Maternal Vitamin C Intake during Pregnancy Influences Long-Term Offspring Growth with Timing- and Sex-Specific Effects in Guinea Pigs.

Our previous work in guinea pigs revealed that low vitamin C intake during preconception and pregnancy adversely affects fertility, pregnancy outcomes, and foetal and neonatal growth in a sex-dependent manner. To investigate the long-term impact on offspring, we monitored their growth from birth to adolescence (four months), recorded organ weights at childhood equivalence (28 days) and adolescence, and assessed physiological parameters like oral glucose tolerance and basal cortisol concentrations. We also investigated the effects of the timing of maternal vitamin C restriction (early vs. late gestation) on pregnancy outcomes and the health consequences for offspring. Dunkin Hartley guinea pigs were fed an optimal (900 mg/kg feed) or low (100 mg/kg feed) vitamin C diet ad libitum during preconception. Pregnant dams were then randomised into four feeding regimens: consistently optimal, consistently low, low during early pregnancy, or low during late pregnancy. We found that low maternal vitamin C intake during early pregnancy accelerated foetal and neonatal growth in female offspring and altered glucose homeostasis in the offspring of both sexes at an age equivalent to early childhood. Conversely, low maternal vitamin C intake during late pregnancy resulted in foetal growth restriction and reduced weight gain in male offspring throughout their lifespan. We conclude that altered vitamin C during development has long-lasting, sex-specific consequences for offspring and that the timing of vitamin C depletion is also critical, with low levels during early development being associated with the development of a metabolic syndrome-related phenotype, while later deprivation appears to be linked to a growth-faltering phenotype.

Effects of Low Vitamin C Intake on Fertility Parameters and Pregnancy Outcomes in Guinea Pigs.

Identifying how specific nutrients can impact fertility, pregnancy, and neonatal outcomes will yield important insights into the biological mechanisms linking diet and reproductive health. Our study investigates how dietary vitamin C intake affects various fertility parameters and pregnancy and neonatal outcomes in the guinea pig, a natural model of vitamin C dependency. Dunkin Hartley guinea pigs were fed an optimal (900 mg/kg feed) or low (100 mg/kg feed) vitamin C diet ad libitum for at least three weeks prior to mating and throughout pregnancy. We found that animals receiving the low vitamin C diet had an increased number of unsuccessful matings, a higher incidence of foetal reabsorption, and, among pregnancies resulting in delivery at term, produced fewer offspring. Neonates from mothers on the low vitamin C diet had significantly decreased plasma vitamin C concentrations at birth and exhibited mild growth impairments in a sex-dependent manner. We conclude that a diet low of vitamin C induces a state of subfertility, reduces overall fecundity, and adversely impacts both pregnancy outcomes and growth in the offspring. Our study provides an essential foundation for future investigations to determine whether these findings translate to humans. If so, they could have important clinical implications for assisted reproductive technologies and nutritional recommendations for couples trying to conceive, pregnant women, and breastfeeding mothers.

Single-Sided Magnet System for Quantitative MR Relaxometry and Preclinical In-Vivo Monitoring.

OBJECTIVE: We have developed a single-sided magnet system that allows Magnetic Resonance relaxation and diffusion parameters to be measured. METHODS: A single-sided magnet system has been developed, using an array of permanent magnets. The magnet positions are optimised to produce a B0 magnetic field with a spot that is relatively homogenous and can project into a sample. NMR relaxometry experiments are used to measure quantitative parameters such as T2, T1 and apparent diffusion coefficient (ADC) on samples on the benchtop. To explore preclinical application, we test whether it can detect changes during acute global cerebral hypoxia in an ovine model. RESULTS: The magnet produces a 0.2 T field projected into the sample. Measurements of benchtop samples show that it can measure T1, T2 and ADC, producing trends and values that are in line with literature measurements. In-vivo studies show a decrease in T2 during cerebral hypoxia that recovers following normoxia. CONCLUSION: The single-sided MR system has the potential to allow non-invasive measurements of the brain. We also demonstrate that it can operate in a pre-clinical environment, allowing T2 to be monitored during brain tissue hypoxia. SIGNIFICANCE: MRI is a powerful technique for non-invasive diagnosis in the brain, but its application has been limited by the requirements for magnetic field strength and homogeneity that imaging methods have. The technology described in this study provides a portable alternative to acquiring clinically significant MR parameters without the need for traditional imaging equipment.

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.

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.

Low dose or very low dose phenylephrine and cyclopentolate microdrops for retinopathy of prematurity eye examinations (The Little Eye Drop Study): a randomised controlled non-inferiority trial.

OBJECTIVE: To determine if very low dose (VLD, 0.5% phenylephrine, 0.1% cyclopentolate) mydriatic microdrop (approximately 7 µL) administration (up to three doses) is non-inferior to low dose (LD, 1% phenylephrine, 0.2% cyclopentolate) mydriatic microdrop administration for ophthalmologist-determined successful retinopathy of prematurity eye examination (ROPEE). DESIGN: Multicentre, prospective, randomised controlled, non-inferiority clinical trial. SETTING: Four neonatal intensive care units in Aotearoa, New Zealand from October 2019 to September 2021. PATIENTS: Infants with a birth weight less than 1250 g or gestational age less than 30+6 weeks and who required a ROPEE. INTERVENTIONS: The intervention: microdrop (approximately 7 µL) of VLD (0.5% phenylephrine and 0.1% cyclopentolate) to both eyes, or the comparison: microdrop of LD (1% phenylephrine and 0.2% cyclopentolate) to both eyes. Up to three doses could be administered. MAIN OUTCOME MEASURES: The primary outcome measure was an ophthalmologist-determined successful ROPEE. RESULTS: One hundred and fifty preterm infants (LD mean GA=27.4±1.8 weeks, mean birth weight=1011±290 g, VLD mean GA=27.5±1.9 weeks, mean birth weight=1049±281 g,) were randomised. Non-inferiority for successful ROPEE was demonstrated for the VLD group compared with the LD group (VLD successful ROPEE=100%, LD successful ROPEE=100%, 95% CI no continuity correction -0.05 to 0.05) and for Maori (95% CI no continuity correction -0.02 to 0.19). CONCLUSION: VLD microdrops enable safe and effective screening for ROPEE in both Maori and non-Maori preterm infants. TRIAL REGISTRATION NUMBER: ACTRN12619000795190.

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.

Examining Neurosteroid-Analogue Therapy in the Preterm Neonate For Promoting Hippocampal Neurodevelopment.

Background: Preterm birth can lead to brain injury and currently there are no targeted therapies to promote postnatal brain development and protect these vulnerable neonates. We have previously shown that the neurosteroid-analogue ganaxolone promotes white matter development and improves behavioural outcomes in male juvenile guinea pigs born preterm. Adverse side effects in this previous study necessitated this current follow-up dosing study, where a focus was placed upon physical wellbeing during the treatment administration and markers of neurodevelopment at the completion of the treatment period. Methods: Time-mated guinea pigs delivered preterm (d62) by induction of labour or spontaneously at term (d69). Preterm pups were randomized to receive no treatment (Prem-CON) or ganaxolone at one of three doses [0.5 mg/kg ganaxolone (low dose; LOW-GNX), 1.0 mg/kg ganaxolone (mid dose; MID-GNX), or 2.5 mg/kg ganaxolone (high dose; HIGH-GNX) in vehicle (45% ß-cyclodextrin)] daily until term equivalence age. Physical parameters including weight gain, ponderal index, supplemental feeding, and wellbeing (a score based on respiration, activity, and posture) were recorded throughout the preterm period. At term equivalence, brain tissue was collected, and analysis of hippocampal neurodevelopment was undertaken by immunohistochemistry and RT-PCR. Results: Low and mid dose ganaxolone had some impacts on early weight gain, supplemental feeding, and wellbeing, whereas high dose ganaxolone significantly affected all physical parameters for multiple days during the postnatal period when compared to the preterm control neonates. Deficits in the preterm hippocampus were identified using neurodevelopmental markers including mRNA expression of oligodendrocyte lineage cells (CSPG4, MBP), neuronal growth (INA, VEGFA), and the GABAergic/glutamatergic system (SLC32A1, SLC1A2, GRIN1, GRIN2C, DLG4). These deficits were not affected by ganaxolone at the doses used at the equivalent of normal term. Conclusion: This is the first study to investigate the effects of a range of doses of ganaxolone to improve preterm brain development. We found that of the three doses, only the highest dose of ganaxolone (2.5 mg/kg) impaired key indicators of physical health and wellbeing over extended periods of time. Whilst it may be too early to see improvements in markers of neurodevelopment, further long-term study utilising the lower doses are warranted to assess functional outcomes at ages when preterm birth associated behavioural disorders are observed.

Acute liver failure secondary to therapeutic paracetamol dosing in an extremely preterm neonate.

We report the first case of standard therapeutic dose paracetamol for patent ductus arteriosus closure causing acute liver failure in an extremely preterm infant. After 5 days of treatment, he presented with jaundice, acute severe hepatitis and coagulopathy. Treatment with N-acetyl cysteine resulted in full recovery.

Effects of Freshly Irradiated vs Irradiated and Stored Red Blood Cell Transfusion on Cerebral Oxygenation in Preterm Infants: A Randomized Clinical Trial.

Importance: Gamma irradiation of leukoreduced red blood cells (RBCs) prevents transfusion-associated graft-vs-host disease but also exacerbates storage lesion formation in RBCs. It is unknown whether freshly irradiated RBCs are more efficacious than irradiated and stored RBCs in preterm infants with high transfusion requirements. Objective: To examine whether transfusion of freshly irradiated vs irradiated and stored RBC components improves cerebral oxygen delivery in preterm infants with anemia. Design, Setting, and Participants: This single-center, double-blinded, proof-of-concept randomized clinical trial was conducted at the neonatal intensive care unit of Wellington Regional Hospital in Wellington, New Zealand, between December 1, 2017, and November 30, 2018. Participants were preterm infants (<34 weeks' gestation at birth) who were at least 14 days of age and had anemia. Participants underwent nonurgent transfusions, and these episodes were randomized to the intervention group (in which the infants received a transfusion of RBCs that were freshly irradiated on the day of transfusion) or control group (in which the infants received a transfusion of RBCs that were irradiated and stored for up to 14 days). Data were analyzed using the evaluable population approach. Intervention: Transfusion of freshly irradiated RBCs. Main Outcomes and Measures: The prespecified primary outcome was the change in cerebral regional oxygen saturation (crSO2) from baseline (immediately before) to immediately after the transfusion. The prespecified secondary outcomes were the change in cerebral fractional tissue oxygen extraction (cFTOE) at different time points (immediately after, 24 hours after, and 120 hours or 5 days after transfusion). Outcomes were measured by blinded clinicians using near-infrared spectroscopy. A covariate-adjusted linear mixed model was used to quantify mean treatment effects and account for multiple transfusions in some infants. Results: A total of 42 infants (mean [SD] gestational age, 26 [10] weeks and 3 days; 29 [69%] boys) were enrolled in the trial and underwent 64 transfusion episodes, which were randomized to the intervention (n = 31) or control (n = 33) group. Compared with infants in the control group, those in the intervention group showed a covariate-adjusted mean increase in crSO2 (2.0 percentage points; 95% CI, 1.2-2.8 percentage points) and a mean decrease in cFTOE (0.02; 95% CI, 0.01-0.04) immediately after transfusion. These differences were sustained up to 120 hours or 5 days after transfusion. There were negligible mean changes in crSO2 or cFTOE in infants in the control group at any of the follow-up time points. Conclusions and Relevance: Results of this trial showed that transfusion of freshly irradiated RBCs conferred a small advantage in cerebral oxygenation for at least 5 days after transfusion compared with transfusion of irradiated and stored RBC components. On-demand irradiation of RBC components may be considered to optimize oxygen delivery in the recipient, but this physiological finding requires further research. Trial Registration: ANZCTR Identifier: ACTRN12617001581358.

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.

Palliative care in a tertiary neonatal intensive care unit: a 10-year review.

OBJECTIVES: When active treatment is no longer in the best interests of the patient, redirection of care to palliation is an important transition. We review, within a tertiary neonatal intensive care unit (NICU), the journey leading to the decision to redirect care, the means of symptom control and the provision of psychosocial supports. METHODS: A retrospective review of all 166 deaths of NICU-affiliated patients during a 10- year epoch. Medical notes were reviewed, and the provision and type of, or barriers to, effective palliative care was defined. RESULTS: Extreme prematurity accounted for 71/145 (49%) of deaths with relatively high proportions of Maori 17/71 (25%) and Pacific Islanders 9/71 (13%). Almost all eligible infants received some form of palliation. Transition from curative to palliative care was refused by the family in a single case. Median time from decision to redirect care until first recorded action was 80 min, and median time from action until death was 60 min. The majority of infants received some form of comfort cares, (128/166) most commonly morphine (94/128, 73%). Three infants had documented seizure activity or respiratory distress but did not receive any pharmacological intervention. Psychosocial supports were offered in 98/145 (67%) of cases, but only 71/145 (49%) of families were formally offered an opportunity to discuss the infant's clinical course after their death. CONCLUSIONS: Clinical documentation of care plans was often incomplete, potentially leading to inconsistent delivery of care, increased risk of symptom breakthrough and/or inadequate psychosocial supports for family. Formal individualised palliative care plans are under development to standardise documentation and improve therapeutic and psychosocial interventions available to the infant and their family.

COVID-19: can we treat the mother without harming her baby?

Medical care is predicated on 'do no harm', yet the urgency to find drugs and vaccines to treat or prevent COVID-19 has led to an extraordinary effort to develop and test new therapies. Whilst this is an essential cornerstone of a united global response to the COVID-19 pandemic, the absolute requirements for meticulous efficacy and safety data remain. This is especially pertinent to the needs of pregnant women; a group traditionally poorly represented in drug trials, yet a group at heightened risk of unintended adverse materno-fetal consequences due to the unique physiology of pregnancy and the life course implications of fetal or neonatal drug exposure. However, due to the complexities of drug trial participation when pregnant (be they vaccines or therapeutics for acute disease), many clinical drug trials will exclude them. Clinicians must determine the best course of drug treatment with a dearth of evidence from either clinical or preclinical studies, where at least in the short term they may be more focused on the outcome of the mother than of her offspring.

Differential effects of four intramuscular sedatives on cardiorespiratory stability in juvenile guinea pigs (Cavia porcellus).

BACKGROUND: Non-invasive physiological monitoring can induce stress in laboratory animals. Sedation reduces the level of restraint required, thereby improving the validity of physiological signals measured. However, sedatives may alter physiological equilibrium introducing unintended bias and/or, masking the experimental outcomes of interest. We aimed to investigate the cardiorespiratory effects of four short-acting sedatives in juvenile guinea pigs. METHOD: 12 healthy, 38 (26-46) day-old Dunkin Hartley guinea pigs were included in this blinded, randomised, crossover design study. Animals were sedated by intramuscular injection using pre-established minimum effective doses of either alfaxalone (5 mg/kg), diazepam (5 mg/kg), ketamine (30 mg/kg), or midazolam (2 mg/kg) administered in random order with a minimum washout period of 48 hours between agents. Sedative depth, a composite score comprised of five assessment criteria, was observed every 5-min from dosing until arousal. Physiological monitoring of cardiorespiratory status included measures of heart rate, blood pressure, respiratory rate, and peripheral microvascular perfusion. RESULTS: Ketamine and alfaxalone were most effective in inducing stable sedation suitable for physiological monitoring, and diazepam less-so. Midazolam was unsuitable due to excessive hypersensitivity. All sedatives significantly increased heart rate above non-sedated control rates (P<0.0001), without altering blood pressure or microvascular perfusion. Alfaxalone and ketamine reduced respiratory rate relative to their control condition (P<0.0001, P = 0.05, respectively), but within normative ranges. CONCLUSION: Ketamine and alfaxalone are the most effective sedatives for inducing short duration, stable sedation with minimal cardiorespiratory depression in guinea pigs, while diazepam is less-so. However, alfaxalone is the most appropriate sedative for longitudinal studies requiring multiple physiological timepoints.

Intrauterine growth restriction alters the activity of drug metabolising enzymes in the maternal-placental-fetal unit.

PURPOSE: Ten percent of pregnancies are affected by intrauterine growth restriction (IUGR), and evidence suggests that affected neonates have reduced activity of hepatic cytochrome P450 (CYP) drug metabolising enzymes. Given that almost all pregnant individuals take medications and additional medications are often required during an IUGR pregnancy, we aimed to determine the impact of IUGR on hepatic CYP activity in sheep fetuses and pregnant ewes. METHODS: Specific probes were used to determine the impact of IUGR on the activity of several CYP isoenzymes (CYP1A2, CYP2C19, CYP2D6 and CYP3A) in sheep fetuses and pregnant ewes. Probes were administered intravenously to the ewe at 132 days (d) gestation (term 150 d), followed by blood sampling from the maternal and fetal circulation over 24 h. Maternal and fetal liver tissue was collected at 139-140 d gestation, from which microsomes were isolated and incubated with probes. Metabolite and maternal plasma cortisol concentrations were measured using Liquid Chromatography - tandem mass spectrometry (LC-MS/MS). RESULTS: Maternal plasma cortisol concentration and maternal hepatic CYP1A2 and CYP3A activity was significantly higher in IUGR pregnancies. Maternal hepatic CYP activity was higher than fetal hepatic CYP activity for all CYPs tested, and there was minimal CYP1A2 or CYP3A activity in the late gestation fetus when assessed using in vitro methods. CONCLUSIONS: The physiological changes to the maternal-placental-fetal unit in an IUGR pregnancy have significant effects on maternal drug metabolism, suggesting changes in medications and/or doses may be required to optimise maternal and fetal health.

Open or closed: Changes in ductus arteriosus flow patterns at birth using 4D flow MRI in newborn piglets.

The ductus arteriosus (DA) functionally closes during the transition from fetal to postnatal life because of lung aeration and corresponding cardiovascular changes. The thorough and explicit measurement and visualization of the right and left heart output during this transition has not been previously accomplished. We combined 4D flow MRI (dynamic volumetric blood flow measurements) and T2 relaxometry (oxygen delivery quantification) in surgically instrumented newborn piglets to assess the DA. This was performed in Large White-Landrace-Duroc piglets (n = 34) spanning four age groups: term-9 days, term-3, term+1, and term+5. Subject's DA status was classified using 4D flow: closed DA, forward DA flow, reversed DA flow, and bidirectional DA flow. Over all states, vessel diameters and flows normalized to body weight increased with age (for example in the ascending aorta flow-term-9: 126.6 ± 45.4; term+5: 260.2 ± 80.0 ml/min per kg; p = 0.0005; ascending aorta diameter-term-9: 5.2 ± 0.8; term+5: 7.7 ± 0.4 mm; p = 0.0004). In subjects with reversed DA blood flow there was lower common carotid artery blood flow (forward: 37.5 ± 9.0; reversed: 20.0 ± 7.4 ml/min per kg; p = 0.032). Linear regression revealed that as net DA flow decreases, common carotid artery flow decreases (R2  = 0.32, p = 0.004), and left (R2  = 0.33, p = 0.003) and right (R2  = 0.34, p = 0.003) pulmonary artery flow increases. Bidirectional DA blood flow changed oxygen saturation as determined by MRI between the ascending and descending aorta (ascending aorta: 90.1% ± 8.4%; descending aorta: 75.6% ± 14.2%; p < 0.05). Expanded use of these techniques in preterm animal models will aid in providing new understandings of normal versus abnormal DA transition, as well as to test the effectiveness of related clinical interventions.

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.