Preterm‐born individuals: a vulnerable population at risk of cardiovascular morbidity and mortality during thermal extremes?

New Findings: What is the topic of this review? Thermal extremes disproportionately affect populations with cardiovascular conditions. Preterm birth, across all gestational age ranges below 37 weeks, has been identified as a non‐modifiable risk factor for cardiovascular disease. The hypothesis is presented that individuals born preterm are at an increased risk of cardiovascular morbidity and mortality during thermal extremes. What advances does it highlight? Cardiovascular stress tests performed in preterm‐born populations, from infancy through adulthood, highlight a progression of cardiovascular dysfunction accelerating through adolescence and adulthood. This dysfunction has many similarities with populations known to be at risk in thermal extremes. Abstract: Preterm‐born individuals are a uniquely vulnerable population. Preterm exposure to the extrauterine environment and the (mal)adaptations that occur during the transitional period can result in alterations to their macro‐ and micro‐physiological state. The physiological adaptations that increase survival in the short term may place those born preterm on a trajectory of lifelong dysfunction and later‐life decompensation. Cardiovascular compensation in children and adolescents, which masks this trajectory of dysfunction, is overcome under stress, such that the functional cardiovascular capacity is reduced and recovery impaired following physiological stress. This has implications for their response to thermal stress. As the Anthropocene introduces greater changes in our environment, thermal extremes will impact vulnerable populations as yet unidentified in the climate change context. Here, we present the hypothesis that individuals born preterm are a vulnerable population at an increased risk of cardiovascular morbidity and mortality during thermal extremes

In Search of an Integrative Measure of Functioning

International trends towards people-centred, integrative care and support require any measurement of functioning and disability to meet multiple aims. The information requirements of two major Australian programs for disability and rehabilitation are outlined, and the findings of two searches for suitable measures of functioning and disability are analysed. Over 30 current measures of functioning were evaluated in each search. Neither search found a generic measure of functioning suitable for these multibillion dollar programs, relevant to a wide range of people with a variety of health conditions and functioning experiences, and capable of indicating support needs, associated costs, progress and outcomes. This unsuccessful outcome has implications internationally for policy-relevant information for disability, rehabilitation and related programs. The paper outlines the features of an Integrative Measure of Functioning (IMF) based on the concepts of functioning and environmental factors in the International Classification of Functioning, Disability and Health (ICF). An IMF would be applicable across a variety of health conditions, settings and purposes, ranging from individual assessment to public health. An IMF could deliver person-centred, policy-relevant information for a range of programs, promoting harmonised language and measurement and supporting international trends in human services and public health.Centre for Disability Research and Polic

Maternal Fructose Intake Causes Developmental Reprogramming of Hepatic Mitochondrial Catalytic Activity and Lipid Metabolism in Weanling and Young Adult Offspring

Excess dietary fructose is a major public health concern, yet little is known about its influence on offspring development and later-life disease when consumed in excess during pregnancy. To determine whether increased maternal fructose intake could have long-term consequences on offspring health, we investigated the effects of 10% w/v fructose water intake during preconception and pregnancy in guinea pigs. Female Dunkin Hartley guinea pigs were fed a control diet (CD) or fructose diet (FD; providing 16% of total daily caloric intake) ad libitum 60 days prior to mating and throughout gestation. Dietary interventions ceased at day of delivery. Offspring were culled at day 21 (D21) (weaning) and at 4 months (4 M) (young adult). Fetal exposure to excess maternal fructose intake significantly increased male and female triglycerides at D21 and 4 M and circulating palmitoleic acid and total omega-7 through day 0 (D0) to 4 M. Proteomic and functional analysis of significantly differentially expressed proteins revealed that FD offspring (D21 and 4 M) had significantly increased mitochondrial metabolic activities of β-oxidation, electron transport chain (ETC) and oxidative phosphorylation and reactive oxygen species production compared to the CD offspring. Western blotting analysis of both FD offspring validated the increased protein abundances of mitochondrial ETC complex II and IV, SREBP-1c and FAS, whereas VDAC1 expression was higher at D21 but lower at 4 M. We provide evidence demonstrating offspring programmed hepatic mitochondrial metabolism and de novo lipogenesis following excess maternal fructose exposure. These underlying asymptomatic programmed pathways may lead to a predisposition to metabolic dysfunction later in life

Understanding microvascular function in preterm neonates

Research Doctorate - Doctor of Philosophy (PhD)Appropriate regulation of microvascular blood flow in the neonate is crucial for cardiorespiratory stability and survival in the period immediately following birth. Inappropriate microvascular dilatation in the first few days of extrauterine life is associated with poor outcomes in preterm neonates. Male very preterm neonates (≤28 weeks completed gestation) have significantly higher flows than females of the same gestational age. This is of clinical importance as preterm males are twice as likely to die as females (Chapter 1). Very little is known about the mechanisms underlying microvascular tone regulation in the perinatal period. Previous studies suggest a role for the gasotransmitters nitric oxide and carbon monoxide, however, differences in levels of these molecules do not account for all the variation observed, suggesting another player (Chapter 2). In this thesis, the role of the third gasotransmitter – hydrogen sulphide – as a potential mediator of microvascular tone (dys)regulation in the preterm is explored. The aim of this thesis was to further characterise early microvascular events in the neonate associated with poor outcome and characterise the mechanisms underlying vascular tone regulation, in particular, the role of the gasotransmitter hydrogen sulphide. As studies in preterm neonates are restricted mainly to observational studies, we established an animal model of prematurity using the guinea pig that would allow us to explore the underlying mechanisms of microvascular function in the newborn (Chapter 3). Delivery of pups at 0.87 gestation resulted in significant mortality, with a greater proportion of male than female pups dying in the first 24h of life, in line with large cohort studies of preterm human infants. Additionally, physiological instability as measured by a novel scoring matrix and microvascular blood flow were significantly higher in preterm than term neonates. The mortality, morbidity and blood flow results suggest the guinea pig delivered at this time point is a suitable model for human infants born prematurely. Using a cohort of neonates recruited in the John Hunter Children’s Hospital and our established guinea pig model, we further characterised microvascular behaviour in the early extrauterine period and how this behaviour is affected by gestational age, postnatal age and sex (Chapter 4). It has been hypothesised that preterm infants may undergo a hypoperfusion-reperfusion cycle in the first 24-48h of life, with the reperfusion stage responsible for circulatory compromise and vascular damage frequently observed in preterm neonates. We observed no such cycle, with blood flow increasing following birth in male preterm neonates, both human and guinea pig. We investigated the potential of hydrogen sulphide to regulate microvascular blood flow both on its own (Chapter 5) and through its interactions with the other gasotransmitters (Chapter 6) and showed for the first time that it may play a role in physiological tone regulation during circulatory transition, with overproduction potentially associated with dysregulation in the human preterm male neonate. Interaction analysis revealed that in female neonates, carbon monoxide negated the effect of hydrogen sulphide on vascular tone, suggesting some protective role of this molecule against inappropriate vasodilatation in the female; whilst in males nitric oxide levels were associated with higher hydrogen sulphide levels and higher microvascular blood flow. We further characterised this production using our guinea pig model and investigated the effect of gestational age, postnatal age and sex (Chapter 7). Vascular hydrogen sulphide production increased during fetal-to-neonatal transition. Hydrogen sulphide produced by cystathionine γ-lyase (the key production enzyme in the vasculature) increased postnatally. Hydrogen sulphide produced via this pathway correlated with skin microvascular blood flow in males, suggesting that cystathionine γ-lyase dependent mechanisms may drive the observed increase of hydrogen sulphide production over the first 3 days of life in male preterm babies, which in turn is associated with both central and peripheral cardiovascular stability. Cystathionine γ-lyase thus represents a potential target for therapies in cases of microvascular dysfunction

The SH2-containing inositol polyphosphate 5-phosphatase-2 (SHIP-2) regulates the actin cytoskeleton

Abstract not availabl

The SH2-containing inositol polyphosphate 5-phosphatase-2 (SHIP-2) regulates the actin cytoskeleton

Abstract not availabl

Maternal Fructose Intake, Programmed Mitochondrial Function and Predisposition to Adult Disease

Fructose consumption is now recognised as a major risk factor in the development of metabolic diseases, such as hyperlipidaemia, diabetes, non-alcoholic fatty liver disease and obesity. In addition to environmental, social, and genetic factors, an unfavourable intrauterine environment is now also recognised as an important factor in the progression of, or susceptibility to, metabolic disease during adulthood. Developmental trajectory in the short term, in response to nutrient restriction or excessive nutrient availability, may promote adaptation that serves to maintain organ functionality necessary for immediate survival and foetal development. Consequently, this may lead to decreased function of organ systems when presented with an unfavourable neonatal, adolescent and/or adult nutritional environment. These early events may exacerbate susceptibility to later-life disease since sub-optimal maternal nutrition increases the risk of non-communicable diseases (NCDs) in future generations. Earlier dietary interventions, implemented in pregnant mothers or those considering pregnancy, may have added benefit. Although, the mechanisms by which maternal diets high in fructose and the vertical transmission of maternal metabolic phenotype may lead to the predisposition to adult disease are poorly understood. In this review, we will discuss the potential contribution of excessive fructose intake during pregnancy and how this may lead to developmental reprogramming of mitochondrial function and predisposition to metabolic disease in offspring