPA exposure and vascular disease in human populations, whereas the vascular effects of BPA substitutes remain largely unknown. OBJECTIVES: To determine the effect of BPS, a commonly used BPA substitute, on redox balance, nitric oxide (NO) availability and microvascular NO-dependent dilation. METHODS: In human umbilical vein endothelial cells (HUVEC), production of reactive oxygen species (ROS) and NO after exposure to BPS was measured using fluorescent probes for DCFDA and DAF-FM diacetate, respectively. The contribution of endothelial NO synthase (eNOS) uncoupling to ROS generation was determined by measuring ROS in the presence or absence of an eNOS inhibitor (L-NAME) or eNOS co-factor, BH4, while the contribution of mitochondria-derived ROS was determined by treating cells with mitochondria-specific antioxidants prior to BPS exposure. Bioenergetic profiles were assessed using Seahorse extracellular flux analysis and mitochondria membrane polarization was measured with TMRE and JC-1 assays. In a mouse model of low dose BPS exposure, NO-mediated endothelial function was assessed in pressurized microvessels by inducing endothelium-dependent dilation in the presence or absence of L-NAME. RESULTS: BPS exposure (≥25 nM) reduced NO and increased ROS production in HUVEC, the latter corrected by treating cells with L-NAME or BH4. BPS exposure led to a loss of mitochondria membrane potential but had no impact on bioenergetic parameters except for a decrease in the spare respiratory capacity. Treatment of HUVEC with mitochondria-specific antioxidants abolished the effect of BPS on NO and ROS. NO-mediated vasodilation was impaired in male mice exposed to BPS. DISCUSSION: Exposure to BPS may promote cardiovascular disease by perturbing NO-mediated vascular homeostasis through the induction of oxidative stress.

Adverse childhood experiences, adult anxiety and social capital among women in rural Kenya.

Hundreds of millions of people suffer anxiety disorders globally, demonstrating need for scalable and effective interventions. Adverse childhood experiences contribute to this mental health burden. The stress-buffering hypothesis, which posits social factors moderate prior adversity and subsequent mental health outcomes, provides one theoretical avenue to consider observations that group-based microfinance programs improve social capital. We investigate associations between adverse childhood experiences, generalized anxiety among adults and social capital associated with participation in a group-based microfinance program in rural Kenya. Adult participants (n = 400 women) responded to standardized measures of childhood adversity in June 2018, group-affiliated social capital and generalized anxiety in June 2019. Cumulative adverse childhood experiences predicted higher anxiety, which was statistically moderated by the presence of group-affiliated interpersonal trust. This study is the first to find social capital associated with participation in a group-based microfinance program statistically moderates expected associations between adverse childhood experiences and adult generalized anxiety. Future study should be conducted using a cluster-randomized control design to further assess the potential of this intervention method to ameliorate associations between past adversity and current mental health.

Non-bacterial thrombotic endocarditis and coronary thrombectomy in a patient with metastatic small cell lung carcinoma.

A 66-year-old Caucasian man was initially admitted with a metastatic small cell lung carcinoma, hyponatraemia and obstructive pneumonia. His transthoracic echocardiogram (TTE) was normal. Ten days after admission, he was diagnosed with a non-ST segment elevation myocardial infarction (MI). Both a repeated TTE and a transoesophageal echocardiogram identified thickened, myxomatous mitral valve leaflet tips with small, mobile masses identified as vegetations, and new, eccentric, severe mitral regurgitation. Subsequent cardiac catheterisation recorded thrombotic occlusion of the right coronary artery. Successful coronary thrombectomy was carried out, but the patient died. A diagnosis of non-bacterial thrombotic endocarditis leading to coronary embolisation and MI was made. The clinical course and treatment choices are discussed.