PurposeThe triterpene oleanolic acid (OA) is known to possess antihypertensive actions. In the present study we to compared the effects of the triterpene on mean arterial blood pressure (MAP) and kidney function following acute administration in normotensive animals with those of its related oleanane synthetic derivatives (brominated oleanolic acid, Br-OA and oleanolic acid methyl ester, Me-OA). We also used experimental models of hypertension to further explore the effects of sub-chronic oral OA treatment and evaluated influences on oxidative status.MethodsOA was extracted from dried flower buds of Syzygium aromaticum using a previously validated protocol in our laboratory. Me-OA and Br-OA were synthesized according to a method described. Rats were supplemented with lithium chloride (12 mmol L-1) prior to experimentation in order to raise plasma lithium to allow measurements of lithium clearance and fractional excretion (FELi) as indices of proximal tubular Na+ handling. Anaesthetized animals were continuously infused via the right jugular with 0.077M NaCl. MAP was measured via a cannula inserted in the carotid artery, and urine was collected through a cannula inserted in the bladder. After a 3.5 h equilibration, MAP, urine flow, electrolyte excretion rates were determined for 4 h of 1 h control, 1.5 h treatment and 1.5 h recovery periods. OA, Me-OA and Br-OA were added to the infusate during the treatment period. We evaluated sub-chronic effects on MAP and kidney function in normotensive Wistar rats and in two animal models of hypertension, spontaneously hypertensive rats (SHR) and Dahl salt-sensitive (DSS) rats, during 9-week administration of OA (p.o.). Tissue oxidative status was examined in these animals at the end of the study. Increasing evidence suggests that and renal function disturbances and oxidative stress play major roles in the pathogenesis of hypertension.ResultsAcute infusion OA and oleanane derivatives displayed qualitatively similar effects in decreasing MAP and increasing urinary Na+ outputs. The drugs increased the FENa and FELi without influencing GFR indicating that at least part of the overall natriuretic effect involved proximal tubular Na+ reabsorption. Sub-chronic OA administration (p.o.) also elicited hypotensive responses in Wistar, DSS and SHR rats. The MAP lowering effect was more marked in hypertensive animals and were positively correlated with increased urinary Na+ excretion. Compared with respective control rats, OA treatment reduced malondialdehyde (MDA, a marker of lipid peroxidation) and increased activities of antioxidant enzymes; superoxide dismutase and glutathione peroxidase in hepatic, cardiac and renal tissues.ConclusionsOA and oleanane derivatives have similar effects on MAP, kidney function and oxidative stress. The amelioration of oxidative stress and blood pressure lowering effects by OA are more marked in hypertensive animals and correlated with an increased urinary Na+ output.Novelty of the WorkThe results of this study are novel in that they show 1) a correlatio...

Purpose Heterogeneous findings exist on antiretroviral treatment (ART) use in pregnancy and preterm delivery (PTD) or infants born small-for-gestational age (SGA). Whether reported differences may be explained by methods used to ascertain gestational age(GA) has not been explored. Methods We enrolled consecutive pregnant women attending a large primary care antenatal clinic in South Africa. Public-sector midwives assessed GA by last menstrual period (LMP) and symphysis-fundal height (SFH). Separately, if clinical GA was <24weeks, ultrasound (US) was performed by a research sonographer blinded to midwife assessments. In analysis, the impact of measurement error on the association between HIV/ART status and birth outcome by GA method was assessed, and factors associated with clinical GA under- or over-estimation identified. Results In 1787 women included overall, estimated PTD incidence was 36% by LMP, 17% by SFH and 11% by US. PTD risk was higher for HIV-infected than HIV-uninfected women using US-GA (adjusted odds ratio (aOR) 1.95; 95% CI 1.10–3.46); for LMP/SFH-GA the associations were smaller and not significant. These findings persisted after adjustment for age, parity, height and previous PTD. PTD risk did not vary by timing of ART initiation (before or during pregnancy) for any method. Elevated BMI and older age were associated with decreased risk of under-estimation by both LMP and SFH; HIV status and obesity were associated with increased risk of over-estimation by SFH. There were no differences in SGA incidence across GA methods. Conclusions Findings for an association between HIV/ART and birth outcomes are substantially influenced by GA assessment method. With growing public health interest in this association, future research efforts should seek to standardize optimal measures of gestation.

Oxidation of fatty acids is a major source of energy in the heart, liver, and skeletal muscle. It can be measured accurately using respirometry in isolated mitochondria, intact cells, and permeabilized cells or tissues. This technique directly measures the rate of oxygen consumption or flux at various respiratory states when appropriate substrates, uncouplers, and inhibitors are used. Acylcarnitines such as palmitoylcarnitine or octanoylcarnitine are the commonly used substrates. The β-oxidation pathway is prone to feedforward inhibition resulting from accumulation of short-chain acyl-CoA and depletion of CoA, but inclusion of malate or carnitine prevents accumulation of these intermediaries and CoA depletion.

Objectives: Increased risk of morbidity and hospitalization has been observed in children who are HIV-exposed uninfected (HEU) compared with HIV-unexposed uninfected (HUU). Studies in the era of universal maternal antiretroviral treatment (ART) are limited.Design: Prospective cohort. Methods:We investigated hospitalization between 29 days and 12 months of life in a South African cohort of infants born between February 2017 and January 2019 (HEU ¼ 455; HUU ¼ 458). All mothers known with HIV during pregnancy received ART. We reviewed hospital records and classified and graded infectious diagnoses using a standardized tool. We examined factors associated with infectious-cause hospitalization using mixed-effects Poisson regression.Results: Infants HEU vs. HUU had higher all-cause and infectious-cause hospitalization (13 vs. 7%, P ¼ 0.004 and 10 vs. 6%, P ¼ 0.014, respectively). Infectious causes accounted for most hospitalizations (77%). More infants HEU were hospitalized with severe or very severe infections than those HUU (9 vs. 6%; P ¼ 0.031). Mortality (<1%) did not differ between groups. HIV exposure was a significant risk factor for infectious-cause hospitalization [adjusted incidence rate ratios (aIRRs) ¼ 2.8; 95% confidence interval (CI) 1.5-5.4]. Although increased incidence of preterm birth (14 vs. 10%; P < 0.05) and shorter duration of breastfeeding (44 vs. 68% breastfed for !3 months, P < 0.001) among infants HEU vs. HUU contributed to increased hospitalization, they did not account for all the increased risk. Conclusion:Infectious-cause hospitalization incidence was higher among infants HEU vs. HUU, likely partly because of higher incidence of preterm birth and lower breastfeeding rates among infants HEU. The increased infectious disease burden in HEU infants has important implications for health services in sub-Saharan Africa.

a,d , for the PIMS Study Group Objective: To examine the association between timing of antiretroviral treatment (ART) initiation in HIV-infected women and placental histopathology. Design: A nested substudy in a larger cohort of HIV-infected women which examined the association between ART status and birth outcomes. Methods: Placentas (n ¼ 130) were examined for histopathology from two ART groups: stable (n ¼ 53), who initiated ART before conception and initiating (n ¼ 77), who started ART during pregnancy [median (interquartile range) 15 weeks gestation (11)(12)(13)(14)(15)(16)(17)(18)]. Using binomial regression we quantified associations between ART initiation timing with placental histopathology and pregnancy outcomes. Results: One-third of all placentas were less than 10th percentile weight-for-gestation and there was no significant difference between ART groups. Placental diameter, thickness, cord insertion position and foetal-placental weight ratio were also similar by group. However, placentas from the stable group showed increased maternal vascular malperfusion (MVM) (39.6 vs. 19.4%), and decreased weight (392 vs. 422 g, P ¼ 0.09). MVM risk was twice as high [risk ratios 2.03 (95% confidence interval: 1.16-3.57); P ¼ 0.01] in the stable group; the increased risk remaining significant when adjusting for maternal age [risk ratios 2.04 (95% confidence interval: 1.12-3.72); P ¼ 0.02]. Furthermore, MVM was significantly associated with preterm delivery and low birth weight (P ¼ 0.002 and <0.0001, respectively). Conclusion: Preconception initiation of ART was associated with an increased MVM risk, and may contribute to placental dysfunction. The association between MVM with preterm delivery and low birth weight suggests that a placenta-mediated mechanism likely links the putative association between long-term use of ART and adverse birth outcomes.

Studies indicate that Syzygium spp-derived oleanolic acid (OA) enhances renal function of streptozotocin (STZ)-induced diabetic rats as evidenced by its reversal of the previously reported inability of the kidney to excrete Na þ in these animals. We postulated that OA influences Na þ excretion in the proximal tubule, the site where two-thirds of filtered NaCl is reabsorbed through a process mediated by transport proteins. Therefore, the study investigated the effects of OA on proximal tubular Na þ handling in male Sprague-Dawley rats using renal lithium clearance (C Li ). Renal C Li has been used widely in animal and clinical studies to assess proximal tubular function. Sub-chronic doses of OA were administered to rats twice every third day for 5 weeks. Rats treated with deionized water served as control animals. Cytotoxicity of OA on kidney and liver cell lines was assessed by the MTT and comet assays. OA increased Na þ excretion of conscious male Sprague-Dawley rats from week 3 to week 5. By the end of the 5-week experimental period, OA treatment significantly reduced (p < 0.05) plasma creatinine concentration of STZ-induced diabetic rats with a concomitant elevation in glomerular filtration rate (GFR). Acute OA infusion was also associated with increases in fractional excretion of sodium (FE Na ) and lithium (FE Li ) in anesthetized rats in the absence of significant changes in GFR. The MTT assay studies demonstrated that OA increased the metabolic activity of kidney and liver cell lines. Taken together with previous observations, this study implicates the proximal tubule in OA-evoked increases in urinary Na þ output.

Background Successful scale-up of antiretroviral therapy (ART) during pregnancy has minimized infant HIV acquisition, and over 1 million infants are born HIV-exposed but uninfected (HEU), with an increasing proportion also exposed in utero to maternal ART. While benefits of ART in pregnancy outweigh risks, some studies have reported associations between in utero ART exposure and impaired fetal growth, highlighting the need to identify the safest ART regimens for use in pregnancy. Methods We compared birth anthropometrics of infants who were HEU with those HIV-unexposed (HU) in Cape Town, South Africa. Pregnant women had gestational age assessed by ultrasound at enrolment. Women living with HIV were on ART (predominately tenofovir-emtricitabine-efavirenz) either prior to conception or initiated during pregnancy. Birth weights and lengths were converted to weight-for-age (WAZ) and length-for-age (LAZ) z-scores using Intergrowth-21st software. Linear regression was used to compare mean z-scores adjusting for maternal and pregnancy characteristics. Results Among 888 infants, 49% (n = 431) were HEU and 51% (n = 457) HU. Of 431 HEU infants, 62% (n = 268) were exposed to HIV and antiretrovirals (ARVs) from conception and 38% (n = 163) were exposed to ARVs during gestation but after conception (median fetal ARV exposure of 21 weeks [IQR; 17–26]). In univariable analysis, infants who were HEU had lower mean WAZ compared with HU [β = − 0.15 (95% Confidence Interval (CI): − 0.28, − 0.020)]. After adjustment for maternal age, gravidity, alcohol use, marital and employment status the effect remained [adjusted β − 0.14 (95%CI: − 0.28, − 0.01]. Similar differences were noted for mean LAZ in univariable [β − 0.20 (95%CI: − 0.42, − 0.01] but not multivariable analyses [adjusted β − 0.18 (95%CI: − 0.41, + 0.04] after adjusting for the same variables. Mean WAZ and LAZ did not vary by in utero ARV exposure duration among infants who were HEU. Conclusion In a cohort with high prevalence of ART exposure in pregnancy, infants who were HEU had lower birth WAZ compared with those HU. Studies designed to identify the mechanisms and clinical significance of these disparities, and to establish the safest ART for use in pregnancy are urgently needed.

objectives To examine the association between maternal body mass index (BMI) and gestational weight gain (GWG) and adverse birth outcomes in HIV-infected and HIV-uninfected women.methods In an urban South African community, 2921 consecutive HIV-infected and HIVuninfected pregnant women attending primary healthcare services were assessed at their first antenatal visit. A subset of HIV-infected women enrolled in a longitudinal study was assessed three times during pregnancy. All women had birth outcome data from medical records and study questionnaires. In analyses, the associations between BMI, GWG, maternal factors and adverse birth outcomes were assessed with logistic regression models.results The estimated pre-pregnancy BMI median was 29 kg/m 2 (IQR, 24-34) overall, 29 kg/m 2 (IQR, 24-34) for HIV-uninfected and 28 kg/m 2 (IQR, 24-34) for HIV-infected women; HIV prevalence was 38%. In adjusted models, increased BMI in the overall cohort was positively associated with age, haemoglobin and parity at first antenatal visit. Maternal obesity was associated with increased likelihood of having high birthweight (aOR 2.54, 95% CI 1.39-4.66) and large size for gestational age (aOR 1.66, 95% CI 1.20-2.31) infants. In the subset cohort, GWG was associated with increased likelihood of spontaneous preterm delivery (aOR 4.35, 95% CI 1.55-12.21) and high birthweight (aOR 3.00, 95% CI 1.22-7.34) infants.conclusion Obesity during pregnancy is prevalent in this setting and appears associated with increased risk of adverse birth outcomes in both HIV-infected and HIV-uninfected women. Weight management interventions targeting women of child-bearing age are needed to promote healthy pregnancies and reduce adverse birth outcomes.keywords body mass index, gestational weight gain, preterm delivery, birthweight, size for gestational age Sustainable Development Goals (SDGs): SDG 3 (good health and well-being), SDG 17 (partnerships for the goals) Tropical Medicine and International Health