A novel whole-body thermal stress test for monitoring cardiovascular responses in guinea pigs.

Cardiovascular disease is a leading cause of morbidity and mortality worldwide. Stress tests are frequently employed to expose early signs of cardiovascular dysfunction or disease and can be employed, for example, in the context of preterm birth. We aimed to establish a safe and effective thermal stress test to examine cardiovascular function. Guinea pigs were anaesthetized using a 0.8% isoflurane, 70% N2O mix. ECG, non-invasive blood pressure, laser Doppler flowmetry, respiratory rate, and an array of skin and rectal thermistors were applied. A physiologically relevant heating and a cooling thermal stress test was developed. Upper and lower thermal limits for core body temperature were set at 41.5 OC and 34 OC, for the safe recovery of animals. This protocol therefore presents a viable thermal stress test for use in guinea pig models of health and disease that facilitates exploration of whole-system cardiovascular function.

Oxygen saturation-dependent effects on blood transverse relaxation at low fields.

OBJECTIVE: Blood oxygenation can be measured using magnetic resonance using the paramagnetic effect of deoxy-haemoglobin, which decreases the [Formula: see text] relaxation time of blood. This [Formula: see text] contrast has been well characterised at the [Formula: see text] fields used in MRI (1.5 T and above). However, few studies have characterised this effect at lower magnetic fields. Here, the feasibility of blood oximetry at low field based on [Formula: see text] changes that are within a physiological relevant range is explored. This study could be used for specifying requirements for construction of a monitoring device based on low field permanent magnet systems. METHODS: A continuous flow circuit was used to control parameters such as oxygen saturation and temperature in a sample of blood. It flowed through a variable field magnet, where CPMG experiments were performed to measure its [Formula: see text]. In addition, the oxygen saturation was monitored by an optical sensor for comparison with the [Formula: see text] changes. RESULTS: These results show that at low [Formula: see text] fields, the change in blood [Formula: see text] due to oxygenation is small, but still detectable. The data measured at low fields are also in agreement with theoretical models for the oxy-deoxy [Formula: see text] effect. CONCLUSION: [Formula: see text] changes in blood due to oxygenation were observed at fields as low as 0.1 T. These results suggest that low field NMR relaxometry devices around 0.3 T could be designed to detect changes in blood oxygenation.

The Epigenetic Role of Vitamin C in Neurodevelopment.

The maternal diet during pregnancy is a key determinant of offspring health. Early studies have linked poor maternal nutrition during gestation with a propensity for the development of chronic conditions in offspring. These conditions include cardiovascular disease, type 2 diabetes and even compromised mental health. While multiple factors may contribute to these outcomes, disturbed epigenetic programming during early development is one potential biological mechanism. The epigenome is programmed primarily in utero, and during this time, the developing fetus is highly susceptible to environmental factors such as nutritional insults. During neurodevelopment, epigenetic programming coordinates the formation of primitive central nervous system structures, neurogenesis, and neuroplasticity. Dysregulated epigenetic programming has been implicated in the aetiology of several neurodevelopmental disorders such as Tatton-Brown-Rahman syndrome. Accordingly, there is great interest in determining how maternal nutrient availability in pregnancy might affect the epigenetic status of offspring, and how such influences may present phenotypically. In recent years, a number of epigenetic enzymes that are active during embryonic development have been found to require vitamin C as a cofactor. These enzymes include the ten-eleven translocation methylcytosine dioxygenases (TETs) and the Jumonji C domain-containing histone lysine demethylases that catalyse the oxidative removal of methyl groups on cytosines and histone lysine residues, respectively. These enzymes are integral to epigenetic regulation and have fundamental roles in cellular differentiation, the maintenance of pluripotency and development. The dependence of these enzymes on vitamin C for optimal catalytic activity illustrates a potentially critical contribution of the nutrient during mammalian development. These insights also highlight a potential risk associated with vitamin C insufficiency during pregnancy. The link between vitamin C insufficiency and development is particularly apparent in the context of neurodevelopment and high vitamin C concentrations in the brain are indicative of important functional requirements in this organ. Accordingly, this review considers the evidence for the potential impact of maternal vitamin C status on neurodevelopmental epigenetics.

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 ß-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.

Haemodynamics and cerebral oxygenation of neonatal piglets in the immediate ex utero period supported by mechanical ventilation or ex utero oxygenator.

KEY POINTS: The margin of human viability has extended to the extremes of gestational age (<24 weeks) when the lungs are immature and ventilator-induced lung injury is common. Artificial placenta technology aims to extend gestation ex utero in order to allow the lungs additional time to develop prior to entering an air-breathing environment. We compared the haemodynamics and cerebral oxygenation of piglets in the immediate period post-oxygenator (OXY) transition against both paired in utero measures and uniquely against piglets transitioned onto mechanical ventilation (VENT). Post-transition, OXY piglets became hypotensive with reduced carotid blood flow in comparison with both paired in utero measures and VENT piglets. The addition of a pump to the oxygenator circuit may be required to ensure haemodynamic stability in the immediate post-transition period. ABSTRACT: Gestational age at birth is a major predictor of wellbeing; the lower the gestational age, the greater the risk of mortality and morbidity. At the margins of human viability (<24 weeks gestation) immature lungs combined with the need for early ventilatory support means lung injury and respiratory morbidity is common. The abrupt haemodynamic changes consequent on birth may also contribute to preterm-associated brain injury, including intraventricular haemorrhage. Artificial placenta technology aims to support oxygenation, haemodynamic stability and ongoing fetal development ex utero until mature enough to safely transition to a true ex utero environment. We aimed to characterize the impact of birth transition onto either an oxygenator circuit or positive pressure ventilation on haemodynamic and cerebral oxygenation of the neonatal piglet. At 112 days gestation (term = 115 days), fetal pigs underwent instrumentation surgery and transitioned onto either an oxygenator (OXY, n = 5) or ventilatory support (VENT, n = 8). Blood pressure (BP), carotid blood flow and cerebral oxygenation in VENT piglets rose from in utero levels to be significantly higher than OXY piglets post-transition. OXY piglet BP, carotid blood flow and carotid oxygen delivery (DO2 ) decreased from in utero levels post-transition; however, cerebral regional oxygen saturation (rSO2 ) was maintained at fetal-like levels. OXY piglets became hypoxaemic and retained CO2 . Whether OXY piglets are able to maintain cerebral rSO2 under these conditions for a prolonged period is yet to be determined. Improvements to OXY piglet oxygenation may lie in maintaining piglet BP at in utero levels and enhancing oxygenator circuit flow.

Long-term coordinated microstructural disruptions of the developing neocortex and subcortical white matter after early postnatal systemic inflammation.

Severe postnatal systemic infection is highly associated with persistent disturbances in brain development and neurobehavioral outcomes in survivors of preterm birth. However, the contribution of less severe but prolonged postnatal infection and inflammation to such disturbances is unclear. Further, the ability of modern imaging techniques to detect the underlying changes in cellular microstructure of the brain in these infants remains to be validated. We used high-field ex-vivo MRI, neurohistopathology, and behavioral tests in newborn rats to demonstrate that prolonged postnatal systemic inflammation causes subtle, persisting disturbances in brain development, with neurodevelopmental delays and mild motor impairments. Diffusion-tensor MRI and neurite orientation dispersion and density imaging (NODDI) revealed delayed maturation of neocortical and subcortical white matter microstructure. Analysis of pyramidal neurons showed that the cortical deficits involved impaired dendritic arborization and spine formation. Analysis of oligodendrocytes showed that the white matter deficits involved impaired oligodendrocyte maturation and axonal myelination. These findings indicate that prolonged postnatal inflammation, without severe infection, may critically contribute to the diffuse spectrum of brain pathology and subtle long-term disability in preterm infants, with a cellular mechanism involving oligodendrocyte and neuronal dysmaturation. NODDI may be useful for clinical detection of these microstructural deficits.

Anti-Inflammatory Therapies for Treatment of Inflammation-Related Preterm Brain Injury.

Despite the prevalence of preterm brain injury, there are no established neuroprotective strategies to prevent or alleviate mild-to-moderate inflammation-related brain injury. Perinatal infection and inflammation have been shown to trigger acute neuroinflammation, including proinflammatory cytokine release and gliosis, which are associated with acute and chronic disturbances in brain cell survival and maturation. These findings suggest the hypothesis that the inhibition of peripheral immune responses following infection or nonspecific inflammation may be a therapeutic strategy to reduce the associated brain injury and neurobehavioral deficits. This review provides an overview of the neonatal immunity, neuroinflammation, and mechanisms of inflammation-related brain injury in preterm infants and explores the safety and efficacy of anti-inflammatory agents as potentially neurotherapeutics.

Management of anaemia in pre-term infants.

Pre-term infants have one of the highest transfusion requirements within the hospital-setting. The vast majority of blood transfusions performed in Neonatal Intensive Care Units (NICUs) are for medically stable pre-term infants with anaemia of prematurity, with the aim of improving oxygen delivery to the vital organs during the crucial phase of growth and development. However, despite the frequency of transfusion in this population, the potential benefits and harms of 'top up' transfusion are not fully understood, leading to practice variation between clinicians, institutions and countries. Significant advances have been made in the prevention of anaemia of prematurity, with recent emphasis on optimising infants' circulatory volume at birth via placental transfusion and preserving infants' own blood volume through innovative minimal sampling techniques. More research is urgently needed to establish optimal transfusion thresholds for these high-risk pre-term infants, for whom benefits as well as adverse outcomes may have consequences that extend for decades throughout the recipients' life-course. In this review, we will discuss some of the consensus and controversies regarding optimal management of anaemia in pre-term infants and highlight potential areas for future research.

Docosahexaenoic Acid and Bronchopulmonary Dysplasia in Preterm Infants.

BACKGROUND: Studies in animals and in humans have suggested that docosahexaenoic acid (DHA), an n-3 long-chain polyunsaturated fatty acid, might reduce the risk of bronchopulmonary dysplasia, but appropriately designed trials are lacking. METHODS: We randomly assigned 1273 infants born before 29 weeks of gestation (stratified according to sex, gestational age [<27 weeks or 27 to <29 weeks], and center) within 3 days after their first enteral feeding to receive either an enteral emulsion providing DHA at a dose of 60 mg per kilogram of body weight per day or a control (soy) emulsion without DHA until 36 weeks of postmenstrual age. The primary outcome was bronchopulmonary dysplasia, defined on a physiological basis (with the use of oxygen-saturation monitoring in selected infants), at 36 weeks of postmenstrual age or discharge home, whichever occurred first. RESULTS: A total of 1205 infants survived to the primary outcome assessment. Of the 592 infants assigned to the DHA group, 291 (49.1% by multiple imputation) were classified as having physiological bronchopulmonary dysplasia, as compared with 269 (43.9%) of the 613 infants assigned to the control group (relative risk adjusted for randomization strata, 1.13; 95% confidence interval [CI], 1.02 to 1.25; P=0.02). The composite outcome of physiological bronchopulmonary dysplasia or death before 36 weeks of postmenstrual age occurred in 52.3% of the infants in the DHA group and in 46.4% of the infants in the control group (adjusted relative risk, 1.11; 95% CI, 1.00 to 1.23; P=0.045). There were no significant differences between the two groups in the rates of death or any other neonatal illnesses. Bronchopulmonary dysplasia based on a clinical definition occurred in 53.2% of the infants in the DHA group and in 49.7% of the infants in the control group (P=0.06). CONCLUSIONS: Enteral DHA supplementation at a dose of 60 mg per kilogram per day did not result in a lower risk of physiological bronchopulmonary dysplasia than a control emulsion among preterm infants born before 29 weeks of gestation and may have resulted in a greater risk. (Funded by the Australian National Health and Medical Research Council and others; Australian New Zealand Clinical Trials Registry number, ACTRN12612000503820 .).

Arginine vasopressin improves cerebral perfusion following controlled haemorrhage in adult ewes.

KEY POINTS: Traumatic haemorrhagic shock carries significant morbidity and mortality related to the severity and duration of tissue hypoperfusion, much of which occurs in the pre-hospital environment where therapy must be easy to use and would augment, not replace, local haemorrhage control measures. Vasopressor therapy use in haemorrhagic shock remains controversial. Potential benefits from improved blood pressure and tissue perfusion need to be weighed against possible harm from increased blood loss if haemorrhage is uncontrolled. We demonstrate that 20 IU I.M. vasopressin produces a progressive, sustained and clinically significant increase in blood pressure and carotid blood flow compared to 1 mg I.M. adrenaline or placebo in an animal model of controlled haemorrhagic shock. I.M. vasopressin may play a role in the early management of haemorrhagic shock by improving cerebral perfusion and haemodynamic stability; however, further studies are required to establish the potential benefit against the risk of exacerbating haemorrhage, if it is uncontrolled. ABSTRACT: Haemorrhagic shock causes significant morbidity and mortality. Novel pre-hospital therapy to improve haemodynamic stability and cerebral perfusion may improve outcomes but remains controversial. In an ovine model of controlled haemorrhagic shock, the effects of early intramuscular arginine vasopressin (AVP), adrenaline or placebo on haemodynamic stability and cerebral perfusion were compared. Carotid pressure and flow catheters were placed in healthy, anaesthetized adult ewes. Frontal cortex cerebral oxygenation was measured using near infrared spectroscopy. Controlled, rapid, haemorrhage (∼30% estimated blood volume) was induced. Five minutes post-bleed a 1 ml intramuscular dose of 0.9% saline, adrenaline 1 mg or AVP 20 IU was administered. Carotid blood pressure and flow improved significantly in the AVP group over the first 30 min post-intervention. To emulate standard trauma care, 1 L of 0.9% saline was infused 30 min post-bleed followed by re-transfusion of the sheep's own blood at 60 min post-bleed. Carotid blood pressure and flow in the AVP group remained significantly higher post-crystalloid infusion, but this difference was lost post-blood transfusion. Data were analysed by two-way ANOVA with time, group as the main factors. When compared to saline or adrenaline, a single dose of intramuscular AVP resulted in a progressive and sustained increase in carotid artery blood pressure and flow with commensurate increase in cerebral oxygenation. Intramuscular AVP has potential as an emergency pre-hospital therapy following exsanguinating haemorrhage; however, further studies are required to investigate whether the benefit of improved perfusion pressure outweighs the risks of exacerbating ongoing bleeding.

Microvascular circulatory dysregulation driven in part by cystathionine gamma-lyase: A new paradigm for cardiovascular compromise in the preterm newborn.

OBJECTIVE: H2 S may explain the dysregulation of microvascular tone associated with poor outcome following preterm birth. In adult vasculature, H2 S is predominantly produced by CSE. We hypothesized that vascular CSE activity contributes to microvascular tone regulation during circulatory transition. METHODS: Preterm (GA62) and full-term (GA69) guinea pig fetuses and neonates were studied. Microvascular blood flow was assessed by laser Doppler flowmetry. Thiosulfate, primary urinary metabolite of H2 S, was determined by high-performance liquid chromatography. Real-time H2 S production was assessed using a microrespiration system in fetal and postnatal (10, 24 hours) skin and heart samples. CSE contribution was investigated by inhibition via propargylglycine. RESULTS: In preterm animals, postnatal H2 S production capacity in peripheral vasculature increased significantly and was significantly reduced by the inhibition of CSE. Urinary thiosulfate correlated with both microvascular blood flow and capacity of the vasculature to produce H2 S. H2 S produced via CSE did not correlate directly with microvascular blood flow. CONCLUSIONS: In preterm neonates, H2 S production increases during fetal-to-neonatal transition and CSE contribution to total H2 S increases postnatally. CSE-dependent mechanisms may therefore underpin the increase in H2 S production over the first 72 hours of life in preterm human neonates, associated with both central and peripheral cardiovascular instability.

Neurosteroid replacement therapy using the allopregnanolone-analogue ganaxolone following preterm birth in male guinea pigs.

BACKGROUND: Children born preterm, especially boys, are at increased risk of developing attention deficit hyperactivity disorder (ADHD) and learning difficulties. We propose that neurosteroid-replacement therapy with ganaxolone (GNX) following preterm birth may mitigate preterm-associated neurodevelopmental impairment. METHODS: Time-mated sows were delivered preterm (d62) or at term (d69). Male preterm pups were randomized to ganaxolone (Prem-GNX; 2.5 mg/kg subcutaneously twice daily until term equivalence), or preterm control (Prem-CON). Surviving male juvenile pups underwent behavioural testing at d25-corrected postnatal age (CPNA). Brain tissue was collected at CPNA28 and mature myelinating oligodendrocytes of the hippocampus and subcortical white matter were quantified by immunostaining of myelin basic protein (MBP). RESULTS: Ganaxolone treatment returned the hyperactive behavioural phenotype of preterm-born juvenile males to a term-born phenotype. Deficits in MBP immunostaining of the preterm hippocampus and subcortical white matter were also ameliorated in animals receiving ganaxolone. However, during the treatment period weight gain was poor, and pups were sedated, ultimately increasing the neonatal mortality rate. CONCLUSION: Ganaxolone improved neurobehavioural outcomes in males suggesting that neonatal treatment may be an option for reducing preterm-associated neurodevelopmental impairment. However, dosing studies are required to reduce the burden of unwanted side effects.

Blood transfusion for anaemia of prematurity: Current practice in Australia and New Zealand.

AIM: To characterise the current transfusion practice among clinicians in Australasian neonatal units and factors that influence their decision-making. METHODS: Members of the Australia and New Zealand Neonatal Network (ANZNN) and practitioners at their local institutions were invited to participate in a 15-question web-based survey between 1 June and 31 July 2016. The survey was designed to assess (i) haemoglobin-based transfusion thresholds; (ii) presence of local guidelines; (iii) preference for a restrictive or liberal transfusion policy; (iv) perceived benefits and risks of transfusion; and (v) use of clinical adjuncts to assist decision-making. RESULTS: Overall, 130 participants responded to at least one question. Haemoglobin transfusion thresholds for anaemia of prematurity (AOP) varied significantly from <60 to <120 g/L. Of 103 participants, 36 (35%) reported that they do not have access to local transfusion guidelines. The majority utilise multiple clinical and haematological parameters to guide their decision-making, and approximately half (45/84, 54%) believe that tissue hypoxia detected by near-infrared spectroscopy (NIRS) may better inform transfusion thresholds. Of 102 participants, 51 (50%) support a restrictive rather than liberal transfusion policy. The most commonly reported perceived risks of transfusion for AOP were suppression of endogenous erythropoiesis and increased rates of necrotising enterocolitis. CONCLUSIONS: There is a significant variation in transfusion practice in Australasian neonatal units. Quality and safety initiatives may assist with improved consistency of transfusion practice across the ANZNN. However, further research is required to better define optimal transfusion thresholds, quantify potential risks of transfusion and determine clinical utility of newer adjuncts such as NIRS.

Guinea pig models for translation of the developmental origins of health and disease hypothesis into the clinic.

Over 30 years ago Professor David Barker first proposed the theory that events in early life could explain an individual's risk of non-communicable disease in later life: the developmental origins of health and disease (DOHaD) hypothesis. During the 1990s the validity of the DOHaD hypothesis was extensively tested in a number of human populations and the mechanisms underpinning it characterised in a range of experimental animal models. Over the past decade, researchers have sought to use this mechanistic understanding of DOHaD to develop therapeutic interventions during pregnancy and early life to improve adult health. A variety of animal models have been used to develop and evaluate interventions, each with strengths and limitations. It is becoming apparent that effective translational research requires that the animal paradigm selected mirrors the tempo of human fetal growth and development as closely as possible so that the effect of a perinatal insult and/or therapeutic intervention can be fully assessed. The guinea pig is one such animal model that over the past two decades has demonstrated itself to be a very useful platform for these important reproductive studies. This review highlights similarities in the in utero development between humans and guinea pigs, the strengths and limitations of the guinea pig as an experimental model of DOHaD and the guinea pig's potential to enhance clinical therapeutic innovation to improve human health.

Improving pregnancy outcomes in humans through studies in sheep.

Experimental studies that are relevant to human pregnancy rely on the selection of appropriate animal models as an important element in experimental design. Consideration of the strengths and weaknesses of any animal model of human disease is fundamental to effective and meaningful translation of preclinical research. Studies in sheep have made significant contributions to our understanding of the normal and abnormal development of the fetus. As a model of human pregnancy, studies in sheep have enabled scientists and clinicians to answer questions about the etiology and treatment of poor maternal, placental, and fetal health and to provide an evidence base for translation of interventions to the clinic. The aim of this review is to highlight the advances in perinatal human medicine that have been achieved following translation of research using the pregnant sheep and fetus.

Storage after gamma irradiation affects in vivo oxygen delivery capacity of transfused red blood cells in preterm infants.

BACKGROUND: Gamma irradiation of red blood cells (RBCs) is well recognized to exacerbate storage lesion formation, but the effect of storage after irradiation on in vivo oxygen delivery capacity of transfused RBCs is currently not known. STUDY DESIGN AND METHODS: In 24 preterm infants with anemia receiving nonurgent transfusion of irradiated RBCs, we examined cerebral regional tissue oxygenation (crSO2 ) and time spent with peripheral arterial saturation (SpO2 ) less than 88%. Physiologic data were obtained immediately before, immediately after, and 5 days after transfusion. RESULTS: We observed linear negative moderate correlations between time since irradiation and the magnitude of change in crSO2 (r = -0.60; 95% CI, -0.81 to -0.27; p = 0.0018) and time spent with SpO2 of less than 88% (r = -0.42; 95% CI, -0.71 to 0.003; p = 0.04) immediately after transfusion. In infants (n = 9) who received fresher RBCs (irradiated <10 days before transfusion), there was a sustained increase in mean crSO2 up to 5 days after transfusion (3.0%; 95% CI, 0.3% to 5.7%; p = 0.04). Conversely, in infants (n = 15) who received older RBCs (irradiated ≥10 days before transfusion), there were negligible changes in crSO2 after transfusion at any time point. CONCLUSION: Our findings indicate that storage after gamma irradiation may have a detrimental effect on the oxygen delivery capacity of RBCs given to anemic preterm infants.

Does poor fetal growth influence the extent of fetal exposure to maternal medications?

A large proportion of women are prescribed a medication during pregnancy, and the conditions requiring treatment with these medicines are often also associated with placental dysfunction and abnormal fetal growth. For the fetus, exposure to maternal illness or medications can alter fetal growth trajectory, which is a key indicator of fetal and postnatal wellbeing. There is a large amount of human and animal evidence highlighting the hormonal and/or metabolic changes that occur in both the mother and the fetus as a result of maternal illness or either excessive or restricted fetal growth. These changes can affect the expression of drug metabolising enzymes and drug transporters in the both the mother and her fetus, and may ultimately alter fetal drug exposure. This review aims to explore the complex and multidirectional interplay between maternal illness, fetal growth trajectory, maternal drug treatment, and fetal drug exposure.

Intrauterine growth restriction may reduce hepatic drug metabolism in the early neonatal period.

The effects of intrauterine growth restriction (IUGR) extend well into postnatal life. IUGR is associated with an increased risk of adverse health outcomes, which often leads to greater medication usage. Many medications require hepatic metabolism for activation or clearance, but hepatic function may be altered in IUGR fetuses. Using a sheep model of IUGR, we determined the impact of IUGR on hepatic drug metabolism and drug transporter expression, both important mediators of fetal drug exposure, in late gestation and in neonatal life. In the late gestation fetus, IUGR decreased the gene expression of uptake drug transporter OATPC and increased P-glycoprotein protein expression in the liver, but there was no change in the activity of the drug metabolising enzymes CYP3A4 or CYP2D6. In contrast, at 3 weeks of age, CYP3A4 activity was reduced in the livers of lambs born with low birth weight (LBW), indicating that LBW results in changes to drug metabolising capacity in neonatal life. Together, these results suggest that IUGR may reduce hepatic drug metabolism in fetal and neonatal life through different mechanisms.

Long-term effects of preterm birth on behavior and neurosteroid sensitivity in the guinea pig.

BACKGROUND: Ex-preterm children and adolescents are at risk of developing late-onset neurodevelopmental and behavioral disorders. The mechanisms by which this happens are poorly understood and relevant animal models are required. METHODS: Ex-preterm (delivered at 62 d gestation) and term (spontaneously delivered) juvenile guinea pigs underwent behavioral testing at 25 d corrected postnatal age, with tissues collected at 28 d. Neurodevelopmental markers (myelin basic protein (MBP) and glial fibrillary acidic protein (GFAP)) were analyzed in the hippocampus and subcortical white matter by immunohistochemistry. Gamma-aminobutyric acid A (GABAA) receptor subunit mRNA levels were quantified by reverse transcription polymerase chain reaction (RT-PCR), and salivary cortisol measured by enzyme-linked immunosorbent assay. RESULTS: Preterm males travelled greater distances, were mobile for longer, spent more time investigating objects, and approached or interacted with familiar animals more than controls. Myelination and reactive astrocyte coverage was lower in the hippocampus and the subcortical white matter in preterm males. Hippocampal levels of the α5 subunit were also lower in the preterm male brain. Baseline salivary cortisol was higher for preterm males compared to controls. CONCLUSION: We conclude that juvenile ex-preterm male guinea pigs exhibit a hyperactive phenotype and feature impaired neurodevelopment, making this a suitable model for future therapeutic studies.

Influence of sympathetic activity in the control of peripheral microvascular tone in preterm infants.

BACKGROUND: Microvascular dysregulation following preterm birth is associated with increased illness severity and hypotension, particularly in males. Sympathetic nervous vascular regulation is evident in females. We hypothesized that sympathetic dysfunction in male preterm infants may contribute to a failure of peripheral microvascular vasoconstriction. METHODS: Microvascular blood flow of infants 24-43 wk gestational age was assessed at 6, 24, and 72 h of age by laser Doppler. Blood flow Fourier transformed frequency distribution spectra (low frequency/high frequency ratio) were used to assess the influence of sympathetic tone on microvascular regulation. Total sympathetic output was assessed as urinary normetanephrine. RESULTS: Microvascular sympathetic activity at 24 h postnatal age decreased in early preterm males, but not females. Peripheral sympathetic activity increased with advancing postnatal age in females, but decreased in males. In early preterm infants, total normetanephrine outputs increase significantly with postnatal age, in both sexes. CONCLUSION: Sympathetic activation following preterm birth is sexually dimorphic, with preterm males having reduced sympathetic tone and reduced upregulation of sympathetic tone following birth. There is evidence of a disconnect between central sympathetic activity and local peripheral microcirculatory sympathetic drive. This may relate to autonomic nervous immaturity and highlights the need to understand how preterm birth may affect autonomic function.