Vasodilator factors in the systemic and local adaptations to pregnancy

We postulate that an orchestrated network composed of various vasodilatory systems participates in the systemic and local hemodynamic adaptations in pregnancy. The temporal patterns of increase in the circulating and urinary levels of five vasodilator factors/systems, prostacyclin, nitric oxide, kallikrein, angiotensin-(1–7) and VEGF, in normal pregnant women and animals, as well as the changes observed in preeclamptic pregnancies support their functional role in maintaining normotension by opposing the vasoconstrictor systems. In addition, the expression of these vasodilators in the different trophoblastic subtypes in various species supports their role in the transformation of the uterine arteries. Moreover, their expression in the fetal endothelium and in the syncytiotrophoblast in humans, rats and guinea-pigs, favour their participation in maintaining the uteroplacental circulation. The findings that sustain the functional associations of the various vasodilators, and their participation by endocrine, paracrine and autocrine regulation of the systemic and local vasoactive changes of pregnancy are abundant and compelling. However, further elucidation of the role of the various players is hampered by methodological problems. Among these difficulties is the complexity of the interactions between the different factors, the likelihood that experimental alterations induced in one system may be compensated by the other players of the network, and the possibility that data obtained by manipulating single factors in vitro or in animal studies may be difficult to translate to the human. In addition, the impossibility of sampling the uteroplacental interface along normal pregnancy precludes obtaining longitudinal profiles of the various players. Nevertheless, the possibility of improving maternal blood pressure regulation, trophoblast invasion and uteroplacental flow by enhancing vasodilation (e.g. L-arginine, NO donors, VEGF transfection) deserves unravelling the intricate association of vasoactive factors and the systemic and local adaptations to pregnancy

Prediction of disability-free survival in healthy older people

Prolonging survival in good health is a fundamental societal goal. However, the leading determinants of disability-free survival in healthy older people have not been well established. Data from ASPREE, a bi-national placebo-controlled trial of aspirin with 4.7 years median follow-up, was analysed. At enrolment, participants were healthy and without prior cardiovascular events, dementia or persistent physical disability. Disability-free survival outcome was defined as absence of dementia, persistent disability or death. Selection of potential predictors from amongst 25 biomedical, psychosocial and lifestyle variables including recognized geriatric risk factors, utilizing a machine-learning approach. Separate models were developed for men and women. The selected predictors were evaluated in a multivariable Cox proportional hazards model and validated internally by bootstrapping. We included 19,114 Australian and US participants aged ≥65 years (median 74 years, IQR 71.6–77.7). Common predictors of a worse prognosis in both sexes included higher age, lower Modified Mini-Mental State Examination score, lower gait speed, lower grip strength and abnormal (low or elevated) body mass index. Additional risk factors for men included current smoking, and abnormal eGFR. In women, diabetes and depression were additional predictors. The biased-corrected areas under the receiver operating characteristic curves for the final prognostic models at 5 years were 0.72 for men and 0.75 for women. Final models showed good calibration between the observed and predicted risks. We developed a prediction model in which age, cognitive function and gait speed were the strongest predictors of disability-free survival in healthy older people. Trial registration Clinicaltrials.gov (NCT01038583

In vitro human placental studies to support an adenovirusmediated VEGF-DΔNΔC maternal gene therapy for the treatment of severe early-onset fetal growth restriction

Severe fetal growth restriction (FGR) affects 1 in 500 pregnancies, is untreatable, and causes serious neonatal morbidity and death. Reduced uterine blood flow (UBF) is one cause. Transduction of uterine arteries in normal and FGR animal models using an adenovirus (Ad) encoding VEGF isoforms increases UBF and improves fetal growth in utero. Understanding potential adverse consequences of this therapy before first-in-woman clinical application is essential. The aims of this study were to determine whether Ad.VEGF-DΔNΔC (1) transfers across the human placental barrier and (2) affects human placental morphology, permeability and primary indicators of placental function, and trophoblast integrity. Villous explants from normal term human placentas were treated with Ad.VEGF-DΔNΔC  (5 × 107–10 virus particles [vp]/mL), or virus formulation buffer (FB). Villous structural integrity (hematoxylin and eosin staining) and tissue accessibility (LacZ immunostaining) were determined. Markers of endocrine function (human chorionic gonadotropin [hCG] secretion) and cell death (lactate dehydrogenase [LDH] release) were assayed. Lobules from normal and FGR pregnancies underwent ex vivo dual perfusion with exposure to 5 × 1010 vp/mL Ad.VEGF-DΔNΔC or FB. Perfusion resistance, para-cellular permeability, hCG, alkaline phosphatase, and LDH release were measured. Ad.VEGF-DΔNΔC  transfer across the placental barrier was assessed by quantitative polymerase chain reaction in DNA extracted from fetal-side venous perfusate, and by immunohistochemistry in fixed tissue. Villous explant structural integrity and hCG secretion was maintained at all Ad.VEGF-DΔNΔC  doses. Ad.VEGF-DΔNΔC  perfusion revealed no effect on placental permeability, fetoplacental vascular resistance, hCG secretion, or alkaline phosphatase release, but there was a minor elevation in maternal-side LDH release. Viral vector tissue access in both explant and perfused models was minimal, and the vector was rarely detected in the fetal venous perfusate and at low titer. Ad.VEGF-DΔNΔC  did not markedly affect human placental integrity and function in vitro. There was limited tissue access and transfer of vector across the placental barrier. Except for a minor elevation in LDH release, these test data did not reveal any toxic effects of Ad.VEGF-DΔNΔC  on the human placenta

Sugar-sweetened beverage (SSB) consumption, correlates and interventions among Australian Aboriginal and Torres Strait Islander communities: a scoping review

OBJECTIVES: Sugar-sweetened beverage (SSB) consumption in Australian Aboriginal and Torres Strait Islander people is reported to be disproportionally high compared with the general Australian population. This review aimed to scope the literature documenting SSB consumption and interventions to reduce SSB consumption among Australian Aboriginal and Torres Strait Islander people. Findings will inform strategies to address SSB consumption in Aboriginal and Torres Strait Islander communities. METHODS: PubMed, SCOPUS, CINAHL, Informit, Joanna Briggs Institute EBP, Mura databases and grey literature were searched for articles published between January 1980 and June 2018. Studies were included if providing data specific to an Australian Aboriginal and/or Torres Strait Islander population's SSB consumption or an intervention that focused on reducing SSB consumption in this population. DESIGN: Systematic scoping review. RESULTS: 59 articles were included (1846 screened). While reported SSB consumption was high, there were age-related and community-related differences observed in some studies. Most studies were conducted in remote or rural settings. Implementation of nutrition interventions that included an SSB component has built progressively in remote communities since the 1980s with a growing focus on community-driven, culturally sensitive approaches. More recent studies have focused exclusively on SSB consumption. Key SSB-related intervention elements included incentivising healthier options; reducing availability of less-healthy options; nutrition education; multifaceted or policy implementation (store nutrition or government policy). CONCLUSIONS: There was a relatively large number of studies reporting data on SSB consumption and/or sales, predominantly from remote and rural settings. During analysis it was subjectively clear that the more impactful studies were those which were community driven or involved extensive community consultation and collaboration. Extracting additional SSB-specific consumption data from an existing nationally representative survey of Aboriginal and Torres Strait Islander people could provide detailed information for demographic subgroups and benchmarks for future interventions. It is recommended that a consistent, culturally appropriate, set of consumption measures be developed

Low bone mineral density and fat-free mass in younger patients with a femoral neck fracture

Background Reduced bone mineral density (BMD) together with muscle wasting and dysfunction, that is sarcopenia, emerges as a risk factor for hip fracture. The aim of this study was to examine body composition and BMD and their relationship with trauma mechanisms in young and middle-aged patients with femoral neck fracture. Materials and methods Altogether, 185 patients with femoral neck fracture aged 20-69 were included. BMD, body composition and fat-free mass index (FFMI) were determined by dual-X-ray absorptiometry (DXA), and trauma mechanisms were registered. Results Ninety per cent of the whole study population had a femoral neck BMD below the mean for age. In the young patients (&lt;50years), 27% had a Z-score of BMD-2 SD. More than half of the middle-aged patients (50-69years) had osteopenia, that is T-score -1 to -25, and 35% had osteoporosis, that is T-score&lt;-25, at the femoral neck. Patients with low-energy trauma, sport injury or high-energy trauma had a median standardised BMD of 0702, 0740 vs. 0803g/cm(2) (P=003), and a median FFMI of 159, 177 vs. 175kg/m(2) (P&lt;0001), respectively. FFMI&lt;10th percentile of an age- and gender-matched reference population was observed in one-third. Conclusions A majority had low BMD at the femoral neck, and one-third had reduced FFMI (i.e. sarcopenia). Patients with fracture following low-energy trauma had significantly lower femoral neck BMD and FFMI than patients with other trauma mechanisms. DXA examination of both BMD and body composition could be of value especially in those with low-energy trauma.</p

Animal Models for Prenatal Gene Therapy: Choosing the Right Model

Testing in animal models is an essential requirement during development of prenatal gene therapy for -clinical application. Some information can be derived from cell lines or cultured fetal cells, such as the efficiency of gene transfer and the vector dose that might be required. Fetal tissues can also be maintained in culture for short periods of time and transduced ex vivo. Ultimately, however, the use of animals is unavoidable since in vivo experiments allow the length and level of transgene expression to be measured, and provide an assessment of the effect of the delivery procedure and the gene therapy on fetal and neonatal development. The choice of animal model is determined by the nature of the disease and characteristics of the animal, such as its size, lifespan, and immunology, the number of fetuses and their development, parturition, and the length of gestation and the placentation. The availability of a disease model is also critical. In this chapter, we discuss the various animal models that can be used and consider how their characteristics can affect the results obtained. The projection to human application and the regulatory hurdles are also presented