Time Mating Guinea Pigs by Monitoring Changes to the Vaginal Membrane throughout the Estrus Cycle and with Ultrasound Confirmation.

One of the greatest challenges to the development and implementation of pregnancy therapeutics is the ability to rigorously test treatments in clinically relevant animal models. Guinea pigs offer a unique advantage in studying the placenta, fetal development, and reproductive health as they have similar developmental milestones to humans, both throughout gestation and following birth. Tracking the guinea pig estrus cycle is imperative to ensuring appropriately timed mating and can be performed by monitoring the guinea pig vaginal membrane.

Protocol-dependence of middle cerebral artery dilation to modest hypercapnia.

There is a need for improved understanding of how different cerebrovascular reactivity (CVR) protocols affect vascular cross-sectional area (CSA) to reduce error in CVR calculations when measures of vascular CSA are not feasible. In human participants, we delivered ∼±4 mm Hg end-tidal partial pressure of CO (PCO) relative to baseline through controlled delivery, and measured changes in middle cerebral artery (MCA) CSA (7 Tesla magnetic resonance imaging (MRI)), blood velocity (transcranial Doppler and Phase contrast MRI), and calculated CVR based on a 3-minute steady-state (+4 mm Hg PCO) and a ramp (-3 to +4 mm Hg of PCO). We observed that (1) the MCA did not dilate during the ramp protocol (slope for CSA across time > 0.

Vasodilatation by carbon dioxide and sodium nitroglycerin reduces compliance of the cerebral arteries in humans.

New Findings: What is the central question of this study? Vascular compliance importantly contributes to the regulation of cerebral perfusion and complex mechanisms are known to influence compliance of a vascular bed: while vasodilatation mediates changes in vascular resistance, does it also affect compliance, particularly in the cerebral vasculature? What is the main finding and its importance? Cerebral vasodilatation, elicited by hypercapnia and sodium nitroglycerin administration, reduced cerebrovascular compliance by approximately 26% from baseline. This study provides new insight into mechanisms mediating cerebrovascular compliance.

Abstract: Changes in vascular resistance and vascular compliance contribute to the regulation of cerebral perfusion.

Impaired dynamic cerebral autoregulation in trained breath-hold divers.

Breath-hold divers (BHD) experience repeated bouts of severe hypoxia and hypercapnia with large increases in blood pressure. However, the impact of long-term breath-hold diving on cerebrovascular control remains poorly understood. The ability of cerebral blood vessels to respond rapidly to changes in blood pressure represents the property of dynamic autoregulation.

Fetal Growth Restriction Is Associated With Decreased Number of Ovarian Follicles and Impaired Follicle Growth in Young Adult Guinea Pig Offspring.

Background: The mechanisms mediating the impacts of fetal growth restriction (FGR) on follicular development are commonly studied in mouse/rat models, where ovarian development occurs largely during the early postnatal period. These models have shown that FGR is associated with premature follicle loss, early pubertal onset, and accelerated ovarian aging. Whether the same occurs in precocious species is unknown.

The lifelong impact of fetal growth restriction on cardiac development.

Background: Maternal nutrient restriction (MNR) is a widespread cause of fetal growth restriction (FGR), an independent predictor of heart disease and cardiovascular mortality. Our objective was to examine the developmental and long-term impact of MNR-induced FGR on cardiac structure in a model that closely mimics human development.

Methods: A reduction in total caloric intake spanning pregestation through to lactation in guinea pig sows was used to induce FGR.

Maternal nutrient restriction in guinea pigs as an animal model for studying growth-restricted offspring with postnatal catch-up growth.

We determined the impact of moderate maternal nutrient restriction (MNR) in guinea pigs with fetal growth restriction (FGR) on offspring body and organ weights, hypothesizing that FGR-MNR animals will show catch-up growth but with organ-specific differences. Guinea pig sows were fed ad libitum (Control) or 70% of the control diet from 4 weeks preconception, switching to 90% at midpregnancy (MNR). Control newborns >95 g [appropriate for gestational age (AGA); n = 37] and MNR newborns <85 g (FGR; n = 37) were monitored until neonatal (~25 days) or adult (~110 days) necropsy.

Maternal nutrient restriction in guinea pigs leads to fetal growth restriction with evidence for chronic hypoxia.

BackgroundWe determined whether maternal nutrient restriction (MNR) in guinea pigs leading to fetal growth restriction (FGR) impacts markers for tissue hypoxia, implicating a mechanistic role for chronic hypoxia.MethodsGuinea pigs were fed ad libitum (Control) or 70% of the control diet before pregnancy, switching to 90% at mid-pregnancy (MNR). Near term, hypoxyprobe-1 (HP-1), a marker of tissue hypoxia, was injected into pregnant sows.

Brain Injury and Inflammatory Response to Umbilical Cord Occlusions Is Limited With Worsening Acidosis in the Near-Term Ovine Fetus.

We hypothesized that repetitive umbilical cord occlusions (UCOs) with worsening fetal acidemia will lead to an inflammatory response within the brain and thereby brain injury which will be exacerbated by chronic hypoxemia and low-grade infection. Chronically instrumented fetal sheep served as controls (N = 10) or underwent repeated UCOs for up to 4 hours or until arterial pH was <7.00.

Accelerated acidosis in response to variable fetal heart rate decelerations in chronically hypoxic ovine fetuses.

Background: Due to limitations of technology, clinicians are typically unable to determine if human fetuses are normoxic or moderately, chronically hypoxic. Risk factors for chronic hypoxia include fetal growth restriction, which is associated with an increased incidence of oligohydramnios and thus a risk for umbilical cord occlusion (UCO) and variable fetal heart rate (FHR) decelerations. At delivery, fetal growth restriction infants (<3rd percentile) have nearly twice the incidence of low Apgar scores and umbilical pH <7.

Maternal Nutrient Restriction in Guinea Pigs as an Animal Model for Inducing Fetal Growth Restriction.

We determined the impact of moderate maternal nutrient restriction (MNR) in guinea pigs on pregnancy outcomes, maternal/fetal growth parameters, and blood analytes to further characterize the utility of this model for inducing fetal growth restriction (FGR). Thirty guinea pig sows were fed ad libitum (Control) or 70% of the control diet prepregnant switching to 90% at midpregnancy (MNR). Animals were necropsied near term with weights obtained on all sows, fetuses, and placenta.

Adaptive shut-down of EEG activity predicts critical acidemia in the near-term ovine fetus.

In fetal sheep, the electrocorticogram (ECOG) recorded directly from the cortex during repetitive heart rate (FHR) decelerations induced by umbilical cord occlusions (UCO) predictably correlates with worsening hypoxic-acidemia. In human fetal monitoring during labor, the equivalent electroencephalogram (EEG) can be recorded noninvasively from the scalp. We tested the hypothesis that combined fetal EEG - FHR monitoring allows for early detection of worsening hypoxic-acidemia similar to that shown for ECOG-FHR monitoring.

The Ovine Fetal and Placental Inflammatory Response to Umbilical Cord Occlusions With Worsening Acidosis.

We hypothesized that repetitive umbilical cord occlusions (UCOs) leading to severe acidemia will stimulate a placental and thereby fetal inflammatory response which will be exacerbated by chronic hypoxemia and low-grade bacterial infection. Chronically instrumented fetal sheep served as controls or underwent repetitive UCOs for up to 4 hours or until fetal arterial pH was <7.00.

Synaptic development and neuronal myelination are altered with growth restriction in fetal guinea pigs.

This study examines aberrant synaptogenesis and myelination of neuronal connections as possible links to neurological sequelae in growth-restricted fetuses. Pregnant guinea pig sows were subjected to uterine blood flow restriction or sham surgeries at midgestation. The animals underwent necropsy at term with fetuses grouped according to body weight and brain-to-liver weight ratios as follows: appropriate for gestational age (n = 12); asymmetrically fetal growth restricted (aFGR; n = 8); symmetrically fetal growth restricted (sFGR; n = 8), and large for gestational age (n = 8).

Correlation of arterial fetal base deficit and lactate changes with severity of variable heart rate decelerations in the near-term ovine fetus.

Objective: Recent guidelines classify variable decelerations without detail as to degree of depth. We hypothesized that variable deceleration severity is highly correlated with fetal base deficit accumulation.

Study Design: Seven near-term fetal sheep underwent a series of graded umbilical cord occlusions resulting in mild (30 bpm decrease), moderate (60 bpm decrease), or severe (decrease of 90 bpm to baseline <70 bpm) variable decelerations at 2.

The impact of intermittent umbilical cord occlusions on the inflammatory response in pre-term fetal sheep.

Fetal hypoxic episodes may occur antepartum with the potential to induce systemic and cerebral inflammatory responses thereby contributing to brain injury. We hypothesized that intermittent umbilical cord occlusions (UCOs) of sufficient severity but without cumulative acidosis will lead to a fetal inflammatory response. Thirty-one chronically instrumented fetal sheep at ∼0.

Maturational changes and effects of chronic hypoxemia on electrocortical activity in the ovine fetus.

We have studied the maturation of electrocortical (ECoG) activity in fetal sheep and the impact of chronic hypoxemia using a growth restriction model with placental embolizations. Twenty chronically catheterized fetal sheep (control, n=9; hypoxemic, n=11) were monitored at 116-119, 121-126 and 128-134 days gestational age (term=145 days), with ECoG activity scored using automated analysis of amplitude and frequency components to distinguish low-voltage/high frequency (LV/HF) and high-voltage/low frequency (HV/LF) state epochs, along with indeterminate voltage/frequency (IV/F) and transition period activities. We have shown that multiple aspects of ECoG state activity in the ovine fetus undergo maturational change as electrophysiologic measures of brain development.

Electrocortical activity in the near-term ovine fetus: automated analysis using amplitude frequency components.

We have designed an automated method for analyzing electrocortical (ECoG) activity in the near-term ovine fetus to process and quantitatively classify large amounts of data rapidly and objectively. Seven chronically catheterized fetal sheep were studied for 8h each at ~0.9 of gestation with continuous recording of ECoG activity using a computerized data acquisition system.

Cerebral protein synthesis in the ovine fetus near term with amino acid infusion and insulin-induced hypoaminoacidemia.

Background: Studies during early development have shown that the precursor availability of amino acids directly affects protein synthesis both at the whole-body level and for select organ tissues, although this has not been studied for the brain.

Objective: We utilized a mixed amino acid infusate and an insulin euglycemic clamp technique in the ovine fetus near term, with increases and decreases in circulating amino acid levels of ∼30 to 40% on average, and determined the impact on cerebral protein synthesis.

Methods: Fetal sheep received a 6-hour infusion of Primene® 10% (amino acid infusate group) or a co-infusion of insulin and 10% dextrose (insulin/dextrose infusate group) together with a continuous infusion of L-[1-(13)C]-leucine.

Induced hyper and hypo amino acidemia in the ovine fetus near term: effects on electrocortical activity.

Amino acid infusate (Primene) and insulin euglycemic (insulin + 10% dextrose) clamp techniques were used in the ovine fetus near term and the impact on the incidence of low-voltage and high-voltage electrocortical (ECOG) activities was determined. Fetal sheep were studied over a 2-hour control period and a subsequent 6-hour experimental period.With the Primene infusion, the basic and neutral amino acids were increased by 43% and 25%, respectively, whereas the acidic amino acids showed little change.